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DESIGNING A PACKAGE FOR PHARMACEUTICAL
TABLETS IN RELATION TO MOISTURE AND DISSOLUTION

presented by
Seungyil Yoon

has been accepted towards fulfillment
of the requirements for the

Ph.D. degree in Packaging

MM E. 35%

V Major Professor’s Signature
777445;~ 5L} SI 0&3

Date

 

 

MSU is an Affirmative Action/Equal Opportunity Institution

PLACE IN RETURN Box to remove this checkout from your record.
To AVOID FINES return on or before date due.
MAY BE RECALLED with earlier due date if requested.

DATE DUE

 

DATE DUE DATE DUE

 

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6/01 cJCIRC/DateDuepes-pJS

DESIGNING A PACKAGE FOR PHARMACEUTICAL TABLETS IN RELATION TO
MOISTURE AND DISSOLUTION

By

Seungyil Yoon

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
School of Packaging

2003

ABSTRACT

DESIGNING A PACKAGE FOR PHARMACEUTICAL TABLETS IN RELATION TO
MOISTURE AND DISSOLUTION

By

Seungyil Yoon

Dissolution can be used as a measure of bioavailability and as a stability-
indicating parameter for pharmaceutical tablets. Therefore, it is very important to
predict the dissolution of pharmaceutical tablets in a package in order to design a package
for stability testing. In order to predict the dissolution, the relationship between
dissolution, storage time and relative humidity must be determined. So, tablets were
stored in open dishes at two different temperatures (25 and 40°C) and five different
relative humidities (O, 50, 65, 75, 90% RH) for 6 months.

Dissolution was measured every month for 6 months, and the dissolution was
plotted with storage time to determine a dissolution retardation rate (R, dissolution
change/day). At each relative humidity, tablets have a specific dissolution retardation
rate. Therefore, dissolution retardation rates can be plotted as a function of relative
humidity to determine the relationship between dissolution retardation rate and relative
humidity. Based on that relationship, a dissolution prediction model can be developed.
From the dissolution prediction model, dissolution can be calculated at any relative
humidity for a given amount of storage time. The relative humidity of the package
headspace changes in the unsteady state, so the dissolution of tablets stored at any

condition is very hard to estimate. However, computer programs make it possible.

A Windows based dissolution prediction program was developed in this study.
The dissolution prediction program can calculate the dissolution change of tablets in a
package as a function of storage time. In order to calculate the dissolution change, a
pr0prietary moisture prediction program was also developed in the dissolution prediction
program. The moisture prediction program can calculate the moisture content of solids
in a package and RH of the package headspace. The program can be used to save time
and money in a variety of applications such as determining the amount of desiccant and
package barrier requirement for a given shelf life.

The moisture and dissolution prediction programs were verified by using
experimental results. Uncoated drug tablets and silica gel were inserted into LDPE bags
and HDPE bottles. The moisture content of the tablets and silica gel was measured as a
function of storage time, and then this was compared to the results from the moisture
prediction program. The differences between predicted and experimental moisture
contents ranged from 0% to 0.39% for tablets and 0.11 to 6.50% for silica gel. Also,
dissolution results from the dissolution prediction program were compared with the
experimental results to verify the program. The differences between predicted and
experimental dissolution ranged from 1.3 to 13.5% for LDPE bags and 0 to 18.3% for
HDPE bottles. The differences are fairly large because tablets behave in a variety of
manners. In this study, a new theory of the relationship between dissolution retardation
and relative humidity is proposed.

The Open dish study and computer simulation programs are useful in providing an

effective way to select an appropriate package for registration stability testing.

DEDICATION

This dissertation is dedicated to my wife Youngmi Shin, my family, and my friends.

iv

ACKNOWLEDGEMENTS

I would like to express my gratitude to all those who gave me the possibility to
complete this research. I am deeply indebted to my major professor, Dr. Lockhart
whose help, stimulating suggestions and encouragement helped me in all the time of
research for and writing of this dissertation. I researched for 6 years with him for
master and Ph.D. He guided me right things, and I am sure I followed right things. I
am so lucky because I met Dr. Lockhart for my career. I am also grateful to thank Dr.
Selke for her prompt and thoughtful discussion of this research. We had meetings very
often, sometimes every week or every two weeks. She taught me how to approach the
correct things. And, I am also grateful to thank Dr. Burgess and Dr. Worden for their
research guidance. Initiating a research correctly is very hard and important. They
guided me a right path for this research.

Also, I want to thank Eli Lilly and Company for giving me the permission to use
a product and generous supporting equipment and material used for this research. I
have furthermore specially to thank the senior packaging engineer at Lilly, Mark and the
senior analytical chemist at Lilly, Sharon for discussing my Ph.D. work. They advised
me and sometimes encouraged me to go ahead with my dissertation.

Especially, I would like to give my special thanks to my wife Youngmi whose

patient love enabled me to complete this work.

TABLE OF CONTENTS

 

 

 

 

LIST OF TABLES ................................................................................ viii
LIST OF FIGURES .............................................................................. xix
LIST OF SYMBOLS ........................................................................... xxvi
INTRODUCTION 1
CHAPTER 1 BACKGROUND AND LITERATURE REVIEW (DISSOLUTION
PREDICTION MODELS) 6
1. Dissolution profile (The mechanism of dissolution) ................................................ l3
2. Dissolution rate (k) .................................................................................................... 14
3. Dissolution reduction rate (K) ................................................................................... 16
4. Relationship between dissolution reduction rate and moisture content .................... 17
CHAPTER 2 EXPERIMENTAL DESIGN, MATERIALS AND METHODS ......... 19
1. Experimental design .................................................................................................. l9
2. Materials and methods .............................................................................................. 24
CHAPTER 3 RESULTS AND DISCUSSION 42
l. Permeability .............................................................................................................. 45
(1) LDPE bags ............................................................................................................ 48
(2) HDPE bottles ........................................................................................................ 49
2. Moisture content ....................................................................................................... 49
(1) Initial moisture content ......................................................................................... 49
(2) Moisture sorption isotherms ................................................................................. 50
(a) Moisture sorption isotherms of drug X tablets (coated and uncoated) ............. 51
(b) Moisture sorption isotherms of silica gel .......................................................... 54
3. Dissolution ................................................................................................................ 56
(1) Initial dissolution profiles ..................................................................................... 57
(2) Dissolution profiles from open dish study ............................................................ 60
(a) Drug X uncoated tablets stored in open dishes at 40°C .................................... 60
(b) Drug X coated tablets stored in open dishes at 40°C ........................................ 68
(3) Summary of dissolution behavior ......................................................................... 74
CHAPTER 4 DISSOLUTION PREDICTION PROGRAMMING AND
VERIFICATION 76
1. Technical review of Nakabayashi’s method ............................................................. 76
2. Dissolution retardation rate (R) ................................................................................. 84
3. Verification of dissolution prediction program ......................................................... 95
(1) Stepwise storage conditions (open dish study) ..................................................... 95
(2) Continuous storage conditions .............................................................................. 99

vi

(3) Tablets in LDPE bags without silica gel and tablets with silica gel (0.5 g, l g,

 

 

and 2 g) stored in LDPE bags at 40°C/90% RH ..................................................... 102
(b) Tablets in HDPE bottles without silica gel and tablets with 0.5 g silica gel
stored in HDPE bottles at 40°C/90% RH ............................................................... 106
4. Proposed theory of dissolution retardation as a function of relative humidity ....... 109
CHAPTER 5 PACKAGE DESIGN 112
CHAPTER 6 CONCLUSIONS AND FUTURE WORK 118
APPENDICES
Appendix A Background and Literature Review (Moisture and Shelf life Prediction
Models) ....................................................................................................................... 123
Appendix B Moisture and Shelf Life Prediction Programming, and Verification ..... 150
Appendix C Tablet Formulation, Manufacturing, and Interaction ............................. 173
Appendix D Summary Tables of Permeability, Moisture Sorption Isotherms, and
Moisture Content Verification .................................................................................... 183
Appendix E Dissolution Raw Data and Dissolution Profiles at 25°C ........................ 191
Appendix F Dimensions (Swelling) and Raw Data .................................................... 229
Appendix G Hardness and Raw Data ......................................................................... 241
BIBLIOGRAPHY 257

 

vii

LIST OF TABLES

Table 1 Apparent dissolution reduction rate constants (K) of dissolution for prednisolone

tablets with various moisture content (N akabayashi et al., 1981) ............................ 18
Table 2 Testing plan for open dish study .......................................................................... 22
Table 3 Comparison of physical properties between drug X fresh tablets and 2 year old

tablets ........................................................................................................................ 24
Table 4 Salt solutions used to provide the required range of relative hurnidities ............. 25

Table 5 The combination of components in LDPE bags and HDPE bottles used to verify

the moisture and shelf life prediction program ......................................................... 32
Table 6 Dissolution calibration data of drug X ................................................................. 38
Table 7 Stepwise storage conditions used to verify the dissolution prediction model ..... 41
Table 8 Initial moisture content and equilibrium RH of tablets and silica gel ................. 50
Table 9 GAB constants of tablets and Langmuir constants of silica gel .......................... 50
Table 10 Initial dissolution profile data for uncoated tablets ............................................ 58
Table 11 Initial dissolution profile data for drug X coated tablets ................................... 59

Table 12 p-values from t-test using 1 month and 2 month intervals for tablets stored at
40°C/90% RH ........................................................................................................... 61

Table 13 p-values from t-test using 1 month and 2 month intervals for tablets stored at
40°C/75% RH ........................................................................................................... 63

Table 14 p-values from t-test using 1 month and 2 month intervals for tablets stored at
40°C/65% RH ........................................................................................................... 65.

Table 15 p-values from t-test using 1 month and 2 month intervals for tablets stored at
40°C/50% RH ........................................................................................................... 66

Table 16 Variation of dissolution for drug X uncoated tablets stored at 40°C (coefficient
of variance greater than 0.1 is bold-faced.) ............................................................... 78

Table 17 Dissolution retardation rates (R) of drug X uncoated tablets stored in open
dishes at 40°C ........................................................................................................... 91

viii

 

Table 18 Comparison of the results from experimental and predicted dissolution stored at
stepwise conditions ................................................................................................... 95

Table 19 The dissolution change calculated from the dissolution prediction program at
each RH for a given storage time .............................................................................. 96

Table 20 Dissolution differences between experimentally measured average dissolution
and predicted dissolution ........................................................................................ 100

Table 21 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets stored in LDPE bag without
desiccant) ................................................................................................................ 102

Table 22 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets in LDPE bag containing 0.5 g
silica gel) ................................................................................................................. 103

Table 23 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets in LDPE bag containing 1 g silica
gel) .......................................................................................................................... 104

Table 24 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets in LDPE bag containing 2 g silica
gel) .......................................................................................................................... 105

Table 25 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets in HDPE bottle without desiccant)
................................................................................................................................. 107

Table 26 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets in HDPE bottle containing 0.5 g
silica gel) ................................................................................................................. 108

Table 27 Initial moisture content of MCC and corn starch ............................................. 144

Table 28 Comparison between experimental and calculated moisture content, and
between actual storage time and calculated shelf life of tablets stored in LDPE bags
without desiccant .................................................................................................... 166

Table 29 Comparison between experimental and calculated moisture content of tablets
and 0.5 g silica gel stored in LDPE bag, and between actual storage time and
calculated shelf life. ................................................................................................ 168

Table 30 Comparison between experimental and calculated moisture content of tablets
and 1 g silica gel stored in LDPE bag, and between actual storage time and
calculated shelf life. ................................................................................................ 169

ix

 

Table 31 Comparison between experimental and calculated moisture content of tablets
and 2 g silica gel stored in LDPE bag, and between actual storage time and
calculated shelf life. ................................................................................................ 170

Table 32 Comparison between experimental and calculated moisture content of tablets
stored in HDPE bottle without silica gel, and between actual storage time and
calculated shelf life. ................................................................................................ 171

Table 33 Comparison between experimental and calculated moisture content of tablets
and 0.5 g silica gel in HDPE bottle, and between actual storage time and calculated

shelf life. ................................................................................................................. 172
Table 34 Drug X tablet formulation ................................................................................ 174
Table 35 Moisture gain (g) of LDPE bags using CaClz at 40°C .................................... 184
Table 36 Moisture gain (g) of HDPE bottles using CaClz at 40°C ................................. 184
Table 37 Moisture gain (g) of HDPE bottle blanks at 40°C ........................................... 184
Table 38 Moisture sorption isotherm data of uncoated tablets at 25°C .......................... 185
Table 39 Moisture sorption isotherm data of coated tablets at 25°C .............................. 185
Table 40 Moisture sorption isotherm data of uncoated tablets at 40°C .......................... 186
Table 41 Moisture sorption isotherm data of coated tablets at 40°C .............................. 186
Table 42 Moisture sorption isotherm data of silica gel at 25°C ..................................... 187
Table 43 Moisture sorption isotherm data of silica gel at 40°C ..................................... 187

Table 44 Moisture content of tablets in LDPE bags without silica gel as a function of
storage time ............................................................................................................. 188

Table 45 Moisture content of tablets and 0.5 g silica gel in LDPE bags as a function of
storage time ............................................................................................................. 188

Table 46 Moisture content of tablets and 1 g silica gel in LDPE bags as a function of
storage time ............................................................................................................. 189

Table 47 Moisture content of tablets and 2 g silica gel in LDPE bags as a function of
storage time ............................................................................................................. 189

Table 48 Moisture content of tablets only in HDPE bottles as a function of storage time
................................................................................................................................. 190

Table 49 Moisture content of tablets and 0.5 g silica gel in HDPE bottles as a function of

storage time ............................................................................................................. 190
Table 50 Initial dissolution raw data of uncoated tablets ................................................ 192
Table 51 Initial dissolution raw data of coated tablets .................................................... 192

Table 52 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/90% ..... 192
Table 53 Dissolution raw data of coated tablets stored for 1 month at 40°C/90% ......... 192
Table 54 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/75% ..... 193
Table 55 Dissolution raw data of coated tablets stored for 1 month at 40°C/75% ......... 193
Table 56 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/65% ..... 193
Table 57 Dissolution raw data of coated tablets stored for 1 month at 40°C/65% ......... 193
Table 58 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/50% ..... 194
Table 59 Dissolution raw data of coated tablets stored for 1 month at 40°C/50% ......... 194
Table 60 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/0% ....... 194
Table 61 Dissolution raw data of coated tablets stored for 1 month at 40°C/0% ........... 194
Table 62 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/90% ..... 195
Table 63 Dissolution raw data of coated tablets stored for 1 month at 25°C/90% ......... 195
Table 64 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/75% ..... 195
Table 65 Dissolution raw data of coated tablets stored for 1 month at 25°C/75% ......... 195
Table 66 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/65% ..... 196
Table 67 Dissolution raw data of coated tablets stored for 1 month at 25°C/65% ......... 196
Table 68 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/50% ..... 196
Table 69 Dissolution raw data of coated tablets stored for 1 month at 25°C/50% ......... 196
Table 70 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/0% ....... 197

Table 71 Dissolution raw data of coated tablets stored for 1 month at 25°C/0% ........... 197

xi

Table 72 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/90% 197
Table 73 Dissolution raw data of coated tablets stored for 2 months at 40°C/90% ....... 197
Table 74 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/75% 198
Table 75 Dissolution raw data of coated tablets stored for 2 months at 40°C/75% ....... 198
Table 76 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/65% 198
Table 77 Dissolution raw data of coated tablets stored for 2 months at 40°C/65% ....... 198
Table 78 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/50% 199
Table 79 Dissolution raw data of coated tablets stored for 2 months at 40°C/50% ....... 199
Table 80 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/0% ..... 199
Table 81 Dissolution raw data of coated tablets stored for 2 months at 40°C/0% ......... 199
Table 82 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/90% 200
Table 83 Dissolution raw data of coated tablets stored for 2 months at 25°C/90% ....... 200
Table 84 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/75% 200
Table 85 Dissolution raw data of coated tablets stored for 2 months at 25°C/75% ....... 200
Table 86 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/65% 201
Table 87 Dissolution raw data of coated tablets stored for 2 months at 25°C/65% ....... 201
Table 88 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/50% 201
Table 89 Dissolution raw data of coated tablets stored for 2 months at 25°C/50% ....... 201
Table 90 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/0% ..... 202
Table 91 Dissolution raw data of coated tablets stored for 2 months at 25°C/0% ......... 202
Table 92 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/90% 202
Table 93 Dissolution raw data of coated tablets stored for 3 months at 40°C/90% ....... 202

Table 94 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/75% 203

xii

Table 95 Dissolution raw data of coated tablets stored for 3 months at 40°C/75% ....... 203
Table 96 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/65% 203
Table 97 Dissolution raw data of coated tablets stored for 3 months at 40°C/65% ....... 203
Table 98 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/50% 204
Table 99 Dissolution raw data of coated tablets stored for 3 months at 40°C/50% ....... 204
Table 100 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/0% 204
Table 101 Dissolution raw data of coated tablets stored for 3 months at 40°C/0% ....... 204
Table 102 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/90% . 205
Table 103 Dissolution raw data of coated tablets stored for 3 months at 25°C/90% ..... 205
Table 104 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/75% .205
Table 105 Dissolution raw data of coated tablets stored for 3 months at 25°C/75% ..... 205
Table 106 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/65% .206
Table 107 Dissolution raw data of coated tablets stored for 3 months at 25°C/65% ..... 206
Table 108 Dissolution raw data of uncoated tablets stored for 3 months at25°C/50% .206
Table 109 Dissolution raw data of coated tablets stored for 3 months at 25°C/50% ..... 206
Table 110 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/0% 207
Table 11 1 Dissolution raw data of coated tablets stored for 3 months at 25°C/0% ....... 207
Table 112 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/90% . 207
Table 113 Dissolution raw data of coated tablets stored for 4 months at 40°C/90% ..... 207
Table 114 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/75% . 208
Table 115 Dissolution raw data of coated tablets stored for 4 months at 40°C/75% ..... 208
Table 116 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/65% . 208

Table 117 Dissolution raw data of coated tablets stored for 4 months at 40°C/65% ..... 208

xiii

Table 118 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/50%

Table 119 Dissolution raw data of coated tablets stored for 4 months at 40°C/50% .....

Table 120 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/0% .

Table 121 Dissolution raw data of coated tablets stored for 4 months at 40°C/0% .......

Table 122 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/90%

Table 123 Dissolution raw data of coated tablets stored for 4 months at 25°C/90% .....

Table 124 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/75%

Table 125 Dissolution raw data of coated tablets stored for 4 months at 25°C/75% .....
Table 126 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/65%.
Table 127 Dissolution raw data of coated tablets stored for 4 months at 25°C/65% .....
Table 128 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/50%.
Table 129 Dissolution raw data of coated tablets stored for 4 months at 25°C/50% .....
Table 130 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/0%

Table 131 Dissolution raw data of coated tablets stored for 4 months at 25°C/0% .......

Table 132 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/90%

Table 133 Dissolution raw data of coated tablets stored for 5 months at 40°C/90% .....

Table 134 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/75%
Table 135 Dissolution raw data of coated tablets stored for 5 months at 40°C/75% .....
Table 136 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/65%.
Table 137 Dissolution raw data of coated tablets stored for 5 months at 40°C/65% .....
Table 138 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/50%.
Table 139 Dissolution raw data of coated tablets stored for 5 months at 40°C/ 50% .....

Table 140 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/0%

xiv

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Table 141 Dissolution raw data of coated tablets stored for 5 months at 40°C/0% .......

Table 142 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/90%

Table 143 Dissolution raw data of coated tablets stored for 5 months at 25°C/90% .....

Table 144 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/75%

Table 145 Dissolution raw data of coated tablets stored for 5 months at 25°C/75% .....

Table 146 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/65%

Table 147 Dissolution raw data of coated tablets stored for 5 months at 25°C/65% .....

Table 148 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/50%

Table 149 Dissolution raw data of coated tablets stored for 5 months at 25°C/50% .....
Table 150 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/0%

Table 151 Dissolution raw data of coated tablets stored for 5 months at 25°C/0% .......

Table 152 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/90%

Table 153 Dissolution raw data of coated tablets stored for 6 months at 40°C/90% .....

Table 154 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/75%

Table 155 Dissolution raw data of coated tablets stored for 6 months at 40°C/75% .....

Table 156 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/65%

Table 157 Dissolution raw data of coated tablets stored for 6 months at 40°C/65% .....

Table 158 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/50%

Table 159 Dissolution raw data of coated tablets stored for 6 months at 40°C/50% .....
Table 160 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/0%
Table 161 Dissolution raw data of coated tablets stored for 6 months at 40°C/0% .......
Table 162 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/90%.

Table 163 Dissolution raw data of coated tablets stored for 6 months at 25°C/90% .....

XV

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Table 164 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/75% . 220
Table 165 Dissolution raw data of coated tablets stored for 6 months at 25°C/75% ..... 220
Table 166 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/65% . 221
Table 167 Dissolution raw data of coated tablets stored for 6 months at 25°C/65% ..... 221
Table 168 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/50% . 221
Table 169 Dissolution raw data of coated tablets stored for 6 months at 25°C/50% ..... 221
Table 170 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/0% 222

Table 171 Dissolution raw data of coated tablets stored for 6 months at 25°C/0% ....... 222

Table 172 Dimensions (mm) of initial tablets ................................................................ 233
Table 173 Dimensions (mm) of tablets stored for 20 days at 40°C/90% ....................... 233
Table 174 Dimensions (mm) of tablets stored for 20 days at 40°C/75% ....................... 233
Table 175 Dimensions (mm) of tablets stored for 20 days at 40°C/65% ....................... 233
Table 176 Dimensions (mm) of tablets stored for 20 days at 40°C/50% ....................... 234
Table 177 Dimensions (mm) of tablets stored for 20 days at 40°C/0% ......................... 234
Table 178 Dimensions (mm) of tablets stored for 20 days at 25°C/90% ....................... 234
Table 179 Dimensions (mm) of tablets stored for 20 days at 25°C/75% ....................... 234
Table 180 Dimensions (mm) of tablets stored for 20 days at 25°C/65% ....................... 235
Table 181 Dimensions (mm) of tablets stored for 20 days at 25°C/50% ....................... 235
Table 182 Dimensions (mm) of tablets stored for 20 days at 25°C/0% ......................... 235
Table 183 Dimensions (mm) of tablets stored for 70 days at 40°C/90% ....................... 235
Table 184 Dimensions (mm) of tablets stored for 70 days at 40°C/75% ....................... 236
Table 185 Dimensions (mm) of tablets stored for 70 days at 40°C/65% ....................... 236
Table 186 Dimensions (mm) of tablets stored for 70 days at 40°C/50% ....................... 236

xvi

Table 187 Dimensions (mm) of tablets stored for 70 days at 40°C/0% ......................... 236

Table 188 Dimensions (mm) of tablets stored for 70 days at 25°C/90% ....................... 237
Table 189 Dimensions (mm) of tablets stored for 70 days at 25°C/75% ....................... 237
Table 190 Dimensions (mm) of tablets stored for 70 days at 25°C/65% ....................... 237
Table 191 Dimensions (mm) of tablets stored for 70 days at 25°C/50% ....................... 237
Table 192 Dimensions (mm) of tablets stored for 70 days at 25°C/0% ......................... 238
Table 193 Dimensions (mm) of tablets stored for 180 days at 40°C/90% ..................... 238
Table 194 Dimensions (mm) of tablets stored for 180 days at 40°C/75% ..................... 238
Table 195 Dimensions (mm) of tablets stored for 180 days at 40°C/65% ..................... 238
Table 196 Dimensions (mm) of tablets stored for 180 days at 40°C/50% ..................... 239
Table 197 Dimensions (mm) of tablets stored for 180 days at 40°C/0% ....................... 239
Table 198 Dimensions (mm) of tablets stored for 180 days at 25°C/90% ..................... 239
Table 199 Dimensions (mm) of tablets stored for 180 days at 25°C/75% ..................... 239
Table 200 Dimensions (mm) of tablets stored for 180 days at 25°C/65% ..................... 240
Table 201 Dimensions (mm) of tablets stored for 180 days at 25°C/50% ..................... 240
Table 202 Dimensions (mm) of tablets stored for 180 days at 25°C/0% ....................... 240
Table 203 Average hardness of drug X uncoated and coated tablets ............................. 242
Table 204 p-values from t-test between initial and 7 day aged tablet hardness .............. 243
Table 205 p-values from AN OVA between 7 to 190 day aged tablet hardness ............. 244
Table 206 p—values from t-test between hardness of tablets stored at 25°C and 40°C (p-
values greater than 0.05 are bold-faced) ................................................................. 249
Table 207 The results of PVC blister opening tests (the number of broken tablets/the
number of trials) ...................................................................................................... 252
Table 208 Hardness (kp) of initial tablets ....................................................................... 253

xvii

Table 209 Hardness (kp) of tablets stored at 40°C/90% as a function of storage time .. 253
Table 210 Hardness (kp) of tablets stored at 40°C/75% as a function of storage time .. 253
Table 211 Hardness (kp) of tablets stored at 40°C/65% as a function of storage time .. 254
Table 212 Hardness (kp) of tablets stored at 40°C/50% as a function of storage time .. 254
Table 213 Hardness (kp) of tablets stored at 40°C/0% as a function of storage time 254
Table 214 Hardness (kp) of tablets stored at 25°C/90% as a function of storage time .. 255
Table 215 Hardness (kp) of tablets stored at 25°C/75% as a function of storage time .. 255
Table 216 Hardness (kp) of tablets stored at 25°C/65% as a function of storage time .. 255
Table 217 Hardness (kp) of tablets stored at 25°C/50% as a function of storage time .. 256

Table 218 Hardness (kp) of tablets stored at 25°C/0% as a fimction of storage time 256

xviii

LIST OF FIGURES

Figure 1 Dissolution of coated aspirin tablets stored for 3 months at 25°C/90% ............. 12
Figure 2 The S-shaped dissolution curve of solid dosage forms (Abdou, 1989) .............. 14
Figure 3 Exponential relationship between % undissolved and stirring time ................... 15
Figure 4 Dissolution rate (k) ............................................................................................. 16
Figure 5 Dissolution reduction rate (K) ............................................................................ 17
Figure 6 Diagram of the experimental design ................................................................... 21
Figure 7 Graphical representation of the humidity sensor placed on the top of desiccator
................................................................................................................................... 26
Figure 8 The sketch of the symmetrical gravimetric analyzer (SGA-IOO) ....................... 30
Figure 9 The moisture gain of HDPE bottles .................................................................... 33
Figure 10 Sketch of the HT-300 hardness tester ............................................................... 36
Figure 11 The calibration curve for the spectrophotometer using drug X ........................ 38
Figure 12 Outline of the experiment ................................................................................. 44
Figure 13 Relationship between water vapor transmission rate (WVTR), permeance,
thickness normalized WVTR, and permeability ....................................................... 45
Figure 14 Relationship between water vapor transmission rate (WVTR) and permeance
using whole package instead of thickness and area .................................................. 47
Figure 15 WVTR of LDPE bags at 40°C/90% RH .......................................................... 48
Figure 16 WVTR of HDPE bottles at 40°C/75% RH ....................................................... 49
Figure 17 Moisture sorption isotherms of drug X tablets at 25°C .................................... 51
Figure 18 Moisture sorption isotherms of drug X tablets at 40°C .................................... 52
Figure 19 Moisture sorption isotherms calculated by GAB equation for tablets at 25°C
and 40°C .................................................................................................................... 53
Figure 20 Moisture sorption isotherm of silica gel at 25°C .............................................. 54

xix

Figure 21 Moisture sorption isotherm of silica gel at 40°C .............................................. 55

Figure 22 Moisture sorption isotherms calculated by Langmuir equation for silica gel at

25°C and 40°C .......................................................................................................... 55
Figure 23 The typical dissolution curve constructed experimentally ............................... 56
Figure 24 Initial dissolution profile of drug X uncoated tablets ....................................... 58
Figure 25 Initial dissolution profile of drug X coated tablets ........................................... 59

Figure 26 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/90% (each point is average value for 6 tablets) .............................. 61

Figure 27 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/75% (each point is average value for 6 tablets) .............................. 63

Figure 28 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/65% (each point is average value for 6 tablets) .............................. 64

Figure 29 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/50% (each point is average value for 6 tablets) .............................. 66

Figure 30 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/0% (each point is average value for 6 tablets) ................................ 68

Figure 31 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 40°C/90% (each point is average value for 6 tablets) ........................................... 69

Figure 32 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 40°C/75% (each point is average value for 6 tablets) ........................................... 71

Figure 33 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 40°C/65% (each point is average value for 6 tablets) ........................................... 71

Figure 34 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 40°C/50% (each point is average value for 6 tablets) ........................................... 72

Figure 35 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 40°C/0% (each point is average value for 6 tablets) ............................................. 73

Figure 36 Dissolution rates (k) of uncoated tablets stored in open dishes for 6 months at
40°C/50% RH ........................................................................................................... 81

Figure 37 Dissolution reduction rate (K) of uncoated tablets stored at 40°C/50% RH 81

XX

Figure 38 Dissolution reduction rate as a function of RH (%) ......................................... 82

Figure 39 Dissolution of tablets in HDPE bottles stored at 40°C/90% RH as a function of

storage time ............................................................................................................... 84
Figure 40 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/90% (each month has 6 dissolution values) .................................... 86
Figure 41 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/75% (each month has 6 dissolution values) .................................... 86
Figure 42 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/65% (each month has 6 dissolution values) .................................... 87
Figure 43 30 minute dissolution. of drug X uncoated tablets stored in open dishes for 6
months at 40°C/50% (each month has 6 dissolution values) .................................... 87
Figure 44 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/0% (each month has 6 dissolution values) ...................................... 88
Figure 45 Graph ofy = -e" ...................................................................................... 89
Figure 46 Graph of y = -e" + (D,+1) ................................................................................. 89
Figure 47 A typical graph for 30 minute dissolution change as a fimction of storage time
................................................................................................................................... 89
Figure 48 Dissolution retardation rate (R) ........................................................................ 90
Figure 49 Dissolution retardation rate of drug X uncoated tablets at various relative
humidities at 40°C .................................................................................................... 91

Figure 50 Dissolution retardation rate (R) as a function of relative humidity at 40°C ..... 93
Figure 51 Algorithm used to calculate the dissolution at various relative humidities ...... 94
Figure 52 Dissolution of tablets stored at stepwise Conditions (I) .................................... 97
Figure 53 Dissolution of tablets stored at stepwise conditions (11) .................................. 98

Figure 54 Dissolution of tablets in LDPE bags stored at 40°C/90% RH as a function of
storage time ............................................................................................................. 102

Figure 55 Dissolution of tablets in LDPE bags containing 0.5 g silica gel stored at
40°C/90% RH as a function of storage time ........................................................... 103

xxi

Figure 56 Dissolution of tablets in LDPE bags containing 1 g silica gel stored at
40°C/90% RH as a function of storage time ........................................................... 104

Figure 57 Dissolution of tablets in LDPE bags containing 2 g silica gel stored at
40°C/90% RH as a function of storage time. .......................................................... 105

Figure 58 Dissolution of tablets in HDPE bottles stored at 40°C/90% RH as a function of
storage time. ............................................................................................................ 106

Figure 59 Dissolution of tablets in HDPE bottles containing 0.5 g silica gel stored at
40°C/90% RH as a function of storage time. .......................................................... 107

Figure 60 The hardness of uncoated tablets stored for 6 months at 40°C as a function of
relative humidity ..................................................................................................... 110

Figure 61 30 minute dissolution of uncoated tablets stored for 6 months at 40°C as a
function of relative humidity .................................................................................. 1 10

Figure 62 RH of Aclar blister headspace calculated by the moisture prediction program
and 30 minute dissolution calculated by the dissolution prediction program as a
function of storage time. ......................................................................................... 1 14

Figure 63 RH of the HDPE bottle headspace calculated by the moisture prediction

program and 30 minute dissolution calculated by the dissolution prediction program
as a function of storage time ................................................................................... 115

Figure 64 RH of a package (P=0.0004 g/day-pkg-ps) headspace calculated by the moisture
prediction program and 30 minute dissolution calculated by the dissolution
prediction program as a function of storage time ................................................... 117

Figure 65 Graphical representation of linear and nonlinear relationships between M and
aw ............................................................................................................................. 130

Figure 66 Graphical representation of changes inimoisture during equilibration between
MCC and corn starch .............................................................................................. 144

Figure 67 Graphical representation of moisture transfer and moisture equilibrium in the
closed system .......................................................................................................... 145

Figure 68 Hypothetical graphic representation of piecewise linear equations for two
sorption isotherms for components A and B ........................................................... 153

Figure 69 Algorithm used to calculate the equilibrium (p/ps)", ...................................... 157

xxii

Figure 70 Example of an algorithm used to calculate the relative humidity of the
headspace and moisture content of components in a package at each time interval j
over the total storage time t ..................................................................................... 159

Figure 71 Algorithm used to determine the GAB or Langmuir constants ...................... 160

Figure 72 Example spreadsheet from the proprietary moisture prediction program ...... 162

Figure 73 Example spreadsheet from the shelf life prediction program ......................... 164
Figure 74 Comparison between experimental and calculated moisture content of tablets
stored in LDPE bags without silica gel ................................................................... 166
Figure 75 Comparison between experimental and calculated moisture content of tablets
and silica gel (0.5 g) stored in LDPE bags .............................................................. 167
Figure 76 Comparison between experimental and calculated moisture content of tablets
and silica gel (1 g) stored in LDPE bags ................................................................. 168
Figure 77 Comparison between experimental and calculated moisture content of tablets
and silica gel (2 g) stored in LDPE bags ................................................................. 170
Figure 78 Comparison between experimental and calculated moisture content of tablets
stored in HDPE bottles without silica gel ............................................................... 171
Figure 79 Comparison between experimental and calculated moisture content of tablets
and silica gel (0.5 g) in HDPE bottles ..................................................................... 172
Figure 80 Graphical representation of the manufacturing of drug X tablets .................. 176
Figure 81 Structural formula of mannitol ....................................................................... 178
Figure 82 Moisture sorption-desorption isotherm of mannitol (Kibbe, 2000) ............... 178
Figure 83 Structural formula of povidone ....................................................................... 179
Figure 84 Moisture sorption isotherm of povidone (Kibbe, 2000) ................................. 179
Figure 85 Structural formula of microcrystalline cellulose (MCC) ................................ 180

Figure 86 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/90% RH (each point is average value for 6 tablets) ...................... 223

Figure 87 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/75% RH (each point is average value for 6 tablets) ...................... 223

xxiii

Figure 88 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/65% RH (each point is average value for 6 tablets) ...................... 224

Figure 89 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/50% RH (each point is average value for 6 tablets) ...................... 224

Figure 90 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/0% RH (each point is average value for 6 tablets) ........................ 225

Figure 91 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 25°C/90% RH (each point is average value for 6 tablets) .................................. 226

Figure 92 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 25°C/75% RH (each point is average value for 6 tablets) .................................. 226

Figure 93 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 25°C/65% RH (each point is average value for 6 tablets) .................................. 227

Figure 94 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 25°C/50% RH (each point is average value for 6 tablets) .................................. 227

Figure 95 Dissolution profiles of drug X coated tablets stored in open dishes for 6 months
at 25°C/0% RH (each point is average value for 6 tablets) .................................... 228

Figure 96 Percent thickness dimension change of drug X tablets as a function of RH
(each point is average value for 5 tablets) ............................................................... 231

~ Figure 97 Percent diameter dimension change of drug X tablets as a function of RH (each
point is average value for 5 tablets) ........................................................................ 231

Figure 98 Hardness of drug X uncoated tablets stored at 25°C as a function of storage
time (each point is average value for 10 tablets) .................................................... 245

Figure 99 Hardness of drug X coated tablets stored at 25°C as a function of storage time
(each point is average value for 10 tablets) ............................................................. 245

Figure 100 Hardness of drug X uncoated tablets stored at 40°C as a function of storage
time (each point is average value for 10 tablets) .................................................... 246

Figure 101 Hardness of drug X coated tablets stored at 40°C as a function of storage time
(each point is average value for 10 tablets) ............................................................. 246

Figure 102 Hardness of drug X uncoated tablets at 25°C as a function of RH (%) (each
point is average value for 10 tablets) ...................................................................... 247

Figure 103 Hardness of drug X coated tablets at 25°C as a function of RH (%) (each
point is average value for 10 tablets) ...................................................................... 248

xxiv

Figure 104 Hardness of drug X uncoated tablets at 40°C as a function of RH (%) (each

point is average value for 10 tablets) ...................................................................... 248
Figure 105 Hardness of drug X coated tablets at 40°C as a function of RH (%) (each

point is average value for 10 tablets) ...................................................................... 249
Figure 106 Graphical representation of the tablet squeezing in the thickness and diameter

directions by fingers ................................................................................................ 251
Figure 107 Graphical representation of the tablet breaking by fingers ........................... 251

XXV

LIST OF SYMBOLS

A: surface area

AH: absolute humidity at given temperature, g H 20/g dry air

a.,,: water activity

awn-,0: water activity of air inside package

am”): water activity of air outside package

,6: slope of M(%) and aw (or RH(%) or p/p,)

Ci: concentration of drug initially in tablet (mg drug initially in tablet/mL medium)
Cm: concentration of drug dissolved in medium afier stirring for time s (mg drug '
dissolved in medium/ml. medium) ,

C3: concentration of drug still left in tablet after stirring for time 5 (mg drug left in
tablet/mL medium)

D: dissolution (%) at 30 minute stirring time

0,: initial dissolution (%) at 30 minute stirring time

EMC: equilibrium moisture content

K: dissolution reduction rate (day'I)

k: dissolution rate (minute'l

k,~: dissolution rate (minute' ) of the initial tablet

k,: dissolution rate (minute") at storage time t

Z: thickness of material

M(%): moisture content (%) (dry weight), g H 20/g dry weight of solid x 100
Mw(%): moisture content (%) (wet weight), g HZO/g wet weight of solid x100
M(%): initial moisture content (%), g H20/g dry weight of solid x 100

M: moisture content (dry weight), g H20/g dry weight of solid

MA: moisture content of solid A, g H20/g dry weight of solid A

M4,: initial moisture content of solid A, g H20/g dry weight of solid A

My. final moisture content of solid A, g H 20/g dry weight of solid A

M3: moisture content of solid B, g H 20/g dry weight of solid B

M,: initial moisture content, g H 20/g dry weight of solid

Mf. final moisture content, g HZO/g dry weight of solid

Mm: initial moisture content (wet weight), g H 20/g wet weight of solid

m: mass of moisture

me: mass of moisture at equilibrium

mh: mass of moisture in the package headspace

m,-: mass of moisture at initial time

mr: total mass of moisture inside package

P: permeability of package

Pi: initial weight of product

Pf. final weight of product

p: vapor pressure of water at given temperature

Pam: atmospheric pressure at given temperature

pm: vapor pressure of water inside package at given temperature

pow: vapor pressure of water outside package at given temperature

p,: saturation vapor pressure of water at given temperature

p/p,: relative water vapor pressure

xxvi

R: dissolution retardation rate (% dissolution change/day)
RH(%): relative humidity (%)

s: stirring time

t: storage time

V: volume of the package headspace

W: weight of solid

Wd: dry weight of solid

WM: dry weight of solid A

de: dry weight of solid B

W): final weight of solid

W5: initial weight of solid

w: mass of moisture permeated into the package

xxvii

INTRODUCTION

Pharmaceutical companies must submit stability data for new drug applications
(NDA) to the U.S. Food and Drug Administration (FDA) before pharmaceutical products
go to market. The submitted stability data must be approved by FDA. FDA recommends
that the length of the studies and the storage conditions should be sufficient to cover
storage, shipment and subsequent use. Therefore, FDA recommends that drug products
be tested in long-term testing (25i2°C, 60-15% RH) for 12 months and accelerated testing
(40i2°C, 75i5% RH) for 6 months in the market package. If a significant change occurs
due to accelerated testing, a minimum of 6 months’ data from an ongoing 12 months
study at an intermediate condition (30i2°C, 60:5% RH) should be included for the initial
application. A significant change in dissolution is defined as failure to meet the
specification limit for 12 tablets or capsules [USP Stage 2“]. If a significant change
occurs during intermediate testing, it may not be appropriate to label the drug product for
CRT (controlled room temperature) storage with the proposed expiration dating period
even if the stability data from the full long-term studies at 25i2°C, 60i5% RH appear
satisfactory. After new drug products obtain market approval from FDA, they can launch

to market. Stability data in long-term testing (25i2°C, 60i5% RH) must be reported to

 

' If the quantities of active ingredient dissolved from the units tested conform to the accompanying
Acceptance Table, the requirements are met. Continue testing through the three stages unless the results
confirm at either S. or S2. The quantity, Q, is the amount of dissolved active ingredient specified in the
individual monograph (USP <71 I> Dissolution).

 

 

 

 

Acceptance Table
Stage Number Tested Acceptance Criteria
S. 6 Each unit is not less than Q + 5%.
$2 6 Average of 12 units (S.+ 82) is equal to or greater than Q, and no unit is less
than Q;15%.
33 12 Average of 24 units (S.+ 82+ 8;) is equal to or greater than Q, not more than
2 units are less than Q — 15%, and no unit is less than Q — 25%.

 

 

 

 

 

FDA annually for the proposed expiration dating period (USP <1196>, 1995 and
Guidance for Industry, Stability Testing of Drug Substances and Drug Products, 1998).

A package must be designed properly to meet the FDA requirements for
accelerated stability testing. Ideally, the packaged product should meet the stability
requirement at the end of the six month accelerated storage period. This study shows
how to select a suitable package for pharmaceutical tablets by using an open dish study
and computer simulation programs focused on moisture content and dissolution.
Dissolution is one parameter that may change as a function of temperature, humidity, and
storage time. It has been accepted by the United States Pharmacopeial Convention
(U SPC) as a measure of bioavailability and as a stability-indicating parameter for solid
oral dosage forms.

When solid oral dosage forms are packaged in blisters or plastic bottles, they can
be protected from environmental hazards such as light, oxygen, and moisture. However,
the packages cannot protect them completely, so the properties of solid dosage forms may
deteriorate as a function of storage time. Since dissolution is affected by temperature and
moisture, determining the relationship among dissolution, temperature, and moisture is
very important in designing a package for solid oral dosage forms that will maintain the
specification limit of dissolution.

To measure this relationship and the effect of the package on it, an experimental
program can be conducted. It consists of two parts: an open dish study of the product and
a separate evaluation of the permeation behavior of the package. This program differs
from and is faster than the stability testing program. In the open dish study, the product

is brought to equilibrium quickly with a series of temperature and humidity environments.

Once that equilibrium is achieved, the product properties, including dissolution, can be
measured. At the same time, the permeability of the package can be measured over the
range of temperatures encountered in distribution. Specifically, this information can be
obtained for the accelerated storage condition (40°C/75% RH).

Then, using mathematical relationships developed by researchers over the last 20
years, and in this research, product researchers and packagers can select a barrier package

that will meet the requirements of the accelerated stability testing program.

More formally, the hypothesis for this research is that there is a general method
for design of a barrier package that will protect the dissolution property of a drug product
when it is exposed to ICH (International Conference on Harmonization) accelerated
stability conditions. The general hypothesis is supported by the following three
subordinate hypotheses:

1. The relationship between moisture content and dissolution of drug tablets can be
found using open dish studies.

2. Moisture content and dissolution of drug tablets in a permeable package can be
predicted based on the unsteady state vapor pressure of the package headspace.

3. A suitable package for stability testing can be chosen using computer simulation

programs.

In order to prove the hypotheses, the following steps were taken:
1. Develop mathematical models that can calculate the shelf life, moisture content, and

dissolution of drug tablets in a package.

2. Determine moisture sorption isotherm equations.
3. Determine dissolution retardation rates at a variety of relative humidities.

4. Determine permeabilities of packages.

In this study, coated and uncoated drug tablets were placed in open dishes at 25
and 40°C at 0%, 50%, 65%, 75%, and 90% RH, for 6 months. The moisture, dissolution,
hardness, and dimensions of the tablets were measured at scheduled times during the
open dish study. It was found that dissolution, hardness, and dimensions changed as a
fimction of moisture and storage time. The relationship between moisture and dissolution
obtained from the Open dish study was used to predict the dissolution of tablets in a
package as a function of storage time. The hardness and dimensions were used to explain
the theory of dissolution retardation as a function of relative humidity. The
permeabilities of packages (LDPE bags and HDPE bottles) at 40°C were measured
separately. Tablet properties from the open dish study were used along with package
permeabilities to design a suitable package for stability testing.

In order to formulate the relationship between moisture and dissolution, a
property called the dissolution reduction rate (K) was developed by Nakabayashi and
coworkers (1981). However, their approach did not work for this study because of
variation inherent in the dissolution measurements. While logical in theory, the
dissolution reduction rate did not work well enough in practical application to be useful.
Therefore, a different approach to formulate the relationship between moisture and
dissolution was used in this study. This different approach uses the dissolution

retardation rate (R), dissolution change/day. Dissolution is dependent on moisture as well

as storage time, so a dissolution retardation rate including storage time is necessary to
formulate the relationship with moisture in order to predict the dissolution of tablets in a
package as a function of storage time. Dissolution retardation rates must be determined

at each relative humidity and temperature.

CHAPTER 1
BACKGROUND AND LITERATURE REVIEW
(DISSOLUTION PREDICTION MODELS)

Literature related to dissolution prediction models is reviewed here. Literature
related to moisture and shelf lifeb prediction models is reviewed in Appendix A because
shelf life and moisture prediction models are not directly related to dissolution prediction
for tablets in a package. They are, however, necessary tools for estimating dissolution
shelf life or selection of barrier packages, so the necessary background is provided
separately.

Dissolution is a critical parameter in determining performance and defining
quality control, regulatory compliance, and bioavailability of solid oral dosage forms
such as tablets and capsules (see USP <1191>). The U.S. Food and Drug Administration
(FDA) requires that any drug product on the market must at all times meet the
requirements of the USP monograph or other monographs specifying its properties.
Otherwise, it will be recalled from the market. The monograph specifies a dissolution
requirement for many products. Compared with the chemical stability of the drug
substance in solid dosage forms, the effect of aging on in-vitro dissolution (physical
stability) has been neither thoroughly investigated nor fully understood (Chowhan,
September 1994).

Dissolution prediction models for drug substance particles have been developed
by using the film theory (diffusion layer model). The thickness of a drug particle is
assumed, and then the model can be developed from Fick’s second law of diffusion. It is

a cube-root law as shown in Equation 1 (Higuchi, 1963).

 

b . . . . . . . . .
Shelf life IS defined as the time requrred to reach the final morsture content from the Inlllal moisture content.

fire] 3 DC. (1)

3 Ph

W. =w0 “If/3’ kr3=[

where w = the particle weight at time t, wo = the initial particle weight, k = the composite
rate constant, p = the density of the particle, D = the diffusion coefficient, C, = the
solubility, h = the diffusion layer thickness

Almeida et al. (1997) demonstrated the inadequacy of the cube-root law (Equation
1) to predict the dissolution of ibuprofen, as the assumptions associated with this model
are not valid in the case of multisized powders.

Wang and Flanagan (1999) showed that an assumption used in the derivation of
the cube-root law may not be accurate under all conditions for diffusion-controlled
particle dissolution. They found the cube-root law was most appropriate when particle
size is much larger than the diffusion layer thickness. A two-thirds-root expression
(Equation 2) applied when the particle size is much smaller than the diffusion layer
thickness. The square-root expression (Equation 3) is intermediate between these two

models.

4;: “20C
W2 3 = Wri 3 "k2 3’ kr-r =[—£) —" (2)
3 p
1,2
WI 2 =Wri‘2 'kr 2’ kl 2 =(fl) _D2_ (3)
2 k'p

where k ’ = the constant

These models (Equations 1-3) are just for drug substance particles. If a drug is

mixed with excipients, and then compressed to form a tablet, the models cannot be

applied to predict the dissolution of the tablet because it is impossible to determine the
diffusion layer thickness.

F u et al. (1976) developed a mathematical model for the estimation of the drug
release rate from drug-polymer composite tablets. The drug-polymer composite tablets
do not disintegrate in the dissolution medium, but the drug can dissolve into the medium
through the polymer. The model (Equation 4) predicts the drug released from a drug-

polymer composite tablet as a function of storage time:

 

 

~

M (v exp: —Da mt)” “Mfl D3,. 1)
M(Q) —[28a 2 ":zsol—— 2:0— (4)

where Z = half of the thickness of the drug-polymer composite tablet, a = the radius of the
drug-polymer composite tablet, D = the difiusion coefficient of the drug in the drug-
polymer composite tablet, t = storage time, a", = the roots of Jg(aa) = 0; Jo = the zero-
(2n + 1);:

order Bessel function, A, = 23

Siepmann et al. (1998) also developed a dissolution prediction model for swollen
hydroxypropyl methylcellulose (HPMC) tablets numerically by using finite differences.
The model was used to calculate the required shape and dimensions of HPMC tablets to
achieve desired drug release profiles. The model mentioned above cannot be applied to
starch based (or sugar based) tablets because these tablets disintegrate. If tablets lose
their original shape, the prediction model cannot be used.

Based on review of the literature, it can be concluded that there is no available
dissolution prediction model that can predict the dissolution of aged tablets stored at a
specific condition for a certain amount of time. It may be impossible to develop. So, the

dissolution behavior as a function of storage time has only been determined by stability

testing.

Taborsky-Urdinola et al. (1981) reported the effects of packaging and storage in
multiple-unit and unit-dose containers on the dissolution rate of prednisone tablets. USP
prednisone dissolution calibrator tablets that were packaged in polyethylene bags and
unpackaged (open dish) tablets were selected to compare their dissolution. Both sets of
tablets were placed in a tropical microenvironment of approximately 40 °C and 85%
relative humidity for three months. Dissolution was measured at pre-determined intervals
during storage. This study clearly demonstrated that packaging and storage affect
product integrity. It showed a relationship between dissolution of the pharmaceutical
product and the moisture barrier of its packaging. The dissolution of tablets stored in
open dishes decreased a lot more quickly than the dissolution of tablets stored in
packages. Her study is very useful to understand the dissolution behaviors among opened,
low barrier packaged and high barrier packaged tablets. However, she did not explain
how much dissolution was different as a function of package barrier and how dissolution
changed as a function of storage time. Her study does not predict the dissolution
behavior of tablets in a package.

Chowhan (March 1994) reported that the particle size, aqueous solubility, drug
substance concentration, excipients and their concentration in the formulation, and the
process used in manufacturing all play a significant role in determining drug product
dissolution. And, Chowan (September 1994) reported the factors affecting in vitro
dissolution of tablets include formulation, manufacturing method, processing variables,
in-process controls, and dissolution method. Tablets formulated, manufactured, and

processed differently were stored at differing storage conditions for differing storage

times in open dishes. His study is helpful for selecting the initial tablet formulations, but
does not predict the dissolution behavior of aged tablets in a package.

As mentioned above, much research on developing pharmaceutical dosage forms
has been done, and is still being done for each new product. However, the dissolution
behavior of aged tablets in a package has still not been fiilly investigated and understood.
It has been established that the dissolution of tablets in a package is changed as a function
of storage conditions and storage time, but little research has been done to find how much
the dissolution of tablets in a package is changed as a fimction of storage conditions and
storage time.

When the dissolution shelf life of solid dosage forms was estimated, fit factors,
critical storage condition, and dissolution reduction rate were used. Moore and Flanner
(1996) presented two new fit factors to compare the difference between the percent drug
dissolved per unit time for a test and a reference formulation. The fit factors are denoted

by f, and f2, and they can be defined by Equation 5 and Equation 6.

x 100% (5)

 

 

 

-—0.5
n
f2 =5010g [1+12w,(R,—T,)2:l x100 (6)
n

i=1

where, R, = the reference dissolution at stirring time point t
T, = the test dissolution at stirring time point t
n = the number of sampling (stirring time) points
w, = the optional weight factorc

 

° It can be used to minimize the analysis error.

10

Equation 5 is a perturbation of the relative error formula. It can approximate the
percent error between reference and test dissolution profiles. The percent error is zero
when two profiles are identical and increases proportionally with the dissimilarity
between the two profiles. Equation 6 is a logarithmic transformation of the sum of
squares error. It takes the average sums of squares of the difference between reference
and test dissolution profiles and fits the result between 0 and 100. The fit factor (73) is
100 when two profiles are identical and approaches zero as the dissimilarity increases.
Moore and Flanner said the fit factor (f2) may provide a linear relationship if it is plotted
as a function of storage time; then the dissolution shelf life can be predicted by
extrapolation. However, it is hard to get a linear relationship between either fit factor (f,
or f2) and storage time.

The dissolution was used to decide the failure point of solid dosage forms and the
moisture content at the failure point was used to estimate the dissolution shelf life (Qian,
1996, Wu, 1996, Kokitkar, 1997, Adams, 1999, Yoon, 2000, Thomas, 2000, Suemag,
2001). Adams (1999) stored hydroxypropyl methyl cellulose coated aspirin tablets in
open dishes for 90 days at three different temperatures (25, 30, and 40 °C) and several
different relative humidities. Dissolution and moisture content were measured at planned
intervals. If the dissolution fell below a specification limit at a condition, that condition
was used for a failure storage condition. So, the package was designed to maintain the
package headspace below that failure storage condition for a desired dissolution shelf life.
However, it has been found that the dissolution is not dependent on moisture content
alone. Figure 1 shows dissolution for 3 months storage time for a coated aspirin. The

tablets reached equilibrium moisture content in 6 days. Even though the moisture content

11

at 6 days and 90 days were the same, dissolution at 6 days and 90 days was not the same.

Therefore, the dissolution is not dependent on moisture alone. It depends on storage time

as well as moisture.

 

 

 

 

 

125 1. ----- 2...----.M-.--..-- --m----_.u - . .- I-.. MW:
;'
<r—————___.,_.—~——e- ‘
an
100 a a.“
“Ht
2 75 -
'0
I
5
a! 50 ~
25 -
0 ‘l . . . T . I
0 15 30 45 60 75 90 105
Storage time (days)

Figure l Dissolution of coated aspirin tablets stored for 3 months at 25°C/90%
(Figure was plotted with data obtained from Adams, 1999)

Finding the relationship among the dissolution, moisture, and storage time is very
important for predicting the dissolution of tablets in a package. Many researchers
(Chowan, 1980, Taborsky, 1981, Kadir, 1986, Carstensen, 2000) tried to find the effects
of storage conditions (e.g. temperature, RH, storage time) or packaging on the dissolution
of solid dosage forms. They found the dissolution is affected by moisture, temperature,
packaging, and storage time. However, no one except for Nakabayashi in 1981 explained
how much the dissolution is affected by temperature, moisture, and storage time and what
the relationship is among them. Nakabayashi tried to predict the dissolution of

prednisolone tablets in a package by using the dissolution rate (k) and dissolution

12

reduction rate (K). In order to understand dissolution rate (k), the mechanism of

dissolution in medium should be understood first.

1. Dissolution profile (The mechanism of dissolution)

Abdou (1989) explained the mechanism of tablet dissolution. If a fresh tablet is
dropped into a dissolution medium (e. g. water or 0.02N HCl), the tablet is wetted by the
medium. Water penetrates through the pores in the tablet, and disintegrants are swollen.
The swelling of disintegrants can make boundaries in the tablet weak. Finally, the tablet
is disintegrated and deaggregated into fine particles. Stirring by the stirring bar
accelerates the tablet disintegration. Afier that, more drug particles become exposed to
the water and dissolution proceeds effectively. If drug particles become exposed quickly
to the water, the dissolution value reaches a peak in a short time. Figure 2 shows the S-

shaped dissolution curve based on the theory of dissolution.

l3

Dissolution

% Dissolved

Mechanical Lag
and Wetting

4— Disaggregation
Disintegration

 

 

 

Stirring Time
Figure 2 The S-shaped dissolution curve of solid dosage forms (Abdou, 1989)

2. Dissolution rate (k)

Based on the dissolution theory, a dissolution mechanism (1) was proposed by El-

Yazigi (1981) as shown below.
A ——kd——> A p -—kf——> A S Mechanism (1)

where A is the amount of drug in the tablet, kd is the disintegration rate constant, A p is the
amount of drug in the small particles (after disintegration). A, is the amount of drug in
solution and k, is the dissolution rate constant.

When the fresh tablet is dropped into the dissolution medium, it is disintegrated
immediately. So, the disintegration rate (kd) can be ignored for the fresh tablet. The

mechanism (1) can be simplified as shown in mechanism (II).

14

A p —> As Mechanism (II)

where k is the dissolution rate.

Equation 7 can be used to determine the dissolution rate (k). The dissolution rate

(k) is an apparent first-order kinetic rate.
C. = C.- -e"° (7)

The dissolution profile shown in Figure 3 is plotted with % undissolved versus stirring

time to represent the exponential Equation 7.

 

 

 

 

100%
(Ct)
75% —
U
Q
2
3
g 50% F
U
C
:3
25% ~
0% . . 3
0 10 20 C1)

Stirring time (ninutes)

Figure 3 Exponential relationship between % undissolved and stirring time

The concentration of drug (C,, mg drug left in tablet/mL medium) still left in the

tablet afier stirring time s can be calculated by Equation 7 and the concentration of drug

15

dissolved in the medium (Cm, mg drug dissolved in medium/mL medium) afier stirring

time s can be calculated by Equation 8.
C,,, = C,- — C,- .e“’“ ' (8)

The natural log is applied to both sides of Equation 8, then it is rearranged to get a

dissolution rate (k) as shown in Equation 9.

C ,- _

By plotting the data as ln[C/(C,~-C,,J] vs. stirring time (s), a dissolution rate (k) can be

determined as shown in Figure 4.

InICI/(Cr-Cnd]
N

 

 

O 5 10 15 20 25 30
stirring time (a)

Figure 4 Dissolution rate (k)

3. Dissolution reduction rate (K)
The theory of the dissolution rates as a function of storage time has not been
explained clearly yet. So, the relationship between dissolution rate and storage time

should be determined experimentally. Nakabayashi used an exponential relationship

16

(first order kinetics) between dissolution rate and storage time. Obviously, the
relationship is very dependent on the product formulation.
Equation 10 can be used to fit the relationship between dissolution rate (k) and

storage time (t).
k, =ki-e'K" (10)

The natural log is applied to both sides of Equation 10, then it is rearranged to get a
dissolution reduction rate (K) as shown in Equation 11.

1n[7'::—_]=—K-r (11)

By plotting the data as ln[k/kJ vs. storage time (t), a dissolution reduction rate (K) can be

determined as shown in Figure 5.

storage time (t)

0 30 60 90 120 150 180
o r 1 1 1 1 1

 

 

-3 - ..___.-. ______..-_. ... __-__ .. .. .. . .. _ . _. _ .W .. _ ..

Figure 5 Dissolution reduction rate (K)

4. Relationship between dissolution reduction rate and moisture content
Nakabayshi and coworkers used the multiple regression method to determine the

relationship between the dissolution reduction rate, moisture, and temperature. Table 1

17

shows the dissolution reduction rates for various moisture contents at 25, 40, and 50°C

and Equation 12 shows the equation determined from a multiple regression method.

Table l Apparent dissolution reduction rate constants (K) of dissolution for prednisolone
tablets with various moisture content (Nakabayashi et al., 1981)

 

 

 

 

 

 

 

 

 

Temperature, °C M (%) Dissolution Reduction Rate, K
25 4.77 0.0049
25 5.60 0.0091
40 3.54 ' 0.0037
40 4.12 0.0055
40 4.64 0.0092
40 5.41 0.0165
50 3.10 0.0038

 

 

 

 

The constants of Equation 12 can be determined by using a multiple regression function

in a statistics computer program.
an = 4.5241+3.4936-lnM-4556.0491/T (12)

where T is the absolute temperature ( °K)

They found that each term of Equation 12 was statistically significant, and the
multiple correlation coefficient was as high as 0.994. Thus, Equation 12 was considered

to be suitable for expressing the dependence of the K value on moisture and temperature.

18

CHAPTER 2

EXPERIMENTAL DESIGN, MATERIALS AND METHODS

1. Experimental design

Open dish exposure at various relative humidities causes faster dissolution change
than the stability testing that is done with tablets in a package. In this study, therefore,
the product and package are tested separately, then their experimental data are combined
to predict the product properties in package as a function of storage time. First, tablets
were stored in open dishes at 25 and 40°C at 0, 50, 65, 75, and 90% RH for 6 months.
They were tested to determine the relationship between moisture content and dissolution
for 6 months. Second, the permeabilities of packages (LDPE bags and HDPE bottles)
were determined. Finally, the product results (initial moisture content, sorption isotherms,
relationship between moisture content and dissolution) and package permeabilities were
used to design a barrier package.

The product tablets were 2 years old, so it was necessary to determine if they still
met specifications before using them in this study. First, the product quality was tested in
terms of moisture, dissolution, and hardness. After determining that the product could be
used for this study, initial moisture contentsd and sorption isotherms were measured.
These are better to be measured prior to preparing the storage conditions for the open
dish study. Based on the initial moisture content and sorption isotherm, initial
equilibrium relative humidity can be determined. Storage conditions above initial

equilibrium relative humidity are recommended because tablet deterioration may be more

 

" In this study, initial moisture content is defined as a moisture content of the tablets which are inserted into
a package.

19

severe than at low humidities. After determining the storage conditions, tablets were set
up in open dishes for dissolution, hardness, and dimension measurement.

Figure 6 shows the diagram of the experimental design. Careful attention to
matching the solid and broken lines with the description in the following text will help
the reader to visualize the several relationships that exist among the parts of the 'work.
The solid lines all represent the main theme of the research, from beginning through
“Design a Package”. The dotted and dashed lines represent the application of theories
and procedures which are tools for accomplishing the main task.

Figure 6 also shows the package part of the work (permeability) and the product
part of the work (moisture content, dissolution, dimensions, and hardness). Permeability
and moisture content are used to verify the shelf life and moisture prediction program.
These are all connected by dotted lines. Permeability, moisture content, and dissolution
are used to verify the dissolution prediction program. These are all connected by a solid
line. Moisture content, dissolution, dimensions, and hardness are used to explain the
dissolution behavior as a function of relative humidity. These are connected by dashed
lines. Table 2 shows the testing plan for the open dish study. The package permeability
and product/package set up for the model verification were started with the open dish

study at the same time.

20

 

Product quality test

I

 

 

 

 

 

Determine initial moisture contents and sorption isotherms

 

 

 

v

 

 

Prepare the storage conditions for open dish study based on the sorption isotherm data

 

 

l

l

I
I T

j

 

Permeability

 

Moisture content

 

 

 

 

 

 

Dissolution Dimensions Hardness

 

 

 

 

l
and HDPE
bottles

 

 

I l

o lnrtraldrssolutron for . Thickness

coated and uncoated
tablets

. Dissolution profiles
(Dissolution as a
function of stirring time):
coated and uncoated
tablets at 40°C and 25°C

 

a oaaaooaoooouaoooaaoooooono.one-oooooooaaoo
-——-----

5 ......... -L _______ L___.l_

 

V

. Diameter

l

. By hardness tester
. By blister package

I
I
I
I
I
I
I
I
.I

I
V

 

 

 

In order to verify

Moisture prediction program
Shelf life prediction program

Product & package setup

0 Tablets in LDPE bags without
silica gel and tablets with silica
gel (0.5 g, 1 g, 2 g) in LDPE

bags

0 Tablets in HDPE bottles
without silica gel and tablets
with silica eel (0.5 2) in HDPE

 

 

In order to verify
Dissolution prediction program

. Tablets in LDPE bags without
silica gel and tablets with silica
gel (0.5 g, l g, 2 g) in LDPE bags

. Tablets in HDPE bottles without
silica gel and tablets with silica
gel (0.5 g) in HDPE bottles

. Tablets in open dishes at stepwise
conditions

 

 

 

 

 

 

In order to explain the
dissolution retardation
as a function of RH

 

 

 

 

Figure 6 Diagram of the experimental design

 

 

Design a package

 

 

 

21

Table 2 Testing plan for open dish study

 

Storag: time (months)

 

 

Prior to open dish study 1 2 3 I 4 5 I 6
Initial moisture contents (coated and . .
uncoated tablets, silica gel), Moisture Package permeabllrty
Ll

sorption isotherms (coated and uncoated
tablets, silica gel at 25°C/40°C),
Dissolution (calibration curve, initial
dissolution profiles for coated and
uncoated tablets), Initial hardness, Initial

 

 

 

Product and package were set up for the model verification

 

 

I

I

Finding the relationship between moisture and dissolution

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

dimension .
Tests of tablet properties k _
Stora e conditions
D) D(200rpm,
90% D,H,d D,H D,H,d D,H m),H D,H,d
D. D(200rpm,
75% D, H,d D,Hl D, H,d D,H ”pH D,H,d
D, thoorpm
40°C 65% D, H, d D, H D, H, d D, H 1L” H D, H, d
D, Dow
50% D, H, d D, H D, H, d D, H .29, H D, H, d
D, thoOrpm.
0% D,H,d D,H D,H,d D,H .Jm, D,H,d
D, D(200rpm,
90% D,H,d D,H D,H,d D,H ”th D,H,d
Dr D(200rpm,
75% D, H,d D,H D, H,d D,H ”pH D,H,d
D9 D(200rpm,
25°C 65% D, H, d D, H D, H, d D, H ILrLH D, H, d
D, 9000an
50% D,H,d D,H D,H,d D,H ".1:er D,H,d
D, Dawn“.
0% D,H,d D,H D,H,d D,H ӣer D,H,d

 

 

 

 

 

D: the dissolution testing of coated and uncoated tablets using lOOrpm for 30 minute stirring (6 samples for

each condition at each testing)

0000an m): the dissolution of coated and uncoated tablets using lOOrpm for 30 minute stirring and 200rpm
for additional 30 minute stirring (6 samples for each condition)
H: the hardness of coated and uncoated tablets (10 samples for each condition at each testing)
d: the dimension of coated and uncoated tablets (5 samples for each condition at each testing)

During dissolution tests, it was recognized that dissolution of tablets stored at 40°C

changed very rapidly as a function of storage time. Dissolution is defined as a physical

property of tablets, so dissolution must be explained by physical phenomena such as a

physical interaction among ingredients in tablets. Excipient and drug particles

compressed into tablets are disintegrated by the dissolution medium. If the disintegration

22

 

time increases, the dissolution value will decrease (Carstensen et al., 1980). The
dissolution value can be changed physically or chemically. Physically, excipients and
drug in tablets can interact such as in crosslinking. Also, a drug can be degraded
chemically. This causes the dissolution value of the drug to decrease. In order to make
sure that the dissolution changed only by physical interactions, tablets needed to be
disintegrated completely in the medium to allow all the drug in the tablet to dissolve into
the medium. If the drug in the tablets is dissolved completely, the dissolution value must
be the same as for the initial tablets (D = 100%) if there is no chemical degradation.
Therefore, tablets at 5 months storage time were stirred using 200 rpm for an additional
30 minutes after the dissolution testing was done to be sure they dissolved completely.
Some of the tablets did not reach 100% dissolution because they did not disintegrate
completely, but some tablets did disintegrate completely, So they reached 100%
dissolution. This meant the drug in 5 month aged tablets did not degrade chemically.

See Appendix E. Dissolution Raw Data and Dissolution Profiles at 25°C for more

information.

23

2. Materials and methods
(1) Drug X coated and uncoated tablets -

Drug X coated and uncoated tablets were obtained from Eli Lilly and Company
(Indianapolis, IN). The tablets were formulated with drug substance X, and the
excipients mannitol (63%), microcrystalline cellulose (MCC) (18%), croscarmellose
sodium, povidone, purified water, magnesium stearate, and color mixture yellow for
coated tablets (see Appendix C for detailed information).

Mannitol can be obtained from hydrogenation of glucose. Glucose is a
monosaccharide, so mannitol is a saccharide derivative. Mannitol is used as a diluent in
formulating tablets. The superdisintegrant, croscarmellose sodium, was used to make
tablets disintegrate quickly in the medium. Magnesium stearate used as a lubricant is
hydrophobic but it enhances tablet granulation processing characteristics.

Table 3 shows that the physical properties of drug X 2 year old tablets are close to

those of drug X fresh tablets.

Table 3 Comparison of physical properties between drug X fresh tablets and 2 year old

 

 

 

 

 

tablets
Moisture content Dissolution at 30 minutes Hardness
Coated I Uncoated Coated I Uncoated Coated I Uncoated
Fresh z2% | * 100% | * 9kp I *
2years old 2.31% | 1.93% 95.9% | 96.2% 9.21 kp | 8.9 kp

 

 

 

 

*Data for uncoated tablets were not available.

24

 

(2) Storage conditions

Two different temperatures (25 and 40°C) and 5 different relative humidities (0,
50, 65, 75, 90%) were used for the open dish study. The relative humidities (50, 65, 75,
and 90%) were prepared by saturating deionized water with salts (Fisher Scientific, PA)
and 0% RH was prepared by using calcium chloride (CaClz, desiccant) in glass
desiccators. Table 4 shows the list of the salts used to provide the desired range of
relative humidities. ASTM E 104-85 shows how to prepare the salt solutions and the

expected RH values for selected salt solutions.

Table 4 Salt solutions used to provide the rguired range of relative humidities

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

25°C
Salts Amount used Nominal RH Actual RH Actual RH
by humidity sensor by moisture content
Calcium Chloride N/A 0% N/A 1.3 — 1.5%
(CaClz)
Magnesium Nitrate l300g/500ml 52.9%:0.2% 50% N/A
, M mom—61120) DI water
Sodium Nitrite 350g/500ml 64.3% 65% N/A
(NaNOz) DI water
Sodium Chloride 300g/500ml 75.3%d:0. 1% 75% N/A
(NaCI) DI water
Potassium Nitrate 500g/500ml 93.6%:0.6% 93% N/A
(KNO3) DI water
, 40°C
Salts Amount used Nominal RH Actual RH Actual RH
by humidity sensor by moisture content
Calcium Chloride N/A 0% N/A 2.9 - 4.1%
(CaCIz)
Magnesium Nitrate l300g/500ml 48.4%i0.4% 50% 47 — 52%
. __(_Mg(N03)2o6HZO) DI water
Sodium Nitrite 350g/500ml 61.3% 64% 63 — 66%
(NaNOz) DI water
Sodium Chloride 300g/500ml 74.7%i0. 1% 75% 73 - 74%
('NaCl) DI water
Potassium Nitrate 500g/500ml 89%: I .2% 89% 86 — 89%
’ (KN03) DI water

 

N/A: It was not measured.

25

 

Environmental chambers (25 and 40°C) in which temperature and relative
humidity are controlled automatically were used. Desiccators were stored in those 25 and
40°C chambers. In order to make sure that each saturated salt solution reached the
desired relative humidity, a humidity sensor was placed in the lid of the desiccator until
equilibrium was reached. The stick-shaped humidity sensor was fitted with a rubber

stopper. Then it was placed in the top of desiccator as shown in Figure 7.

 

 

 

 

 

Salt Solution

 

Figure 7 Graphical representation of the humidity sensor placed on the top of desiccator

The humidity sensor is connected to a humidity transducer by wire. The humidity
transducer detects the voltage change from the sensor. The accuracy of the humidity
sensor is i3% from 0-90% RH between 15 °C and 50 °C (59 to 122 °F). The humidity is
detected by the voltage change (4.0 mA to 20.0 mA). The 4.0 to 20.0 mA output is
proportional to 0% RH to 100% RH.

Also, the relative humidities for 6 months were measured by using the moisture

content of tablets and moisture sorption isotherm curve. Periodically, the moisture

26

content of tablets was measured, and applied to the moisture sorption isotherm curve to
determine the equilibrium relative humidity. Table 4 shows actual relative humidities
determined by this method. There is good agreement. It means desiccators kept the

desired RH well.

(3) Sealing, integrity testing, and volume measuring of packages

The LDPE bags (3” x 3”) were heat sealed by an impulse heat sealer (248C,
Sencorp Inc.). The LDPE film sheet was cut and folded, and then two sides were impulse
heat sealed for two seconds. After tablets were inserted into the LDPE bags, the top was
also heat sealed. The HDPE bottles (50 mL) were induction heat sealed by an induction
heat sealer (LM328502, ENERCON Inc.) after the tablets were inserted into the bottles.

In order to make sure packages were sealed properly, the integrity of packages
was tested visually for induction heat sealed HDPE bottles and by using methylene blue
for impulse heat sealed LDPE bags. Afier each moisture and dissolution test, the
methylene blue was injected into LDPE bags until it covered the seal all around the
package. The methylene blue was allowed to remain in contact with the seal edge for
approximately 10 seconds. The sealed area was visually examined.

In order to determine the volume of LDPE bags and HDPE bottles, water was
injected into LDPE bags and poured into HDPE bottles, and then water was poured into a
100 mL volume flask to measure the volume. The bag was visually flattened to make the

bag volume the same as the actual bag volume containing tablets.

27

(4) Permeability

The permeabilities of LDPE bags and HDPE bottles were measured using calcium
chloride. See procedures ASTM D 895-94 or USP 24 <671> for more information.
Calcium chloride (CaClz) was regenerated at 110°C for 24 hours to have 0% water vapor
pressure, and inserted into the LDPE bags and HDPE bottles. It was assumed that the
internal water vapor pressure was zero. Five LDPE bags containing calcium chloride and
two LDPE bags containing glass beads were stored in a 90% RH desiccator in the 40°C
chamber, and five HDPE bottles containing calcium chloride and two HDPE bottles
containing glass beads were stored in the 40°C/75% chamber. There was not enough
space for HDPE bottles in the 90% RH desiccator, so the bottles were stored in the
40°C/75% chamber. The bags and bottles were taken out periodically and the moisture

gain was measured using a balance (R3008, Sartorius Inc., sensitivity: i0.00005g).

(5) Moisture content
(3) Initial moisture content

The initial moisture contents of tablets and silica gel were determined by using a
Computrac MAX 2000 (Arizona Instrument Inc., AZ) at a temperature of 103°C for 6
hours. Tablets were ground by mortar and pestle, and then placed on the weighing pan.
The granules of silica gel were not ground. The Computrac MAX 2000 has the heating
pan on the top and the balance on the bottom. Therefore, drying and weighing tablets
and silica gel can be achieved at the same time. The moisture change is expressed by

using a graph (weight change vs time) on the screen.

28

(b) Moisture sorption isotherms

The moisture sorption isotherms of tablets and silica gel were constructed using a
SGA-100 Symmetrical Gravimetric Sorption Analyzer (VTI Corporation, FL) (see Figure
8).

The SGA-100 Symmetrical Gravimetric Sorption Analyzer is a continuous gas
flow adsorption instrument for obtaining moisture sorption isotherms at temperatures
ranging from 5°C to 60°C at ambient pressure. It has the capability of performing
sorption isotherms at relative humidities from 0% to 98%. The SGA-100 has an option to
dry the sample to determine the initial moisture content. However, 60°C is not a high
enough temperature to dry out the tablet and silica gel completely. Therefore, the initial
moisture content would be better to be determined before samples were placed on
weighing pan in the analyzer, and then Equation 20 in Appendix A can be used to
calculate the equilibrium moisture content if the initial moisture content, and the initial
and final weights of the tablet and silica gel are available.

The tablet is placed on the quartz sample holder, then the sample holder is
attached to a hang down wire connected to a sensitive microbalance. The temperature is
controlled by a constant temperature bath (sensitivity: i0.01°C) which circulates water
inside the walls of the aluminum block. The humidity is controlled by the wet Mass
Flow Controller (MFC 1 in Figure 8). The humidifier is maintained at constant
temperatures (25 or 40°C) to make a saturated stream of humidity.

At the beginning of each run, the equilibrium criteria must be determined. For
example, if a weight % change does not occur for a given time (e.g., 10 minutes), then the

relative humidity is increased to the next step. Therefore, the user must determine the

29

weight % change and the specific amount of time. These conditions are maintained until
the sample weight reaches equilibrium.

There is a way to determine the minimum equilibrium weight gain. The noise
level for SGA-100 is 1 micrograrn (0.001 mg), so any reading at that level is noise. For
example,

0.001 mg (noise level)
200 mg (sample weight)

x100 = 0.0005%

 

If a 200 mg sample is used, 0.0005% weight change can happen as a result of background

noise. Therefore, a larger weight % change than 0.0005% must be selected.

I \
. PU FIG E
EXHAUST

 

 

 

 

 

 

7T0 cm?
W
1-
I
W

 

 

 

 

HUIIIIDIFIER

 

 

 

 

 

 

Figure 8 The sketch of the symmetrical gravirnetric analyzer (SGA-IOO)
(The sketch was obtained from VTI, and it is modified to simplify.)

where,

SI, 82, S3, and S4 = Solenoid Valves

MFC l and MFC 2 = Mass Flow Controllers

DPA = Dew Point Analyzer

RTD = Resistance Platinum Thermometer

CTB = Constant'Temperature Bath
Principles of operation for SGA-I 00

A dry gas source (nitrogen, air) passes through a 2 micron filter and splits into
two lines. One of the lines, called the purge line, is connected to the microbalance
chamber. The flow rate of the gas continuously purging the microbalance chamber is
regulated by a rotameter. The second line is connected to two solenoid valves which are
provided for shutting on and off the flow to the mass flow controllers which are used to
accurately control the flow of the dry gas. One of the streams (MF C 1) flows through the
humidifier. The second mass flow controller (MFC 2) provides a dry gas stream (see
Figure 8).

The gas leaving the humidifier is mixed with the dry stream via a static mixer.
The dew point of the mixed stream is measured with the dew point analyzer (DPA); Two
solenoid valves downstream from the DPA redirect the stream either to the aluminum
block or to the vent. The stream entering the aluminum block is equilibrated with the
temperature of the block and is equally divided into two streams. One of the streams
enters the sample compartment of the aluminum block. The other stream enters the

reference compartment of the block“. In each of the compartments, a 100 Ohm

Resistance Platinum Thermometer (RTD) is provided for measuring temperature of the

 

‘ If the weight of a sample is larger than the capacity of the balance, a counter weight is used. The balance
measures the difference in weight between the two pans, and the software adds the counter weight to the
difference to get the actual sample weight.

31

process stream. Based on the temperature and dew point, the relative humidity is
determined.

The sample weight changes during adsorption are measured with a Cahn D-200
microbalance (sensitivity: i0.001mg) and recorded in a computer with Flow System
sofiware. The Cahn balance has a capacity of 3.5 grams and is sensitive to changes as

small as l microgram.

(c) Verification of moisture simulation program

Packages (LDPE bags and HDPE bottles) were used to verify the shelf life and
moisture prediction models. The uncoated tablets and silica gel were inserted into the
LDPE bags and HDPE bottles, and they were stored at 40°C/90%. Table 5 shows the
combination of componentsf in each package. Seven different LDPE bags and HDPE
bottles were used for each combination. See Appendix D for raw data of the weight of

components in LDPE bags and HDPE bottles.

Table 5 The combination of components in LDPE bags and HDPE bottles used to verify
the moisture and shelf life prediction program
LDPE bags HDPE bottles |

 

 

Contents Tablets only I Tablets + 0.5 g 7 Tablets + 1 Tablets + 2 Tablets only Tablets + 0.5

7 7 silica el silica el silica el 7 silica el
Before the tablets and silica gel were inserted into the package, the initial weights
of tablets, silica gel and package were measured using a balance (sensitivity: i0.00005 g).

At each weighing time, the total weight of the package and contents was measured first,

then the package was opened, and the tablets were removed for weighing.

 

r It is defined as dry solids such as tablets, capsules, and desiccant.

32

The moisture gain of LDPE bags alone was determined by blanks when the
permeability was determined. It was 0.02 g, and assumed to be the same for all tests.
See Appendix D for raw data. The moisture gain of HDPE bottles alone was also
determined by blanks when the permeability was determined. Figure 9 shows the
moisture gain of empty HDPE bottles as a function of storage time. As explained, the
moisture gain of each of the packages and the tablets was determined. If they are
subtracted from the total moisture gain, the moisture gain of the silica gel can be
calculated without measuring the weight of silica gel. The silica gel in LDPE bags and
HDPE bottles is hard to remove for measuring the weight because it is small granules.

(see example calculations below.)

 

 

0.025 -, _, , .
g 0.02 _
C
3 0015
2 ' _ y=6E-05x+0.012
3 R2=0.9973
.2 0.01 _
O
a
g 0.005 _

O m
0 50 100 150 200

Storage time (days)

Figure 9 The moisture gain of HDPE bottles

The following example calculation shows how to calculate the moisture content
of tablets and silica gel by using Equation 23 from page 125, rewritten here for

convenience.

33

 

 

 

 

 

 

. . . W f ' (M1 + 1)
Mo1sture content based on the dry weight of sol1d: M (%) = W -1 x 100
Calculation of the moistmontent of tabletgnd silica gel in the packages
Example 1. Tablets and silica gel in LDPE bags
Initial weight Final weight _

. Package: 1.1690g . Package (calculated): 1.1890g

. Tablets: 3.7642 g . Tablets: 3.7872 g

. Silica gel: 0.5010g . Silica gel (calculated): 0.6063 g

. Total: 5.4342 g . Total: 5.5825g

. Initial moisture content (tablet:

1.9312%, silica gel: 3.03%)

 

 

The final weight of package = 1.1690g + 0.02 g = 1.1890g (moisture gain of LDPE bag:
0.02 g)

The final weight of silica gel = 5.5825g — 3.7872 g — 1.1890g = 0.6063g

By using the moisture content equation, the M(%) of tablets and silica gel can be

calculated.

3.7872 - (1 + 0.019312)
3.7642 —

0.6063 - (1 + 0.0303)
0.5010 _

 

M(%)tablets = [ l] X 100 = 2.550/0

 

M(%)smca 3,, =[ 1] x 100 = 24.68%

Example 2. Tablets and silica gel in HDPE bottles

 

 

Initial weight Final weight
. Package: 13.9370g . Package (calculated): 13.9498g
. Tablets: 3.7643g . Tablets: 3.7431 g
. Silica gel: 0.5032 g . Silica gel (calculated): 0.5386g
. Total: 18.2045g . Total: 18.2315g
. Initial moisture content (tablet:

 

1.93 12%, silica gel: 3.03%)

 

34

 

 

The final weight of package = 13.9370g + 0.01284g = 13.9498g (moisture gain of HDPE
bottle afier 14 days = 0.00006 x 14 days + 0.012 from the equation in Figure 9)

The final weight of silica gel = 18.2315g — 3.7431 g — 13.9498g = 0.5386g

By using the moisture content equation, the M(%) of tablets and silica gel can be

calculated.

3.7431'03‘0-0‘9313—1 x100=l.36%
3.7643 -

0.5386 . (1 + 0.0303) _ 11 x100 = 10.28%
0.5032 1

 

M (%)tablets = |:

 

 

M (%) silica gel = [

(6) Dimensions

The dimensions of tablets stored at all conditions (25 and 40°C at 0%, 50%, 65%,
75% and 90%) were measured by using a digital caliper (CD-6” BS, Mitutoyo Inc.,
sensitivity: 21:0.005mm). Each time, five tablets were selected to measure the dimensions
(thickness and diameter) for each condition. The tablet has a score. The dimensions
were always measured at the same position relative to the score. The dimensions were
measured initially, and these dimensions were compared to the dimensions of aged

tablets. See Appendix F for raw data of tablet dimensions.

(7) Hardness

The hardness of tablets stored at all conditions (25 and 40°C at 0%, 50%, 65%,
75% and 90%) was measured by HT-300 Hardness tester (Key lntemational, Inc., NJ).
Each time, ten tablets were selected to measure the hardness at each storage condition.

As with the dimensions, the score was used as an index to assure that the hardness was

35

always measured at the same position. See Appendix G for raw data of the tablet
hardness.

Figure 10 shows a sketch of the PIT-300 hardness tester. The plunger moves at a
constant speed towards the specimen. As soon as the plunger touches the specimen and
produces a force on the load cell, a linearly increasing force is produced until the
specimen breaks. Then the decreasing signal from the load cell indicates to the

microprocessor to determine the hardness value.

spindle plunger spring unit

load cell
specimen, -

Figure 10 Sketch of the PIT-300 hardness tester
(The sketch was obtained from the company brochure, and it was modified to simplify.)

 

 

 

 

motor

 

 

 

 

Measuring range: 0.5-30 kp (kilopond) or 5-300 N (1kg = 9.807N)
Resolution: 0.1 kp
Accuracy: il% over the entire readout measuring range
Also, the effect of hardness of tablets on opening blisters was tested using PVC
blister packages. A Klockner — Pentapack blister thermoform-fill-sealer was used to

thermoform PVC blisters, fill tablets, and seal blisters. PVC film (10 mil) was used to

thermoform blisters and 1.9 mil aluminum foil laminated with paper was used for the
backing film. Tablets at equilibrium at each condition (25 and 40°C at 0, 50, 65, 75 and

90% RH) were packaged into the blister. One tablet was placed in each blister, and then

the blister was heat-sealed to the backing film by the thermoform-fill-sealer. The tablets

36

packaged into the blister were used to test whether they had enough hardness to be

pushed out of the blisters without breaking.

(8) Dissolution

In accordance with the USP monograph for drug X, experiments were carried out
with 1000 mL of 0.02N HCl dissolution medium, apparatus 1 (rotating basket), and 100
rpm speed for the stirrer. One tablet was used per vessel and six vessels were used for

each storage humidity and temperature combination.

(a) Dissolution medium (0.02N HCl)
In order to prepare 1 liter 0.02N HCl, 1.7 mL of concentrated HCl (3 7%) was
added to a flask and diluted to 1 liter with purified water. The dissolution medium was

deaerated using helium sparging before testing.

(b) Reference standard solution

For the drug X tablets, the linearity of the response was determined using eight
standard preparations of drug X in the concentration range of 6% to 164% of the 20mg
dose. If 20mg drug X is dissolved in the 1000 mL medium completely, the concentration
of drug X in the medium is 100%. The drug X reference standard was weighed, then
transferred into a 1000 mL volumetric flask. Table 6 shows the concentrations (mg/mL)
to make the entire concentration (%) range. The drug X reference standard was dissolved

in 0.02N HCl dissolution medium by using a sonicator. The absorbance of the solutions

37

was measured by using a UV spectrophotometer (HP8453, Agilent Inc.), then plotted as

absorbance vs. % concentration as shown in Figure 11.

Table 6 Dissolution calibration data of drug X

 

 

 

 

 

 

 

 

 

 

 

Concentration Response
Concentration (%). (mg/mL) (absorbance)
6.58% 0.001315 0.0396795
16.44% 0.003287 0.0988455
32.87% 0.006573 0.192289
65.73% 0.013146 0.395215
92.91% 0.018581 0.561377
98.60% 0.019719 0.583967
131.46% 0.026292 0.775347
164.33% 0.032865 0.979527

 

 

 

Concentration (%) = Dissolution (%)

1.2 ~ ----------

 

Response (absorbance)
O
O)

 

1 - y = 0.5944x + 0.0009
R2 = 0.9998

    

 

0% 50 % 1 00%

150% 200%

Concentration (%)

Figure 11 The calibration curve for the spectrophotometer using drug X

Calculation fl % dissolution

Example. The absorbance of tablets at the 30 minute stirring time: 0.5724. Therefore, by

the equation in Figure l 1, dissolution can be calculated.

0.5724 — 0.0009

% Dissolution = x 100 = 96.14%

 

0.5944

38

(c) Dissolution sampling

A VK 7010 six vessel dissolution sampling apparatus (V ankel, NC) was used for
sampling drug solution. The prepared dissolution medium (0.02N HCl) was poured into
the vessels, then they were covered to increase the temperature to 37i0.5°C. The
temperature was checked with a Curette thermometer (20-40°C, i0.15°C) (YSI Inc., OH).
Tablets were placed into 40 mesh standard baskets (Vankel, NC), then they were
immersed into the medium (see USP <711> for information about dissolution). After the
dissolution sampling apparatus was run, the vessels were covered again to keep the
constant temperature. Samples were collected every 10 minutes with 10 mL syringes
(Becton Dickinson and Company, NJ). A 0.5 um pore size hydrophilic PTFE filter
(Millipore Inc., MA) was attached to the syringe, then about 3 mL sample was flushed
through the filter because there may be dust from a manufacturing process. By flushing
the filter, the dust can be removed. Then, the remaining 7 mL sample was collected into
10 mL disposable glass tubes. The new filter was used in collecting samples each time.

About 10 mL dissolution medium was removed from the vessel at each sampling
and it was-not replaced. For the second sampling, the volume of the dissolution medium
was 990 mL, and for the third sampling, the volume of the dissolution medium was 980
mL. Therefore, the percent dissolution at 20 and 30 minutes stirring time should be

corrected by using Equation 13.

 

V _ _ _V n-l
I... (n I) ..]+_. C, (13)
V V ,

m ml=

Corrected % Dissolution = C,'

where, C" = uncorrected concentration at sample interval n
V,,, = original medium volume (mL)
n = sample interval
V, = sample volume (mL)

39

C,- = uncorrected concentrations of previously removed sample aliquots

Calculation of the corrected % dissolution

Example. Dissolution at 10 minutes stirring time: 68.23%
Dissolution at 20 minutes stirring time: 93.97% (uncorrected)
Dissolution at 30 minutes stirring time: 96.15% (uncorrected)

[1000mL—(2—1)~10mL] + IOmL
IOOOmL 1000mL

[1000M ‘43 “ ”'10le + 10’“ (68.23 + 93.97) = 95.85
1000mL 1000mL

Corrected %Dissolution = 93.97 68.23 = 93. 71

 

Corrected %Dissolution = 96.15

 

The dissolution of tablets stored at 25 and 40°C at 0, 50, 65, 75 and 90% RH was
measured at every month for 6 months. The resulting data were used to determine the

dissolution retardation rate (R).

(d) Dissolution measuring (absorbance)

Based on the USP monograph for drug X tablets, the UV spectrophotometer was
used to measure the UV absorbance at the wavelength of maximum absorbance, 275 nm,
of filtered portions of the solution under test. The cell having 1 cm path length was used.
The absorbance of the blank obtained from the dissolution medium was measured first,
then it was subtracted from the absorbance of the initial and aged tablets to get the true

absorbance of drug X.

(e) Verification of dissolution prediction model
In order to verify the dissolution prediction model, uncoated tablets were placed
in open dishes using stepwise storage conditions. Also, they were packaged into LDPE

bags and HDPE bottles for continuous storage conditions.

40

i. Tablets in open dishes - stepwise storage conditions
The uncoated tablets were placed in open dishes at 40°C/50% initially, and they
were transferred to 40°C/65% afier one month, and so on as shown in Table 7. When

they were transferred to another condition, the dissolution was measured.

Table 7 Stepwise stora e conditions used to verify the dissolution prediction model
Storage time (months) Storage Conditions

50%(1 month)

50%(1 month), 65%(1 month)

50%(1 month), 65%(1 month), 75%(1 month)

50%(1 month), 65%(1 month), 75%(2 months)

50%(1 month), 65%(1 month), 75%(1 month), 90%(1 month)
50%(1 month), 65%(1 month), 75%(3 month)

50%(1 month), 65%(1 month), 75%(1 month), 90%(2 month)

 

 

 

 

 

 

 

 

 

 

 

Utth-b-bWN—t

 

ii. Tablets in packages - continuous storage conditions

The uncoated tablets were packaged into LDPE bags and HDPE bottles to verify
the dissolution prediction model. They were the same as those used to verify the
moisture prediction model. After the moisture gains of tablets were measured, they were
tested for dissolution. Each package has the same number of tablets, 15 tablets, but each
package has a different total tablet weight because of the variation of individual tablet
weights. To make a single continuous smooth plot, the average weights of tablets were

used for the moisture content and dissolution prediction.

41

CHAPTER 3

RESULTS AND DISCUSSION

Figure 12 shows the outline of the whole experiment that has been done for this
research. It is placed here because it is especially relevant to the discussion in this
chapter. Parts of the figure refer to this chapter only. Other parts are found in other
places in the dissertation. Their location and relevance to the whole are described in the
following text and the figure. Careful attention to matching the solid and broken lines
with the description in the following text will help the reader to visualize the several
relationships that exist among the parts of the work. The solid lines all represent the
main theme of the research, from beginning through “Design a Package”. The dotted and
dashed lines represent the application of theories and procedures which are tools for
accomplishing the main task.

Figure 12 shows the package part of the work (permeability) and the product part
of the work (moisture content, dissolution, dimensions, and hardness). Permeability and
moisture content were used to verify the shelf life and moisture prediction program.
These are all connected by dotted lines. Permeability, moisture content, and dissolution
were used to verify the dissolution prediction program. These are all connected by a
solid line. Moisture content, dissolution, dimensions, and hardness were used to explain
the proposed theory of dissolution retardation as a function of relative humidity. These
are connected by dashed lines. Dimensions and hardness are not directly related to the
main purpose of this research (dissolution shelf life), so they are attached as Appendices.
The verification for the moisture and shelf life prediction programs is attached in

Appendix B, and the verification for the dissolution prediction program appears in

42

Chapter 4. Experimental results and discussion of permeability, moisture content, and

dissolution are presented in this chapter.

43

 

Experimental results and discussion

1 1 1I 1 7

Permeability Moisture content Dissolution Dimensions Hardness

I l T I l

. Permeabilities . Initial moisture . Initial dissolution for . Thickness
of LDPE bags content of coated, coated and uncoated

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

. By hardness tester
. Diameter . By blister package

and HDPE uncoated tablets, tablets . .
bottles and silica gel . Dissolution profiles (see Append1x F) (see Appendix G)
. Moisture sorption (Dissolution as a
isotherms of function of stirring time):
coated, uncoated coated and uncoated

tablets, and silica tablets at 40°C and 25°C
gel at 25°C/40°C (see Appendix E for
: dissolution profiles at

25°C)

. Dissolution retardation
(30 minute dissolution as
a function of storage
time): uncoated tablets at
40°C (see Chapter 4)

. Relationship between
dissolution retardation

 

 

 

I
l
I
I
I
I
l
I
I
I
I
I
I
I
I
l
I
I
I
I
.l

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

rate (R) and RH(%) (see
Chapter 4)
I
_ 1
............ S..............'L__.__...__..-L_.....__.._L_--1-
1': 1
Verification for Verification for Proposed theory of
Moisture prediction program Dissolution prediction program dissolution retardation
Shelf life prediction program (see Chapter 4) as a function of RH
(see Appendix B) . Tablets in LDPE bags (see Chapter 5)
Product & package setup without silica gel and tablets
. Tablets in LDPE bags without with silica gel (0.5 g, l g, 2
silica gel and tablets with silica g) in LDPE bags
gel (0.5 g, l g, 2 g) in LDPE . Tablets in HDPE bottles
bags without silica gel and tablets
. Tablets in HDPE bottles with silica gel (0.5 g) in
without silica gel and tablets HDPE bottles
with silica gel (0.5 a) in HDPE
Design a package

 

 

 

Figure 12 Outline of the experiment

44

l. Permeability

Raw data used to determine WVTR are attached in Appendix D.

Figure 13 shows a standardized traditional relationship among water vapor

transmission rate (WVTR), permeance, thickness normalized WVTR, and permeability.

This relationship assumes a homogeneous material in sheet form of some thickness 8.

WVTR is divided by the partial pressure difference between the inside and outside of the

package to calculate the permeance, and then the permeance is multiplied by the package

wall thickness to calculate the permeability (see ASTM E96).

The permeability for a given material is a constant value at the same temperature.

If the package is stored at a high relative humidity, the WVTR will be high due to the

large partial pressure difference, and vice versa. Therefore, the permeability is always

the same at the same temperature.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

WVTR (water vapor transmission rate)
(quantity)
x Ap’ (area)(time) x g
Permeance Thickness Normalized WVTR
(quantity) (quantity) (thickness)
(area)(time)(Ap) (area) (time)
I —l
x Permeability x AP
(quantity) (thickness)
(area)(time)(Ap)

 

 

 

Figure 13 Relationship between water vapor transmission rate (WVTR), permeance,
thickness normalized WVTR, and permeability

45

The pharmaceutical industry does not follow the traditional practice of assuming
the package to be a homogeneous sheet of some thickness 8. Bottles are a complex

combination of varying bottle wall thickness and closure combinations. Blisters are
therrnoformed from sheet, and therefore have varying wall thickness always less than that
of the starting sheet. Furthermore, barrier blisters are not homogeneous in construction,
but rather have two or more materials laminated or coextruded. Use of the model for
packages made of a homogeneous sheet has no practical value. Therefore, the
pharmaceutical industry practice is to use the whole package unit instead of the thickness
and area of the package to determine WVTR and permeability.

USP <671> Containers-Permeation sets the common practice for the drug
industry. Bottles, pouches and blisters are all tested as whole package units without
reference to thickness or closure. They are also tested at a single temperature and
humidity, which mandates a single partial pressure differential (40). Thus, the USP test
yields a water vapor transmission rate (WVTR) which is labeled as “Permeation” in USP
terms. This construction is very limited in comparison with the relationship described in
Figure 13. It is also too limited for use in development of the theories and application
treated in this research.

USP <671> has a built-in discontinuity which makes it very difficult to compare
blister or pouch permeation with bottle permeation. Blister and pouch permeation is
reported as weight gain per package (single pouch or single blister) per day. Bottles are
reported as weight gain per liter (of bottle volume) per day. A bottle tested may contain
any number of product units (e. g. 7 to 500) and it may be of any volume, 45 mL to 500

mL, for example. In any case, bottle permeation (a WVTR) is reported as mg/L/day. A

46

blister or pouch usually contains only one product unit. Blister permeation (WVTR) is
reported as mg/cavity/day; the cavity is the equivalent of 1 unit of product (capsule, tablet,
etc.). This makes it very difficult to compare permeation performance between bottles
and blisters. The need to compare these values is great when planning package changes
between bottles and blisters. Industry practice is moving toward the comparison of
bottles and blisters on a permeation per product unit basis. This trend is anticipated in this
research.

This research is intended for application to bottles, blisters and pouches at any
relative humidity at a single temperature. Therefore, the permeance property of packages
is modeled in Figure 14. In this research WVTR was determined as a quantity per whole
package per a unit of time, so the units for WVTR and permeance are not the same as in

Figure 13. In this work permeance is treated as the permeability of the package.

 

 

 

 

 

WVTR Permeance
(quantity) X Ap"l (quantity)
(time) mackage) (time) @ackageflAp)

 

 

 

 

 

 

Figure 14 Relationship between water vapor transmission rate (WVTR) and permeance
using whole package instead of thickness and area

In this study, WVTR was determined as a quantity per whole package per unit of
time instead of quantity per package area per unit of time. Then this WVTR was divided
by partial pressure differential to obtain permeance as quantity per package per unit
partial pressure differential per unit time.

The total'weight increase of each package was measured for 5 LDPE bags and 5
HDPE bottles at each testing time, then it was reduced by the weight increase of the

blank to calculate the net moisture gain. The net moisture gain was plotted as a function

47

of storage time. WVTR was determined by a trend line as shown in Figure 15 and Figure

16. When the WVTR was determined, the point (0,0) was not included because at this

point the package was not yet at steady-state conditions at 40°C.

(1) LDPE bags

    

 

 

1.6 -. .
A e
3 1.4 «
5 1.2 ~
0
u 1 —
g 0.8
a
'3 0.6 _
E 04 4 y-0.0227x+0.1541
R2 = 0.9937

g 02 4

o 1 r 1 1 I 3

0 1O 20 30 40 50 60
Storage time (days)

 

[ 0 Experimental moisture gain —WVTR (grams/day)

 

Figure 15 WVTR of LDPE bags at 40°C/90% RH

Calculation of the permeability of the LDPE bags
WVTR = 0.0227 grams/day-package
Vapor pressure difference = 90% RH - 0% RH = 90% RH (or 0.9 p,)

Therefore,

Permeability = 0.0227 g x 1 = 0.0252 g at 40°C
day- package 0.9 ps day- package - ps

 

 

48

(2) HDPE bottles

0.06 1
0.05 ~
0.04 4
0.03 «
0.02 ~

   

y = 0.0012x - 0.0009

R2 = 0.9993 g

0 10 20 30 40 50
Time (days)

0.01 4

Net moisture gain (9)

 

 

 

0 Experimental moisture gain —WVTR (grams/dam

 

Figure 16 WVTR of HDPE bottles at 40°C/75% RH

Calculation of the permeability of the HDPE bottles
WVTR = 0.0012 grams/dayopackage
Vapor pressure difference = 75% RH - 0% RH = 75% RH (or 0.75 p,)

Therefore,

 

 

Permeability = 0.0012 g x 1 = 0.0016 g at 40°C
day- package 0.75 ps day- package. ps

2. Moisture content
(1) Initial moisture content

Table 8 shows the experimentally measured initial moisture content of tablets and
silica gel, and the calculated equilibrium relative humidity at each initial moisture content.
The equilibrium relative humidity can be determined by the moisture sorption isotherm
curves or their equations such as GAB or Langmuir equations (see Appendix A 3.(2)(a)

GAB equation and (b) Langmuir equation). The equilibrium relative humidities of

49

tablets were determined by the GAB equation and those of silica gel were determined by

the Langmuir equation.

Table 8 Initial moisture content and guilibrium RH of tablets and silica gel

 

 

 

 

 

 

 

 

Uncoated tablets Coated tablets Silica gel
M 1.93% 2.31% 3.03%
RH at M,- at 25°C 31.72% 40.96% 4.31%
RH at M,- at 40°C 34.23% 42.62% 4.31%

 

(2) Moisture sorption isotherms

The sigmoid-shaped moisture sorption isotherms of tablets fit well with the GAB
equation, and the hyperbolic-shaped moisture sorption isotherms of desiccants such as
silica gel fit well with the Langmuir equation over the range of relative humidities
between 10% and 90%. The choice of equation depends on the shape of the moisture
sorption isotherm. Therefore, the GAB equation was used to describe the relationship
between the moisture content of drug X tablets and water activity (aw) (i.e., p/p, or
%RH/lOO), and the Langmuir equation was used to describe the relationship between the
moisture content of silica gel used in this experiment and aw (i.e., p/p, or %RH/ 100).
Table 9 shows the GAB constants of drug X tablets and Langmuir constants of silica gel

used in this experiment.

Table 9 GAB constants of tablets and Langmuir constants of silica gel

 

 

 

 

 

 

 

 

 

 

 

 

 

GAB constants Langmuir constants
Wt". Cg K Wm CL

Uncoated tablets at 25°C 0.0141 18 75.771 1 0.919386
Uncoated tablets at 40°C 0.013392 113.2096 0.933012
Coated tablets at 25°C 0.014513 297.5468 0.915190
Coated tablets at 40°C 0.014100 324.3921 0.920041

Silica gel at 25°C 1.440803 0.498612

Silica gel at 40°C 0.819364 0.924676

 

 

 

50

 

(a) Moisture sorption isotherms of drug X tablets (coated and uncoated)

Figure 17 shows the moisture sorption isotherms of coated and uncoated tablets at
25°C and Figure 18 shows the moisture sorption isotherms of coated and uncoated tablets
at 40°C. The coated and uncoated tablet isotherms are almost the same, but the moisture
sorption isotherm of coated tablets is a little higher because of the coating material (4%
of tablet). Tablets were formulated with 63% mannitol and 18% microcrystalline
cellulose. If the temperature is increased, the water vapor sorption of mannitol and
celluloses decreases at the same pressure (exothermic process).

The moisture sorption isotherms are almost the same as shown in Figure 19. In

practice, a single sorption isotherm may be able to be used to describe the water-solid

interaction for both coated and uncoated tablets at both 25°C and 40°C in this

temperature range as a function of relative humidity.

 

 

M(%)

 

 

 

MOO-#OIGVGCD

 

 

d

 

 

 

O
1
3

20 4o 60 80 100
RH (%)

O

0 Experimental M (%) of uncoated tablets l Experimental M (%) of coated tablets
— Calculated M (%) by GAB equation for uncoated and coated tablets

Figure 17 Moisture sorption isotherms of drug X tablets at 25°C

51

 

 

 

 

 

 

1

 

M(%)
O-ANOJAOICDVODO

 

 

 

O

20 40 60 80 100
RH (%)

0 Experimental M (%) of uncoated tablets I Experimental M (%) of coated tablets
—— Calculated M (%) by GAB equation for uncoated and coated tablets

Figure 18 Moisture sorption isotherms of drug X tablets at 40°C

The isotherms in Figure 19 from topmost to lowest are in the order: coated tablets

at 25°C, coated tablets at 40°C, uncoated tablets at 25°C, uncoated tablets at 40°C. The

difference in moisture content between highest and lowest at 50% RH is 0.18%. This is

calculated from the values below:

M(%) of coated tablets at 25°C/50% RH: 2.67%
M(%) of coated tablets at 40°C/50% RH: 2.60%
M(%) of uncoated tablets at 25°C/50% RH: 2.57%
M(%) of uncoated tablets at 40°C/50% RH: 2.49%

52

 

 

3 -
7 .
6 -
S 5 i
2 4 .
3 ‘ Coated tablets at 25°C
2 , Coated tablets at 40°C ‘
Uncoated tablets at 25°C
1 « Uncoated tablets at 40°C
0 T r r 1 1 1 1 I r 1
0 10 20 30 40 ‘ 50 60 70 80 90 100

RH(%)

Figure 19 Moisture sorption isotherms calculated by GAB equation for tablets at 25°C
and 40°C

53

(b) Moisture sorption isotherms of silica gel

Figure 20 and Figure 21 show the experimental (dots) and calculated (solid line)
moisture sorption isotherms determined by the Langmuir equation. There is fairly good
agreement between experimental and calculated moisture sorption isotherm data. Also,
the GAB equation was tried to fit moisture sorption isotherms. However, there is little
difference between the sorption isotherms calculated from the Langmuir and GAB
equations (see Appendix D). Therefore, the simple Langmuir equation was used for
silica gel sorption isotherms. The moisture sorption isotherms at 25°C and 40°C are
plotted together in Figure 22. Silica gel is an exothermic material. When the material
absorbs water, the material gives off heat. At the same RH (%), the amount of water that
can be absorbed in the material at 40°C is less than that at 25°C. Therefore, if

temperature is increased, the water vapor sorption is decreased as shown in Figure 22.

 

 

 

 

 

 

i
/
40 e %
‘ I
, ;
30
3
a e
20 a
/ 5
10 .
O
o 7 T T T i
0 20 40 60 80 100

RH(%)

0 Experimental M (%)

 

Calculated M (%) by Langmuir equation
Figure 20 Moisture sorption isotherm of silica gel at 25°C

54

 

 

 

 

 

 

 

501‘" - -~ ~ ~» ~~ —- —~ ~ ~,
40 ‘
e ’ e i
0 . I

30 4 ’

g e

5 l
20 . i
O 1
10 . °
l
0 , , . . J
0 20 40 60 80 100

RH(%)

 

0 Experimental M (%) Calculated M (%) by Langmuir equation

Figure 21 Moisture sorption isotherm of silica gel at 40°C

 

 

 

50 ----.—-——--4~—~—.~-~«~—-—~----—-»-—~-9- - » ”flu—w...
25°C E
40 «
40°C :
30 i i
=3
2 20 a
10 i
O r f r 1 1
0 20 40 60 80 100

RH (%)

Figure 22 Moisture sorption isotherms calculated by Langmuir equation for silica gel at
25°C and 40°C

55

3. Dissolution

In this study, the initial tablet is defined as tablets which are inserted into a
package. When the initial drug X coated tablet is dropped into the dissolution medium
(0.02N HCl), the coating material dissolves quickly in the medium and the
croscarmellose sodium (CAS) among granulesg swell to 4-8 times. This makes tablets
rapidly disintegrate to coarse particles. Also, CAS in the granules swells quickly, making
coarse particles disintegrate into fine particles of excipients. The'dissolution mechanism
of drug X uncoated tablet is exactly the same except for dissolving the coating material.

During dissolution testing, it was observed that the time required for tablet
wetting and disintegration is very short for the initial tablets. If the first dissolution
sample is collected at a 10 minute stirring time, the regions “Mechanical Lag and
Wetting”, “Disintegration”, and “Disaggregation” cannot be obtained. Therefore, the S-

shaped dissolution curve of Figure 2 on page 14 can be represented in practice as shown

in Figure 23.

 

Dissolved

 

 

Stirring Time
Figure 23 The typical dissolution curve constructed experimentally

Coated tablets aged at 40°C at 50-90% RH require a lot more disintegration time

than initial tablets, perhaps because the coating material is degraded physically or

 

3 See Appendix C l. Formulation for the term “granules”.

56

chemically, or excipients are crosslinked to each other above about 50% RH. Uncoated
tablets aged at 40°C at 50-90% RH require a lot more disintegration time than initial

tablets as well. If an aged tablet is dropped into the dissolution medium, the tablet is

wetted and swollen by the medium in the same way as the initial tablet. However, the

aged tablet does not disintegrate rapidly but disintegrates slowly. From this, the
following can be deduced:

a. The intermolecular forces between excipients and drug may be increased due to the
crosslinking of excipients.

b. The hydrophilicity and swelling property of disintegrants may be decreased, so the
boundaries between excipients and drug cannot be weakened quickly by uptake of
water.

0. The porosity of tablets may be decreased, so the water has difficulty getting into

excipients to make them swell, and disintegrate.

(1) Initial dissolution profiles

Table 10 and Figure 24 show the initial dissolution profile for drug X uncoated
tablets, and Table 11 and Figure 25 show the initial dissolution profile for drug X coated
tablets, illustrating how tablets dissolve over 30 minutes at 100 rpm. At each stirring
time, six samples were measured, and the average dissolution is represented by the solid
line.

Dissolution for uncoated tablets at the 10 minute stirring time reaches 81%, but
dissolution for coated tablets at the 10 minute stirring time reaches only 51%. The

dissolution behavior was observed visually. The initial uncoated tablets started to

57

disintegrate immediately afler they were dropped into the medium and the disintegration

proceeded quickly. However, the initial coated tablets took a little time to start to

disintegrate. That is why the dissolution at the 10 minute stirring time for coated tablets

was lower than that for uncoated tablets. However, they reached about the same

dissolution at the 30 minute stirring time.

Table 10 Initial dissolution profile data for uncoated tablets

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dissolution Time Apparatus Position *
Conditions (min) 1 l 2 1 3 4 I 5 l 6 Avg. SD
Dissolved i
0 0% 0% 0% 0% 0% 0% 0% 0.0%
Basket 10 68.2% 81.4% 87.3% 88.8% 84.3% 77.2% 81.2% 7.6%
31100 rpm 20 93.7% 95.4% 94.9% 95.8% 93.8% 95.2% 94.8% 0.9%
30 95.9% 96.5% 95.9% 97.1% 95.3% 96.7% 96.2% 0.6%
100% 1"‘"”"” - -~ ’5
75% «
e
8
2
g 50% .
5
25% 4
0% . . .
0 10 20 30 40
Stirring time (minutes)
0 Dissolution measured experimentally — Average dissolution

Figure 24 Initial dissolution profile of drug X uncoated tablets

58

 

Table 11 Initial dissolution profile data for drug X coated tablets

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Dissolution Time Apparatus Position
Conditions (min) 1 | 2 I 3 I 4 5 6 Avg. SD
Dissolved
0 0% 0% 0% 0% 0% 0% 0% 0.0%
Basket 10 61.7% 63.0% 32.2% 59.4% 72.9% 16.1% 50.9% 21.8%
at100 rpm 20 95.5% 96.8% 96.6% 95.4% 96.6% 92.9% 95.6% 1.5%
30 96.5% 97.2% 89.5% 96.7% 97.7% 97.6% 95.9% 3.1%
1°°°’"1"“""" ~—- ~— — v-~— we“ -~
0
75% ~ ,
i , .
0 50%
5
o
O
25% «
O
0% T I I I I 1
0 5 1O 15 20 25 30 35
Stirring time (minutes)
9 Dissolution measured experimentally —— Average dissolution

Figure 25 Initial dissolution profile of drug X coated tablets

59

 

(2) Dissolution profiles from open dish study

The dissolution of drug X tablets stored in open dishes at 40°C decreased quickly
over the 6 month experiment, but the dissolution of drug X tablets stored in open dishes
at 25°C did not change over the 6 months. Figures 26-30 show the average dissolution at
10, 20, and 30 minutes stirring time obtained for drug X uncoated tablets stored for 6
months at 40°C/90%, 75%, 65%, 50%, and 0%. They show the trend of dissolution
reduction as a function of storage time. Figures 31-35 show the profiles obtained for
drug X coated tablets stored for 6 months at 40°C/90%, 75%, 65%, 50%, and 0%. See
Appendix E for the dissolution raw data including data variability (standard deviation)
and the dissolution profiles of tablets stored for 6 months at 25°C/90%, 75%, 65%, 50%,

and 0%.

(a) Drug X uncoated tablets stored in open dishes at 40°C

Figure 26 shows the dissolution profiles of drug X uncoated tablets stored in open
dishes for 6 months at 40°C/90% and the decrease in the dissolution profiles as a function
of storage time. The solid line represents the dissolution profile of the initial tablets. The
30 minute dissolution of uncoated tablets stored for 6 months is still higher than the 75%
dissolution specification limit in USP monograph. In terms of dissolution, uncoated
tablets passed the 6 month 40°C/90% testing. However, they failed the hardness testing

(see Appendix G. Hardness).

60

75%

 

 

 

50%

Dluolved

25%

 

 

0%

 

10

20
Stirring time (minutes)

 

30

40

I t=initial x t=l month 0 t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 26 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/90% (each point is average value for 6 tablets)

Dissolution at the 30 minute stirring time for months 0-6 was statistically

analyzed using ANOVA. The p-value was 7.0E-11. Statistically, they are Significantly

different because the p-value is lower than 0.05. Next, dissolution at the 30 minute

stirring time for months 0 and 1, 1 and 2, etc., was statistically analyzed using t-tests as

shown in Table 12.

Table 12 pcvalues from t-test using 1 month and 2 month intervals for tablets stored at

 

 

 

 

40°C/90% RH
Storage time 0 and 1 1 and 2 2 and 3 3 and 4 4 and 5 5 and 6
(month)
p-value 1.0E-01 2.1E-06 8.6E-01 3 .2E-01 7.5E-03 1.9E-01
Storage time 0 and 2 1 and 3 2 and 4 3 and 5 4 and 6
(month)
p-value i 3.3E-06 2.9E-05 3.3E-01 9.5E-04 4.9E-04

 

 

 

 

 

 

 

 

61

 

The p—values from t-tests between 1 and 2 months, and between 4 and 5 months
are less than 0.05, so they are significantly different. However, the others are not
significantly different because the p-values are greater than 0.05. By inspection of Figure
26, it can be seen that average dissolution values decrease as a fimction of storage time.
They decrease within a small range of dissolution change with a large variation. Table 12
shows p-values from t-tests using 2 month intervals are generally less than 0.05.
Therefore, it can be concluded that the dissolution decreased as a function of storage time,

but the decrease did not occur in a uniform manner.

Figure 27 shows the dissolution profiles of drug X uncoated tablets stored in open
dishes for 6 months at 40°C/75%. The dissolution profiles decreased as a function of
storage time. The solid line represents the dissolution profile of the initial tablets. The
dissolution at 40°C/75% decreased more quickly than at 40°C/90%. There are many

proposed reasons such as crosslinking and swelling. See Chapter 4.4. Proposed theory of

dissolution retardation as a function of relative humidity for a detailed discussion.

62

"no/o “WW _ ...._ _.

 

 

 

 

 

 

 

———I
[/7 .... x
75% TX _l_e'.:f'
0' -::'-:'. v'x
> .11" .-
e 50% .a w" ,9
a ,' ,:' .'.A
a ’l ' - .
a 1” . XI
ex "'6': .
25% '+;‘ .-
005 1 T I 1
0 10 20 30 40

Stirring time (minutes)

I t=initia| x t=l month 0 t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 27 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/75% (each point is average value for 6 tablets)

Dissolution at the 30 minute stirring time for months 0-6 was statistically
analyzed using ANOVA. The p-value was 8.6E-08. Statistically, they are significantly
different because the p-value is lower than 0.05. Next, dissolution at the 30 minute
stirring time for months 0 and 1, 1 and 2, etc., was statistically analyzed using t-tests as

shown in Table 13.

Table 13 p-values from t-test using 1 month and 2 month intervals for tablets stored at
40°C/75% RH

 

 

 

 

 

 

 

 

 

 

 

Storage time 0 and l l and 2 2 and 3 3 and 4 4 and 5 5 and 6
(month)
p-value 3.5E-05 2.4E-03 6.7E-01 6.6E-01 l . l E-Ol 9.4E-01
Storage time 0 and 2 1 and 3 2 and 4 3 and 5 4 and 6
(month)
p-value 3.0E-08 3.3E-02 8.6E-01 5.3E-02 4.0E-02

 

63

 

The p-values from t-tests between 0 and 1 month, and between 1 and 2 months are
less than 0.05, so they are significantly different. However, the others are not
significantly different because the p-values are greater than 0.05. From inspection of
Figure 27, it can be seen that average dissolution values decrease as a function of storage
time. They decrease within a small range of dissolution change with a large variation.
Table 13 shows p-values from t-tests using 2 month intervals are generally less than 0.05
and close to 0.05. Therefore, it can be concluded that the dissolution decreased as a

function of storage time.

Figure 28 shows the dissolution profiles of drug X uncoated tablets stored in open
dishes for 6 months at 40°C/65%. The dissolution profiles decreased as a function of

storage time. The solid line represents the dissolution profile of the initial tablets.

 

 

 

 

 

 

 

 

 

100%
———I
........ x
ax .......
75% r’
, .o
‘8 ' ' " .+
3 50% "
a a-
5 .' ..0
OX.
25% -- _, - '_
.-.-31f: ml"
0% , 1 ,
0 10 20 30 4O

Stirring time (minutes)

I t=initial x t=l month 0 t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 28 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/65% (each point is average value for 6 tablets)

64

Dissolution at the 30 minute stirring time for months 0-6 was statistically
analyzed using ANOVA. The p-value was 8.3E-08. Statistically, they are significantly
different because the p—value is lower than 0.05. Next, dissolution at the 30 minute
stirring time for months 0 and 1, l and 2, etc., was statistically analyzed using t-tests as

shown in Table 14.

Table 14 p-values from t-test using 1 month and 2 month intervals for tablets stored at

 

 

 

 

40°C/65% RH
Storagetime Oandl land2 2and3 3and4 4and5 5and6
(month)
p—value 1.4E-06 9.9E-04 2.3E-Ol 5.9E-02 1.2E-Ol 9.7E-Ol
Storage time 0 and 2 1 and 3 2 and 4 3 and 5 4 and 6
(month)
p-value 6.7E-05 1.7E-03 2.9E-03 1.4E-03 1 .5E-01

 

 

 

 

 

 

 

 

 

The p-values from t-tests between 0 and 1 month, and between 1 and 2 months are
less than 0.05, so they are significantly different. However, the others are not
significantly different because the p-values are greater than 0.05. From inspection of
Figure 28, it can be seen that average dissolution values decrease as a function of storage
time. They decrease with a large variation. Table 14 shows p-values from t-tests using 2
month intervals are generally less than 0.05 and close to 0.05. Therefore, it can be

concluded that the dissolution decreased as a function of storage time.

Figure 29 shows the dissolution profiles of drug X uncoated tablets stored in open

dishes for 6 months at 40°C/50%. The dissolution profiles decreased as a function of

storage time. The solid line represents the dissolution profile of the initial tablets.

65

1 00%

75%

50%

Dissolved

25%

0%

 

 

 

 

 

 

 

 

 

Sfirring time (minutes)

40

I Finitial x t=l month I t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 29 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/50% (each point is average value for 6 tablets)

Dissolution at the 30 minute stirring time for months 0-6 was statistically

analyzed using ANOVA. The p-value was 1.0E-10. Statistically, they are significantly

different because the p-value is lower than 0.05. Next, dissolution at the 30 minute

stirring time for months 0 and 1, 1 and 2, etc., was statistically analyzed using t-tests as

shown in Table 15.

Table 15 p-values from t-test using 1 month and 2 month intervals for tablets stored at

 

 

 

 

40°C/50% RH
Storage time 0 and l l and 2 2 and 3 3 and 4 4 and 5 5 and 6
(month)
p-value 2.2E-02 5.9E-07 1 813-01 7.7E-01 7.9E-03 l .4E-Ol
Storage time 0 and 2 l and 3 2 and 4 3 and 5 4 and 6
(month)
p—value 7.4E-08 7.8E-03 1.9E-02 4.4E—02 2.4E-05

 

 

 

 

 

 

 

 

66

 

The p-values from t-tests between 0 and 1 month, between 1 and 2 months, and
between 4 and 5 months are less than 0.05, so they are significantly different. However,
the others are not significantly different because the p-values are greater than 0.05. From
inspection of Figure 29, it can be seen that average dissolution values decrease as a
function of storage time. They decrease with a large variation. Table 15 shows all p-
values from t-tests using 2 month intervals are generally less than 0.05. Therefore, it can

be concluded that the dissolution decreased as a function of storage time.

Figure 30 shows the dissolution profiles of drug X uncoated tablets stored in open
dishes for 6 months at 40°C/0%. The dissolution profiles do not change as a function of
storage time. The solid line represents the dissolution profile of the initial tablets. Dried
tablets may exhibit little hydrogen bonding (no physical interaction among excipients).
Therefore, uncoated tablets stored in open dishes at 40°C/0% RH were not affected by
temperature and storage time, so they disintegrated rapidly. There is little moisture in the
tablets, so it is assumed there is no physical reaction among excipients induced by

moisture.

67

1 00%

 

 

 

 

 

 

 

 

 

75%
8
2
§ 50%
5
25%
0% . . .

O 10 20 30 40
Stirring time (minutes)

I t=initial x t=l month I t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 30 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 40°C/0% (each point is average value for 6 tablets)

(b) Drug X coated tablets stored in open dishes at 40°C

The dissolution of drug X coated tablets stored in open dishes at 40°C behaved
very differently compared with drug X uncoated tablets. The coated tablets did not
i follow the dissolution theory (S-shaped dissolution change as a function of stirring time),
so the dissolution at the 30 minute stin'ing time did not change regularly as a function of
storage time.

Figure 31 shows the dissolution of 1 month and 2 month aged coated tablets
stored at 90% RH at the 10 minute stirring time are greater than the dissolution of the

initial coated tablets at the 10 minute stirring time.

68

100% ~

 

75%

50%

 

Dluolved

 

25%

 

 

0%

 

O 10 20 30 40
Stirring time (minutes)

I t=initial x t=l month I t=2 months + t=3 months 6 t=4 months A t=5 months * t=6 months

Figure 31 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 40°C/90% (each point is average value for 6 tablets)

When coated and uncoated tablets were stored at 40°C/90%, they both swelled by
absorbing moisture. The swelling of excipients can make boundaries among excipients
weak. That was why the tablets disintegrated rapidly. It caused the high dissolution
value at the 10 minute stirring time. Afier 3 months, the dissolution of coated tablets at
the 10 minute stirring time was lower than that of the initial coated tablets even if they
still swelled. Dissolution and disintegration are generally directly proportional, if the
tablet disintegrates slowly, dissolution is low. A logical reason for increased
disintegration time is the following:

The properties of the coating material (color mix yellow) might be degraded. It is
soluble in water, so the initial coated tablets started to disintegrate rapidly afier being
dropped into the medium. However, aged coated tablets did not disintegrate rapidly.

They took a longer time to start to disintegrate. They swelled without any disintegration.

69

The coating material was observed to behave like a plastic film. This means the coating
material was degraded either chemically or physically. When aged coated tablets started
to disintegrate, the coating material was broken out suddenly. After that, aged coated
tablets disintegrated rapidly. Therefore, the disintegration of aged coated tablets
happened suddenly, not gradually. For the dissolution of aged coated tablets, the

disintegration starting point was very important.

Figures 32-34 show very low dissolution of aged coated tablets at the 10 minute
stirring time. The aged coated tablets did not disintegrate at all for about 6-8 minutes of
stirring time, and then started to disintegrate suddenly. The profiles do not show a
general decrease in dissolution as a function of storage time. The aged coated tablets did
not dissolve according to the dissolution theory. The dissolution is very much dependent

on the disintegration starting point.

70

100% w

 

 

 

 

 

 

I
X
75% r- .1;
'0 «0’
5",.” ‘A
a .s/
o I .
> -'- ‘L\
a 50% .324 L
a 7’
22""
25% “4T1.
x‘. r'.
0% fii T 1
20 3O 40

 

Stirring time (minutes)

I t=initial x t=l month I t=2 months + t=3 months 0 F4 months A t=5 months * t=6 months

Figure 32 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 40°C/75% (each point is average value for 6 tablets)

 

 

 

 

 

 

1000/o 1 ,
.
75%
u .x
2 six
i 50% 4
...l ;" +
a ,- 4,:
I... ‘44. c
.‘ 5"."
o X-' 13‘
25/0 .-;'.-X’ ‘r‘r'. f
. 3
i‘y'gvz.
00/0 I r 1
20 30 40

 

Stirring time (minutes)
I Finitial x t=l month I t=2 months + t=3 months 0 t=4 months A t=5 months * F6 months

Figure 33 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 40°C/65% (each point is average value for 6 tablets)

71

100% l

 

 

 

 

   

 

 

75% AAA
‘33
'5 'O*
3.. 1
a 50% (4'. fl
- ’ ' .. i .
o . til” '.'
'1’.’.xc
25% “ v. 1
...; i. .".:‘o'
.' 1": v ,,‘°.
‘23:“: ..........
0% 1....3“?????¥f'
0 10 20 30 40

Stirring time (minutes)

I t=initial x t=l month I t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 34 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 40°C/50% (each point is average value for 6 tablets)

The dissolution for the aged coated tablets stored at 40°C/90% RH is high at the
10 minute stirring time. The coating material may be cracked by the tablet swelling, so it
does not behave like a plastic film. The dissolution for the aged coated tablets stored at
40°C/75%, 65%, and 50% RH is low at the 10 minute stirring time; the swelling at those
conditions is not enough to crack the coating material. This low dissolution value can
occur due to a degradation of the coating material and physical interaction among

excipients.

Figure 35 shows the dissolution profiles of drug X coated tablets stored in open
dishes for 6 months at 40°C/0%. They did not swell and they lost moisture. Dried tablets

exhibit little hydrogen bonding (no physical interaction among excipients). Therefore,

72

tablets disintegrated rapidly. From Figure 35, it can be explained that the coating
material may be degraded physically or chemically. Dissolution at the 20 and 30 minute
stirring time is almost the same between the initial and aged tablets. However,
dissolution at the 10 minute stin'ing time is different between initial/1 month aged tablets
and 2-6 month aged tablets. This shows clearly the dissolution difference caused by the
coating material. There is little moisture in the tablets, so it is assumed there is no
physical reaction among excipients affected by moisture. That is why the dissolution of
aged tablets at the 20 and 30 minute stirring time is close to that of the initial tablets. The
reason can be explained why the dissolution of aged coated tablets at the 10 minute
stirring time decreases as a function of storage time. That is because the coating material
is degraded by a high temperature (40°C), so the disintegration starting point took a

longer time.

100% _ _ .. _ ._,-_____---,.-. ...--- ,W ..-...W. ...._._ .-..--sw__v.._,_.-w-.__._......W ”war.-." . .. . .-.-.- ,. .. . . . .. . . . . .

75%

 

50%

 

Diaeolved

25%

 

 

 

0%

 

T H l l

10 20 30 40
Stirring time (minutes)

I t=initial x t=l month I t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 35 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 40°C/0% (each point is average value for 6 tablets)

73

(3) Summary of dissolution behavior
Drug X coated and uncoated tablets dissolve differently in the medium depending

on the storage conditions. In comparison with the initial tablets, tablets stored at

40°C/90% and 0% RH dissolve similarly. Tablets stored at 40°C/75%, 65% and 50%
RH dissolve differently in the medium from those stored at 40°C/90% and 0% RH. They

do dissolve similarly to each other (see Figures 24 - 35 for the initial tablets, uncoated
tablets, and coated tablets).

For uncoated tablets, dissolution profiles for initial, 90%, and 0% RH (Figures 24,
26, 30) look similar to each other. They show the dissolution is still high at 6 months
storage time. And, dissolution profiles for 75%, 65%, and 50% RH (Figures 27, 28, 29)
look similar to each other. They show that dissolution decreased rapidly as a function of
storage time for 6 months. So, dissolution profiles obtained from initial, 90%, and 0%
RH (Figures 24, 26, 30) look different in comparison with dissolution profiles obtained
from 75%, 65%, and 50% RH (Figures 27, 28, 29). Coated tablets show the same
behavior.

For both coated and uncoated initial tablets, there may be no change in physical
interactions among excipients because they have been stored at ambient conditions. So,
dissolution at the 30 minute stirring time is high (96% for both coated and uncoated
tablets). And, for both coated and uncoated tablets stored at 0% RH, there may be no
physical interactions among excipients because there is little moisture in tablets. So,
tablets stored at 0% RH behaves like the initial tablets. Finally, for both coated and
uncoated tablets stored at 90% RH, there may be physical interactions such as

crosslinking. However, the swelling may counteract crosslinking among excipients.

74

Also, the swelling may be able to crack the coating material, so aged coated tablets
disintegrate rapidly to reach high dissolution. Therefore, the dissolution of the initial
tablets, and tablets stored at 0% and 90% RH behaves similarly.

For tablets stored at 75%, 65%, and 50% RH, there may be physical interactions
such as crosslinking, so dissolution decreases rapidly as a function of storage time.
Therefore, dissolution of tablets stored at 75%, 65% and 50% RH behaves similarly. See
Chapter 4.4. Proposed them of dissolution retardation Motion of relative humidity

for more information.

75

CHAPTER 4

DISSOLUTION PREDICTION PROGRAMMING AND VERIFICATION

The dissolution is affected by the following five major factors (Abdou, 1989):
a. Formulation
b. Manufacturing process
c. Packaging and storage conditions
d. Dissolution apparatus

e. Test parameters

The final dosage form, the tablet, is considered in this study, so the factors a and b
can be removed because the same formulation and manufacturing process are used for all
tablets. Also, if the same dissolution method is used consistently, the factors d and e are
assumed to be constant, so they can be removed. Therefore, the effect of aging on in-
vitro dissolution is assumed to depend only on packaging and storage conditions such as
moisture, temperature, oxygen, light and storage time. In this study, the product is
moisture sensitive. The packages such as plastic bags or bottles cannot protect against
temperature, but they can protect against light by using amber color or opaque walls.
Therefore, if the relationship among dissolution, moisture, and storage time is found, the

in-vitro dissolution of products in a package can be predicted at a specific temperature.

1. Technical review of Nakabayashi’s method
As explained in Chapter 1, Nakabayashi’s dissolution reduction rate (K)

represents the log ratio of dissolution rates [lnflc/kJ] as a function of storage time. If the

76

relationship between dissolution reduction rate (K) and RH (or M) is determined, the
dissolution at any storage RH for any storage time can be calculated. Nakabayashi and
coworkers used a multiple regression method to determine the relationship between the
dissolution reduction rate, moisture, and temperature.

Nakabayashi and coworkers determined the dissolution rate (k) by plotting data
In[ C /(C ,~ - C,,)] versus stirring time. They presented dissolution determinations resulting
from samples of three tablets taken every 2 minutes stirring time from about 2 minutes to
16 minutes. From this, they presented straight line plots of ln[C/(C,~ - C,,,)] versus stirring
time. There is very little variation indicated in the data even if they used the rotating
basket model for the dissolution method. The basket dissolution method has poor mixing
system, so it is hard to reproduce data (Ross and Rasis, 1988). Nakabayashi et al. made
no statement of variation at all. Many of the points (average of 3) fall exactly on the
trend lines. However, the variation in dissolution is known to be large, especially at
stirring times of less than 30 minutes.

In this study, six tablets were taken every 10 minutes for a total of 30 minutes
stirring time. Variation in this study is high, especially at the 10 minute stirring time for
short term aged tablets, and at the 20 and 30 minute stirring time for long term aged
tablets as shown in Table 16. Short term (Initial-l month aged) tablets disintegrate
quickly, so the short term aged tablets at the 10 minute stirring time are very active,
causing a large variation at that stirring time. However, tablets at the 30 minute stirring
time disintegrate completely, and reach almost the maximum dissolution value, so, have
little variation. Long term (2 months-6 months aged) tablets disintegrate slowly. The

long term aged tablets before the 10 minutes stirring time are inactive, so dissolution at

77

that stirring time is low, and variation is small. Tablets beyond 10 minutes stirring time
are very active. They rapidly disintegrate into small particles, and the drug in the
particles dissolves into the medium. During this process, the dissolution value for each '

tablet is variable.

Table 16 Variation of dissolution for drug X uncoated tablets stored at 40°C (coefficient
of variance greater than 0.1 is bold-faced.)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Drug X uncoated tablets stored at 40°C/90% RH
(minutes) Initial 1 mo. 2 mo. 3 mo. 4 mo. 5 mo. 6 mo.
SD 7.6 3 7.2 5.2 5.6 5.7 3.6
Mean 81.2 84.9 71 68.6 66.7 58.3 53.7
Coef. of 0.094 0.035 0.101 0.076 0.084 0.098 0.067
10 variation
SD 0.9 1.6 2.4 2.8 3 3.2 2.4
Mean 94.8 94.66 87.7 86 84.5 78.7 75.9
Coef. of 0.009 0.017 0.027 0.033 0.036 0.041 0.032
20 variation
SD 0.6 0.9 1.1 1.7 2 2.2 2
Mean 96.2 96.88 91.3 91.5 90.4 86.2 84.5
Coef. of 0.006 0.009 0.012 0.019 0.022 0.026 0.024
30 variation
Drug X uncoated tablets stored at 40°C/75% RH
Initial 1 mo. 2 mo. 3 mo. 4 mo. 5 mo. 6 mo.
SD 7.6 12.1 3.7 5.2 4 1.9 3.2
Mean 81.2 31 16.8, 19.2 14.8 12.3 11.3
Coef. of 0.094 0.390 0.220 0.27 1 0.270 0.154 0.283
10 variation
SD 0.9 7.2 4.7 11.8 18.4 11.3 11.3
Mean 94.8 767 65.2 62.4 52.8 47.5 37.8
Coef. of 0.009 0.009 0.072 0.189 0.348 0.238 0.299
20 variation
SD 0.6 3.3 2.5 4.7 6.6 10.4 5.7
Mean 96.2 86.7 79.9 80.9 79.4 70.6 71
Coef. of 0.006 0.038 0.031 0.058 0.083 0.147 0.080
30 variation

 

78

 

Table 16 Variation of dissolution for drug X uncoated tablets stored at 40°C (coefficient
of variance greater than 0.1 is bold-faced.) (Continued)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Drug X uncoated tablets stored at 40°C/65% RH
1 mo. 2 mo. 3 mo. 4 mo. 5 mo. 6 mo. 1 mo.
SD 7.6 5.2 2.7 0.8 1.4 1.4 0.7
Mean 81.2 34.5 17.3 11.9 10.4 7.5 7.63
Coef. of 0.094 0.151 0.1-56 0.067 0.135 0.187 0.092
10 variation
SD 0.9 2 13 14 12.7 5.1 8.4
Mean 94.8 81.9 54 45 28.5 17.9 19.8
Coef. of 0.009 0.024 0.241 0.311 0.446 0.285 0.424
20 variation
SD 0.6 1.7 9.6 16 15.3 7.1 11.3
Mean 96.2 88.9 70.5 60.9 41.6 29.8 29.6
Coef. of 0.006 0.019 0.136 0.263 0.368 0.238 0.382
30 variation
Drug X uncoated tablets stored at 40°C/50% RH
1 mo. 2 mo. 3 mo. 4 mo. 5 mo. 6 mo. 1 mo.
SD 7.6 10 5.4 9.3 3.2 3.3 2
Mean 81.2 65.3 30 23.1 20.5 15.7 13.6
Coef. of 0.094 0.153 0.180 0.403 0.156 0.210 0.147
'0 variation
SD 0.9 1.7 3 17.2 7.1 14.3 9.4
Mean 94.8 91.8 73.7 58.4 60.8 34.8 22.6
Coef. of 0.009 0.019 0.041 0.295 0.117 0.411 0.416
20 variation
SD 0.6 1.5 2.7 18.5 6.9 19.2 12.3
Mean 96.2 94.5 I 80.3 69.4 71.8 44.2 29.4
Coef. of 0.006 0.016 0.034 0.267 0.096 0.434 0.418
30 variation
Drug X uncoated tablets stored at 40°C/0% RH
1 mo. 2 mo. 3 mo. 4 mo. 5 mo. 6 mo. 1 mo.
SD 7.6 5.5 2.9 7.5 7.4 5.6 3.7
Mean 81.2 65.2 56.3 68.4 64.1 61.9 65.5
Coef. of 0.094 0.084 0.052 0.110 0.115 0.090 0.056
10 variation
SD 0.9 1.3 0.9 0.8 1.1 1 0.8
Mean 94.8 95.3 89.6 95.4 95.5 95.1 95.8
Coef. of 0.009 0.014 0.010 0.008 0.012 0.01 1 0.008
20 variation
SD 0.6 0.9 0.9 0.3 0.7 0.8 1.6
Mean 96.2 96.9 90.4 97 97.5 96.9 96.1
Coef. of 0.006 0.009 0.010 0.003 0.007 0.008 0.017
30 variation

 

 

 

 

 

 

 

 

 

 

 

SD: standard deviation from six dissolution (%) values
Mean: Mean of six dissolution (%) values
Coef. of variation: coefficient of variation (SD/Mean)

79

As shown in Table 16, there is a large variation in dissolution using the basket

method (average coefficient of variation: 0.041 at 90%, 0.157 at 75%, 0.192 at 65%,

0.187 at 50%, 0.035 at 0%). The average coefficients of variation for 40°C at 75%, 65%,
and 50% RH are four times higher than those of variation for 40°C at 90% and 0% RH.

If the coefficient of variation in Table 16 is higher than 0.1, the value is in bold. There
are many more bold-faced values at 75%, 65%, and 50% RH than at 90% and 0% RH.
The coefficient values at intermediate relative humidities (50, 65, and 75% RH) are
higher than at either 0% or 90% RH. Therefore, it is hard to determine the dissolution
rate (k) with In[ C /(C ,- - C,.)] and stirring time for tablets stored at 40°C at 75%, 65%, and
50% RH (lack of fit).

Figure 36 shows an example of the relationship between In[ C /(C , - C m) ] and
stirring time obtained from drug X uncoated tablets stored for 6 months at 40°C/50% RH.

There was a poor relationship between ln[C/(C,~ - C,.)] and stirring time, and dissolution

rates (k) did not change regularly as a function of storage time.

80

InICI/(CI-Cm)]

 

 

 

O L
0 1o 20 30
stirring time (minutes)

0 (t = initial) A (t = 1 month) I (t = 2months)A (t = 3 months) 0 (t = 4 months) * (t = 5
months) 0 (t = 6 months) — (dissolution rate)

Figure 36 Dissolution rates (k) of uncoated tablets stored in open dishes for 6 months at
40°C/50% RH

The log ratio of dissolution rates (In[ k/kJ) was plotted as a function of storage
time to determine the dissolution reduction rate (K) as shown in Figure 37.

storage time (days)

0 30 60 90 120 150 180 210

0 I I u 1 1 1 I
. I

 

    

 

-1 ,
E
a:
'E‘ 2 y = -0.0119x + 0.1649
‘ - q
R2 = 0.9347 .
-3 -

0 Calculated ln[k/kJ — Dissolution reduction rate
Figure 37 Dissolution reduction rate (K) of uncoated tablets stored at 40°C/50% RH

81

Next, dissolution reduction rates (K) were plotted as a function of relative

humidity giving the relationship shown in Figure 38.

     
     

 

 

 

 

>3
3 y = 0.00009x + 0.0072
2!
C ,
.9
233 y = -0.0009x + 0.0699
3 0'01 i y = 0.0008x — 0.0258 1 ‘
.5 \. ;
g y=-0.0001x+0.0126
(I) .
.2
o

0 . (Initial! equilibrium RH .

0 25 50 75 100

RH (%)
Figure 38 Dissolution reduction rate as a fiinction of RH (%)

By using the relationship in Figure 38, the dissolution of tablets in a package is to
be calculated as a function of storage time. The linear relationship between dissolution

reduction rate and relative humidity can be expressed as Equation 14.
K=a~RH(%)+b (14)

Substitute Equation 14 into Equation 10:

kt = ki .e—(U'RH(o/o)+b)'t (15)

Substitute Equation 15 into Equation 8:

.. —( ~RH(%>+b)-r.
Cm =C,- —C,- 071"“? a 13" (16)

Equation 16 was used to calculate the dissolution at 30 minutes stirring time for a time

interval (t) in the dissolution prediction program.

82

Example calculation: [5 tablets in HDPE bottle stored at 40 CC/90% RH
Initial dissolution rate (ki): 0.111

At storage time 0, the dissolution at 30 minutes stirring time is:

Cm = 1 — 1 x e_[0'1 ' ”X3" = 0.9642 (96.42% dissolution)

After 1 day, the relative humidity of HDPE bottle headspace is 34.63%.

m ...

= 0.964 (96.4% dissolution)
So, the dissolution of tablets at 34.63% RH is changed to 96.4% for 1 day. The
dissolution decreased by 0.02% from the initial dissolution.

After 2 days, the relative humidity of HDPE bottle headspace is 35.44%.

C -1-lx e_[0’l 1 Ixe-(0.0008x35.44—0.0258)x1 1x30
m _

= 0.9639
So, the dissolution of tablets at 35.44% RH is changed to 96.39 for 1 day. The
dissolution decreased by 0.03% from the initial dissolution, and so on.

For 6 days, the accumulated dissolution change is 0.19% (0.02% + 0.03% + 0.04% +

0.05% + 0.05% + 0.06%). Therefore, the dissolution decreased to 96.23% from 96.42%.

Dissolution results using Nakabayashi’s method with this data show poor
agreement between calculated and experimental results, as shown in Figure 39. This is
an illustration of results (tablets in LDPE bags without silica gel, tablets in LDPE bags
with 0.5 g, 1 g, 2 g silica gel, tablets in HDPE bottles without silica gel, and tablets in

HDPE bottles with 0.5 g silica gel).

83

1250/0 2,,..W-,_3-~,-.-_3-,--,-_.-_. ”23-3-40 -.. WWW. .--”.-.m- .-..-.M. -- 3. .........-....._..- ._

 

 

 

 

 

 

m

a:

g, 100%

C

X

g \N‘

.2 75% 4 1 a

o ......... '6'

E . _ .... ' 9 ‘ 3

3 509 . . "

C o . ’ f

2 I

2 ' '

g 25%

.2

o z
0% 1 I T fl

0 50 100 150 200

Storage time (days)

0 Experimentally measured dissolution ---- Relative humidity of the package headspace — Predicted
dissolution using dissolution reduction rate (K)

Figure 39 Dissolution of tablets in HDPE bottles stored at 40°C/90% RH as a function of
storage time — Nakabayashi method
Therefore, in this study, the method for prediction of dissolution of tablets in a package

was approached differently by using the dissolution retardation rate (R).

2. Dissolution retardation rate (R)

Dissolution is dependent on moisture as well as storage time, so a rate
representing dissolution change as a function of storage time must be determined. The
theory of the dissolution change as a function of storage time has not been explained
clearly in the literature, so the rate must be determined experimentally at various relative

humidities to determine the relationship between the rate and relative humidity.

84

As explained in Chapter 3.3 (2) Dissolution profiles from open dish study, the 30
minute dissolution of drug X, both coated and uncoated tablets, stored in open dishes at
25°C did not change over the 6 month period, but it did change at 40°C except for
40°C/0% RH. For the coated tablets stored at 40°C, it was hard to determine the
relationship between the 30 minute dissolution and storage time because the coated
tablets dissolved suddenly, not gradually. They did not follow the dissolution theory.
However, uncoated tablets stored at 40°C did follow the dissolution theory. Figures 40-
44 show 30 minute dissolution values of uncoated tablets stored at 40°C as a function of
storage time.

Based on empirical data fitting methods, it must be determined how the 30 minute
dissolution changes as a function of storage time. A polynomial equation can be applied
to determine the relationship between the 30 minute dissolution and storage time. A
better fit can be made by using the polynomial equation. However, there is no method to
compare the relationships obtained from a variety of relative humidities (50, 65, 75, and
90% RH). The relationship between the 30 minute dissolution and storage time can be
assumed to follow zero order kinetics (linear relationship) or first order kinetics
(exponential relationship). The dissolution prediction model using first order kinetics can
make better results for drug X uncoated tablets. So, the first order kinetic was chosen to

treat the relationship. The average initial 30 minute dissolution (D;) of uncoated tablets is

96.23%.

85

 

 

 

t 0

c ’ t :
£75%~

_3_

O

(D

.9.

°50%~

g

.E

E

025%—

0')

00/0 l l L l l l J
o 30 60 90120150180 21o

storage time (days)

Figure 40 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/90% (each month has 6 dissolution values)

 

 

O
c 2 . 2 0 o
O _
g 75% Q i . :
E 50% ~ °
‘5
.E
g 25% ~
0% l l 1 L 1 L l
O 30 60 90 120 150 180 210
storage time (days)

Figure 41 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/75% (each month has 6 dissolution values)

86

 

 

8
s o ’ .
3 75 /0 +— £ .
8 0 0 o
.2 0 .
E 50% ~ °
2 g z
.- . . .
S 25% ~ 3 ‘
0') 0
00/0 1 1 1 1 1 1 J
0 30 60 90 120 150 180 210
storage time (days)

Figure 42 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/65% (each month has 6 dissolution values)

5 o ‘ ’ g
g 75/0 "‘ . O .
E . 3 3
“4'3 50% — ’
8
E o
0
8 25% « . i
0% H l T l T l l

 

 

O 30 60 90 120 150 180 210
storage time (days)

Figure 43 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/50% (each month has 6 dissolution values)

87

 

 

 

0

C

E 75% ~

0

m

.2

3 50% ~

*5

.E

g 25% -

00/0 1 T T T l l j
0 30 60 90 120 150 180 210

storage time (days)

Figure 44 30 minute dissolution of drug X uncoated tablets stored in open dishes for 6
months at 40°C/0% (each month has 6 dissolution values)

As can be seen in Figures 40-44, the variability of 30 minute dissolutions is large,
especially for 40°C/75%, 65%, and 50% RH. This large variability can make it hard to
determine the relationship between the 30 minute dissolution and storage time.

In order to make the relationship, an exponential equation can be applied. Figure
45 shows a general exponential graph (y = -e"). If plotted function moves up the y-axis
as much as 1+D,- (initial dissolution value), an equation (y = -e" + D; +1) can be obtained

as shown in Figure 46.

88

 

 

 

"2 r 6 \

.3- _1_

 

 

Figure 45 Graph of y = -e" Figure 46 Graph of y = -e" + (D,H)

The equation shown in Figure 46 can be applied to make the relationship between
the 30 minute dissolution and storage time. Figure 47 shows a typical graph for

dissolution change as a function of storage time.

  

50% «
D = —D,-eR’ + (D,- +100%)

 

25% ~

30 minute dissolution

 

0%

 

7* I 1

0 30 6O 90 120 150 180 210
storage time (days)

Figure 47 A typical graph for 30 minute dissolution change as a function of storage time

89

Equation 17 represents the relationship between the 30 minute dissolution and

storage time. R denotes the dissolution retardation rate. R must be determined at each

relative humidity.
D = -D,.eR’ +(D,- +100%) (17)

In order to get the dissolution retardation rate (R), Equation 17 is rearranged.
Plots of the 30 minute dissolution on a logarithmic scale, against storage time on the

abscissa with a linear scale, yield a straight line.

 

In 0“ =—Rt (18)
1),-—1)+1000/o

By plotting In[D/(D,~-D+100%)] versus storage time (t), the dissolution retardation rate

(R) can be determined using a trend line as shown in Figure 48.

storage time (days)
0 30 60 90 120 150 180

J_

43.1 ~

-O.3 ~

-O.5 ~

 

ln[Dr/(DI-D+100%)]

 

-o.7

Figure 48 Dissolution retardation rate (R)

Figure 49 shows dissolution retardation rates determined at various relative
humidities at 40°C. The dissolution retardation rate at 40°C/65% is greatest. It means

that the dissolution of tablets stored at that condition decreases most quickly as a function

90

of storage time. And, the dissolution retardation rate at 40°C/90% is lowest. See 4.

Proposed theory of dissolution retardation as a function of relative humidig for more
information. This result is different from previous research at the School of Packaging in
Michigan State University, and from Nakabayashi (1980) and Kadir (1986). They
concluded that the dissolution decreased more rapidly if tablets are stored at a high
temperature and high relative humidity. See Chapter 1. Background and literature review
for more information.

storage time (days)
0 30 60 90 120 150 180 210

 

 

 

 

 

0 1k 1 1 1 i L 1 4;
_0'1 _\ o A o y=-0.0006x-0.039
" *3 R2: .
'{a‘ -02 . . A (1 09415)
g '03 . 1 °- . A y=-0.0011x-0.0785
$ - (R2=0.8684)
5 -0.4 ~ 1
E A o y = -0.0028x - 0.0013
s -0.5 ~ ‘ . (R2=0.9446)
-0.6 ~ y=-0.0031x-0.0511
-07 __,-_._,,.,_ ., ,. , ' """ ' " (R2=0%37)

O 90% A 75% A 65% 0 50%

Figure 49 Dissolution retardation rate of drug X uncoated tablets at various relative
humidities at 40°C

Table 17 shows dissolution retardation rates (R, % dissolution change/day) at 40°C.

Table 17 Dissolution retardation rates (R) of drug X uncoated tablets stored in open
dishes at 40°C ,
[ RH [ 0% l 50% | 65% | 75% | 90% |
I Dissolution retardation rate 0 I 0.0028 I 0.0031 I 0.0011 I 0.0006 I
(% dissolution change/day)

 

 

 

91

('2

(I)

To predict the dissolution of tablets in a package, the dissolution retardation rate
(% dissolution change/storage time) as a function of relative humidity must be
determined.

Figure 50 shows the relationship between the dissolution retardation rate and
relative humidity. Based on 6 month experimental results, it is assumed that the
dissolution of tablets stored below the initial equilibrium relative humidity does not
change. Dissolution when stored in open dishes at 40°C/0% did not change for 6 months
(see Figure 30). The tablets in the HDPE bottle containing 0.5 g silica gel did not reach
the initial equilibrium RH for 3 months, and the dissolution did not change below that
initial equilibrium RH (34.23%) (see Figure 57). Even though there is no 6 month
dissolution data between 0% RH and initial RH (34.23%), it is assumed in this study that
the dissolution of drug X uncoated tablets stored below initial conditions does not change
for 6 months at 40°C. So, a zero value of the dissolution retardation rate is applied to
calculate the dissolution of tablets between 0% RH and initial equilibrium RH (34.23%
RH). The piecewise equations shown in Figure 50 are used to calculate the dissolution
retardation rate at any RH according to Equation 19.

R=a-RH(%)+b (19)

where a and b = constants of the equation between R and RH (%)

Substitute Equation 19 into 17.
% Dissolution (D) = -D,. -e[“'R”(%)+b1" + 0,- +100% (20)

Equation 20 can be used to calculate the 30 minute dissolution at any RH.

92

5. '1"!

y = 0.00002x + 0,0013

 
 
  
   
  

y = -0.0002x + 0.0161

/

y = 0.0001776x - 0.00608
0.002 F

 
 

/‘

y = -0.0000333x + 0.0036
Jnitial equilibrium RH.

Dissolution retardation rate (R)

 

 

0 20 40 60 80 1 00

RH (%)

Figure 50 Dissolution retardation rate (R) as a function of relative humidity at 40°C

Example Calculation

The following shows how to calculate the dissolution using the dissolution

retardation rate at 40°C/50% RH for 30 days.

D(%) = —96. 23% - .210-000’ 77 MOW-006081 '30 + 96.23% +100% = 91.57%

The dissolution prediction program works with the moisture prediction program.
At each time interval, the tablets in a package have a different moisture content
associated with the equilibrium headspace RH (%) at that time interval. So, the
dissolution prediction program calculates the dissolution of tablets at each equilibrium
RH(%) (or (p/pjm) determined by the moisture prediction program at each time interval j.
Figure 51 shows the algorithm used to calculate the dissolution at various relative

humidities. The dissolution changes for a time interval at various RHs are summed for a

93

storage time, and then the accumulated dissolution change is subtracted from the initial

dissolution to calculate the dissolution of tablets stored for storage time t.

 

Input Data
. Initial dissolution (D,)
. Constants of the relationship between dissolution retardation rate and RH
. Time interval (i)
. Storage time (t)

 

 

 

 

 

 

 

 

 

 

A

 

Equilibrium RH,.1(%) (or w/pjmflj) from the moisture prediction part

 

 

 

 

 

Calculate 30 minute dissolution using a time interval j.

-R1-I -°/ +b-t
..ela nj(°) ] +

Dnj = —D, 0,- +100%

 

 

Calculate 30 minute dissolution change from the initial dissolution value.

an = Di - Dnj

 

 

 

 

——p n=n+1

 

 

 

 

 

 

 

 

 

 

Figure 51 Algorithm used to calculate the dissolution at various relative humidities

94

3. Verification of dissolution prediction program
The stepwise storage conditions and continuous storage conditions were used to

verify the dissolution prediction model.

(1) Stepwise storage conditions (open dish study)
In order to verify that dissolution is dependent on moisture content as well as
storage time, stepwise storage conditions can be used. In addition to that, results from

stepwise storage conditions at 40°C were used to verify the dissolution prediction

program. Table 18 shows the stepwise storage conditions, dissolution obtained
experimentally and the dissolution calculated by use of the dissolution prediction
program. The experimental dissolution was measured when tablets were transferred to

another condition.

Table 18 Comparison of the results from experimental and predicted dissolution stored at
stepwise conditions (at 40°C)

 

 

 

 

 

 

 

 

 

 

 

 

 

No. Storage time Experimental Predicted Storage Conditions
(months) Dissolution (avg) Dissolution

1 l 93% 87.8% 50%(1 month)

2 2 77% 78.4% 50%(1 month), 65%(1 month)

3 3 69% 74.7% 50%(1 month), 65%(1 month), 75%(1 month)

4 4 63% 70.9% 50%(1 month), 65%(1 month), 75%(2 months)

5 4 61% 73.0% 50%(1 month), 65%(1 month), 75%(1 month),
90%(1 month)

6 5 42% 66.9% 50%(1 month), 65%(1 month), 75%(3 month)

7 5 26% 71.2% 50%(1 month), 65%(1 month), 75%(1 month),
90%(2 month)

 

Stepwise (l): 1, 2, 3, 4, and 6 (Results are plotted in Figure 52)
Stepwise (ll): 1, 2, 3, 5, and 7 (Results are plotted in Figure 53)

95

 

Example calculation

Table 19 shows the predicted dissolution changes from the initial dissolution value, and

they are calculated by the dissolution prediction program at each RH for a given storage

time.

Table 19 The predicted dissolution change from the initial dissolution value calculated

by the dissolution prediction program at each RH for a given storage time

 

 

 

 

 

 

 

 

Storage time 1 month 2 months 3 months 4 months
90% 1.7% 3.5% 5.3% 7.2%
75% 3.7% 7.5% 11.5% 15.6%
65% 9.4% 19.7% 31.0% 43.4%
50% 8.4% 17.6% 27.6% 38.4%

 

 

 

 

The following shows an example calculation using value in Table 19 of the dissolution of
tablets stored at 50% for 1 month 65% for 1 month and 75% for 2 months.

[96.23% (initial dissolution) —- 8.4% change for 1 month at 50% — 9.4% change for 1
month at 65% — 7.5% change for 2 months at 75%] = 70.93%

The dissolution decreases to 70.93% from 96.23%.

Table 18 also shows the effect of storage time. Compare rows 3, 4 and 6. In all
three rows, the tablets were stored in open dish at 50% and 65% RH for 1 month each.
But they were stored at 75% RH for 1, 2 and 3 months respectively. The tablets reached
equilibrium with 75% RH within 2-3 days. They remained at equilibrium for l, 2 and 3
months. The increased time at 75% equilibrium resulted in progressively lower
dissolution: 69%, 63%, 42%. This is strong evidence that the dissolution is time

dependent and that this dependence is not linear. Similarly, rows 5 and 7 of Table 18

96

show the effect of time at equilibrium at another relative humidity (90%). Here
dissolution changed from 61% after 1 month to only 26% after 2 months at 90%.
Figure 52 and Figure 53 show the experimental and predicted dissolution. They
show there is fairly good agreement until 4 months. However, beginning at 4 months
storage time, the experimental and predicted results diverge sharply. At that time, high
moisture absorption may accelerate the physical interaction such as crosslinking among
excipients. Perhaps there is a threshold level of interaction between time and moisture

content. This mechanism must be explained in the future.

 

 

 

 

 

100% _..- _ . . .....

5 N A x

1: 750/6 0 ~‘_‘~“ ~~\‘-_ _

.2

D 50% A

q, X

5

E x r

g 25% X

(‘0 :
00/0 I I I l f l:

0 1 2 3 4 5 6

Storage time (months)

+ dissolution stored at 50% for 1 month, 0 dissolution stored at 50% for 1 month and 65% for 1 month,
Cl dissolution stored at 50% for 1 month, 65% for 1 month, and 75% for 1 month, A dissolution stored at
50% for 1 month 65% for 1 month and 75% for 2 months, X dissolution stored at 50% for 1 month, 65%
for 1 month, and 75% for 3 months, —I— dissolution calculated by the dissolution prediction program

Figure 52 Dissolution of tablets stored at stepwise conditions (I) at 40°C

97

1 00%

$
75% M
8
2
X
X
35
X

 

 

 

 

50%

25%

 

30 minute Dissolution

 

 

00/0 I I T f l

 

Storage time (months)

+ dissolution stored at 50% for 1 month, 0 dissolution stored at 50% for 1 month and 65% for 1 month,
El dissolution stored at 50% for 1 month, 65% for 1 month, and 75% for 1 month, A dissolution stored at
50% for 1 month, 65% for 1 month, 75% for 1 month, and 90% for 1 month, X dissolution stored at 50%
for 1 month, 65% for 1 month, 75% for 1 month, and 90% for 2 months, —I— dissolution calculated by
the dissolution prediction program

Figure 53 Dissolution of tablets stored at stepwise conditions (II) at 40°C

Open dish storage at 40°C with stepwise transition from one humidity to the next
higher one reveals an interaction among moisture content, relative humidity and time that
has not yet been fully explained. The prediction methods developed in this work do not
account for this unexplained mechanism. However, when the product is packaged in a
container closure system, and stored at a single temperature and humidity, for example
40°C, 75% RH, the resulting dissolution can be predicted fairly well using the technique

described here. The following section on continuous storage conditions explains this.

98

(2) Continuous storage conditions
Uncoated tablets stored in LDPE bags and HDPE bottles at 40°C/90% RH were

also used to verify the dissolution prediction program. The relative humidity of the
package headspace in the LDPE bags and HDPE bottles changed quickly, so one day
time intervals were used to calculate the dissolution at those relative humidities. The
dissolution calculated using the dissolution retardation rate (R) shows fairly good
agreement with experimentally measured trends in dissolution as shown in Figures 54-59.
Table 20 shows dissolution differences between experimentally measured dissolution and
predicted dissolution. They may occur from the 30 minute dissolution variability. The

dissolution of aged uncoated tablets at 40°C/75%, 65%, and 50% RH has a large

variation (see Figures 40-43). So, dissolution retardation rates determined from that data

can 031186 error.

99

Table 20 Dissolution differences between experimentally measured average dissolution

and predicted dissolution of tablets in package stored at 40°C/90% RH

 

Storage time (days)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

44 58 83 104 136 161
Tablets in LDPE Dexp 75.7% 80.0% 77.3%
bags without Dealc 90.8% 89.8% 88.1%
desiccant Dame... 15.1% 9.8% 10.8%
% demm 19.9% 12.3% 14.0%
Tablets in LDPE Dcxp 80.3% 71.7%
bags with 0.5 g Dcaic 88.1% 86.1%
desiccant Um...“ 7.8% 14.4%
% Damn... 9.7% 20.1%
Tablets in LDPE Dexp 78.5% 72.8%
bags with l g chc 87.5% 84.7%
desiccant demnc. 9.0% 1 1.9%
% Damn...“ 11.5% 16.3%
Tablets in LDPE D...xp 86.3% 70.0%
bags with 2 g Dcalc 87.5% 84.7%
desiccant Ddifimcc 1.2% 14.7%
% Dmflcm 1.4% 21.0%
Tablets in HDPE Deg 86.4% 80.0% 76.6% 57.2% 46.0%
bottles without chc 83.9% 76.6% 70.4% 62.5% 57.6%
desiccant Dam... -2.5% -3.4% -6.2% 5.3% 11.6%
% Um..."cc 2.9% 43% -8.1% 9.3% 25.2%
Tablets in HDPE Data 96.2% 96.7% 96.4% 93.2% 91.2%
bottles with 0.5 g 2%., 96.2% 96.1% 94.5% 88.5% 81.8%
desiccant demm 0% -0.6% 4.9% 4.7% -9.4%
% Dame"... 0% -O.6% -2.0% -5.0% 40.3%

 

 

 

 

 

 

 

 

Dcxp: Experimentally measured average dissolution

Dale: Predicted dissolution

democ: Difference in dissolution between Dexp and Dcalc (Dcalc - Dup)

% deffcmncei % Dissolution difference fi'om experimentally measured average dissolution

(Ddifl'ca-nce/Dexpx 100)

The moisture content of tablets increased as a function of storage time, and

dissolution decreased as a function of the moisture content of tablets and storage time.

Figures 54-59 show relative humidity (dotted line) of the package headspace,

experimentally measured dissolution (dots), and predicted dissolution (solid line) of

100

 

tablets in LDPE bags and HDPE bottles. The following shows an example dissolution

calculation using the dissolution retardation rate determined at each relative humidity.

Example calculation: [5 tablets in LDPE bags stored at 40 °C/90% RH

At storage time 0, the dissolution at 30 minutes stirring time is:

D(%) = —96.23% - e0 + 96.23% +100% =100%
After 1 day, the relative humidity of the LDPE package headspace is 45.61%. So, the
dissolution at that RH (%) is changed to 99.81% for 1 day. The dissolution decreases by

0.19% from the initial dissolution.

D(%) = -96.23% - eIO'OOOl776X45'61—0'006081'l + 96.23% +100% = 99.81%

After 2 days, the relative humidity of the LDPE package headspace is 52.57%. 80, the
dissolution at that RH (%) is changed to 99.73% for 1 day. The dissolution decreases by

0.27% from the initial dissolution, and so on.

D(%) = —96.23% . ei°-°°°°2"52°57+°'°°'31" + 96.23% +100% = 99.73%

After 3, 4, 5, and 6 days, the relative humidities of the LDPE package headspace are
57.35%, 60.89%, 63.65%, and 65.88%. The dissolution decreases by 0.28%, 0.29%,
0.30%, and 0.30% at each relative humidity.

For 6 days, the accumulated dissolution change is 1.63% (0.19% + 0.27% + 0.28% + 0.29

+ 0.30% + 0.30%). Therefore, the dissolution decreases to 94.60% from 96.23%.

101

(a) Tablets in LDPE bags without silica gel and tablets with silica gel (0.5 g, 1 g, and 2 g)
stored in LDPE bags at 40°C/90% RH

Figure 54 shows results from LDPE bags without silica gel. The predicted
relative humidity of the package headspace changed quickly. Tablets reach 75% RH in
13 days. Table 21 shows experimentally measured and predicted dissolution of tablets at

the 30 minute stirring time, and relative humidity of the package headspace.

 

 

 

 

 

 

 

I i

0

8 100% 3-

x i

8 § .‘ .......

a. """""""" 5

«5 75% . . .. ‘ , e X :
O I

I ,’ o i

n: , z

3 50%

r: .

.2 ' i

a

2 25%

o

a

2 l

o 0% . r . a i

0 20 40 60 80 100

Storage time (days)

0 Experimentally measured dissolution --- Relative humidity of the package headspace — Predicted
dissolution using the dissolution retardation rate (R)

Figure 54 Dissolution of tablets in LDPE bags stored at 40°C/90% RH as a function of
storage time

Table21 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets stored in LDPE bag without desiccant)

 

 

 

 

 

 

 

Storage time Experimental Dissolution (%) Predicted Predicted
(days) I 2 3 4 5 6 Avg. Dissolution (%) RH (%)
44 79.9 70.9 63.6 86.1 71.0 82.8 75.7 90.8 84.5
58 85.1 78.3 81.8 82.4 73.7 78.7 80.0 89.8 86.0
83 81.4 82.7 76.1 77.1 69.1 77.8 77.4 88.1 87.6

 

 

 

 

 

 

 

 

 

102

 

Figure 55 shows results from LDPE bags with 0.5 g silica gel. Tablets desorbed
moisture initially, and again reached the initial moisture content after 5 days. The
dissolution is assumed not to change for 5 days. When the dissolution prediction
program was run, the dissolution for the first 5 days was calculated as equal to the initial
dissolution. Table 22 shows experimentally measured and predicted dissolution of tablets

at the 30 minute stirring time, along with the relative humidity of the package headspace.

 

 

 

 

 

 

 

(it 125% —-~~--"-~~"--~~ W.-.“ W e -.- ~ -~ - e .. e M
0
at
g 100%
8
a. ------- '0' """" ...
"5 75% _ . v ’ - ’ %
a: . ’ 0
m .
3 50% , ’
g a
g .
E 25% J
O l
a r
.9 .
a 00/0 fl T t T 1
O 20 40 60 80 100
Storage time (days)
0 Experimentally measured dissolution --- Relative humidity of the package headspace - Predicted

dissolution using the dissolution retardation rate (R)

Figure 55 Dissolution of tablets in LDPE bags containing 0.5 g silica gel stored at
40°C/90% RH as a function of storage time

Table 22 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a fimction of storage time (tablets in LDPE bag containing 0.5 g silica

eel)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Storage time Experimental Dissolution (%) Predicted Predicted
(days) | 2 3 4 5 6 Avg. Dissolution (%) RH (%)

58 82.2 77.0 85.6 77.1 83.3 76.8 80.3 88.9 84.1

83 74.0 65.4 74.2 74.9 75.3 66.6 71.7 87.1 86.5

 

103

 

Figure 56 shows results from LDPE bags with 1 g silica gel. Tablets desorbed
moisture initially, and again reached the initial moisture content after 10 days. The
dissolution is assumed not to change for 10 days. When dissolution prediction program
was run, the dissolution for the first 10 days was calculated as equal to the initial
dissolution. Table 23 shows experimentally measured and predicted dissolution of tablets

at the 30 minute stirring time, along with the relative humidity of the package headspace.

 

 

 

 

 

 

 

1250/0.___-__-- - “...... —-~ -~-~m~w~ ~ -~~ ”w”
m
:l:
a
:100%
x
3 _ _ H
.2 75% , . , """ 3 °
:1: . ' ' ‘
m "
'5 50% ,1
C o
_g ,
g 25% f,
a ’
'2 i
0
00/0 r r I 1 fi'
0 20 40 60 80 100

Storage time (days)

0 Experimentally measured dissolution --- Relative humidity of the package headspace — Predicted
dissolution using the dissolution retardation rate (R)

Figure 56 Dissolution of tablets in LDPE bags containing 1 g silica gel stored at
40°C/90% RH as a function of storage time

Table 23 Experimentally measured and predicted dissolution of tablets at 30 minutes

 

 

 

 

 

stirring time as a function of storage time (tablets in LDPE bag containing 1 silica gel)
Storage time Experimental Dissolution (%) Predicted Predicted
(days) 1 2 3 4 5 6 Avg. Dissolution (%) RH (%)
58 78.6 75.3 81.8 84.6 75.4 75.1 78.5 88.1 81.0
83 66.2 80.1 64.6 68.4 79.4 78.0 72.8 86.l 84.8

 

 

 

 

 

 

 

 

 

 

104

 

Figure 57 shows results from LDPE bags with 2 g silica gel. Tablets desorbed

moisture initially, and again reached the initial moisture content after 19 days. The

dissolution is assumed not to change for 19 days. When dissolution prediction program

was run, the dissolution for the first 19 days was calculated as equal to the initial

dissolution. Table 24 shows experimentally measured and predicted dissolution of tablets

at the 30 minute stirring time, along with the relative humidity of the package headspace.

Dissolution or RH of package HS

125% ,

100%

75%

50%

25%

0%

 

 

an".
“

 

 

 

f l i

20 40 60 80 100
Storage time (days)

0 Experimentally measured dissolution ----- Relative humidity of the package headspace — Predicted
dissolution using the dissolution retardation rate (R)

Figure 57 Dissolution of tablets in LDPE bags containing 2 g silica gel stored at
40°C/90% RH as a fimction of storage time.

Table 24 Experimentally measured and predicted dissolution of tablets at 30 minutes

 

 

 

 

 

stirring time as a function of storage time (tablets in LDPE bag containing 2 silica gel)
Storage time Experimental Dissolution (%) Predicted Predicted
(days) | 2 3 4 5 6 Ang Dissolution (%) RH (%)
58 88.2 80.9 90.1 89.6 81.9 87.0 86.3 87.5 72.1
83 78.7 63.6 73.4 70.1 68.5 65.5 70.0 84.7 80.1

 

 

 

 

 

 

 

 

 

 

105

 

(b) Tablets in HDPE bottles without silica gel and tablets with 0.5 g silica gel stored in
HDPE bottles at 40°C/90% RH

Even if tablets were packaged in relatively high barrier HDPE bottles, the
dissolution decreased a lot in 160 days. Figure 58 shows the predicted relative humidity
of the package headspace as a function of storage time. Predicted dissolution using the
dissolution retardation rate is in the range of experimentally measured dissolution of
tablets in HDPE bottles without silica gel. Table 25 shows measured and predicted

dissolution of tablets at the 30 minute stirring time.

 

 

 

 

 

 

 

125% _ -m m - ,.
{D
I
g 100%
u
x
U
3.
no- 75%
O
I
I:
O 50%
c
.9
2 0
g 25%
.2
0
00/0 F l j l
0 50 100 150 200

Storage time (days)

O Experimentally measured dissolution -—-- Relative humidity of the package headspace — Predicted
dissolution using the dissolution retardation rate (R)

Figure 58 Dissolution of tablets in HDPE bottles stored at 40°C/90% RH as a function of
storage time.

106

Table 25 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets in HDPE bottle without desiccant)

 

 

 

 

 

 

 

 

Storage time Experimental Dissolution (%) Predicted Predicted
(days) 1 2 3 4 5 6 Avg. Dissolution (%) RH (%)
58 81.5 91.2 90.2 88.7 80.3 86.5 86.4 83.9 58.5
83 74.2 78.9 77.8 80.2 84.0 84.9 80.0 76.6 63.1
104 78.2 60.3 82.9 81.2 74.0 82.8 76.6 70.4 65.9
136 62.3 75.7 65.3 49.4 43.3 47.4 57.2 62.5 69.2
161 29.4 59.7 57.4 30.5 69.6 29.6 46.0 57.6 71.2

 

 

 

 

 

 

 

 

 

 

Figure 59 shows results from HDPE bottles with 0.5g silica gel. Tablets desorbed
moisture initially, and again reached the initial moisture content at 75 days. The
dissolution is assumed not to change for 75 days. Figure 59 shows dissolution changes
using the dissolution retardation rate are a little over estimated for tablets in HDPE bottle
containing 0.5 g silica gel. Table 26 shows experimentally measured and predicted

dissolution of tablets at the 30 minute stin'ing time.

 

 

 

 

 

 

 

1250/0 ~.-..A-____._--~---u- -“A--.. .. ...w....... - -_.__-_.----__-_-- .-
(I)
1
° 100%
a
g N
o
a
.. 75%
o
8 50% , .4 - ' ‘
c g - 0
o . . o
a ‘ . t
2 .- a
o 25% . .. ‘ '
.3 . « -
g . ‘ .
0% r r 1 ;
0 50 100 150 200
Storage time (days)
9 Experimentally measured dissolution ----- Relative humidity of the package headspace — Predicted

dissolution using the dissolution retardation rate (R)

Figure 59 Dissolution of tablets in HDPE bottles containing 0.5 g silica gel stored at
40°C/90% RH as a function of storage time.

107

 

Table 26 Experimentally measured and predicted dissolution of tablets at 30 minutes
stirring time as a function of storage time (tablets in HDPE bottle containing 0.5 g silica

gel)

 

 

 

 

 

 

 

 

 

Storage time Ex erimental Dissolution (%) Predicted Predicted
(days) | 2 3 4 5 6 Avg. Dissolution (%) RH (%)

58 97.2 96.5 96.4 96.7 95.4 95.3 96.2 96.2 29.1

83 97.1 97.1 96.2 96.2 95.7 97.7 96.7 96.1 36.2

104 95.5 96.9 95.9 96.5 95.7 98.1 96.4 94.5 41.6

136 94.4 93.5 92.0 93.7 93.4 92.2 93.2 88.5 48.6

161 91.4 92.8 91.7 81.4 95.6 94.3 91.2 81.8 53.2

 

 

 

 

 

 

 

 

 

108

 

4. Proposed theory of dissolution retardation as a function of relative humidity

The phenomenon of dissolution change as a function of RH and storage time is
better understood if we develop a model for dissolution retardation. The mechanism of
tablets aging as a function of storage time at a certain amount of moisture content has not
been understood in terms of physical interactions among excipients. In this section, a
theory of drug X dissolution retardation as a function of relative humidity is proposed.

Drug X tablets consist of 63% mannitol and 18% microcrystalline cellulose
(MCC). Mannitol is a saccharide derivative. Mannitol may be crosslinked by absorbing
moisture. Sugars are generally hydrophilic and therefore interact readily with water. The
physical form of the sugar affects the interaction of the saccharide with water (Derbyshire
et al., 2001 ).

Tablet crosslinking may affect tablet hardness and dissolution. In this experiment,
the dissolution of tablets stored above 50% RH at 40°C decreased as a function of storage
time. The reason for the dissolution reduction may be that the structure inside the tablets
was changed. Tablets might be crosslinked above 50% RH at 40°C. The crosslinking
occurs through increase of intermolecular forces among excipients, and these may
become stronger as a function of storage time.

The dissolution did not decrease for tablets stored at 25°C at O, 50, 65, 75, and
90% RH. Based on the above explanation, tablets may be crosslinked above 50% RH at
25°C, but the intermolecular forces of tablets stored at 25°C may not be as strong as those
of tablets stored at 40°C. In fact, they may be not strong enough to affect crosslinking

and dissolution during the 6 months time of this experiment. The interaction of

109

temperature and moisture may accelerate the crosslinking of tablets, then it may increase
intermolecular forces.

Also, cellulose can form a large aggregate structure held together by hydrogen
bonding (N akai, 1977). This may increase the intermolecular forces among excipients.
Figure 60 shows hardness as a function of relative humidity and Figure 61 shows the 30
minute dissolution as a function of relative humidity. Together, they show the
dissolution of harder tablets is low. The hardness may increase if intermolecular forces
are increased. Tablets having strong intermolecular forces are disintegrated slowly, so
the dissolution at the 30 minute stirring time is low. As intermolecular forces decrease at
even higher RH, the tablet sofiens and dissolution increases. Thus, there isopeak in

intermolecular forces around 45-65% RH at 40°C. At the same conditions, the hardness

reaches a maximum and dissolution reaches a minimum.

 

 

 

 

 

12.0 -. 100%
10.0 a C
A 8 75%
g 8.0 i g
j; 3
3 6.0 4 '13 50%
c 2
13 :1
«‘5 4.0 4 .5
I g 25% —
2.0 4 m
0'0 T I l i 00/0 1 I T i
0 25 50 75 100 0 25 5O 75 100
RH (%) RH (%)
Figure 60 The hardness of uncoated Figure 61 30 minute dissolution of uncoated
tablets stored for 6 months at 40°C as a tablets stored for 6 months at 40°C as a
function of relative humidity function of relative humidity

110

Also, drug X tablets swell above 50% RH as described in Appendix F (see Figure
96 and Figure 99). Drug X tablets are formulated with a hygroscopic swellable material
(croscarmellose sodium (CAS)).

Tablets stored in the range of 50-65% RH at 40°C have the greatest hardness

value as shown in Figure 60, and water in tablets may be bound directly to polymer units.
While tablets stored in the range of 75-90% RH at 40°C have the smallest hardness value,

they contain much more water that may be used for hydrogen bonding (water-water and
water-polymer). Therefore, they may be crosslinked much more than tablets stored in the
range of 50-65% RH. However, they can also swell much more than tablets stored in the
range of 50-65% RH. The swelling may counteract crosslinking among excipients.
Therefore, it may offset intermolecular forces in tablets stored at 75-90% RH.

If excipients in the tablet are crosslinked with each other, intermolecular forces
among excipients may increase, then tablets are hard to disintegrate into the medium.
However, when CAS in the tablet swells, intermolecular forces among excipients may
decrease, finally tablets disintegrate readily into the medium. It may be that the
dissolution of tablets stored at 40°C/65% RH decreased most rapidly as a function of
storage time because excipients were crosslinked but they did not swell much (1.5%
swelling). On the other hand, the dissolution of tablets stored at 40°C/90% RH decreased
less even if tablets may be crosslinked much more than those stored at 40°C/65% RH

because they swelled a lot (by 4.2% of the thickness of tablets).

111

CHAPTER 5

PACKAGE DESIGN

Based on the open dish study, it was found that the dissolution of drug X, both
:oated and coated tablets, was very sensitive to temperature and moisture. The
solution of both uncoated and coated tablets at the 30 minute stirring time did not
mge at all at 25°C at 0, 50, 65, 75, and 90% RH for 6 months, but it declined at 40°C
50, 65, 75, and 90% RH for 6 months. The dissolution of both coated and uncoated

)lets was not reduced when stored at 40°C, 0% RH for 6 months.

Uncoated tablets in the HDPE bottle containing 0.5 g silica gel did not reach
.tial equilibrium RH for 3 months, and the dissolution was not reduced below the initial
uilibrium RH (34.23%) (see Figure 59). Even though there is no 6 month dissolution
ta from the open dish study between 0% RH and initial RH (34.23%), it is assumed that
’dissolution of drug X uncoated tablets stored below initial conditions does not change
‘5 months at 40°C in this study. So, a zero value of the dissolution retardation rate is
flied to calculate the dissolution of tablets between 0% RH and the initial equilibrium
1 (3 4% RH).

The dissolution of tablets in open dishes stored at 25°C at 0, 50, 65, 75, and 90%
H did not change significantly for 6 months, so dissolution retardation rates could not
>e determined. The 6 month accelerated testing is used as an indication of the 24 month
ong~terrn testing.

Assume a company wants to select a package for NDA registration stability
testing. They want drug X tablets to be safe for 6 months at accelerated testing

(40°Ci2°C/75% RH:5%) and 24 months at long-term testing (25°Ci2°C/60% RHi5°/o).

112

available packages are Aclar blister, and 50 mL HDPE bottles, with 0.5 g, l g, or 2 g

L gel canisters.

\clar blister (PVC/2 mil PIE/0.6 mil Aclar, P = 0.00058404 g/day-cavity-ps at 40°C)

The permeability of this Aclar blister was obtained from previous work at the
001 of Packaging. The first example assumes that one tablet (W, = 250 mg) is
:rted into one blister cavity. For the blister package, it is impossible to use silica gel
siccant, so the relative humidity of Aclar blister headspace will increase from the initial
,uilibrium relative humidity as shown in Figure 62. The tablet reaches equilibrium with
te environmental condition (40°C/75%) in 180 days based on the moisture prediction
'TOgl‘atn. The relative humidity inside the package is changed from initial to equilibrium
{H as a function of storage time. Dissolution at each relative humidity between initial
and equilibrium RH is calculated by the dissolution prediction program using 1 day time
interval iterations. The tablet is predicted to reach the specification limit 75% dissolution

in 50 days. Therefore, the Aclar blister is predicted to not be a suitable package for drug

X tablets.

113

100% —. -* ,

75%

 

 

’ ’ RH of package HS Dissolution
50% 4

 

25%

 

Dissolution or RH of package headspace

 

0% . T . 4
o 50 100 150 200

Storage time (days)

 

Figure 62 RH of Aclar blister headspace calculated by the moisture prediction program
and 30 minute dissolution calculated by the dissolution prediction program as a function
of storage time.

2. HDPE bottle (50 mL, P = 0.0016 g/day-pkg-ps at 40°C)

First, assume that 50 tablets (W, = 12.5 g) are inserted into the HDPE bottle
without desiccant. The relative humidity of the package headspace reaches 52.7%
equilibrium RH in 6 months based on the moisture prediction program. Dissolution
behavior at various moisture contents is calculated by the dissolution prediction program
using 1 daytime interval iterations. The prediction is that dissolution significantly
changes for 6 months (see Figure 63), so the HDPE bottle without any amount of
desiccant is not a suitable package for drug X tablets.

Second, it is assumed that 0.5 g silica gel is inserted into HDPE bottles containing

50 tablets (W, = 12.5 g). The RH of the package headspace reaches 41.30% at 6 months

114

based on the moisture prediction program, and the dissolution reaches 79.54% at 6
months based on the dissolution prediction program (see Figure 63).

Based on the above trials, the package for drug X tablets can be designed. If a 0.5
g silica gel canister is inserted into HDPE bottle containing 50 tablets, tablets are
predicted to be safe in terms of dissolution at the accelerated testing condition

(40°C/75%) for 6 months.

 

 

 

 

 

 

‘K 3
8 (1);.
U i
a. :
" 3
E 75% :
O .
= 2
g \ (2)
8 4:
.3 50% - . - %- """" ()1
o ‘ . ‘ a "' . :
fi . (3)
r: i " ‘ - - r '
=3 25% , . - -‘
2 l. ' p
O l‘ ‘
.3 .
O i
0% . . . i
o 50 100 150 200

Storage time (days)

Curves (1) and (2) represent the 30 minute dissolution: (1) 12.5g tablets in HDPE bottle with 0.5 g silica
gel (2) 12.5g tablets in HDPE bottle without silica gel

Curves (3) and (4) represent the RH of the package headspace: (3) 12.5g tablets in HDPE bottle with 0.5 g
silica gel (4) 12.5g tablets in HDPE bottle without silica gel

Figure 63 RH of the HDPE bottle headspace calculated by the moisture prediction

program and 30 minute dissolution calculated by the dissolution prediction program as a
function of storage time

115

 

't. Permeability calculation

The package permeability required to maintain dissolution above the 75%

specification for drug X tablets stored for 6 months at 40°C/75% RH can be determined.

To do so, calculate the required permeability by trial and error using the moisture and

dissolution prediction programs.

Parameters used to calculate thejpermeability usigmoisture and dissolution prediction
pro grams

. Solids
0 Dry weight: 12.5 g (tablets)
0 Initial moisture content: 1,9312% (tablets)

o Sorption isotherm equations: GAB constants (Wm: 0.013392, Cg: 1 13.2096,
K: 0.933012) for tablets

. Package

0 Volume: 0.05 L
. Storage condition

0 Temperature at packaging line: 25°C
Relative humidity at packaging line: 40%
Temperature at storage: 40°C ‘
Relative humidity at storage: 75%
Storage time: 180 days

0000

If a package permeability of 0.0004 g/day-pkg-pS is used for drug X tablets, the
package can maintain the dissolution of tablets above 75% for 6 months at 40°C/75% RH.

Figure 64 shows the dissolution and relative humidity of the package headspace change

for 6 months.

116

 

1 00%

 

 

 

 

 

 

8 \
a
3' Dissolution
3 75%
o
.c:
o
8’
x
o
a
..‘f 50%
o
g .........................
o P i I -
8 R“ of package HS
=3 25%
2
o
a
a
E
0% I I I i
0 50 100 150 200

Storage time (days)

Figure 64 RH of a package (P=0.0004 g/day-pkg-ps) headspace calculated by the
moisture prediction program and 30 minute dissolution calculated by the dissolution
prediction program as a function of storage time

The calculated package permeation (0.0004 g/day-pkg-ps) required is about four
times lower than 50 mL HDPE bottle permeability (0.0016 g/day-pkg-ps). This barrier

package may be very costly, so it may be not a good choice to package drug X tablets. In

this case, HDPE bottle with 0.5 g silica gel may be a better choice.

117

 

 

CHAPTER 6

CONCLUSIONS AND FUTURE WORK

By using an open dish study in this experiment, it was found that coated and

incoated tablets dissolve differently as a function of storage RH. Dissolution of coated
and uncoated tablets stored at 40°C/90% and 0% RH is still high at 6 months storage time
because tablets swell at 90% RH and there may be no physical interactions at 0% RH.
However, dissolution of coated and uncoated tablets stored at 40°C at 75%, 65%, and
50% RH decreases rapidly during 6 months of storage time because they may be
degraded physically such as crosslinking among excipients.

Also, the dissolution variability from six dissolution values of uncoated tablets
stored at 40°C at 90% and 0% RH is small, but the dissolution variability at 40°C at 75%,
65%, and 50% RH is very large (see Table 16 on page 78). Apparently, high temperature
dissolution behavior can be grouped in two different patterns. One group (40°C at 7 5%,
65% and 50% RH) has rapid dissolution change during a 6 month period, so these are not
good conditions for storage of tablets. The other group (40°C at 90% and 0%) can
maintain tablets at a high dissolution value for 6 months but tablets stored at 90% RH are
failed with hardness. Uncoated tablets stored below the initial RH at 40°C show no
dissolution change for 3 months (see Figure 59 on page 107). Therefore, it can be
concluded that drug X coated and uncoated tablets would best be maintained below the
initial RH at the 40°C storage condition.

The dissolution of drug X coated tablets stored in open dishes at 40°C behaved

very differently in comparison with that of drug X uncoated tablets. The coated tablets

118

 

did not follow the dissolution theory (S-shaped dissolution change as a function of
stirring time). Aged coated tablets did not disintegrate rapidly. They took some longer
time to start to disintegrate. They swelled without any disintegration. The coating
material was observed to behave like a plastic film. This means the coating material may
be degraded either chemically or physically. When aged coated tablets started to
disintegrate, the coating material broke open suddenly. After that, aged coated tablets
disintegrated rapidly. Therefore, the dissolution of coated tablets at the 30 minute stirring
time did not change regularly as a function of storage time.

By using the open dish study in this experiment, the relationships between RH (or
moisture) and tablets’ physical properties such as dissolution and hardness were
determined more quickly than doing stability testing. It was found that the dissolution of
drug X tablets was dependent on temperature, moisture content, and storage time. In
order to determine the relationship between moisture and dissolution, Nakabayashi’s
method was tried, but his model did not work well for drug X tablets because of
dissolution variability.

A different approach was deve10ped by using the dissolution retardation rate (R).
The 30 minute dissolution was plotted as a function of storage time at each relative
humidity. Based on empirical data fitting using a first order kinetic method, dissolution
retardation rates were determined at each relative humidity. Dissolution retardation rates
were plotted with RH, and then a dissolution prediction model (Equation 20) was
developed based on that relationship. The dissolution can be calculated simply at any RH
and storage time by using Equation 20. The relative humidity of the package headspace

changes during the unsteady state, so the dissolution of tablets stored at that condition is

119

 

ard to calculate. Therefore, the dissolution prediction computer program was developed

.sing the Visual Basic program language.

Dissolution retardation rates for drug X coated tablets could not be determined in
his study because they did not behave according to the dissolution theory.
Dissolution results from the dissolution prediction program were compared with

the experimental results to verify the program. There is fairly good agreement between
experimental and predicted dissolution. However, the dissolution prediction program still

needs more verification with other products.

As a necessary tool for the dissolution prediction program, a mathematical model

calculating the time required to reach final moisture content was also developed. The
model was deve10ped using piecewise linear equations, which could work for any
number of components in a package. And, the simple approach calculating the moisture
content of components (any number of components) as a function of storage time was
developed. Based on the new mathematical models, moisture and shelf life prediction
computer programs were developed using the Visual Basic program language (see
Appendix B). The moisture content and the time required to reach final moisture content
of drug X tablets were predicted by using the moisture and shelf life prediction programs.
These programs were verified based on the experimental data. The prediction programs
worked well for both one component and two components in packages such as LDPE

bags and HDPE bottles, and they should work for even more than two components in a

package.

. In this study, a small amount of tablets (15 tablets, 3.75g) was used to verify the

moisture and shelf life prediction programs. In the future, it should be verified for bulk

120

 

packages (e. g., 100,000 tablets, 25kg) too. The moisture and shelf life prediction
programs should work for bulk packages but the bulk package must be represented by
some assumptions (see Appendix B for several major assumptions). The equilibrium
between moisture and the solid component inside the package should be reached quickly.
In other words, there should be no gradient of water vapor in the solid component. If this
assumption is satisfied, the moisture and shelf life prediction programs can be used for
bulk package too.

By using the moisture and dissolution prediction programs, a package for NDA
stability testing can be designed as explained in Chapter 5. Package design. An open dish
study was done for 6 months to determine the relationship between dissolution and
moisture content of tablets, and it was used to design a package to make drug X tablets

survive at 40°C/75% RH for 6 months. It seems this is not a useful method because 6

months time was spent to design a package for 6 months accelerated testing. However,
this still can be very useful to select a package without any trial and error approach for
stability testing, and also many situations can be simulated using different permeabilities
and storage conditions. Until now, there were no good models to select a package for the
registration stability testing in terms of dissolution. Now, the correct barrier package can
be selected with greater confidence. The prediction programs cannot be an absolute tool
yet, but they can be useful when further refined to determine a package prior to the
registration stability testing.

It is recommended that the open dish study work be done during drug
development and well before the time when stability tests must be started. Then the

calculation of required barrier can be made in a timely manner. Furthermore, if the open

121

dish data are available when a change in packaging is required for marketing, the choice

of package barrier can be done quickly.

In the future, if a protocol for open dish study is established for every new product,
a barrier package can be selected confidently based on parameters already established
during product development. Also, if the mechanism of tablet aging as a function of RH
and storage time is explained, it will be very helpful in understanding the relationship
between the dissolution retardation rate (R) and RH. The mechanism by which the
disintegration time is increased as a function of storage time must be explained based on
the physical interaction between moisture and ingredients (drug and excipients). In order
to develop that mechanism, the following research is suggested.
1. The properties of each ingredient should be understood as a function of temperature,
RH, moisture sorption rate, and storage time.
2. The physical structure change inside tablets should be explained as a function of
temperature, RH, moisture sorption rate, and storage time.
3. If the dissolution testing is improved to have good reproducibility, a better
relationship between dissolution and moisture content of tablets can be made. This

can result in better dissolution prediction results.

122

Appendix A

Background and Literature Review
(Moisture and Shelf life Prediction Models)

123

The moisture content of solid oral dosage forms such as tablets and capsules in a
package has been the subject of research for a long time because it plays an important
role in properties such as dissolution and hardness of solid dosage forms. Before the
19905, the moisture content of product in a package was predicted using a simple linear
relationship between initial and final points of the moisture sorption isotherm. Van Den
Berg and Bruin (1981) stressed the advantages of using the GAB equation obtained from
Guggenheim-Anderson-De Boer. This is a nonlinear equation for moisture sorption
isotherms (Bizot, 1983). Since then, nonlinear equations have been applied to develop
shelf life and moisture prediction models for one component in a package and for two
components in a package.

Three concepts (moisture content equations, psychrometric equations, moisture
sorption isotherm equations) together are necessary to develop moisture and shelf life

prediction programs.

1. Moisture content equations

Models predicting the shelf life and moisture content of solids are normally
calculated based on the dry weight. When solids change weight during moisture sorption
and desorption, an equation that can be used to calculate the dry-weight-based moisture
content using initial and final wet weight is needed. Equation 23 is the simplest such
equation available. It is used in the PKG 815 Shelf Life class at the School of Packaging,
Michigan State University. The following discussion shows how Equation 23 is derived

from basic principles. Equations 21-31 are regularly used in shelf life calculations.

124

Equations 32 and 33 are added as clarifying equation developing steps to improve
understanding.

The moisture content [M(%)] based on the dry weight of solids can be calculated
by Equation 21:

me

M(%) = W

d

 

x100 (21)

where m. = the mass of moisture at equilibrium, W; = the dry weight of solid

The moisture content based on the wet weight of solids can be calculated by Equation 22.

me

100 22
W x ( )

 

M,(%) =

If solids absorb or desorb moisture as a function of relative humidity, the moisture

content can be determined by Equation 23.

W,-(M,+1)

 

l

M(%) =[ —1:|x 100 (23)

Equation 23 is derived from Equation 21. Equation 21 looks simple, but me and Wd need
to be calculated. So, the following shows how to derive Equation 23 from Equation 21.
There are two parts. One is to calculate the numerator (me) and the other is to calculate

the denominator (Wd) in Equation 21.

(1) Calculation of me, the mass of moisture at equilibrium
Equation 24 can be used to calculate the mass of moisture at equilibrium (me).

me = m, + moisture gain/ loss = m, + (W ,— — WI) (24)

125

Sui

To calculate the mass of moisture at initial time (m,-) using the initial weight of product
(W,-) and initial moisture content (Mm) based on the wet weight of product, Equation 25
can be used.

m, = M m. x W, (25)

If the initial moisture content is calculated based on the dry weight of product,

 

 

 

 

m
M. = ——' 26
. Wd ( )
Then, Mm, the initial moisture content based on the wet weight of product, can be
represented as Equation 27.
m .
M .. = —-'— = m‘ (27)
”/1 Wd + ml
From Equation 26 and Equation 27,
I =Wd+m, =fl+1=_1_+1
Mm mi m: l
Therefore,
M.
M m. = ’ 28
1 + M . ( )
Substitute Equation 28 into Equation 25.
M
m, = ’ x W. 29
1 + M , ( )
Substitute Equation 29 into Equation 24.
Ml
m = xW.+(W,—W,) (30)

 

c 1+M.

126

(2) Calculation of Wd, the dry weight of solid

Equation 31 can be used to calculate the dry weight of product (Wd).
W. = W, -— m. (31)

Substitute Equation 29 into Equation 31,

 

M.
W =W.- ' W 32
d l 1+Mix l ( )

Now, me (Equation 30) and W; (Equation 32) are derived, so substitute them into

Equation 21.

 

M(%): ' M x100 (33)
W.— ' xW.
1+M,

 

 

By simplifying the Equation 33, Equation 23 is obtained.

2. Psychrometric equations

The psychrometric equations and chart are a very useful tool to determine the
relationship between air and the moisture it contains. ASAE (American Society of
Agricultural Engineers) publishes equations of saturation vapor pressure, vapor pressure,
and absolute humidity. They were used to develop the moisture simulation computer

program. Below are three useful psychrometric equations:
(1) Saturation vapor pressure (p,, Pascal)

At a given temperature T, saturation vapor pressure (p,) can be calculated by

Equation 34 which is designed for the unit “pascal” value.

127

A+BT+CT2 +DT3 +ET‘

FT SGT} (273.16 S T S 533.16) (34)

In(ps/R) =

 

where, R = 22,105,649.25 A = -27,405.526 B = 97.5413 C = -O.146244
D = 0.12558x10‘3 E = -0.48502x10'7 F = 4.34903 G = 0.39381x10’2
T = the absolute temperature (°K = °C + 273.16)

(2) Vapor pressure (p)
At a given relative humidity [RH (%)], vapor pressure (p) can be calculated by
Equation 35.

_ x RH(%)
100

 

(35)

(3) Absolute humidity (g H20/g dry air) (AH)

At a given water vapor pressure (p) and atmospheric pressure (pom), absolute
humidity (AH) (or water vapor concentration) can be calculated by Equation 36. AH is
given in grams of water per gram of dry air.

_ 0.6219p
patm _p

AH (255.38 3 T s 533.16, p < p0,," ) (36)

Another Equation 37 for the saturation vapor pressure was published by
ASHRAE (American Society of Heating, Refrigeration and Air Conditioning Engineers).

It is designed for the unit “psia” value.
ln(ps) =_(’.7:f_+C, +C3T+C4TZ +C5T3 +C6 In(T)(32°F S T s 392°F) (37)

where C I = -1.044039E+04 C 2 = -1.1294650E+01 C 3 = -2.7022355E-02
C4 = 1.289036OE-05 C5 = -2.4780681E-09 C6 = 6.5459673
T = the absolute temperature, °R = °F + 459.67

128

Also, the saturation vapor pressure (p3) can be calculated by using Equation 38 which is
used in calculations developed by Downes (1989) at the School of Packaging, Michigan

State University.

-5269

p, (mmHg) = 11325 70000 * e T (33)

where T = the absolute temperature (°K = °C + 273.16)

He obtained the constants (-5269 and 1132570000) used in Equation 38 from an
empirical fit to the known data based on the theoretical model 39. This is an Arrhenius

type of expression.

Acuvamm [Energy

P, = A _e Temperature (39)

where A = a constant

The simple Equation 38 was used to develop the moisture simulation computer
program. The equations (saturation vapor pressure Equations 34, 37, 38 and absolute
humidity Equation 36) given above yield results that agree closely with existing

psychrometric charts.

3. Moisture sorption isotherm equations
A moisture sorption isotherm is a tool for describing the relationship between
equilibrium moisture content (M) and the moisture in the air surrounding a product (aw),

which is necessary to develop the shelf life and moisture prediction programs. It can be

129

determined by storing the products at several humidities over the range 5-95 percent. In
order to represent that relationship mathematically, linear and non-linear equations can be
used.

In this study, 9919991 point ofanisothenn is defined as the intersection of the
initial moisture content and initial equilibrium a,,. on the sorption isotherm curve, and the
final point of an isotherm is defined as the intersection of the final moisture content and
final equilibrium aw on the sorption isotherm curve. The final equilibrium a... can be

chosen to be equal to or below the external ambient condition. It will never be higher

 

than ambient. Figure 65 shows a graphical representation of linear and nonlinear
relationships between M and aw. The slope (,6) shows the linear relationship and the

sorption isotherm curve itself shows the nonlinear relationship.

 

 

 

 

 

M
‘ A M(final)
[3 (Linear)
M(initial) Nonlinear
T
aw(initial) aw(final) aw

Figure 65 Graphical representation of linear and nonlinear relationships between M and
aw

130

(1) Linear equation

The sorption relationship between the initial and final points on the sorption
isotherm curve sometimes can be simplified with a linear equation as shown in Equation
40. When the curvature of the isotherm is small, the linear equation can be a useful
approximation. In this relationship, moisture content is a variable dependent upon water
activity (aw). aw is used interchangeably with equilibrium relative humidity [RH(%)/100]

or relative vapor pressure (p/ps).
M = ,6 - aw + C (40)

M(final) " M

( mmal )

 

where ,B =
aw( final ) - aw( mural )

(2) Nonlinear equations

In order to represent the real path between the initial and final points on the
sorption isotherm curve, nonlinear equations such as GAB and Langmuir equations can
be used (Bell, 2000 and Bizot, 1983).
(a) GAB equation

The GAB equation can be used to describe the relationship between the moisture
content of solids (e.g. tablets) and a... as shown in Equation 41. The GAB equation often
fits sigmoid-shaped moisture isotherm data very well over the range of relative
humidities between 10% and 90% (Bizot, 1983).

M— Wm;Cg-K-aw _
'[I—K-a,]x[1-K-a,+CgK-fl

 

(41)

where Wm, C 3, K = GAB constants

131

Equation 41 can be solved for the constants by rearranging it into a polynomial form of

 

the GAB equation:
£22.". —I——1a“:+il-i a,+ ’ (42)
M Wm Cg Wm Cg Wm KCg

W

. . . . a
So, If the morsture sorption or desorption data are plotted as M— vs aw , the plot can be

represented by a polynomial equation. Then the GAB constants can be calculated from

the polynomial constants:

Q

 

-—‘1-=A-aj+B°aw+C (43)
where A=—K— —l——1, Bz—I— I-i, C: 1
Wm Cg Wm Cg WMKCg

Rearranging and substituting into the above polynomial constants, one ultimately arrives

at the following solutions for the GAB constants:

2— _—
KzJB 4AC B Cg: B +2 W..= 1
2C C-K C-K-Cg

 

 

(44)

(b) Langmuir equation

The Langmuir equation can also be used to describe the relationship between
moisture content of solids (e.g. desiccant) and aw as shown in Equation 45 (Zografi,
1988). The Langmuir equation often fits hyperbolic-shaped moisture isotherm data very

well over the range of relative humidities between 10% and 90%.

132

_ Wm .CL .aw
1+C1. -aw

 

(45)

where Wm" and C L = Langmuir constants.

Equation 45 can be solved for the constants by rearranging it into a polynomial form of
the Langmuir equation:

M Wm W 'CL aw

 

So, if the moisture sorption or desorption data are plotted as 11? vs —1— , the plot can be

W

represented by a linear equation. Then the Langmuir constants can be calculated from

the polynomial constants:

—-——=B.——+C 47
M ( )

 

where B: , C:—
W .

Rearranging and substituting into the above polynomial constants, one ultimately arrives

at the following solutions for the Langmuir constants:

C1. = — W = —‘ (48)

The GAB and Langmuir constants also can be determined by computer fitting the

isotherm data to the GAB or Langmuir equations with a statistical program such as the

 

h W," is the moisture content of the monolayer. Wm used in GAB and Langmuir equations is the same
concept

133

 

 

 

 

pad
Ant

the 1

P00

 

nonlinear regression Solver function in Microsoft Excel. The solver algorithm used in
Microsoft Excel is not available to see, so a simple algorithm to help the reader
understand how Solver works is explained in detail in Appendix B Moisture and Shelf

Life Prediction Programming, and Verification.

4. Shelf life prediction models

Shelf life prediction models have been developed by various researchers using the
linear equation for one or two solids in a package and using the GAB non-linear equation
for one solid in a package.

The basic equations (Equations 49 and 50) for moisture transfer through a
permeable package were derived from Fick’s law in combination with Henry’s law

(Labuza et al., 1972). Either one can be used to develop the shelf life prediction models.

 

fl=P.A-Ps[aw —a . 1 (49)

dt I (out) W(m)

OI'
dM P- A "”3
... WNW-Pm) - - <50)

Equation 49 and Equation 50 provide the same information in terms convenient for
different uses. If the focus is on the mass of moisture change permeating into the
package (dw) in developing the shelf life prediction model, Equation 49 can be used.

And, if the focus is on the mo_i§tgefontent change of a component (dM) in developing

 

 

the shelf life prediction model, Equation 50 can be used. When Downes et al. (1989) and

Pocas (1995) developed shelf life prediction models using the linear equation, Equation

134

49 was used. And, when Diosady (1996) developed the shelf life prediction model using
the GAB non-linear equation, Equation 50 was used. By using Equation 49 and 50, the

time required to reach the final moisture content from the initial moisture content can be

 

----n.w,m..m ~u‘uuirfluq‘.w Ww~rm3~.g¢rn 9"

calculated based on the unsteady state vapor pressure difference between the outside and
inside of the package. The outside vapor pressure is assumed to be constant, so the inside
vapor pressure should be determined as a function of storage time. Linear and non-linear

equations can be used to calculate the vapor pressure of the package headspace.

(1) Linear equation

Downes et al. (1989) at the School of Packaging in Michigan State University
developed a DOS based shelf life prediction program using the linear Equation 51 to
determine the inside air water activity values (awn-,0) used in Equation 49. Equation 51
provides water activity values for known moisture contents. In order to calculate the
water activity of air inside the package (W(m)) simply, aw moves to the y-axis and M
moves to the x-axis in contrast to Equation 40 that represents a typical relationship

between M and aw, with M as the dependent variable.

aw(m)=C+,B-M (51)

a —a . . .
where fl = W(fi’m’) W(mmal)
M (final) " M (initial)

 

Substitute Equation 51 into Equation 49.

dw_P-A-ps

:1;- _ E [aW(0ut) _ C _ fl ' M] (52)

135

Assume the contents in a package absorb the permeated moisture immediately. Then:

M = _W_
Wd
Differentiate Equation 53.
1
dM = ——dw
W (1

Divide by d! on both sides, then rearrange.

62-141
d1 dt "

Substitute Equation 55 into Equation 52.

p. .
flwd=_’4_&

d! 8 [aW(out) _ C _ '6 ' M]

Rearrange equation 56 to integrate.

dM _P-A-psdt
—C—,B~M [-Wd

 

aW(out)

Integrating fi'om M,- to M] (t = 0 to t = t).

M
f dM P-Ap,’

= dt
—C—,6~M €-Wd 0

 

M,‘ aw(0u’)

For integration, let u = aw)” ) - C — flM
du = -,6 dM
dM = —Ldu

fl

136

(53)

(54)

(55)

(56)

(57)

(58)

M, at u = lawmw —aw(m)Jat tzme = 0

a at time =t

Wm}

M, atu=[a

W(nut) _

Substitute u into Equation 58.

iaW(out) “’W(in) L, ,
_i i 51‘: =____.P'A'ps Id: (59)
[a u ['Wd 0
W(out) —aW(in) =0

 

 

 

Integrate Equation 59.
_ i1“ (aW(out) — aW(in))t=t = P - A - pst (60)
)3 (“19(0)“) ‘ aw(in))t=0 g ' W at
Solving 60 for t yields the shelf life equation 61 using the linear equation.
I = — Wd ' g In (aW(0ut) — aW(jn))l=t (61)
fl.P-Aops (aW(0ut) _aW(in))t=O

If the numerator and denominator in the logarithm are switched, the minus sign can be

removed:

 

 

(62)

f:

Wd -Z In (aW(0ut) ‘ aw(,°n))t=0
(aW(0ut) — aWUn) )t=t

Equation 61 or Equation 62 can be used to calculate the shelf life of one component in a
package by using a simple linear relationship between M and aw.

Pocas (1995) developed a mathematical model to predict the shelf life of two
solids in a package by using linear sorption isotherms. She said that when two solids A
and B are packaged together, the total amount of moisture dw permeating through the

package is equal to the moisture change in solid A plus the moisture change in solid B:

137

dszdAdMA+WdBdMB (63)
Substitute Equation 63 into Equation 49, then rearrange:

P-A-ps[

WdAdMA + WdBdMB = aww) — awm) ]dt (64)

The moisture sorption isotherms of the solids can be represented by linear equations:

 

 

dM

MA=CA+flA'0w (“A =flA] (65)
dM

MB=CB+flB°aw [d 8:133] (66)
aw

where C A, ,6," C B, ,8” are the coefficients of each linear equation.

Then, dMA can be expressed as a fimction of dMg and vice versa:

dMA = dMB £1. (67)
.313

dMB = dMA 38— (68)
.3/1

Substitute Equation 68 into Equation 64, then rearrange:

 

 

t3 P - A l- p
dMA(WdA +WdBfl—j = ——€—s—[aw(0w) —aw(m)}1t (69)
Rearrange Equation 69 for dt.
2 dM
dz=——(W6A+de ”3): A 1 (70)
P . A ' p3 flA [aW(0ut) _ aW(in)J

138

Integrate Equation 70.

 

M

MAi aw(0ut) _ aw(in)

The analytical integration of Equation 71 gives Equation 72 (see Equations 58-60 for

more information about integrating).

E

t=———W W l
P-A-ps( dAflA’r dBflB)n[

 

(aW(0u[) — 0190'") )t=0 ] (72)

aW(0ut) " Old/(in) )t=t

Equation 72 will be used to calculate the shelf life of two solid contents (e.g., tablets and

desiccant) in a package by using a simple linear relationship between M and aw.

(2) Nonlinear equation

When the linear equation is too simple to represent real relationships, the use of a
nonlinear equation needs to be considered. Diosady (1996) incorporated the nonlinear
GAB equation into the basic equation for the rate of moisture transfer into a permeable
package, thus obtaining a shelf life prediction model. Equations 75-83, 85, and 89 are
rearranged from Diosady’s (1996) paper, and Equations 73, 74, 84, 86, 87, and 88 are
added by this author as clarifying intermediate steps to improve understanding.

Equation 43 is rearranged as shown in Equation 73.
A-M~aj+(B-M—1)aw+C~M=0 (73)

Equation 73 is modified to the following equation by the quadratic formula:

 

a _ -(B-M—1)—\/(B-M-1)2 -4-A~C-M2
" 2-A~M

 

(74)

139

The polynomial constants A, B, and C are substituted into Equation 74:

 

 

 

 

 

 

 

2+(Wm/M—I)-Cg—J[2+(Wm/M—1)-Cg]2—4+4-Cg (75)
a =
"’ Z-K-(I—Cg)
From awn) = fl and am”) = p ""’ in combination with 75:

_ 2+(Wm/M—1)-Cg-\[[2+(Wm/M-I)-Cg]2—4+4Cg (76
pan—p3 2‘K'(1—Cg) )
and

_ 2+(Wm/Mc—1)-Cg—\/[2+(Wm/Me—I).Cg]2—4+4Cg (77
pout _ps 2'K°(I—Cg) )

where M, = the equilibrium moisture content of solids exposed to the package outside RH
(g HzO/g dry weight of solids)

Substitute 76 and 77 into 50:

 

 

 

dM P. A.
_= p, {(Wm/Me)'Cg
dt Wd -£-(2).K-(1-—Cg)
-fi2+(W,,,/M,).Cg -Cg]2-4+4Cg —(W,,,/A/0-Cg (78)
+\/[2+(W,,,/w-Cg -Cg]2 —4+4Cg}
Assuming constant temperature and external relative humidity, let
P ° A - p.
‘ = constant = (D (79)

 

Wd-€o(2)-K-(1-Cg)

and

140

 

(Wm/M, ) . Cg — \[[2 + (Wm/M, ) - Cg - Cg ]2 — 4 + 4C8 = constant = 17 (80)

Substitute 79 and 80 into 78, and integrate from t = 0 tot = t and M, to M]:

Mf dM
I =01 (81)
Min—(Wm/M-Cg +J12+1Wm/A0-cg-cg]2 _4+4cg

 

 

Expanding the square in the denominator and simplifying:

Mf 61M
1

M, H-(Wm/M-Cg +\/1/M(4W,,,Cg - 2WmC§ )+(W,,,/1w2 cg +C§

 

as: (82)

 

Diosady (1996) said that Equation 82 can be integrated only by numerical methods.
However, if Cg is large so that 4WmCg << 2Wng2, or Cg >> 2i then Equation 82 can be

written as:

Mf dM

11,17 —(W,,,/M)-Cg + f1/M(—2W,,,ng ) +(W,,,/1w2 .ng +ng

 

= $1 (83)

 

In order to simplify the denominator, multiply numerator and denominator by M. Then,

rearrange.

 

 

W M -dM
l

= <15: (84)
14,1714 -W,,,Cg +CgJM2 -2W,,,M+W,,2,

But M" —2W,,M+W,f =(M—Wm)2

Therefore, Equation 84 simplifies to

 

i Diosady wrote Cg >> 2 at that statement but he wrote C8 >> 20 in text. If C, is much greater than 2,
4WmC8 << 2W,,,C,,2 can be obtained. 50, 2 is correct.

141

M
f M-dM

Mi M(17+Cg)-2Wm -Cg

 

(85)

For integration,
Let 5: M(]7+Cg)-2W,,,Cg
d§=dM(/7+Cg)

+2WC
M=—-4—€——, M=§___"'__K
(17+Cg) (174-Cg)

Mfat §=Mj(]7+Cg)-2Wng at time = t

M, at 4==M,(17+Cg)-2 Wng at time = 0

Substitute 5 into Equation 85.

Mf(”+Cg)’2WmC8(§+ 2Wng )/(17+Cg) d6

 

C :0): (86)
M;(I7+Cg)—2Wng 5 (17+ 8)

Rearrange, and split.

1 2 mcg
001 = j ———-—-2-d§ + j 2 d5 (87)
M,-(17+Cg)—2W,,,Cg (”+Cg) M,-(I7+Cg)—2Wng (”+Cg) 4‘

 

Integrate Equation 87.

Mf(17+Cg )-2Wng

a” _ Mi(fl+Cg)—2Wng

_ 1 . le(fl+Cg)—2Wng 2W C (88)
(17+Cg)2

Mi(fl+Cg )-2Wng

 

Therefore, a shelf life equation using the GAB non-linear equation can be derived as

shown in Equation 89.

142

1 2Wng In (174-Cg )Mf —2W,,,C

._ _ , 8
(_(H+Cg)¢ Mf M, J (89)

+—
(17+Cg) (17+Cg)M,--2Wng

 

 

Equation 89 was used by Diosady to calculate the time to reach the final moisture
content from the initial moisture content in a package at a given storage condition by
using the non-linear GAB sorption equation. He said this model is limited to Cg values
greater than about 2 and it can be applied to only one component in a package as shown.
It is very complicated to develop a shelf life prediction model analytically using the GAB
nonlinear equation. If one more component is added into the package to develop the
shelf life prediction model, it will be very complicated, or it might be impossible to

develop a shelf life prediction model using the nonlinear equations.

5. Moisture prediction models

Zografi et al. (1988) developed a mathematical model to predict the final relative
water vapor pressure in a closed system for a multicomponent mixture of solids knowing
the initial water content for each component. The mathematical model for a closed
system is useful for calculating the initial equilibrium water vapor pressure of
components that have different water vapor pressures.

Zografi et a1. put micro crystalline cellulose (MCC) and corn starch in a glass
bottle and they assumed that the bottle was closed completely, there was no moisture
permeation through the bottle. The packaging line was conditioned at 23 °C/65% RH, so
the initial relative humidity of the package headspace was 65% RH. Before MCC and
corn starch were inserted into the bottle, their initial moisture contents were measured as

shown in Table 27.

143

f Table 27 Initial moisture content of MCC and corn starch

 

 

 

| I M,- (%) | Equilibrium RH (%) |
I MCC I 18.1% I 96% RH based on Moisture Desorption lsotherm I
ICom Starch I 0 [0% RH based on Moisture Sorption lsotherrn I

 

MCC has a higher equilibrium vapor pressure than the package head space and
corn starch has a lower one, so water in the MCC will be desorbed into the package
headspace and the corn starch will absorb water from the package head space. Therefore,
the moisture desorption isotherm of MCC and the moisture sorption isotherm of corn
starch must be used'to predict the final RH of the package headspace. Figures 66 and 67

help to explain Zografi et al.’s model more clearly.

 

    

 

 

 

 

A 4 0
5 Corn starch (sorption)
1‘ 3 0 ~ ?
I
I
2 o l
J I
M, (%) of MCC '
1 0 MCC (desorption)
8 0 1 0 0
M,- (%) of corn starch RH (%)

Figure 66 Graphical representation of changes in moisture during equilibration between
MCC and corn starch

As shown in Figure 66, MCC will lose some moisture and corn starch will gain
some moisture to reach equilibrium (somewhere between 0% and 96%). The equilibrium
point between MCC and corn starch is dependent on the relative amOunts of each

component.

I44

There are three different equilibrium vapor pressures in the bottle at the time t=0

when it is closed, as shown in Figure 67-(a). The system is not at equilibrium at this time

 

 

 

 

 

 

 

 

 

 

 

 

(F0).
0 Package head space : 23°C/65% RH (13.71 mmHg)
0 MCC : 23°C/96% RH (20.25 mmHg)
0 Corn Starch : 23°C/0% RH (0 mmHg)
Headspace Headspace
(65% RH) (88% RH)
r: “20 ‘1
| I
MCC Corn starch MCC Corn starch
(96% RH) (~0% RH) (88% RH) (88% RH)
(a) at storage time t = 0 (b) at equilibrium

Figure 67 Graphical representation of moisture transfer and moisture equilibrium in the
closed system

Moisture will be transferred from MCC to corn starch until equilibrium is reached as
shown in Figure 67-(b). At equilibrium the head space, MCC, and corn starch have the
same vapor pressure, but they each have a different moisture content. The water in the
MCC and the water in the corn starch both have the same thermodynamic state as defined
by the chemical potential (Bell, 1990).

Kontny et al. (1992) developed a mathematical model to predict the moisture
content of components in a permeable package using a sorption-desorption moisture

transfer (SDMT) model. They address the situation where an aspirin and desiccant, each

145

with an initial moisture content, are stored together in a permeable container at a given
temperature, initial headspace humidity, and headspace volume. A method is shown in
which the amount of moisture permeating into the container over the storage time can be
determined. Then it is shown how the distribution of the moisture between the aspirin,
desiccant, and headspace can be determined using sorption-desorption moisture transfer
models. Kontny’s description 5 reported in the following paragraphs.

The amount of moisture in the package at time t = 0 (mm a, ,,-,,,e=0) can be

determined by Equation 90.
mT, at time=0 = WdA MA + WdBMB + mh (90)

Once the amount of moisture permeating into the package is calculated for a time

interval j, this mass of water can be added to mm, mm, to obtain mm, my , the amount

of water inside the container at the end of this time increment. After time interval j, the

total moisture in the system (mm, mm] ) can be expressed by:

’"T, at time: j = "77‘, at time=0 + W (91)

The sorption-desorption moisture transfer (SDMT) model also can be utilized to
obtain the relative vapor pressure (p/p,),~,, inside the package at a time equal to time
interval j. This method can then be iterated to obtain @425)»: at each time interval through
the total storage time, where the time associated with a calculated (p/p,),-,, is obtained by
summing the time interval j.

In order to calculate the vapor pressure (p/ps)", inside the package, the relationship

of each component’s moisture content with RH must be known and defined

I46

mathematically. The GAB and Langmuir equations provide a good fit with moisture
sorption isotherm data.
Referring to Equation 90, the mass of moisture (mA) in component A can be

calculated with the GAB or Langmuir equation:
”’14 = WdA x MA(GAB) (or MA(Langmuir)) (92)

where MMGAB) (or MA(Langmuir)) = the moisture content associated with component A as
given by the GAB (or Langmuir) equation for component A at any relative
humidity

The ideal gas law is used to calculate the mass of moisture in the headspace

volume (mh) for the total head space volume.

-V-( / )x18

 

where R = gas constant, 0.08205 Latmlmol-K, T= absolute temperature (°K)

In order to get p,, a psychrometric chart or look-up table can be used. Also, p, can
be calculated by using the saturation vapor pressure Equations 34, 37, and 38. Equation
38 was used to develop the computer program. When the temperature changes, the
saturation vapor pressure at the new temperature is calculated easily by use of Equations
38.

Kontny used the GAB equation for aspirin and the Langmuir equation for

desiccant, so Equation 90 written in its entirety takes the form:

147

 

m . :0 :
T,atttme WdA{[1_KA(p/ps)]xIl—KA(p/ps)+CgAKA(p/Ps)]

+Wd B{ WmBCLB(p/ps)}+ P3 'V'(p/ps)x18
[1+CLB(P/Ps)] R-T

WmACgAKA(P/ps) I
(94)

 

 

where, WM, C8,), KA - the GAB constants of component A
ng, C [,3 the Langmuir constants of component B

The permeated mass of moisture (w) into a package for a time interval j can be

calculated by Equation 95.

w=Px1x[(p/p,)0,.412/12.)th (95)

where j = time interval

Therefore, Equation 91 written in its entirety takes the form:
mT, at time=j = mT, at time=0 + {P x J. x [(P / P3 )out _ 0” P5 )in I} (96)

where (p/ps)”, is the relative water vapor pressure in the equilibrated system at each time
interval j. Rearrange Equation 94 and set (p/pj equalto x to obtain a fifth order

polynomial equation, Equation 97.
x5 +C,x" +C2x3 +C3x2+C,x-C, =0 (97)

C 1, C 2, C3, C4, and C 5 are constants. See Appendix I in the paper “Prediction of moisture
transfer in mixtures of solids: transfer via the vapor phase.” (Zografi et al., 1988) for
more information about the constant terms. To solve Equation 97, the real root between
(p/p,) = 0 and (p/p,) = 1 must be found. Zografi et al. used Newton’s method which is

one of approximation techniques. If one more component is added in the moisture

148

transfer process, Equation 97 will be very complicated even though it is mathematically
possible to calculate the constant values for a high-order system. See Appendix B.
Moisture and Shelf Life Prediction Programming. and Verification for a simple method

to determine (p/ps).

149

Appendix B

Moisture and Shelf Life Prediction Programming, and Verification

150

represent the sorption function between the initial and final points of the isotherm, and
the model using the nonlinear GAB equation has a limitation that it Cannot be applied for
more than one component in a package. Therefore, a model without any limitation, that
represents the real relationship between the initial and final points of the isotherm and
that can be applied for any number of components in a package needs to be developed. A
model using piecewise linear equations can be integrated analytically and can be applied
for any number of components in a package, and is close to the real relationship. The
nonlinear section between the initial and final points is divided into sections, and then
each section is represented by the linear equation.

Figure 68 shows a hypothetical graphical representation of piecewise linear
relationships between M and aw. There are two sorption isotherm curves. One is for
hypothetical component A and the other is for hypothetical component B. MA 1 denotes
the initial equilibrium moisture content of component A, MB, denotes the initial
equilibrium moisture content of component B. M,m+1 ) denotes the final moisture content
of component A, and M3041) denotes the final moisture content of component B. aw; is
the equilibrium water activity at the initial equilibrium moisture content (MA 1 or MB 1),
and awn-+1) is the equilibrium water activity at the final moisture content (MM-+1) or
Man-+1)). The nonlinear sorption isotherm between the initial and final points is divided
into as many as i or pieces, then linear equations are applied to each divided section. As

can be seen in Figure 68, linear slopes 66,) 1, fig A“) for component A and linear slopes

(fig), fig) fig.) for component B can be achieved. Those linear slopes are used to make

a close to real relationship between M and a, (p/p, or RH(%)/100).

152

The moisture prediction computer program consists of two parts. One is the shelf
life prediction program and the other is the moisture prediction program. The shelf life
prediction program is useful for calculating the time required to reach some specific
moisture content from the initial moisture content of components in a package at a given
storage condition. It was developed using piecewise relationships between the initial and
final moisture contents. And, the moisture prediction program is useful for calculating
the moisture content of components in a package and relative humidity of the package

headspace as a function of storage time.

The following are major assumptions for the models used in the moisture
prediction program;
a. Initial concentrations of water in the solids (e.g. tablets, capsules and desiccant)
and headspace reach equilibrium rapidly.
b. The equilibration of moisture with the solid components inside the container is
rapid relative to the permeation of moisture into the container.

c. There is no gradient of water vapor in the headspace surrounding the solids.

1. Shelf life prediction program

A linear sorption isotherm equation can be used to develop the shelf life
prediction models for one and two components in a package, and the nonlinear GAB
sorption isotherm equation can be used to develop the shelf life prediction model for one
component in a package with a limitation that it needs to be integrated (see Appendix A,

Equation 82-84 on page 141). The linear equation may be too simple to adequately

151

represent the sorption function between the initial and final points of the isotherm, and
the model using the nonlinear GAB equation has a limitation that it cannot be applied for
more than one component in a package. Therefore, a model without any limitation, that
represents the real relationship between the initial and final points of the isotherm and
that can be applied for any number of components in a package needs to be developed. A
model using piecewise linear equations can be integrated analytically and can be applied
for any number of components in a package, and is close to the real relationship. The
nonlinear section between the initial and final points is divided into sections, and then
each section is represented by the linear equation.

Figure 68 shows a hypothetical graphical representation of piecewise linear
relationships between M and aw. There are two sorption isotherm curves. One is for
hypothetical component A and the other is for hypothetical component B. M,“ denotes
the initial equilibrium moisture content of component A, M3, denotes the initial
equilibrium moisture content of component B. MM+ 1) denotes the final moisture content
of component A, and Man-+1) denotes the final moisture content of component B. aw, is
the equilibrium water activity at the initial equilibrium moisture content (MA, or M3 1),
and awn-+1) is the equilibrium water activity at the final moisture content (MAM 1) or
Man-+1)). The nonlinear sorption isotherm between the initial and final points is divided
into as many as i or pieces, then linear equations are applied to each divided section. As

can be seen in Figure 68, linear slopes 66,1 1, ,6,” ,BA,) for component A and linear slopes

(fig), ,632 flm) for component B can be achieved. Those linear slopes are used to make

a close to real relationship between M and a,, (p/p, or RH(%)/100).

152

 

MB(i+l)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

. Bat :
MBi :
M A i
i
A
3 B83 . 5
M33 g i
1 [5132
M32
MA(i+l) "
i Bl
MBI B :
MM 0... 3
/
fl [3 BM ...... ‘
BAI A2
._ -.--.l._.--.._..__-.___.._--.-- ”mL-“--- .
aw] awz aw3 .......... awi aw( i+ I )
aw

Figure 68 Hypothetical graphic representation of piecewise linear equations for two
sorption isotherms for components A and B

Equation 98 shows the piecewise linear relationship between M and aw.

Mc(n+l) = flcm ' aw(,,+1) + Ccm (O S n S i, I S m S i) (98)

M — M
where .ch = c(n+l) C(n) , c = the component (e.g., A, B, Z)

“W(Ml) _ “W(H)

 

153

When components are packaged together, the amount of moisture change overall (dw) is

equal to the moisture change in all components (A + B ....+ Z).

dszdAdMA +WdBdMB + ......... +WdszZ (99)

Substitute Equation 99 into Equation 49 in Appendix A, then rearrange it. Equation 100
represents that the moisture change in all components can be calculated by using package
permeability, package thickness and area, and the water vapor partial pressure difference

between the inside and the outside of the package.
P- A - p
WdAdMA +WdBdMB + ...... +WfldMZ =—7-—s-[aw(0w) —aw(in)}it (100)

The moisture sorption isotherms of the components are represented by piecewise linear

equations:

 

. . dM
MAUI-H) =CAm +flAm -aw(,,+l) (OSnSl,1SmSl)[ daA =flA] (101)
W

. . dM
MB(n+l) = CBm + flBm °aw(n+l) (0 -<— n 51:15 m S 1) (_a—B = ’68) (102)
w

 

. . dM
M201“)=CZm+flZm-aw(n+l)(OSnSz,1_<_m.<_z)[d Z =52] (103)

aw

where CA," , flAm , C3,", flBm , ........ ’CZm , '62," are the coefficients of each linear
equation.

Then, dMA, dMB, sz can be expressed as a function of dMB:

154

dMA =dMggi (104)

B

dMB =dMA-—- ’35- (105)
A4

sz =dMAfl—Z (106)
flA

Substitute Equation 105 and Equation 106 into Equation 100, then rearrange:

 

 

,33 fl_z) P'A ' P ]d

dMA (WdA +Wd3 fi+ ...... + Wdz (12.3/1) =——é——S[aw(ow) —aw(in) t (107)
Solve for dt.

dt=—£——(WdA+WdBE£+ ...... +WdZ ’62 ’ am" (108)

P . A ' pS flA flA laW(0u()_ aW(in)]
Integrate Equation 108.
MA]
t=—-[——[WdA+WdB—’—’1+ ...... +Wdz flz] “W" (109)
P-A ° [)3 flA flflA MAi aw(out) “W(in)

Analytical integration and applying piecewise linear equations for Equation 109 gives

Equation 110. See Equations 58-60 in Appendix A for more information about

integrating.

i (a —a ' )='
——Z (WM/3A...+WdBflBm~-+Wdzflz,.)ln “0“” “’“"’ ’ ’ (110)
m1: (“W(out) — “W(m) )t=i+l

 

=-PAp———S

155

 

 

MA(n+l) - M A(n) M B(n+l) '- M301)
where 16A = 9flB = 9 flZ
m aw(n+l) ' aw(n) m aw(n+l) — aw(n) m aw(n+l) - (Mn)

_ M Z(n+1) - M202)

 

(0 _< n _< i)
Equation 110 can be used to calculate the shelf life of any number of components in a

package by using the piecewise linear relationship between M and aw.

2. Moisture prediction model

In Appendix 1 of the paper “Prediction of moisture transfer in mixtures of solids:
transfer via the vapor phase”, Zografi and coworkers (1988) showed that the polynomial
constants C1, C2, C 3, C4, and C 5 in Equation 97 are very complex even though only two
components were considered. If one more component is added in the moisture transfer
process, an increase of two additional roots results in Equation 97 in Appendix A. It
makes finding the real root of the equation between (p/p,) = O and (p/ps) = 1 much more
complex. The “Solver” function is a statistical program in Microsofi Excel that uses
nonlinear regression. If it is used to determine the @/p,),,, at each time interval j, the
complex polynomial Equation 97 does not need to be developed. The Solver algorithm
used in Excel is not available for inspection. The simple algorithm in Figure 69 describes
how Solver works.

Equation 111 and Equation 112 can be extended to consider any number of
components in a package, and (1)/me can be determined easily by using the “Solver”

function.

mT,attime=O=Wd4MA+WdBMB+ ...... +WdZMZ+mh (11])

156

 

WmACgAKA(p/ps) }

m . = =W
T,atume o dA{[1_KA(p/ps)]x[l—KA(p/ps)+CgAKA(P/Ps)]

 

+Wd B{WmBCLB(p/p5)}+ ...... +WdZGABZ(0r Langmuirz) (112)
[1+CLB(p/ps)]

+ps-V-(p/ps)><18
R-T

 

 

n = 0
j = time interval
1 = Increment

 

 

 

v

09409:». ry =
(0 < MUM 01)

 

 

 

 

 

 

 

 

mT=Wd-M, (Component A)+Wd -M (Component B)+m,,+w
WMCM K ....(p/p)

W‘“ [I-K (p/p)lxl1-K<p/p.)+c,,.1<(p/p )]

WmBCw (1” Pg)

1+CLB(p/ps)

mic:

mr

 

 

dli’ +mh+w

 

 

 

 

 

 

 

(P/pgin: m] = WW.» I! i I

 

 

i

n=n+1

 

 
   
 

 

 

 

 

_mcalcl<C(w) N0

 

 

 

 

(p/p,),~,,, ,.,- = Equilibrium (p/p,),-,, at time interval j.

 

Figure 69 Algorithm used to calculate the equilibrium (p/ps)",

157

Since m7 remains constant for a time interval j, an estimate for the relative water

calc

vapor pressure (1)/pi)”. can be used to determine m7. , a calculated total moisture content

calc

in the system (components + package headspace). If m, is close to m, in the range of

C (Convergence), then the program stops. Otherwise, another estimated (1)/p5)». will be

calc

tried to make m7. close to mr in the range of C by changing m/pjm in a series of very

small increments (e. g., I = 0.0000001). Finally estimated (p/ps)", is the predicted final
relative water vapor pressure in the system following moisture transfer.

Figure 70 shows an example of an algorithm used to calculate the relative
humidity of the headspace and moisture content of components in a package at each time
interval over the total storage time t. The (p/me determined at each time interval j is
used to calculate the moisture content of components by using the GAB or Langmuir

equation.

158

 

Product information

o GAB constants for component A and Langmuir constants for component B

0 W4 and M, of component A and component B

Package information

0 Package permeability, package volume, packaging conditions (Temp and RH)
Storage information

0 Exterior conditions (Temp and RH), storage time

 

 

 

 

 

Time interval j
n = 0

 

 

 

 

‘

 

mm = W d -M, (Component A) + W d -M, (Component B) + m,

 

 

 

 

 

 

 

mTJm-l); = mm; + W

 

t

 

 

w=PXjX[(P/P,g)ou,"(P/173),».n1]

 

 

 

 

n=n+l

 

 

 

Moisture distribution based on the sorption isotherms of each component
[Equilibrium (p/p,),,, determination (see Figure 69)]

i

Calculate the moisture content of components by using GAB or Langmuir
equation with the (p/PJm determined at each time interval j.

 

 

 

 

 

 

No

 

 

    

Storage time = n x j

 

Stop

 

 

 

Figure 70 Example of an algorithm used to calculate the relative humidity of the

headspace and moisture content of components in a package at each time interval j over

the total storage time t

159

 

 

 

Figure 71 shows how the program determines the GAB and Langmuir constants
with the experimental moisture sorption isotherm data. The program runs until the sum

of square error between experimental and calculated data is minimized.

 

Experimental moisture sorption isotherm data
° M9 "ff, ”/1
Initial GAB or Langmuir constants
. GAB: Wm = 0.5, Cg= 0.5, K = 0.5
. Langmuir: Wm = 0.5, CL= 0.5
n = the number of moisture isotherm data points

 

 

 

 

 

Calculate the experimental equilibrium moisture content (It/1“”)
[W, .(1 + M,) ]
Me"p = -1

 

W

I

 

 

 

 

 

v
Calculate the theoretical equilibrium moisture content (Mm)
_ W9C, K (1)/p...)

_ [1- K(p/p.>fll — K(p/p.) +C,K<p/p,
W MCI. 09/ pg)
1 + CL 0” Pg)

 

the

 

)] for GAB constants

or Mlhe _

 

for Langmuir constants

 

 

 

 

 

l Constants are changed by using a
variety of fitting methods in
“Solver” function in MS Excel.

 
 
 

 

 

 

   
 

No T

Minimize i (M:"" - M f" )2

n=|

Yes i

 

 

Final Constants

 

 

Figure 71 Algorithm used to determine the GAB or Langmuir constants

160

3. Verification of the moisture and shelf life prediction program

Figure 72 shows a result spreadsheet example from the moisture prediction
program. It shows the relative humidities of the package headspace and moisture content
of the solids at each time interval for a desired storage time. And, Figure 73 shows the
shelf life prediction program. By changing the input data such as dry weight of solids,
the final moisture content, and storage conditions, the shelf life can be calculated for a

variety of situations. An example considering two solids in a package is shown below.

Parameters used in the moisture simulation program

. Solids
0 Dry weight: 3.6929g (tablets), 0.4863 g (silica gel)
0 Initial moisture content: 1.93 12% (tablets), 3.0310% (silica gel)
0 Sorption isotherm equations: GAB constants (Wm: 0.013392, Cg: 113.2096,
K: 0.933012) for tablets, Langmuir constants (Wm: 0.819364, CL:
0.924676) for silica gel
. Package (LDPE bag)
0 Volume: 0.02 L
o Permeability: 0.0252 g/[day-package-ps]
. Storage condition
0 Temperature at packaging line: 25°C
Relative humidity at packaging line: 40%
Temperature at storage: 40°C
Relative humidity at storage: 90%
Storage time (for moisture prediction part): 7 days
Final storage condition (for shelf life prediction part): 70% RH
Number of piecewise calculations (for shelf life prediction part): 100

O O O 0 O 0

Example spreadsheet showing results calculated by using above parameters
Figure 72 shows results obtained from the moisture prediction program. It shows

the RH of the package headspace and moisture content of each solid at each time interval.

161

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162

The package volume, temperature and relative humidity at the packaging line are
used to calculate the amount of initial moisture in the package. If temperatures at the
packaging line and storage are different, another sorption isotherm at the temperature of
the packaging line is needed to calculate the amount of initial moisture in the package.
However, as explained in Chapter 3.2.(2)(a) Moisture sorption isotherms of drug X
tablets, the moisture sorption isotherms do not vary much over the range of 20-50°C.
Therefore, for the purpose of simplifying computer programming, the moisture sorption
isotherm obtained at the storage temperature (40°C) was used to calculate the amount of
initial moisture in tablets packaged at 25°C. If two different sets of GAB constants are

used, the program will be much larger.

163

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164

To verify the moisture and shelf life prediction models, moisture content of
tablets in LDPE bags and HDPE bottles was determined experimentally over time, and
compared to moisture content calculated by the moisture prediction part in the moisture
simulation program (see Figures 74-79). Each bag and bottle had different weights of
tablets and silica gel, so the moisture prediction program was run 7 times using each
weight of tablets and silica gel, and a different storage time. Moisture content was
calculated for a given storage time using 1 day time intervals.

The results, initial equilibrium and final moisture content, obtained from the
moisture prediction program were inserted into the shelf life prediction program, and then
the shelf life was calculated at given storage conditions. The results were compared with
the actual storage time to verify the shelf life program (see Tables 28-33). They show
good agreement between the actual storage time and the shelf life calculated from the
shelf life prediction program. The sorption isotherm curve between the initial and final
points was divided into just 100 piecewise calculations to save program rumiing time. It
was very close to the shelf life result using 1000 piecewise calculations. Based on the
example below, shelf life calculated using 100 piecewise calculations was 39.77 days,
and shelf life calculated using 1000 piecewise calculations was 39.78 days. So, it is
almost the same as the shelf life result would be using infinite piecewise calculations.

Appendix D shows all moisture raw data used to calculate moisture content of

solids and shelf life.

165

(1) Tablets in LDPE bags without silica gel and with silica gel (0.5 g, 1 g, and 2 g) in
LDPE bags

Each bag had a slightly different weight of tablets and silica gel, so the moisture

prediction program was run 7 times using actual weights of tablets and silica gel at each

storage time. Figure 74 and Table 28 show good agreement between the moisture

content of tablets in LDPE bags without desiccant measured experimentally and

calculated by the moisture prediction program in the moisture simulation program.

M(%)

 

 

 

 

 

 

 

 

 

a.» - «A . ~ —
e
7 a 3
6 . 1
5 0
I
4 r
3
2t
1 1
o r . T .
o 20 4o 60

Storage time (days)

100

O M(%) of tablets measured experimentally I M(%) of tablets calculated by the moisture prediction

program

Figure 74 Comparison between experimental and calculated moisture content of tablets
stored in LDPE bags without silica gel

Table 28 Comparison between experimental and calculated moisture content, and
between actual storage time and calculated shelf life of tablets stored in LDPE bags
without desiccant

 

Storage time

M(%) of tablets measured

M(%) of tablets calculated

Shelf life (days) calculated

 

 

 

 

 

 

 

 

(days) experimentally by moistugprediction program by SL prediction program
7 3.91% 3.62% 7.5
14 4.58% 4.50% 14.7
28 5.23% 5.57% 28.9
35 5.90% 5.95% 36
44 6.46% 6.33% 45
58 6.74% 6.77% 59
82 7.17% 7.29% 83.5

 

 

 

 

166

 

Figure 75 and Table 29 show the moisture content of tablets stored in LDPE bags
containing 0.5 g silica gel measured experimentally and calculated by the moisture
prediction program. The M (%) of silica gel at 58 and 82 days storage time had
differences of 1.63 and 2.35%, respectively, between the experimental and calculated
values. The moisture gain of tablets was measured easily, but the “experimental”
moisture gain of the silica gel was calculated by difference (see Chapter 2.2.(5)(c)
Verification of moisture simulation program). In this case, only 0.5 g silica gel was used.
The M (%) of silica gel is changed greatly by even a small amount of moisture change
(e.g., 2% M (%) difference results from 0.01 g moisture change). Therefore, 1.63 and

2.35% M (%) differences at 58 and 82 days storage time are not bad.

 

 

 

 

 

 

 

 

 

. O
35 , r- t i s
30 4
25 a
£5 20
E
15
10
g 5
5 4' at“ J
0 . .
O 20 40 60 80 100

Storage time (days)

0 M(%) of tablets measured experimentally I M(%) of tablets calculated by the moisture prediction
program A M(%) of silica gel by difference 9 M(%) of silica gel calculated by the moisture prediction

program

Figure 75 Comparison between experimental and calculated moisture content of tablets
and silica gel (0.5 g) stored in LDPE bags

167

Table 29 Comparison between experimental and calculated moisture content of tablets
and 0.5 g silica gel stored in LDPE bag, and between actual storage time and calculated
shelf life.

 

 

 

 

 

 

 

 

 

 

Storage time M(%) measured M(%) calculated by the moisture Shelf life (days)
(days) experimentally predictiorgrogram calculated by SL
Tablets Silica gel Tablets Siliflel prediction program
7 2.55% 24.69% 2.25% 23.78% 7
14 3.49% 30.76% 3.18% 29.95% 14.5
28 4.72% 34.08% 4.57% 33.80% 28.8
35 5.24% 35.31% 5.08% 34.60% 35
44 5.50% 35.34% 5.59% 35.23% 45
58 6.45% 34.21% 6.19% 35.84% 59
82 7.01% 34.03% 6.88% 36.38% 83.4

 

 

 

 

 

 

 

Figure 76 and Table 30 show the moisture content of tablets stored in LDPE bags
containing 1 g silica gel measured experimentally and calculated by the moisture
prediction program. The M (%) of silica gel measured experimentally are 1.49-3.45%

higher than the M(%) calculated by the moisture prediction program.

40 .
35 - . .
30
25
20
15
10

5 3 r

? i
O l l l l T j‘

 

0'
“I

 

 

‘D

 

M(%)
O D

 

 

 

 

 

 

Storage time (days)

9 M(%) of tablets measured experimentally I M(%) of tablets calculated by the moisture prediction
program A M(%) of silica gel by difference 0 M(%) of silica gel calculated by the moisture prediction

program
Figure 76 Comparison between experimental and calculated moisture content of tablets
and silica gel (1 g) stored in LDPE bags

168

Table 30 Comparison between experimental and calculated moisture content of tablets
and 1 g silica gel stored in LDPE bag, and between actual storage time and calculated

 

 

 

 

 

 

 

 

 

 

shelf life.
Storage time M(%) measured M(%) calculated by the Shelf life (days)
(days) experimentally moisture prediction program calculated by SL
Tablets Silica gel Tablets Silica gel prediction program

7 1.82% 18.51% 1.74% 16.30% 7
14 2.62% 26.94% 2.33% 24.51% 14
28 3.81% 33.68% 3.47% 31.06% 28.6
35 4.39% 34.69% 4.02% 32.66% 35.7
44 5.00% 37.54% 4.75% 34.10% 44.9
58 5.54% 38.60% 5.52% 35.15% 59
82 6.08% 37.37% 6.36% 35.98% 83

 

 

 

 

 

 

169

 

Figure 77 and Table 31 show the same situation as shown in Figure 76 and Table
30. The M (%) of silica gel measured experimentally is 1.37-6.50% higher than the M
(%) calculated by moisture prediction program. The 6.50% difference is large, but the
trend of silica gel moisture content is predicted well, as shown in Figure 77. The M (%)

of tablets measured experimentally and calculated by the moisture prediction program are

very close.

35 A i
30 ‘ ‘
25
20
15
10

5 f 3

0 f T T I I l
20 40 60 80 1 00

di

 

 

11

 

M(%)

 

 

 

Storage time (days)

0 M(%) of tablets measured experimentally I M(%) of tablets calculated by the moisture prediction
program A M(%) of silica gel by difference 0 M(%) of silica gel calculated by the moisture prediction

program
Figure 77 Comparison between experimental and calculated moisture content of tablets
and silica gel (2 g) stored in LDPE bags

Table 31 Comparison between experimental and calculated moisture content of tablets
and 2 g silica gel stored in LDPE bag, and between actual storage time and calculated

shelf life.

 

 

 

 

 

 

 

 

 

Storage time M(%) measured M(%) calculated by the Shelf life (days)
(days) experimentally moisture prediction program calculated by SL
Tablets Silica fl Tablets Silica gel prediction program
7 1.42% 12.21% 1.51% 10.84% 7
14 1.84% 23.02% 1.76% 16.65% 14
28 2.24% 30.59% 2.37% 24.91% 28
35 2.72% 34.37% 2.77% 27.87% 35
44 3.33% 34.72% 3.30% 30.43% 44.6
58 4.44% 36.51% 4.05% 32.71% 59
82 5.17% 39.09% 5.24% 34.81% 83

 

 

 

 

 

 

 

 

170

(2) Tablets in HDPE bottles without silica gel and with 0.5 g Silica gel in HDPE bottles

Each bottle had a slightly different weight of tablets and silica gel, so the moisture

prediction program was rim 7 times using actual weights of tablets and silica gel at each

storage time. AS shown in Figure 78 and Table 32, there is good agreement between the

moisture content measured experimentally and calculated by the moisture prediction

program.

M(%)

 

 

 

 

 

 

5 .
4 ..
a l
. t

3 s 6 .
3 1
2 ’
i
1 i
l
l
0 T Y T fl

0 50 100 150

Storage time (days)

200

O M(%) of tablets measured experimentally l M(%) of tablets calculated by the moisture prediction

program

Figure 78 Comparison between experimental and calculated moisture content of tablets
stored in HDPE bottles without silica gel

Table 32 Comparison between experimental and calculated moisture content of tablets
stored in HDPE bottle without Silica gel, and between actual storage time and calculated

 

 

 

 

 

 

 

 

 

shelf life.
Storage time M(%) of tablets measured M(%) of tablets calculated by the Shelf life (days) calculated
(days) experimentally moisture flediction program by SL prediction program
14 2.21% 2.22% 13.8
35 2.60% 2.60% 34.5
58 2.81% 2.93% 57
83 2.91% 3.18% 82
103 3.35% 3.46% 102
135 3.65% 3.77% 133.8
160 3.86% 3.98% 158.8

 

 

 

 

 

171

Figure 79 and Table 33 Show good agreement between the moisture content

measured experimentally and calculated by the moisture prediction program. The M (%)

of silica gel at 160 days storage time had difference of 2.59% between the experimental

and calculated values. The moisture gain of tablets was measured easily, but the

“experimental” moisture gain of the Silica gel was calculated by difference. As explained

before, 2.59% M (%) difference at 160 days storage time is not bad.

M(%)

25

20

15

10

ii.

CD

.A.. —_‘.H .

 

 

150

Storage time (days)

200

O M(%) of tablets measured experimentally I M(%) of tablets calculated by the moisture prediction
program A M(%) of silica gel by difference 0 M(%) of silica gel calculated by the moisture prediction

program

Figure 79 Comparison between experimental and calculated moisture content of tablets

and Silica gel (0.5 g) in HDPE bottles

Table 33 Comparison between experimental and calculated moisture content of tablets
and 0.5 g Silica gel in HDPE bottle, and between actual storage time and calculated Shelf

 

 

 

 

 

 

 

 

 

life.
Storage time M(%) measured M(%) calculated by moisture Shelf life (days)
(days) experimentally prediction program calculated by SL
Tablets Silica 5i Tablets Silica El prediction program
14 1.36% 10.27% 1.48% 9.96% 13.9
35 1.43% 13.96% 1.63% 13.76% 34.9
58 1.69% 18.93% 1.79% 17.30% 57.8
83 1.77% 20.80% 1.98% 20.44% 82.6
103 2.07% 21.62% 2.14% 22.56% 102.4
135 2.23% 23.36% 2.40% 25.23% 134.3
160 2.47% 24.29% 2.62% 26.88% 159.2

 

 

 

 

 

 

 

172

 

Appendix C

Tablet Formulation, Manufacturing, and Interaction

173

1. Formulation

Table 34 Shows the drug X tablet formulation.

Table 34 Drug X tablet formulation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

”L “/o Functions Characteristics
Wet Granulation
Active pharmaceutical Sensitive to moisture and light,
‘ Drug X 20.40 8.16 Medient (API) Poorly soluble in water
Non-hygroscopic (up to ~75%),
Mannitol (granular) 157.72 63.09 diluent soluble in water
Enhance dissolution of poorly soluble
binder, dissolution aid, drugs, very hygroscopic, soluble in
Povidone 10.00 4.00 disintegrant acids and water
Croscarmellose Insoluble, high absorption,
Sodium 3.75 1.50 superdisintegrant high swelling (4~8 times)
Microcrystalline Hygroscopic, insoluble in water and
Cellulose (MCC) 25.00 10.00 binder, disinfigrant dilute acids
Extragranulation
Croscannellose
Sodium 1 .25 0.50 swerdisintegrant
Microcrystalline
Cellulose (MCC) 20.00 8.00 binder, disintegrant
Promote the flow of powder,
‘ Magnesium Stearate 1.88 0.75 lubricant insoluble in water, hydrophobic
Coating
Color Mixture Yellow 10.00 4.00 Soluble in water
Camauba Trace Natural wax
Total 250.00 100.00

 

Drug X, mannitol, povidone, and portions of the croscarmellose sodium and

microcrystalline cellulose were screened (10 mesh) into the high shear granulator. The

powders were then dry mixed for 5 minutes to make a uniform blend prior to granulation

(main blade: 200rpm, chopper blade: 1800rpm). Purified water was then used to

granulate the powder mix in the high shear granulator for about 4 minutes (wet

granulation). The granulation was dried using a fluid bed drying process. The milled

granulation was then placed into an appropriately Sized tumble bin.

The appropriate quantities of croscarmellose sodium (20 mesh), microcrystalline

cellulose (20 mesh), and magnesium stearate (30 mesh) were sieved and added to the

174

 

tumble bin. The mixture was blended for 5 minutes, then compressed on a rotary tablet
presser.

The color mixture yellow was mixed with purified water to form the coating
suspension. The core tablets were placed into a side vented, perforated coating pan. The
tablets were then spray coated with the suspension until an approximate 4.0% weight gain
was achieved. Figure 80 shows the graphical representation of the manufacturing of drug

X tablets.

175

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33333on “fig «5.3953 002 30
Ill,
I Allll Allll
@520 9:2an

 

oo .96 .885on
2332 .x was

From the extra granulation process, the granules were surrounded by
croscarmellose sodium, microcrystalline cellulose, and magnesium stearate. The
magnesium stearate is a lubricant and is hydrophobic, so the tablet dissolution rate
decreases as the time of blending increases, but magnesium stearate increases tablet
friability (Bolhuis, 1981 and Chowan, 1986). Blending times with magnesium stearate
should thus be carefully controlled. Croscarmellose sodium and microcrystalline
cellulose are hygroscopic, especially croscarmellose sodium absorbs moisture quickly,
then it swells to 4-8 times its original volume (Kibbe, 2000). With the swelling of
croscarmellose sodium, the boundary strength among granules becomes weak. It makes
the tablet disintegrate quickly.

The general characteristics of excipients used for drug X tablets were reviewed
based on the USP monograph, Handbook of Pharmaceutical Excipients (Kibbe, 2000),

and Modern Pharmaceutics (Marshall et al., 1989).

(1) Drug X (API, Active Pharmaceutical Ingredient)

Drug X is sensitive to moisture and light, and it is poorly soluble in water.

(2) Mannitol

Mannitol can be used as a sweetening agent, diluent, or binder in tablets, and
occurs as white, odorless, crystalline, or free-flowing granules. Figure 81 shows the
structural formula of mannitol. Manniol is not hygroscopic, so it may be used with
moisture sensitive active ingredients. Mannitol resists moisture sorption, even at high

relative humidity as Shown in Figure 82. Granulations containing mannitol have the

177

advantage of being dried easily. Granular mannitol flows well and imparts improved
flow properties to other materials. Suitable binders for preparing granulations of
powdered mannitol are gelatin, methylcellulose 400, starch paste, povidone, and sorbitol.
Usually, 3-6 times as much magnesium stearate or 1.5-3 times as much calcium stearate

is needed for lubrication of mannitol granulations than as needed for other excipients.

 

 

 

 

 

12
O 10 r
CH2 H
l i 8 ~
HO—C—H g
I 5 1-
HO — C -— H
I 4 r-
H -— C -—- OH
| 2 .
H —— (I: — 0H -
CH20H o‘233393525737715100
' Behave hum (st)
0 sorption I desorption
Figure 81 Structural formula of Figure 82 Moisture sorption-desorption
mannitol isotherm of mannitol (Kibbe, 2000)

(3) Povidone

Povidone can be used as a disintegrant, dissolution aid, and tablet binder. It is a
fine, white to creamy-white colored, odorless or almost odorless, hygroscopic powder.
Figure 83 Shows the structural formula of povidone and Figure 84 Shows that significant
amounts of moisture can be absorbed at low relative humidity. In tableting, povidone
solutions are used as binders in wet-granulation processes. Povidone is also added to
powder blends in dry form and granulated in situ by the addition of water, alcohol, or
hydroalcoholic solutions. Povidone is used as a disintegrant and has been shown to

enhance dissolution of poorly soluble drugs from solid—dosage forms. The solubility of a

178

number of poorly soluble active drugs may be increased by mixing with povidone.
Povidone is freely soluble in acids, chloroform, ethanol, ketones, methanol, and water. It

is practically insoluble in ether, hydrocarbons, and mineral oil.

50

 

§

i
L

O
mmuas-cm
8 8

 

 

 

 

 

_ _ .... r -l
L CH CH2 .. a
101- -l
l- 4
nib—{o 33 4b East? To ail—tibiae
autoimmune)
Figure 83 Structural formula of Figure 84 Moisture sorption isotherm of povidone

povidone (Kibbe, 2000)

(4) Croscarmellose sodium

Croscarmellose sodium can be used as a tablet super disintegrant due to its high
swelling property. When croscarmellose sodium is used in wet granulations, it is best
added in both the wet and dry stages of the process (intra and extragranularly) so that the
wicking and swelling ability of the disintegrant is best utilized. It is insoluble, although
croscarmellose sodium rapidly swells to 4-8 times its original volume on contact with
water. Thibert and Hancock (1996) observed directly the hydration behavior of
croscarmellose sodium particles by using ESEM (Environmental Scanning Electron
Microscopy). At 40% RH, the croscarmellose sodium particles comprised twisted fibers.

Upon exposure to 80% RH the particles experienced considerable additional twisting and

179

expansion. After the RH was reduced to 40% the particles did not regain their original
shape. This may be linked to the hysteresis observed in the water vapor sorption

isotherm for croscarmellose sodium.

(5) Microcrystalline cellulose

Microcrystalline cellulose (MCC) is a purified, partially depolymerized cellulose
that occurs as a white, odorless, tasteless, crystalline powder composed of porous
particles. MCC can be used as a diluent, binder, or disintegrant in tablets. It is "
hygroscopic and slightly soluble in 5% w/v sodium hydroxide solution, and practically
insoluble in water, dilute acids, and most organic solvents. MCC has been shown to be
highly porous, with strong “wicking” tendencies, so it is a good disintegrant. Also, MCC
can enhance poor compression characteristics of starch (Banker and Rhodes, 1989).
However, Thibert and Hancock observed that there were no changes in the particle
morphology nor was there any swelling of the MCC particles after prolonged exposure to
80% RH. These results are consistent with the limited disintegrant properties of MCC
and its low level of water vapor sorption. Figure 85 shows the structural formula of

microcrystalline cellulose (MCC).

H OH ‘ cnzorp H OH anon
H H H H H
OH H H 0 OH H H ‘ OH
H 0- OH H H H o- OH H H
H 0 H
CHZOH , H on CH,0H H on
J
‘- 0' II

 

 

Figure 85 Structural formula of microcrystalline cellulose (MCC)

180

(6) Magnesium stearate

Magnesium stearate is a fine, white, precipitated or milled, impalpable powder of
low bulk density, having a faint odor of stearic acid and a characteristic taste. It can be
used as a lubricant in tablets. It is practically insoluble in ethanol, ethanol (95%), ether
and water, and slightly soluble in warm benzene and warm ethanol (95%). Magnesium
stearate is hydrophobic and may retard the dissolution of a drug from a solid dosage form,
so the lowest possible concentration should be used. Tablet dissolution rate and crushing
strength decrease as the time of blending increases (Chowan, 1986). It may also increase
tablet friability. Blending time with magnesium stearate should thus be carefully

controlled. The structural formula is [CH3(CH2)16COO]2Mg.

(7) Coating material

Many tablets are now coated because this can minimize the unpleasant taste of
certain medicaments, protect the ingredients against decomposition, improve the
manufacturing process (no dust), and enhance the appearance. The coating material must

be soluble in water.

2. Manufacturing — wet granulation

The components of the formulation are mixed with a granulating liquid such as
water to produce granules which will readily compress to give tablets. The wet
granulated tablets are more robust than those produced by direct compression, so the
content uniformity is better than with direct compression. The general purpose of wet

granulation is (1) to enlarge the particle size, (2) to improve the particle Shape and make

181

it fairly spherical, (3) to make the surface of the particles and the tablet hydrophilic (to
promote wetting, and consequently disintegration and dissolution), and (4) to promote
compressibility (Carstensen, 1993). The disintegration of the tablet must be followed by
granular disintegration in order to promote rapid dissolution and hence absorption

(Banker and Rhodes, 1989).

182

Appendix D

Summary Tables of Permeability, Moisture Sorption Isotherms, and Moisture
Content Verification

183

 

1. Permeability

Table 35 Moisture gain (g) of LDPE bag's using CaClyg at 40°C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Leaking
Days 0 7 l4 16 18 30 37 57 Test
l 11.3793 11.6928 11.8640 11.9128 11.9580 12.2448 12.3765 12.8089 Pass
2 10.9961 11.2880 11.4496 11.5225 11.5463 11.8114 11.9720 12.4051 Pass
3 11.7248 12.0478 12.1979 12.2482 12.3484 12.6051 12.7953 13.2500 Pass
4 11.8688 12.2805 12.5254 12.6198 12.7951 13.3334 13.6869 14.6863 Fail
5 11.6610 12.0170 12.1322 12.1802 12.2300 12.4880 12.6593 13.0937 Pass
Net Moisture Gain (g)
1 0 0.3035 0.4747 0.5235 0.5687 0.8555 0.9872 1.4196
2 0 0.2819 0.4435 0.5164 0.5402 0.8053 0.9659 1.3990
3 0 0.3130 0.4631 0.5134 0.6136 0.8703 1.0605 1.5152
4 0 0.4017 0.6466 0.7410 0.9163 1.4546 1.8081 2.8075
5 0 0.3460 0.4612 0.5092 0.5590 0.8170 0.9883 1.4227
Table 36 Moisture gain (g) of HDPE bottles using CaClz at 40°C
Days 0 7 21 28 46 Leaking Test
1 45.9352 45.9550 45.9720 45.9805 46.0033 Pass
2 45.5874 45.6076 45.6245 45.6332 45.6559 Pass
3 45.6107 45.6307 45.6481 45.6567 45.6792 Pass
4 45.7392 45.7598 45.7760 45.7841 45.8062 Pass
5 45.9762 45.9962 46.0132 46.0214 46.0437 Pass
Net Moisture Gain (g)
1 0 0.0072 0.02355 0.03175 0.05375
2 0 0.0076 0.02385 0.03225 0.05415
3 0 0.0074 0.02415 0.03245 0.05415
4 0 0.0080 0.02355 0.03135 0.05265
5 0 0.0074 0.02375 0.03165 0.05315
Table 37 Moisture gain (g) of HDPE bottle blanks at 40°C
Days I 0 7 21 28 46 160 I Leaking Test
1 | 75.6306I 75.6430] 75.6437] 75.6440] 75.6445 | 75.6516] Pass
2 | 75.8447I 75.8575 | 75.8581 | 75.8584I 75.8595] 75.8662I Pass
Net Moisture Gain (g) 7
l I 0] 0.0124] 0.0131 | 0.0134] 0.0139] 0.0210]
2 | 0| 0.0128I 0.0134] 0.0137] 0.0148] 0.0215]
. Average | 0| 0.0126] 0.0132] 0.0136] 0.0143] 0.0213 I

 

 

184

 

2. Moisture Sorption Isotherms

Table 38 Moisture sorption isotherm data of uncoated tablets at 25°C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

EMC (%)
IMC (%) RH (%) Pi (g) Pf (g) EMC (%) using GAB equation
1 2.1 199 0.00 251.060 0 0
2 4.95 251.060 248.694 1.1574 1.1587
3 9.87 251.060 249.071 1.31 1 1 1.3713
4 14.89 251.060 249.494 1.4829 1.5100
5 19.93 251.060 249.880 1.6401 1.6326
6 25.02 251.060 250.254 1.7922 1.7561
7 29.86 251.060 250.573 1.9217 1.8805
8 35.07 251.060 250.903 2.0562 2.0275
9 40.01 251.060 251.247 2.1961 2.1837
10 44.92 251.060 251.660 2.3640 2.3608
1 1 50.13 251.060 252.317 2.6313 2.5788
12 55.14 251.060 252.996 2.9073 2.8269
13 60.06 251.060 253.788 3.2295 3.1 193
14 64.87 251.060 254.612 3.5648 3.4671
15 69.85 251.060 255.595 3.9644 3.9170
16 74.86 251.060 256.787 4.4494 4.5023
17 80.31 251.060 258.537 5.1611 5.3715
18 85.07 251.060 261.103 6.2050 6.4552
19 89.99 251.060 266.394 8.3570 8.1570
Table 39 Moisture sorption isotherm data of coated tablets at 25°C
EMC (%)
IMC (%) RH (%) Pi (g) Pr (g) EMC (%) using GAB equation

1 2.3410 0.00 261.593 0 0
2 5.01 261.593 259.118 1.3727 1.4217
3 10.19 261.593 259.399 1.4826 1.5500
4 14.92 261 .593 259.873 1.6678 1.6458
5 19.91 261.593 260.201 1.7963 1.7482
6 24.97 261.593 260.562 1.9376 1.8600
7 30.05 261.593 260.919 2.0773 1.9842
8 34.97 261.593 261.251 2.2073 2.1 192
9 40.02 261.593 261.584 2.3374 2.2767
10 45.04 261.593 262.010 2.5039 2.4573
1 1 49.91 261.593 262.614 2.7403 2.6611
12 55.04 261.593 263.263 2.9943 2.9147
13 59.89 261.593 264.002 3 .2833 3.2026
14 64.94 261.593 264.819 3.6030 3.5695
15 70.01 261.593 265.895 4.0241 4.0321
16 74.88 261.593 267.064 4.4813 4.6050
17 80.03 261.593 268.874 5.1895 5.4166
18 85.01 261.593 271.618 6.2628 6.5301
19 89.95 261.593 277.21 I 8.451 1 8.2021

 

 

 

 

 

 

 

 

185

 

 

Table 40 Moisture sorption isotherm data of uncoated tablets at 40°C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

EMC (%)
IMC (%) RH (%) Pi (g) Pf (g) EMC (%) using GAB equation
1 1.9312 0.00 O 0
2 4.80 248.612 246.730 1.1597 1.1797
3 9.72 248.612 247.048 1.2902 1.3528
4 14.94 248.612 247.444 1.4526 1.4756
5 19.85 248.612 247.775 1.5880 1.5821
6 24.88 248.612 248.113 1.7267 1.6944
7 29.99 248.612 248.457 1.8680 1.8181
8 34.88 248.612 248.800 2.0083 1.9497
9 39.97 248.612 249.198 2.1717 2.1042
10 44.93 248.612 249.667 2.3641 2.2780
11 49.91 248.612 250.184 2.5758 2.4812
12 54.85 248.612 250.805 2.8304 2.7198
13 59.87 248.612 251.506 3.1177 3.0126
14 64.92 248.612 252.290 3.4392 3.3773
15 69.89 248.612 253.205 3.8145 3.8311
16 74.91 248.612 254.436 4.3191 4.4310
17 79.87 248.612 256.087 4.9962 5.2404
18 84.86 248.612 259.070 6.2189 6.4155
19 90.00 248.612 264.708 8.5305 8.3418
Table 41 Moisture sorption isotherm data of coated tablets at 40°C
EMC (%)
IMC (%) RH (%) Pi (g) Pr(g) EMC (%) using GAB equation
1 2.3086 0.00 0 O
2 4.94 260.046 257.524 1.3167 1.3873
3 9.82 260.046 257.896 1.4630 1.5033
4 14.78 260.046 258.276 1.6126 1.6005
5 19.95 260.046 258.630 1.7515 1.7037
6 24.98 260.046 258.972 1.8863 1.81 19
7 29.86 260.046 259.306 2.0177 1.9283
8 34.99 260.046 259.684 2.1663 2.0660
9 39.91 260.046 260.085 2.3240 2.2164
10 45.13 260.046 260.566 2.5132 2.4005
1 1 49.86 260.046 261.085 2.7177 2.5957
12 54.85 260.046 261.71 1 2.9637 2.8380
13 60.04 260.046 262.394 3.2325 3.1420
14 64.94 260.046 263.080 3.5023 3.4954
15 70.00 260.046 263.990 3.8606 3.9538
16 74.96 260.046 265.204 4.3382 4.5366
17 79.71 260.046 267.064 5.0698 5.2816
13 85.08 260.046 269.998 6.2240 6.4843
19 90.03 260.046 275.693 8.4645 8.2053

 

 

 

 

 

 

 

 

186

 

 

Table 42 Moisture sorption isotherm data of silica gel at 25°C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

IMC RH Pt Pr EMC EMC (%) EMC (%)
(%) (%) (g) (g) (%) using Langmuir equ. using GAB equ.
1 3.031 0.00 22.04 0 0.0000 0.0000
2 5.14 22.04 22.653 5.8966 3.6003 3 .6006
3 10.12 22.04 23.183 8.3742 6.9210 6.9215
4 15.08 22.04 23.645 10.5339 10.0759 10.0764
5 20.13 22.04 24.139 12.8433 13.1423 13.1427
6 25.1 22.04 24.613 15.0591 16.0262 16.0265
7 29.97 22.04 25.132 17.4853 18.7314 18.7315
8 35.16 22.04 25.693 20.1078 21.4913 21.4912
9 39.92 22.04 26.271 22.8098 23.9178 23.9176
10 45.15 22.04 26.909 25.7922 26.4756 26.4752
1 1 49.88 22.04 27.531 28.6999 28.6968 28.6962
12 54.95 22.04 28.148 31.5842 30.9863 30.9857
13 60.02 22.04 28.719 34.2535 33.1867 33.1861
14 65.1 22.04 29.205 36.5254 35.3073 35.3067
15 69.94 22.04 29.639 38.5543 37.2536 37.2531
16 75.1 1 22.04 29.987 40.181 1 39.2571 39.2567
17 79.94 22.04 30.302 41.6536 41.0621 41.0620
13 85.16 22.04 30.598 43 .0373 42.9442 42.9445
19 90.18 22.04 30.807 44.0143 44.6904 44.691 1
20 95.25 22.04 30.921 44.5473 46.3939 46.3952

Table 43 Moisture sorption isotherm data of silica gel at 40°C

IMC RH Pi Pf EMC EMC (%) EMC (%)
(%) (%) (g) (g) (%) using Langmuir equ. using GAB equ.
1 0 0.00 1 10.059 0 0.0000 0.0000
2 5.28 110.059 114.359 3.9071 3.8156 3.8158
3 10.02 110.059 1 17.074 6.3734 6.9486 6.9488
4 14.85 1 10.059 1 19.634 8.6995 9.8907 9.8909
5 20.10 110.059 122.383 11.1975 12.8427 12.8427
6 25.10 110.059 125.211 13.7671 15.4362 15.4361
7 29.91 110.059 128.130 16.4188 17.7518 17.7515
8 35.08 1 10.059 131.116 19.1318 20.0687 20.0683
9 40.06 1 10.059 134.246 21.9761 22.1492 22.1486
10 45.04 1 10.059 137.269 24.7226 24.0899 24.0893
1 1 50.04 110.059 140.100 27.2948 25.9182 25.9176
12 55.05 1 10.059 142.61 1 29.5768 27.6402 27.6396
13 60.08 1 10.059 144.615 31.3973 29.2634 29.2629
14 65.16 1 10.059 146.053 32.7042 30.8067 30.8062
15 69.92 110.059 146.986 33.5516 32.1737 32.1734
16 75.02 1 10.059 147.694 34.1949 33.5600 33.5599
17 79.63 1 10.059 148.203 34.6571 34.7473 34.7475
13 84.90 110.059 148.751 35.1553 36.0360 36.0365
19 89.99 110.059 149.282 35.6378 37.2131 37.2139
20 95.38 1 10.059 149.774 36.0845 38.3987 38.4000

 

 

 

 

 

 

 

 

 

187

 

 

3. Verification

Table 44 Moisture content of tablets in LDPE bags without silica gel as a function of
storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

lnitial Afier Storage
Package Product Product Total Storage time Total Product Leaking

(g) (g) dry weight (g) (g) (DaYS) (g) (g) Test
1 1.1010 3.7609 3.6896 4.8619 7 3.8340 Pass
2 1.1728 3.7666 3 .6952 4.9394 14 3.8646 Pass
3 1.0943 3.7749 3 .7034 4.8692 28 3 .8970 Pass
4 1.1 199 3.7658 3.6945 4.8857 35 3.9124 Pass
5 1.1239 3.7668 3.6954 4.8907 44 3.9342 Pass
6 1.1532 3.7673 3.6959 4.9205 58 3.9450 Pass
7 1.2387 3.7752 3.7037 5.0139 82 3.9692 Pass

 

 

Table 45 Moisture content of tablets and 0.5 g silica gel in LDPE bags as a function of

storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Initial
Package Product Product Silica gel Silica gel
(g) (g) dry weight (g) (g) dry weight (g) Total (g)
1 1.1690 3.7642 3.6929 0.5010 0.4863 5.4342
2 1.1062 3.7665 3.6951 0.5043 0.4895 5.3770
3 1.1428 3.7751 3 .7036 0.5051 0.4902 5.4230
4 1.0884 3.7569 3.6857 0.5031 0.4883 5.3484
5 1.1603 3.7672 3.6958 0.5038 0.4890 5.4313
6 1.2139 3.7800 3.7084 0.5009 0.4862 5.4948
7 1.1861 3.7698 3.6984 0.5095 0.4945 5.4654
Afier Storage
Storage time Total Package Product Silica gel Leaking

(DayS) (g) (g) (g) (g) Test

7 5.5825 1.1890 3.7872 0.6063 Pass

14 5.5904 1.1262 3.8242 0.6400 Pass

28 5.6985 1.1628 3.8784 0.6573 Pass

35 5.6481 1.1084 3.8790 0.6607 Pass

44 5.7413 1.1803 3.8992 0.6618 Pass

58 5.8338 1.2339 3 .9474 0.6525 Pass

82 5.8265 1.2061 3.9576 0.6628 Pass

 

 

 

188

Table 46 Moisture content of tablets and 1 g silica gel in LDPE bags as a function of
storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Initial
Package Product Product Silica gel Silica gel
_ (g) (g) dry weight (g) (g) dtxweight (g) Total (g)
1 1.1528 3.7754 3 .7039 1.0709 1.0394 5.9991
2 1.1497 3 .7707 3.6993 1.0060 0.9764 5.9264
3 1.2255 3.7788 3.7072 1.0714 1.0399 6.0757
4 1.1396 3.7715 3.7000 1.0763 1.0446 5.9874
5 1.1655 3.7666 3.6952 1.0148 0.9849 5.9469
6 1.1501 3.7645 3 .6932 1.0063 0.9767 5.9209
7 1.1657 3.7585 3 .6873 1.0533 1.0223 5.9775
Afier Storage
Storage time Total Package Product Silica gel Leaking

(daYS) (g) (g) (g) (g) Test

7 6.1758 1.1728 3.7712 1.2318 Pass

14 6.2051 1.1697 3 .7960 1.2394 Pass

28 6.4842 1.2455 3.8486 1.3901 Pass

35 6.4292 1 .1 596 3 .8626 1 .4070 Pass

44 6.4203 1.1855 3.8801 1.3547 Pass

58 6.4217 1.1701 3.8979 1.3537 Pass

82 6.5015 1.1857 3.9114 1.4044 Pass

 

Table 47 Moisture content of tablets and 2 g silica gel in LDPE bags as a function of
storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Initial
Package Product Product Silica gel Silica gel
__ (g) (g) dry weight (Q (g) dry weiflgr) Total (g)
1 1.1897 3.7747 3.7032 2.0570 1.9965 7.0214
2 1.1550 3.7793 3.7077 2.0225 1.9630 6.9568
3 1.2203 3.7801 3 .7085 2.0346 1.9747 7.0350
4 1.1423 3.7632 3.6919 2.0053 1.9463 6.9108
5 1.1456 3.7806 3 .7090 2.0020 1.9431 6.9282
6 1.1847 3.7551 3.6840 2.0490 1.9887 6.9888
7 1.1772 3.7747 3 .7032 2.0174 1.9581 6.9693
After Storage
Storage time Total Package Product Silica gel Leaking

(days) (g) (g) (g) (g) Test

7 7.2059 1.2097 3.7559 2.2403 Pass

14 7.3658 1.1750 3.7760 2.4148 Pass

28 7.6107 1.2403 3.7915 2.5789 Pass

35 7.5700 1.1623 3.7925 2.6152 Pass

44 7.6159 1.1656 3.8325 2.6178 Pass

58 7.7670 1.2047 3 .8475 2.7148 Pass

82 7.8152 1.1972 3.8945 2.7235 Pass

 

189

 

 

Table 48 Moisture content of tablets only in HDPE bottles as a function of storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Initial After Storage
Package Product Product Total Storage time Total Product Leaking
__ (g) (g) dry weight (g) (g) (days) (g) (g) Test
1 13.8743 3.7781 3.7065 17.6524 14 3.7885 Pass
2 13.9523 3.7743 3.7028 17.7266 35 3.7989 Pass
3 13.9853 3.7759 3.7044 17.7612 58 3.8085 Pass
4 13.9199 4.0327 3.9563 17.9526 83 4.0716 Pass
5 13.8608 3.7972 3.7253 17.6580 103 3.8501 Pass
6 13.9392 3.7796 3.7080 17.7188 135 3.8432 Pass
7 13.9496 3.7759 3 .7044 17.7255 160 3.8472 Pass

 

 

 

 

Table 49 Moisture content of tablets and 0.5 g Silica gel in HDPE bottles as a function of

 

storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Initial
Package Product Product Silica gel Silica gel
_ (g) (g) dngeight (g) (g) dry weight (g) Total (g)
1 13.9370 3.7643 3.6930 0.5032 0.4884 18.2045
2 13.9006 3.7762 3.7047 0.5004 0.4857 18.1772
3 13.8637 3.7689 3.6975 0.5010 0.4863 18.1336
4 13.9122 3.7789 3.7073 0.5040 0.4892 18.1951
5 13.9266 3 .7700 3.6986 0.5038 0.4890 18.2004
6 13.8595 3.7863 3.7146 0.5038 0.4890 18.1496
7 13.8869 3.7761 3.7046 0.5022 0.4874 18.1652
After Storage
Storage time Total Package Product Silica gel
(days) (5) (g) (g) (g) Leaking Test
14 18.2315 13.9498 3.7431 0.5386 Pass
35 18.2260 13.9147 3.7578 0.5535 Pass
58 18.2176 13.8792 3.7601 0.5783 Pass
83 18.2931 13.9292 3.7730 0.5909 Pass
103 18.3146 13.9448 3.7751 0.5947 Pass
135 18.2801 13.8796 3.7973 0.6032 Pass
160 18.3105 13.9085 3.7962 0.6058 Pass

 

190

 

Appendix E

Dissolution Raw Data and Dissolution Profiles at 25°C

191

1. Dissolution raw data

Table 50 Initial dissolution raw data of uncoated tablets

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minuteS) 1 I 2 ] 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.4065] 0.4846] 0.5200] 0.5287] 0.5019] 0.4597
20 0.5595] 0.5688] 0.5657I 0.5707] 0.5587I 0.5676
30 0.5724] 0.5753] 0.5715] 0.5783] 0.5684] 0.5772
% Dissolved
10 68.23] 81.38] 87.34] 88.79] 84.28] 77.18 81.20 7.603
20 93.71] 95.39] 94.94] 95.79] 93.75] 95.16 94.79 0.868
30 95.85I 96.46] 95.90] 97.05] 95.34] 96.74 96.23 0.635
Table 51 Initial dissolution raw data of coated tablets
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance 7 7
10 0.3677I 0.3754] 0.1924] 0.3538] 0.4342 I 0.0965
20 0.5705] 0.5785I 0.5791] 0.5700] 0.5762] 0.5577
30 0.5768] 0.5807] 0.5361] 0.5782I 0.5830] 0.5864
% Dissolved
10 61.71] 63.00I 32.22] 59.37] 72.90] 16.09 50.88 21.82
20 95.48I 96.83] 96.63] 95.38] 96.55] 92.90 95.63 1.470
30 96.52] 97.19] 89.53I 96.74] 97.67] 97.63 95.88 3.144
Table 52 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/90%
Stirring time Number of trial
(minuteS) 1| 2] 3] 4] 5| 6 Average SD
7 7 . Absorbance
10 0.4697] 0.5088 | 0.5177] 0.5096] 0.5096] 0.5165
20 0.5478] 0.5707] 0.5686] 0.5578] 0.56721 0.5729
30 0.5737] 0.5837] 0.5760I 0.5739] 0.5734] 0.5848
7 I % Dissolved I
10 78.87I 85.45 | 86.94] 85.59] 85.58] 86.74 84.86 3.004
20 91.88] 95.75] 95.42] 93.62] 95.18] 96.13 94.66 1.614
30 96.15] 97.90] 96.64] 96.27I 96.20I 98.10 96.88 0.888
Table 53 Dissolution raw data of coated tablets stored for 1 month at 40°C/90%
Stirring time Number of trial
(minuteS) 1 | 2 | 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.3739] 0.4833] 0.414] 0.5039] 0.4767] 0.4907
20 0.5545] 0.5441] 0.5595] 0.5660] 0.5551] 0.5545
30 0.5858I 0.5602I 0.5822I 0.5781I 0.5722] 0.5709
1 % Dissolved
10 62.75] 81.15] 69.50] 84.62] 80.04I 82.40 76.74 8.633
20 92.83] 91.29] 93.72] 94.97] 93.10] 93.03 93.16 1.204
30 98.00] 93.94] 97.47] 96.97] 95.92] 95.73 96.34 1.463

 

 

 

192

 

 

 

Table 54 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
7 7 Absorbance
10 0.1146] 0.1131] 0.2890] 0.2109] 0.2359] 0.1463
20 0.4007] 0.4257] 0.5018I 0.4862] 0.5013] 0.4423
30 0.5020] 0.5047] 0.5343] 0.5189] 0.5500] 0.5106
1 % DiSSolved 7
10 19.13] 18.88] 48.47I 35.33] 39.54] 24.46 30.97 12.062
20 66.78] 70.93] 83.90] 81.18I 83.74] 73.76 76.72 7.236
30 83.48I 83.96I 89.27] 86.57] 91.77] 85.02 86.68 3.255
Table 55 Dissolution raw data of coated tablets stored for 1 month at 40°C/75%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.0609 I 0.0241] 0.0435 I 0.0285] 0.0194] 0.0255
20 0.3616] 0.0652I 0.3154] 0.3655I 0.2450] 0.1655
30 0.4913] 0.3483I 0.4857I 0.5075] 0.4425 I 0.4588
% Dissolved
10 10.10] 3.90] 7.17] 4.64] 3.11] 4.15 5.51 2.638
20 60.17] 10.74] 52.45] 60.77] 40.69I 27.46 42.05 19.910
30 81.57] 57.42] 80.53] 84.18I 73.25] 75.81 75.46 9.689
Table 56 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/65%
Stirring time Number Of 17181
(minutes) 1 | 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance 7
10 0.2179] 0.1698] 0.2293] 0.2457] 0.1708] 0.2030
20 0.4913] 0.4690] 0.5011] 0.4999] 0.4934] 0.4873
30 0.5326] 0.5242] 0.5456] 0.5438I 0.5269] 0.5237
% Dissolved
10 36.50] 28.4II 38.42] 41.18] 28.59I 34.00 34.52 5.220
20 82.04I 78.25] 83.70] 83.52I 82.32] 81.35 81.86 1.984
30 88.85] 87.35] 91.02] 90.75] 87.84I 87.35 88.86 1.666
Table 57 Dissolution raw data of coated tablets stored for 1 month at 40°C/65%
Stirring time Number of trial
(1111110185) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.0157] 0.0200] 0.0317] 0.0384] 0.0176I 0.0182
20 0.1068] 0.2162] 0.1604] 0.2604] 0.0483I 0.0395
30 0.3701] 0.3948] 0.4399] 0.4699] 0.3193] 0.0745
% Dissolved
10 2.49] 3.21] 5.18] 6.30] 2.81] 2.91 3.82 1.549
20 17.66I 35.90] 26.62] 43.29] 7.92] 6.45 22.97 14.973
30 61.07] 65.33] 72.70] 77.82] 52.60] 12.22 56.96 23.622

 

 

 

 

 

193

 

 

 

Table 58 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stin'ing time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance 7
10 0.3926] 0.3456] 0.4145] 0.4895] 0.3730] 0.3206
20 0.5509] 0.5342] 0.5532] 0.5550] 0.5578] 0.5378
30 0.5685] 0.5498] 0.5665] 0.5687] 0.5732] 0.5589
% Dissolved
10 65.90] 57.98] 69.57] 82.20] 62.60I 53.79 65.34 9.976
20 92.27] 89.41] 92.68] 93.11] 93.39] 89.96 91.80 1.694
30 95.16] 91.97] 94.88] 95.37] 95.92] 93.43 94.46 1.476
Table 59 Dissolution raw data of coated tablets stored for 1 month at 40°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.0236] 0.0354] 0.0227] 0.0238] 0.0209] 0.0352
20 0.1808] 0.1956] 0.0670] 0.1729] 0.1151] 0.2843
30 0.4506] 0.4846] 0.3995] 0.4704] 0.4417] 0.4590
1 % Dissolved
10 3.82] 5.81] 3.66] 3.85] 3.37] 5.77 4.38 1.105
20 29.99] 32.48] 11.05] 28.69I 19.06] 47.26 28.09 12.351
30 74.48] 80.14] 65.87I 77.73] 72.90] 76.07 74.53 4.934
Table 60 Dissolution raw data of uncoated tablets stored for 1 month at 40°C/0%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.3537] 0.3793] 0.3809] 0.4063] 0.4440] 0.3652
20 0.5557] 0.5670] 0.5693] 0.5708I 0.5734] 0.5786
30 0.5729] 0.5757] 0.5745] 0.5809] 0.5807] 0.5869
% Dissolved 7
10 59.35] 63.65] 63.93] 68.20] 74.58] 61.29 65.17 5.487
20 92.99] 94.92] 95.30] 95.61] 96.10] 96.83 95.29 1.307
30 95.83] 96.36] 96.16] 97.27] 97.31] 98.20 96.86 0.890
Table 61 Dissolution raw data of coated tablets stored for 1 month at 40°C/0%
Stirring time Number of trial
(minuteS) 1 ] 2 | 3 I 4 I 5 I 6 Avergge SD
' Absorbance
10 0.3537] 0.2786] 0.3278I 0.3102] 0.1825] 0.2527
20 0.5561] 0.5674] 0.5624] 0.5716] 0.5652] 0.5750
30 0.5754] 0.5808] 0.5712] 0.5779] 0.5763] 0.5831
% Dissolved
10 59.36] 46.72] 54.99] 52.04] 30.55] 42.36 47.67 10.311
20 93.07] 94.82] 94.08] 95.57] 94.29] 96.04 94.64 1.073
30 96.25] 97.03] 95.51] 96.61] 96.13] 97.38 96.48 0.670

 

 

 

 

 

194

 

 

Table 62 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Avera e SD
7 Absorbance
10 0.5340] 0.5316] 0.5475] 0.5392 I 0.5469] 0.5258
20 0.5635] 0.5588I 0.5736I 0.5661] 0.5708] 0.5550
30 0.5728] 0.5673] 0.5833I 0.5767I 0.5757] 0.5612
7 % Dissolved
10 89.69] 89.28] 91.96] 90.55] 91.86] 88.30 90.3 1.462
20 94.6] 93.8] 96.3I 95.0] 95.8I 93.2 94.8 1.191
30 96.1] 95.2] 97.9] 96.8] 96.6] 94.2 96.1 1.294
Table 63 Dissolution raw data of coated tablets stored for 1 month at 25°C/90%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Averae SD
Absorbance
10 0.5528 I 0.5540] 0.5498] 0.5608] 0.5625] 0.5556
20 0.5686] 0.5728] 0.5704] 0.5762] 0.5744] 0.5782
30 0.5733] 0.5789] 0.5726I 0.5824] 0.5787I 0.5822
1 % Dissolved
10 92.86] 93.06] 92.35] 94.20] 94.49] 93.33 93.4 0.817
20 95.5] 96.2] 95.8] 96.8] 96.5] 97.1 96.3 0.601
30 96.3] 97.2] 96.1] 97.8] 97.2] 97.7 97.0 0.707

 

 

 

Table 64 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.5598] 0.5500] 0.5634] 0.5594] 0.5572] 0.5470
20 0.5806] 0.5721] 0.5737 I 0.5723] 0.5678I 0.5620
30 0.5872] 0.5780] 0.5770] 0.5770] 0.5728] 0.5650
, %Dissolved 7 7
10 94.03] 92.38] 94.64] 93.95] 93.58] 91.88 93.4 1.062
20 97.5] 96.1] 96.4] 96.1] 95.4] 94.4 96.0 1.042
30 98.6] 97.0] 96.9] 96.9] 96.2] 94.9 96.8 1.191
Table 65 Dissolution raw data of coated tablets stored for 1 month at 25°C/75%
Stirring time Number of trial
(minutes) 1 I 2 | 3 I 4 I 5 I 6 Avera e SD
Absorbance 7
10 0.5018] 0.4577] 0.4737] 0.2351] 0.5411] 0.5636
20 0.5661] 0.5875] 0.5819] 0.5794] 0.5709] 0.5718
30 0.5710] 0.5931] 0.5879] 0.5860] 0.5734] 0.5762
% Dissolved 7 7
10 84.27I 76.84] 79.55] 39.40] 90.88] 94.67 77.6 19.880
20 95.0] 98.5] 97.6] 96.7] 95.8] 96.0 96.6 1.261
30 95.8I 99.4] 98.5I 97.8] 96.3I 96.8 97.4 1.399

 

 

 

 

 

195

 

 

Table 66 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance
10 0.5458] 0.5527] 0.5463] 0.5460] 0.5509] 0.5422
20 0.5767] 0.5709] 0.5778 1 0.5679] 0.5708] 0.5818
30 0.5811] 0.5760] 0.5849] 0.5767] 0.5780] 0.5853
%Dissolved 7
10 91.67] 92.84] 91.76] 91.70] 92.54] 91.06 91.9 0.647
20 96.8] 95.9] 97.0] 95.4] 95.8] 97.7 96.4 0.875
30 97.5] 96.7] 98.2] 96.8I 97.0] 98.2 97.4 0.687
Table 67 Dissolution raw data of coated tablets stored for 1 month at 25°C/65%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance 7
10 0.5259] 0.3704] 0.4167I 0.4045] 0.2629I 0.0729
20 0.5453] 0.5665] 0.5703] 0.5776] 0.5805] 0.5558
30 0.5681] 0.5847] 0.5739] 0.5855] 0.5863] 0.5775
1 % Dissolved I
10 88.32] 62.17] 69.95] 67.91] 44.07] 12.12 57.4 26.363
20 91.6] 94.8I 95.5] 96.7] 97.0] 92.5 94.7 2.214
30 95.3] 97.8I 96.1] 98.0] 97.9] 96.1 96.9 1.176
Table 68 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/50%
Stirring time Number Of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance
10 0.5214] 0.5364] 0.5581] 0.5328I 0.5333] 0.5445
20 0.5690] 0.5653] 0.5759] 0.5750] 0.5749] 0.5697
30 0.5775] 0.5730] 0.5809] 0.5789] 0.5770] 0.5749
7 %Dissolved 7 77
10 87.57] 90.10] 93.73] 89.48] 89.58] 91.46 90.3 2.088
20 95.5] 94.9] 96.7] 96.5] 96.5] 95.6 96.0 0.723
30 96.9] 96.2] 97.5] 97.2I 96.8I 96.5 96.9 0.477
Table 69 Dissolution raw data of coated tablets stored for 1 month at 25°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.3319] 0.0929] 0.2139] 0.2264] 0.4708] 0.1924
20 0.5702] 0.5410] 0.5890] 0.5836] 0.5638] 0.5593
30 0.5873 I 0.5679I 0.5949] 0.5983] 0.5715] 0.5735
%Dissolved
10 55.69] 15.47] 35.83] 37.94] 79.06] 32.22 42.7 21.964
20 95.4] 90.1] 98.3] 97.4] 94.5] 93.3 94.8 2.958
30 98.2] 94.5] 99.3] 99.8] 95.8] 95.7 97.2 2.177

 

 

 

 

 

196

 

 

 

 

Table 70 Dissolution raw data of uncoated tablets stored for 1 month at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.3577] 0.4806] 0.4195] 0.3970] 0.3735] 0.3481
20 0.5619] 0.5717] 0.5819I 0.5774] 0.5757] 0.5774
30 0.5825] 0.5779] 0.5892] 0.5828] 0.5796I 0.5824
7 * %DisSolved
10 60.02] 80.70I 70.42] 66.64] 62.69] 58.41 66.5 8.233
20 94.0] 95.9] 97.5] 96.7] 96.4] 96.6 96.2 1.169
30 97.4] 96.9] 98.7I 97.6] 97.0] 97.4 97.5 0.635
Table 71 Dissolution raw data of coated tablets stored for 1 month at 25°C/0%
Stirring time Number of trial
(minutes) 1 I 2 ] 3 ’I 4 I 5 I 6 Averagg SD
Absorbance
10 0.2047] 0.3557] 0.2964] 0.1247] 0.1951] 0.3762
20 0.5836] 0.5686] 0.5721] 0.5640I 0.5832] 0.5636
30 0.5968] 0.5711] 0.5789] 0.5729] 0.5923] 0.5678
%Dissolved '
10 34.28I 59.69] 49.71] 20.83I 32.68I 63.13 43.4 16.745
20 97.4] 95.2] 95.6] 94.0] 97.3] 94.3 95.6 1.449
30 99.6] 95.6] 96.8] 95.5] 98.8I 95.0 96.9 1.900
Table 72 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/90%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.3798] 0.3650I 0.4209] 0.4650] 0.4404] 0.4672
20 0.5169] 0.5022] 0.5194] 0.5330] 0.5244] 0.5421
30 0.5517] 0.5330] 0.5439] 0.5463] 0.5470] 0.5495
%Dissolved
10 63.74I 61.25] 70.67I 78.08] 73.94] 78.44 71.02 7.239
20 86.59] 84.11] 87.06] 89.40I 87.93], 90.92 87.67 2.361
30 92.32] 89.19] 91.11] 91.59] 91.65] 92.15 91.33 1.135
Table 73 Dissolution raw data of coated tablets stored for 2 months at 40°C/90%
Stirring time Number of trial
(MINES) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.4153] 0.2295] 0.3584] 0.3664I 0.4144] 0.3978
20 0.5165] 0.4744] 0.5142] 0.5011] 0.5213 @5183
30 0.5438] 0.5277] 0.5460 L0.5301| 0.5476] 0.5464
1 % Dissolved
10 69.71] 38.46] 60.14] 61.49] 69.56] 66.78 61.02 11.761
20 86.58] 79.24] 86.10] 83.93] 87.38I 86.85 85.01 3.067
30 91.07] 88.03] 91.33] 88.71] 91.70] 91.47 90.39 1.588

 

 

 

 

 

 

197

Table 74 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance
10 0.1058] 0.0765] 0.0851] 0.1028] 0.0937] 0.1401
20 0.3867] 0.3843I 0.4105] 0.3607I 0.3696] 0.4363
30 0.4895] 0.4700] 0.4894] 0.4673] 0.4650] 0.5016
%Dissolved I
10 17.64] 12.73] 14.17] 17.14] 15.61] 23.43 16.78 3.732
20 64.44] 63.99I 68.36] 60.10I 61.56] 72.76 65.20 4.655
30 81.39] 78.12I 81.38I 77.68] 77.29] 83.52 79.89 2.546
Table 75 Dissolution raw data of coated tablets stored for 2 months at 40°C/75%
Stirring time Number of trial
(minutes) 1 I 2 | 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.0171] 0.0028I 0.0048] 0.0225] 0.0157] 0.0036
20 0.1354] 0.0164] 0.0657] 0.2832] 0.0220] 0.2446
30 0.4002] 0.2451] 0.4185] 0.4273] 0.2977] 0.4034
1 %Dissolved , I
10 2.73] 0.32] 0.65] 3.64] 2.49] 0.46 1.71 1.413
20 22.42] 2.59] 10.79] 47.06] 3.54] 40.59 21.16 19.040
30 66.08] 40.28] 68.96] 70.82] 48.99] 66.77 60.32 12.566
Table 76 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/65%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7 7
10 0.0947] 0.1070] 0.1044] 0.1334] 0.0885] 0.0937
20 0.3008] 0.3278] 0.3879] 0.4350] 0.2179] 0.2755
30 0.4469I 0.4251] 0.4663] 0.4936] 0.3731] 0.3414
7 %Dissolved
10 15.77]. 17.84] 17.40] 22.29] 14.73] 15.62 17.28 2.720
20 50.10] 54.63] 64.63] 72.53] 36.28] 45.90 54.01 13.050
30 74.20] 70.67I 77.56] 82.19] 61.88] 56.75 70.54 9.629
Table 77 Dissolution raw data of coated tablets stored for 2 months at 40°C/65%
Stirring time Number of trial
(1111110165) 1 I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance 7
10 0.0296 U.0256I 0.0215] 0.0201] 0.0229] 0.0192
20 0.0396] 0.0430] 0.0805I 0.0389] 0.1309] 0.2603
30 0.2632] 0.2145] 0.3239] 0.2169] 0.3539] 0.4435
%Dissolved
10 4.83] 4.15] 3.47] 3.23] 3.70] 3.08 3.74 0.654
20 6.49] 7.05] 13.30] 6.36] 21.69] 43.24 16.35 14.451
30 43.37] 35.33] 53.42] 35.71] 58.46] 73.44 49.96 14.808

 

 

 

 

 

198

Table 78 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance 7
10 0.1244] 0.1731] 0.2085] 0.2121] 0.1852] 0.1728
20 0.4073] 0.4503] 0.4529 I 0.4534] 0.4389I 0.4467
30 0.4509] 0.4836] 0.4994] 0.4847I 0.4850] 0.4862
%Dissolved 7
10 20.77] 28.97] 34.93] 35.53] 31.01] 28.93 30.02 5.354
20 67.89] 75.13] 75.62] 75.71] 73.26] 74.53 73.69 2.981
30 75.08] 80.62I 83.30I 80.89] 80.86I 81.05 80.30 2.741
Table 79 Dissolution raw data of coated tablets stored for 2 months at 40°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.0085] 0.0124] 0.0052] 0.0091] 0.0113] 0.0118
20 0.1757] 0.1560] 0.4489] 0.0543] 0.1866I 0.2139
30 0.4034] 0.3699] 0.5322] 0.4364] 0.3799] 0.3737
% Dissolved I
10 1.28] 1.94] 0.72] 1.38] 1.75] 1.83 1.48 0.455
20 29.12] 25.85] 74.63] 8.90I 30.95] 35.49 34.16 21.827
30 66.66I 61.12] 88.35] 71.91] 62.81I 61.84 68.78 10.391
Table 80 Dissolution raw data of uncoated tablets stored for 2 months at 40°C/0%
Stirring time Number of trial
(minUtes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.3132] 0.3224] 0.3405] 0.3263I 0.3568] 0.3523
20 0.5359] 0.5325] 0.5407] 0.5316I 0.5414] 0.5289
30 0.5455] 0.5428] 0.5434] 0.5384I 0.5422] 0.5304
%Dissolved I
10 52.54] 54.08] 57.13] 54.74] 59.87] 59.11 56.25 2.927
20 89.63] 89.08] 90.48] 88.94I 90.63 I 88.53 89.55 0.856
30 91.22 F9079] 90.93] 90.06] 90.76] 88.78 90.42 0.888
Table 81 Dissolution raw data of coated tablets stored for 2 months at 40°C/0%
Stirring time Number of trial
(minutes) 1 I 2 ] 3 I 4 | 5 I 6 Average SD
7 Absorbance
10 0.2389] 0.2300] 0.1606] 0.1198] 0.0988] 0.2447
20 0.5421] 0.5412] 0.5311] 0.5523] 0.5336] 0.5442
30 0.5493] 0.5546] 0.5384] 0.5676] 0.5532] 0.5554
1 %Dissolved ,
10 40.04] 38.55] 26.87] 20.00] 16.46] 41.01 30.49 10.832
20 90.55 F 90.37] 88.57] 92.03] 88.89I 90.90 90.22 1.292
30 91.72] 92.59] 89.78] 94.56I 92.11] 92.75 92.25 1.555

 

 

 

 

 

199

 

 

 

Table 82 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 ] 4 I 5 I 6 Averagg SD
Absorbance
10 0.5353] 0.5472] 0.5389] 0.5515] 0.5467] 0.5488
20 0.5666] 0.5661] 0.5655] 0.5683I 0.5636I 0.5669
30 0.5782I 0.5709] 0.5750] 0.5728I 0.5679I 0.5718
7 %Dissolved I
10 89.91I 91.90] 90.51] 92.62] 91.83I 92.17 91.49 1.048
20 95.11] 95.05] 94.93] 95.44] 94.63] 95.20 95.06 0.271
30 97.03] 95.85] 96.50] 96.17] 95.35] 96.00 96.15 0.575
Table 83 Dissolution raw data of coated tablets stored for 2 months at 25°C/90%
Stirring time Number Of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Avegg: SD
Absorbance
10 0.5427] 0.5438] 0.5531] 0.5494] 0.5701] 0.5558
20 0.5669] 0.5596] 0.5759] 0.5731] 0.5754] 0.5767
30 0.5700] 0.5683] 0.5816] 0.5723] 0.5788I 0.5822
% Dissolved ,
10 91.15] 91.33] 92.90] 92.27] 95.76] 93.35 92.79 1.687
20 95.18] 93.97] 96.70] 96.22I 96.65] 96.84 95.93 1.136
30 95.68] 95.40] 97.64] 96.09] 97.21] 97.74 96.63 1.027
Table 84 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/75%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Averaje SD
7 Absorbance
10 0.5446] 0.5480] 0.5544] 0.5565] 0.5502 I 0.5556
20 0.5750] 0.5685] 0.5701] 0.5698] 0.5710] 0.5700
30 0.5781 I 0.5714] 0.5740] 0.5729] 0.5754] 0.5760
1 %Dissolved
10 91.47] 92.05] 93.12] 93.47] 92.41] 93.33 92.64 0.796
20 96.54] 95.46] 95.74] 95.69] 95.88] 95.71 95.84 0.368
30 97.05] 95.94] 96.38] 96.19] 96.60] 96.71 96.48 0.394
Table 85 Dissolution raw data of coated tablets stored for 2 months at 25°C/75%
Stirring time Number of trial
(minutes) 1 I 2 ] 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.3726] 0.4290] 0.4652] 0.5070] 0.4862I 0.5384
20 0.5747] 0.5477] 0.5661] 0.5616] 0.5673] 0.5662
30 0.5803I 0.5799] 0.5744] 0.5679J 0.5801] 0.5741
7 %Dissolved I
10 62.53I 72.03] 78.10] 85.15] 81.64] 90.43 78.31 9.934
20 96.20] 91.79] 94.91] 94.24] 95.15] 95.05 94.56 1.496
30 97.12] 97.10] 96.29] 95.28I 97.26] 96.36 96.57 0.754

 

 

 

 

 

200

 

 

 

Table 86 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 J 3 I 4 I 5 I 6 Average so
Absorbance 7
10 0.4999] 0.5131] 0.5053] 0.5137] 0.5174] 0.4799
20 0.5346] 0.5398] 0.5446] 0.5334] 0.5279] 0.5331
30 0.5330] 0.5386] 0.5477] 0.5351] 0.5341] 0.5434
7 %Dissolved
10 83.95] 86.18] 84.86] 86.28] 86.89] 80.58 84.79 2.322
20 89.72] 90.61] 91.41] 89.55] 88.64] 89.45 89.90 0.974
30 89.46] 90.42] 91.92] 89.84] 89.67] 91.14 90.41 0.958
Table 87 Dissolution raw data of coated tablets stored for 2 months at 25°C/65%
Stirring time Number Of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance
10 0.1695] 0.0159] 0.3646] 0.2401] 0.4130] 0.0441
20 0.5382] 0.5417] 0.5384] 0.5497] 0.5340] 0.5446
30 0.5508] 0.5480] 0.5441] 0.5555] 0.5413] 0.5584
%Dissolved
10 28.37] 2.53] 61.18] 40.24] 69.33] 7.27 34.82 27.419
20 89.77] 90.09] 90.13] 91.80] 89.48] 90.62 90.31 0.823
30 91.85] 91.13] 91.07] 92.77] 90.69] 92.90 91.74 0.931
Table 88 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/50%
Stirring time Number Of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 7 Absorbance
10 0.5306] 0.5694] 0.5699] 0.5500] 0.5599] 0.5207
20 0.5700 F 0.5808] 0.5735] 0.5751] 0.5711] 0.5590
30 0.5760] 0.5853] 0.5800] 0.5821] 0.5777] 0.5708
7 I %Dissolved 7
10 89.11] 95.65] 95.73] 92.38] 94.04] 87.45 92.39 3.453
20 95.68] 97.54] 96.32] 96.56] 95.91] 93.83 95.97 1.234
30 96.66] 98.28] 97.39] 97.71] 96.99] 95.77 97.14 0.873
Table 89 Dissolution raw data of coated tablets stored for 2 months at 25°C/50%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance
10 0.3814] 0.2371] 0.3502] 0.1131] 0.3438] 0.4319
20 0.5668] 0.5778] 0.5702] 0.5086] 0.5752] 0.5739
30 0.5724] 0.5796] 0.5751] 0.5408] 0.5874] 0.5841
%Dissolved
10 64.01] 39.74] 58.77] 18.87] 57.69] 72.50 51.93 19.446
20 94.88] 96.49] 95.40] 84.74] 96.23] 96.15 93.98 4.566
30 95.82] 96.78] 96.21] 90.06] 98.24] 97.84 95.82 2.972

 

 

 

 

 

 

201

Table 90 Dissolution raw data of uncoated tablets stored for 2 months at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Averae so
7 Absorbance
10 0.3957] 0.3955] 0.4178] 0.4242] 0.3904] 0.3841
20 0.5706] 0.5718] 0.5746] 0.5685] 0.5786] 0.5710
30 0.5807] 0.5793] 0.5784] 0.5757] 0.5877] 0.5828
7 %Dissolved
10 66.41] 66.39] 70.14] 71.21] 65.52] 64.47 67.36 2.689
20 95.54] 95.74] 96.25] 95.24] 96.87] 95.60 95.88 0.587
30 97.21] 96.98] 96.87] 96.44] 98.38] 97.53 97.24 0.667
Table 91 Dissolution raw data of coated tablets stored for 2 months at 25°C/0%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.2369] 0.3447] 0.2596] 0.3483] 0.1093] 0.1025
20 0.5694] 0.5748] 0.5954] 0.5746] 0.5691] 0.5441
30 0.5726] 0.5820] 0.5893] 0.5798] 0.5805] 0.5865
7 %Dissolved
10 39.70] 57.83] 43.51] 58.45] 18.24] 17.08 39.14 18.249
20 95.08] 96.16] 99.45] 96.14] 94.82] 90.65 95.38 2.847
30 95.61] 97.35] 98.45] 96.99] 96.70] 97.64 97.12 0.954
Table 92 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/90%
Stirring time Number Of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance '
10 0.4412] 0.4009] 0.4099] 0.3733] 0.3793] 0.4480
20 0.5310] 0.5083] 0.5210] 0.4998] 0.4887] 0.5281
30 0.5598] 0.5453 I 0.5536] 0.5382] 0.5334] 0.5481
7 %Dissolved 7
10 74.07] 67.30] 68.81] 62.65] 63.67] 75.22 68.62 5.201
20 89.02] 85.17] 87.31] 83.73] 81.88] 88.56 85.95 2.836
30 93.77] 91.28] 92.68] 90.04] 89.26] 91.85 91.48 1.666
Table 93 Dissolution raw data of coated tablets stored for 3 months at 40°C/90%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.3580] 0.2260] 0.3109] 0.0543] 0.3575] 0.2876
20 0.5105] 0.4494] 0.5194] 0.3896] 0.4899] 0.4889
30 0.5532] 0.5241] 0.5682] 0.5054] 0.5357] 0.5400
%Dissolved
10 60.08] 37.87] 52.15] 8.99] 59.99] 48.24 44.55 19.288
20 85.47] 75.09] 86.87] 64.83] 82.04] 81.76 79.34 8.197
30 92.51] 87.39] 94.92] 83.91] 89.59] 90.19 89.75 3.853

 

 

 

 

 

202

 

 

 

 

Table 94 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance 7
10 0.0692] 0.1048] 0.1007] 0.1608] 0.1286] 0.1242
20 0.2379] 0.3960] 0.3972] 0.4445] 0.3923] 0.3778
30 0.4401] 0.4935] 0.4964] 0.5249] 0.4860] 0.4776
% Dissolved
10 11.49] 17.48] 16.78] 26.90] 21.48] 20.74 19.15 5.199
20 39.58] 65.93] 66.17] 74.15] 65.40] 62.97 62.37 11.786
30 72.93] 82.06] 82.53] 87.41] 80.85] 79.44 80.87 4.733
Table 95 Dissolution raw data of coated tablets stored for 3 months at 40°C/75%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.0438] 0.0178] 0.0487] 0.0276] 0.0167] 0.0169
20 0.0982] 0.0374] 0.4051] 0.2999] 0.0373] 0.0309
30 0.4201] 0.2803] 0.4965] 0.4488] 0.2755] 0.2891
7 %Dissolved 7
10 7.22] 2.84] 8.04] 4.49] 2.66I 2.68 4.65 2.416
20 16.27] 6.10] 67.40] 49.85] 6.10] 5.02 25.12 26.850
30 69.34] 46.16] 82.47] 74.40] 45.36] 47.59 60.89 16.460
Table 96 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/65%
Stirring time Number of trial
(minutes) 1 I 2 L 3 I 4 I 5 I 6 Avera e so
7 7 Absorbance
10 0.0707] 0.0634] 0.0784] 0.0725] 0.0739] 0.0692
20 0.3165] 0.1977] 0.2880] 0.3364] 0.3456] 0.1376
30 0.4215] 0.3283] 0.3756] 0.4540] 0.4275 I 0.1922
%Dissolved
10 11.75] 10.51] 13.04] 12.04] 12.28] 11.49 11.85 0.847
20 52.68] 32.89] 47.95] 56.00] 57.53] 22.87 44.99 14.014
30 69.99] 54.41] 62.39] 75.38] 71.03] 31.89 60.85 16.005
Table 97 Dissolution raw data of coated tablets stored for 3 months at 40°C/65%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.0139] 0.0163] 0.0211] 0.0164] 0.0178] 0.0231
20 0.0326] 0.0359] 0.0441] 0.0364] 0.0434] 0.1951
30 0.2732] 0.2262 I 0.3344] 0.2721] 0.0735] 0.4013
%Dissolved
10 2.18] 2.59] 3.40] 2.60] 2.84] 3.74 2.89 0.575
20 5.31] 5.86] 7.23] 5.94] 7.11] 32.38 10.64 10.678
30 44.97] 37.24] 55.10] 44.80] 12.07] 66.39 43.43 18.379

 

 

 

 

 

203

 

 

Table 98 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.1669] 0.1313] 0.0921] 0.1088] 0.0947] 0.2359
20 0.4216] 0.3408] 0.2946] 0.4058] 0.1774] 0.4595
30 0.4888] 0.4440] 0.3655] 0.4826] 0.2148] 0.5043
7 "/6 Dissolved 7
10 27.92] 21.93] 15.35] 18.16] 15.78] 39.54 23.11 9.305
20 70.35] 56.82] 49.06] 67.61 I 29.56] 76.78 58.37 17.245
30 81.42] 73.85] 60.76] 80.28I 35.72] 84.16 69.36 18.488
Table 99 Dissolution raw data of coated tablets stored for 3 months at 40°C/50%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance
10 0.0250] 0.0213] 0.0319] 0.0177] 0.0522] 0.0263
20 0.2823] 0.1861] 0.1384] 0.0425] 0.2148] 0.2607
30 0.4489] 0.3064] 0.3792] 0.2883] 0.3929] 0.4406
7 "/6 Dissolved
10 4.06] 3.43] 5.21] 2.83] 8.62] 4.27 4.74 2.066
20 46.91] 30.88] 22.95] 6.96] 35.71] 43.31 31.12 14.625
30 74.38] 50.71 I 62.65] 47.49] 65.08] 72.98 62.21 11.149
Table 100 Dissolution raw data of uncoated tablets stored for 3 months at 40°C/0%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance 7
10 0.3255] 0.4356] 0.4508] 0.3949] 0.4168] 0.4218
20 0.5625 I 0.5698] 0.5733] 0.5725] 0.5727] 0.5654
30 0.5800] 0.5755] 0.5790] 0.5808] 0.5807] 0.5772
7 7 %Dissolved 7
10 54.60] 73.13] 75.68] 66.2fl 69.97] 70.82 68.42 7.464
20 94.09] 95.49] 96.10] 95.87] 95.93] 94.73 95.37 0.794
30 96.97] 96.42] 97.04] 97.24] 97.25] 96.68 96.93 0.328
Table 101 Dissolution raw data of coated tablets stored for 3 months at 40°C/0%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.1588] 0.1404] 0.1819] 0.1098] 0.0811] 0.1220
20 0.5394] 0.5572] 0.5506] 0.5513] 0.4910] 0.5411
30 0.5554] 0.5585] 0.5647] 0.5590] 0.5366] 0.5691
%Dissolved I
10 26.57] 23.47] 30.45] 18.31] 13.50] 20.38 22.11 6.048
20 89.96] 92.90] 91.85] 91.85] 81.76] 90.18 89.75 4.069
30 92.60] 93.10] 94.18] 93.12] 89.28] 94.79 92.84 1.920

 

 

 

 

 

204

 

 

 

Table 102 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stin'ing time Number of trial
(minutes) I I 2 I 3 I 4 j 5 I 6 Average SD
Absorbance 7
10 0.5300] 0.5364] 0.5118] 0.5354] 0.5277] 0.5415
20 0.5718]0.5683] 0.5608 I 0.5616] 0.5586] 0.5757
30 0.5809] 0.5776] 0.5693] 0.5686] 0.571tfl 0.5823
7 %Dissolved
10 89.02] 90.09] 85.95 I 89.92] 88.62] 90.95 89.09 1.743
20 95.97] 95.41] 94.11] 94.28] 93.78] 96.64 95.03 1.150
30 97.48] 96.94] 95.51] 95.44] 95.81 r9773 96.49 1.024
Table 103 Dissolution raw data of coated tablets stored for 3 months at 25°C/90%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
A Absorbance '
10 0.5295] 0.5665] 0.5494] 0.5497] 0.5426] 0.5437
20 0.5698] 0.5749] 0.5784] 0.5777] 0.5696] 0.5724
30 0.5763] 0.5842] 0.5853] 0.5845] 0.5747 I 0.5799
%Dissolved 7
10 88.93] 95.16] 92.28] 92.33] 91.13] 91.32 91.86 2.034
20 95.64] 96.55] 97.10] 96.99] 95.62] 96.09 96.33 0.650
30 96.71] 98.08] 98.24] 98.12] 96.48] 97.34 97.49 0.769

 

Table 104 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/75%

 

Stirring time

Number of trial

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.5591] 0.5586] 0.5550] 0.5483] 0.5559] 0.5454
20 0.5779] 0.5747] 0.5686] 0.5637] 0.5696 I 0.5668
30 0.5848] 0.5801] 0.5789] 0.5708] 0.5755] 0.5732
% Dissolved 7 _
10 93.92] 93.83] 93.22] 92.08] 93.37] 91.61 93.01 0.948
20' 97.04] 96.51] 95.48] 94.66] 95.64] 95.17 95.75 0.879
30 98.17] 97.40] 97.18] 95.82] 96.63] 96.22 96.90 0.853
Table 105 Dissolution raw data of coated tablets stored for 3 months at 25°C/75%
Stin'ing time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Averagg so
Absorbance 7
10 0.4896] 0.3429] 0.5264] 0.4363] 0.4643] 0.4495
20 0.5662] 0.5574] 0.5650] 0.5793] 0.5736 I 0.5725
30 0.5806] 0.5787] 0.5692] 0.5847] 0.5825] 0.5801
%Dissolved 7
10 82.22] 57.54] 88.40] 73.24] 77.97] 75.46 75.81 10.438
20 94.98] 93.26] 94.83] 97.06] 96.16] 95.96 95.38 1.321
30 97.35] 96.77] 95.53] 97.96] 97.63 I 97.21 97.08 0.856

 

 

 

 

 

205

 

Table 106 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 ] 3 I 4 I 5 I 6 Average so
7 Absorbance 7
10 0.5396] 0.5449] 0.5227] 0.5558] 0.5315] 0.5419
20 0.5653] 0.5726] 0.5706] 0.5732 I 0.5696] 0.5700
30 0.5695] 0.5749] 0.5776] 0.5732 I 0.5775] 0.5752
%Dissolved
10 90.62] 91.52] 87.79] 93.36] 89.26] 91.01 90.59 1.915
20 94.90] 96.14] 95.76] 96.25] 95.61] 95.69 95.73 0.478
30 95.60] 96.52] 96.92] 96.25] 96.91] 96.56 96.46 0.495
Table 107 Dissolution raw data of coated tablets stored for 3 months at 25°C/65%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.1445] 0.0923] 0.3389] 0.1542] 0.1771] 0.1875
20 0.5371] 0.5633] 0.5793] 0.5574] 0.5654] 0.5722
30 0.5766] 0.5804] 0.5871] 0.5712] 0.5793] 0.5820
7 %DissOlved
10 24.16] 15.38] 56.87] 25.79] 29.63] 31.38 30.54 14.055
20 89.55] 93.82] 96.91] 92.95] 94.32] 95.46 93.84 2.510
30 96.06] 96.65] 98.20] 95.21] 96.60] 97.07 96.63 0.999
Table 108 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance 7
10 0.5486] 0.5325] 0.5362] 0.5408] 0.4899] 0.5682
20 0.5641] 0.5745] 0.5726] 0.5735] 0.5777] 0.5782
30 0.5713] 0.5790 L0.5723I 0.5788] 0.5846] 0.5847
7 %Dissolved I
10 92.14] 89.43] 90.05] 90.83] 82.26] 95.43 90.02 4.357
20 94.72] 96.42] 96.12] 96.27 I 96.88] 97.11 96.25 0.841
30 95.91] 97.18] 96.07] 97.15] 98.02] 98.18 97.08 0.950
Table 109 Dissolution raw data of coated tablets stored for 3 months at 25°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.1335] 0.5076] 0.4506] 0.5087] 0.2102] 0.1359
20 0.5482] 0.5743] 0.5750] 0.5760] 0.5758] 0.5608
30 0.5823] 0.5825] 0.5810] 0.5835] 0.5846] 0.5832
7 %Dissolved 7
10 22.30] 85.24] 75.66] 85.43] 35.22] 22.71 54.43 30.883
20 91.37] 96.36] 96.38] 96.63] 96.11] 93.47 95.05 2.150
30 97.00] 97.71] 97.36] 97.88] 97.56] 97.17 97.45 0.333

 

 

 

 

 

206

 

 

 

 

Table 110 Dissolution raw data of uncoated tablets stored for 3 months at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance
10 0.4340] 0.3970] 0.3927] 0.3733] 0.4039] 0.4364
20 0.5749] 0.5802] 0.5752] 0.5754] 0.5664] 0.5757
30 0.5850] 0.5888] 0.5859] 0.5929] 0.5776] 0.5805
* %Dissolved 7
10 72.86] 66.63] 65.92] 62.65] 67.79] 73.27 68.19 4.147
20 96.33] 97.14] 96.31] 96.31] 94.86] 96.46 96.24 0.748
30 97.99] 98.56] 98.07] 99.20] 96.71] 97.26 97.97 0.892
Table 111 Dissolution raw data of coated tablets stored for 3 months at 25°C/0%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance
10 0.2546] 0.2923] 0.3037] 0.2249 I 0.2307] 0.3025
20 0.5666] 0.5787] 0.5782] 0.5772] 0.5766] 0.5646
30 0.5762] 0.5850] 0.5854] 0.5924] 0.5878] 0.5649
A %Dissolved *
10 42.68] 49.03] 50.94] 37.68] 38.66 I 50.74 44.95 6.061
20 94.64] 96.73] 96.67] 96.37] 96.27] 94.39 95.84 1.046
30 96.24] 97.76] 97.84] 98.87] 98.11] 94.44 97.21 1.607

 

Table 112 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance 7
10 0.3775] 0.3485] 0.3986] 0.3914] 0.4305] 0.4366
20 0.4950] 0.4906] 0.5085 L0.48I8I 0.5216] 0.5271
30 0.5356] 0.5378] 0.5432 I 0.5192] 0.5490] 0.5534
7 7 %Dissolved . '
10 63.36] 58.48] 66.90 I 65.70] 72.28] 73.30 66.67 5.558
20 82.93] 82.15] 85.22] 80.76] 87.44] 88.37 84.48 3.036
30 89.63] 89.92] 90.94] 86.92] 91.96] 92.71 90.35 2.046
Table 113 Dissolution raw data of coated tablets stored for 4 months at 40°C/90%
Stirring time Number of trial
(minUtCS) 1 I 2 T 3 I 4 I 5 I 6 Average so
Absorbance
10 0.2658] 0.2279] 0.3542] 0.2056] 0.2249] 0.2131
20 0.4569] 0.4355] 0.5024] 0.4292] 0.4105] 0.4383
30 0.5234] 0.5025] 0.5416] 0.5111] 0.4948] 0.5147
%Dissolved _ A
10 44.57] 38.19] 59.44] 34.44] 37.68] 35.70 41.67 9.380
20 76.40] 72.76] 84.11] 71.67] 68.60] 73.20 74.46 5.357
30 87.36] 83.81] 90.58] 85.19] 82.49] 85.81 85.87 2.847

 

207

 

 

Table 114 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.1247] 0.0694] 0.0693] 0.0701] 0.1099] 0.0895
20 0.4232] 0.2989] 0.1965] 0.1772] 0.4012] 0.4055
30 0.5248] 0.4625] 0.4465] 0.4269] 0.5114] 0.4969
%Dissolved
10 20.82] 11.53] 11.50] 11.65] 18.33] 14.91 14.79 4.007
20 70.54] 49.76] 32.70] 29.48] 66.86] 67.54 52.81 18.366
30 87.29] 76.72] 73.90] 70.64] 85.02] 82.60 79.36 6.606
Table 115 Dissolution raw data of coated tablets stored for 4 months at 40°C/75%
Stirring time Number Of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.0104] 0.0380] 0.0235] 0.0240] 0.0572] 0.0752
20 0.1876] 0.2375] 0.2912] 0.1197] 0.3812] 0.3739
30 0.3855] 0.4263] 0.4850 I 0.3708] 0.5001] 0.4961
%Dissolved
10 1.59] 6.25] 3.80] 3.89] 9.47] 12.50 6.25 4.066
20 31.11] 39.48] 48.39] 19.83] 63.44] 62.26 44.08 17.327
30 63.74] 70.59] 80.34] 61.23] 83.05] 82.40 73.56 9.710
Table 116 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/65%
Stin'ing time Number of trial
(minutes) 1 I 2 I 3 I 4 ] 5 I 6 Averae so
Absorbance
10 0.0531] 0.0594] 0.0675] 0.0561] 0.0633] 0.0752
20 0.1111] 0.1296] 0.2545] 0.1162] 0.2821] 0.1357
30 0.1990] 0.2107] 0.3651] 0.1720] 0.3718] 0.1857
7 %Dissolved ,
10 8.78] 9.83] 11.21] 9.29] 10.50] 12.51 10.35 1.360
20 18.44] 21.54] 42.36] 19.30] 46.94] 22.57 28.52 12.662
30 32.93] 34.91] 60.59] 28.49] 61.73] 30.82 41.58 15.322
Table 117 Dissolution raw data of coated tablets stored for 4 months at 40°C/65%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance
10 0.0244] 0.0166] 0.0203] 0.0226] 0.0227] 0.0306
20 0.0972] 0.0355] 0.0384] 0.0442] 0.0466] 0.1764
30 0.3606] 0.1741] 0.2843] 0.2938] 0.3925] 0.3579
7 %Dissolved
10 3.95] 2.65] 3.25] 3.65] 3.67] 5.00 3.70 0.783
20 16.08] 5.79] 6.28] 7.24] 7.65] 29.29 12.05 9.254
30 59.51] 28.64] 46.82] 48.40] 64.67] 59.21 51.21 13.043

 

208

 

Table 118 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance 7 7
10 0.1374] 0.1380] 0.0988] 0.1134] 0.1065] 0.1435
20 0.3190] 0.3706] 0.4066] 0.4219] 0.3409] 0.3284
30 0.3705] 0.4270] 0.4674] 0.4770] 0.4501] 0.3976
7 %Dissolved
10 22.97] 23.07] 16.48] 18.92] 17.76] 23.99 20.53 3.195
20 53.21 I 61.81 | 67.73 | 70.30] 56.81 | 54.78 60.77 7.057
30 61.70] 71.11] 77.77] 79.39] 74.80] 66.19 71.83 6.872
Table 119 Dissolution raw data of coated tablets stored for 4 months at 40°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.0227] 0.0474] 0.0231] 0.0245 I 0.1167 I— 0.0237
20 0.0391] 0.3745] 0.2525] 0.1210] 0.4187] 0.0561
30 0.2851] 0.5097] 0.4277] 0.3555] 0.5123] 0.3241
7 %Dissolved
10 3.67] 7.83] 3.74] 3.97] 19.48] 3.84 7.09 6.282
20 6.41] 62.30] 41.94] 20.05] 69.78] 9.23 34.95 27.235
30 46.96] 84.59] 70.83] 58.71 I 85.21] 53.42 66.62 16.186

 

 

 

Table 120 Dissolution raw data of uncoated tablets stored for 4 months at 40°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(MINES) l I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.3988] 0.3950] 0.4526] 0.3313] 0.3723] 0.3421
20 0.5571] 0.5743] 0.5743] 0.5743] 0.5738] 0.5701
30 0.5764] 0.5820] 0.5820] 0.5889] 0.5859] 0.5816
%Dissolved *
10 66.94] 66.30] 76.00] 55.59] 62.48] 57.41 64.12 7.406
20 93.30] 96.16] 96.27] 96.06] 96.04] 95.37 95.53 1.138
30 96.49] 97.43] 97.54] 98.46] 98.04] 97.26 97.54 0.676
Table 121 Dissolution raw data of coated tablets stored for 4 months at 40°C/0%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7 ‘
10 0.1449] 0.0443] 0.0279] 0.2971] 0.1719] 0.1092
20 0.5576] 0.5158] 0.4608 I 0.5654] 0.5676] 0.5656
30 0.5764] 0.5877] 0.5708] 0.5813] 0.5818] 0.5738
7 % Dissolved
10 24.22] 7.30] 4.54] 49.83] 28.77] 18.22 22.15 16.495
20 92.97] 85.83 I 76.64] 94.52] 94.67] 94.24 89.81 7.276
30 96.05] 97.68] 94.78] 97.13] 97.02] 95.59 96.38 1.093

 

209

 

 

 

 

Table 122 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.5149] 0.5177] 0.5218] 0.5142] 0.5151] 0.5234
20 0.5522] 0.5593] 0.5589] 0.5489] 0.5410] 0.5663
30 0.5620] 0.5732] 0.5760] 0.5659] 0.5565] 0.5753
% Dissolved I
10 86.47] 86.94] 87.63] 86.35] 86.51] 87.91 86.97 0.657
20 92.68] 93.87] 93.82] 92.13] 90.82] 95.05 93.06 1.497
30 94.30] 96.16] 96.64] 94.94] 93.37] 96.53 95.32 1.335
Table 123 Dissolution raw data of coated tablets stored for 4 months at 25°C/90%
Stirring time Number of trial
(minutes) i I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.5436] 0.5362] 0.5487] 0.5375] 0.5333] 0.5317
20 0.5669] 0.5708] 0.5798] 0.5686] 0.5661] 0.5704
30 0.5789] 0.5775] 0.5906] 0.5762] 0.5742] 0.5758
7 %Dissolved
10 91.29] 90.06] 92.15] 90.27] 89.56] 89.31 90.44 1.085
20 95.18] 95.82] 97.34] 95.46] 95.04] 95.75 95.77 0.832
30 97.16] 96.93] 99.12] 96.71] 96.36] 96.63 97.15 1.000
Table 124 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/75%
Stirring time Number of trial
(minutes) I I 2 I 3 L 4 I 5 I 6 Avera e SD
Absorbance
10 0.5550] 0.5700] 0.5444] 0.5488] 0.5419] 0.5532
20 0.5820] 0.5812] 0.5722] 0.5856] 0.5667] 0.5803
30 0.5891] 0.5901] 0.5787] 0.5909] 0.5738] 0.5855
%Dissolved I
10 93.23] 95.75] 91.43] 92.18] 91.02] 92.92 92.75 1.690
20 97.72] 97.61] 96.06] 98.31] 95.14] 97.44 97.05 1.194
30 98.88] 99.07] 97.15] 99.18] 96.32] 98.29 98.15 1.169
Table 125 Dissolution raw data of coated tablets stored for 4 months at 25°C/75%
Stirring time Number Of trial
(minutes) 1 I 2 I 3 I 4 J 5 I 6 Average SD
Absorbance 7
10 0.5483] 0.1944] 0.4424] 0.4404] 0.4579] 0.1451
20 0.5741] 0.5717] 0.5644] 0.5758] 0.5776] 0.5496
30 0.5861 I 0.5845 I 0.5751 | 0.5790] 0.5834] 0.5721
%Dissolved
10 92.09] 32.56] 74.28] 73.93] 76.88] 24.26 62.33 27.240
20 96.39] 95.40] 94.60] 96.49] 96.82] 91.63 95.22 1.942
30 98.37] 97.51] 96.35] 97.02] 97.78] 95.35 97.06 1.084

 

 

 

210

 

 

Table 126 Dissolution raw data of uncoated tablets stored for 4 months at 25 °C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.4958] 0.5500] 0.5069] 0.5148] 0.5260] 0.5409
20 0.5726] 0.5759] 0.5697] 0.5783] 0.5741] 0.5686
30 0.5791] 0.5809] 0.5729] 0.5854] 0.5796] 0.5759
%Dissolved
10 83.25] 92.38] 85.13] 86.46] 88.33] 90.84 87.73 3.466
20 96.04] 96.68] 95.59] 97.03] 96.35] 95.46 96.19 0.615
30 97.12] 97.51] 96.11] 98.20] 97.26] 96.66 97.14 0.716
Table 127 Dissolution raw data of coated tablets stored for 4 months at 25°C/65%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.2172] 0.0854] 0.1228] 0.3418] 0.0636] 0.0363
20 0.5628] 0.5462] 0.5731] 0.5825] 0.5258] 0.5284
30 0.5875] 0.5928] 0.5828] 0.5879] 0.5842] 0.5774
7 %Dissolved
10 36.38] 14.21] 20.51] 57.36] 10.54] 5.96 24.16 19.392
20 93.95] 90.96] 95.51] 97.44] 87.53] 87.92 92.22 4.077
30 98.02] 98.64] 97.11] 98.33] 97.16] 96.00 97.54 0.975
Table 128 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/50%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.5392] 0.5510] 0.5574] 0.5676] 0.4996] 0.5521
20 0.5680] 0.5706] 0.5722] 0.5772] 0.5782] 0.5722
30 0.5744] 0.5763] 0.5798] 0.5773] 0.5871] 0.5797
%Dissolved
10 90.56] 92.55] 93.62] 95.33] 83.90] 92.73 91.45 4.010
20 95.36] 95.82] 96.09] 96.94] 96.99] 96.08 96.21 0.641
30 96.42] 96.75] 97.34] 96.95] 98.46] 97.32 97.21 0.705
Table 129 Dissolution raw data of coated tablets stored for 4 months at 25°C/50%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance
10 0.3728] 0.2678] 0.2065] 0.1076] 0.3896] 0.2662
20 0.5624] 0.5489] 0.5470] 0.5784] 0.5569] 0.5605
30 0.5746] 0.5754] 0.5681] 0.5945] 0.5709] 0.5823
%Dissolved
10 62.57] 44.89] 34.60] 17.94] 65.40] 44.63 45.01 17.694
20 94.15] 91.72] 91.31] 96.37] 93.26] 93.65 93.41 1.825
30 96.15] 96.09] 94.78] 99.03] 95.57] 97.24 96.48 1.484

 

 

 

 

 

211

 

 

 

 

Table 130 Dissolution raw data of uncoated tablets stored for 4 months at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.3704] 0.3879] 0.4135] 0.4275] 0.4181] 0.4519
20 0.5825] 0.5736] 0.5601] 0.5765] 0.5670] 0.5743
30 0.5968] 0.5816] 0.5687] 0.5827] 0.5726] 0.5813
%Dissolved 7
10 62.16] 65.11] 69.42] 71.78] 70.19] 75.88 69.09 4.867
20 97.49] 96.04] 93.83] 96.58] 94.98] 96.27 95.87 1.286
30 99.84] 97.35] 95.25] 97.62] 95.92] 97.42 97.23 1.591
Table 131 Dissolution raw data of coated tablets stored for 4 months at 25°C/0%
Stin'ing time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Avera e SD
Absorbance
10 0.1605] 0.3679] 0.3295] 0.3720] 0.3859] 0.1001
20 0.5688] 0.5797] 0.5714] 0.5740] 0.5650] 0.5644
30 0.5894] 0.5893] 0.5816] 0.5802] 0.5746] 0.5890
%Dissolved
10 26.85] 61.75] 55.28] 62.43] 64.76] 16.69 47.96 20.779
20 94.86] 97.02] 95.58] 96.07] 94.60] 94.02 95.36 1.087
30 98.26] 98.60] 97.25] 97.10] 96.19] 98.08 97.58 0.897
Table 132 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/90%
Stirring time Number of trial
(minutes) 1 ] 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.3259] 0.3722] 0.3023] 0.3313] 0.3587] 0.3939
20 0.4624] 0.4777] 0.4499] 0.4553] 0.4713] 0.5016
30 0.5129] 0.5217] 0.4987] 0.5057] 0.5176] 0.5362
%Dissolved
10 54.68 62.47 50.71 55.59 60.19 66.12 58.29 5.661
20 77.41 80.04 75.29 76.23 78.95 84.05 78.66 3.158
30 85.74 87.29 83.33 84.54 86.58 89.76 86.21 2.244
60 (200 rpm) 95.64 94.77 94.95 95.49 96.32 96.32 95.58 0.658
Table I33 Dissolution raw data of coated tablets stored for 5 months at 40°C/90%
Stirring time Number of trial
(minutes) I J 2 I 3 I 4 I 5 I 6 Average SD
7 Absorbance 7
10 0.0278] 0.0555] 0.1077] 0.0712 I 0.0671] 0.0360
20 0.1550] 0.1838] 0.3106] 0.2361] 0.2700] 0.1451
30 0.3110] 0.2871] 0.4133] 0.3456] 0.3843] 0.2615
%Dissolved
10 4.53 9.18 17.97 11.82 11.13 5.90 10.09 4.806
20 25.71 30.56 51.76 39.29 44.93 24.08 36.06 11.105
30 51.43 47.58 68.69 57.34 63.78 43.26 55.35 9.747
60(200 rpm) 91.54 89.90 94.22 89.64 91.63 91.32 91.38 1.638

 

 

 

 

 

 

 

 

 

 

212

 

 

 

Table I34 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.0673] 0.0697] 0.0760] 0.0576] 0.0825] 0.0895
20 0.3141] 0.2534] 0.3355 LO.I645I 0.3472] 0.2987
30 0.4669] 0.4248] 0.4780] 0.3188] 0.4749] 0.3906
% Dissolved
10 11.16 11.58 12.63 9.54 13.73 14.91 12.26 1.917
20 52.27 42.17 55.85 27.34 57.82 49.74 47.53 11.302
30 77.47 70.42 79.35 52.78 78.87 64.89 70.63 10.414
60 (200 rpm) 95.58 96.27 97.35 96.26 96.73 96.03 96.37 0.608
Table I35 Dissolution raw data of coated tablets stored for 5 months at 40°C/75%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 r 5 I 6 Average SD
Absorbance
10 0.0198] 0.0333] 0.0314] 0.0460] 0.0206] 0.0282
20 0.0352] 0.0622] 0.3075] 0.2490] 0.0898] 0.2093
30 0.3396] 0.3062] 0.4875] 0.4359] 0.3585] 0.4510
% Dissolved I
10 3.18 5.45 5.13 7.59 3.32 4.59 4.88 1.622
20 5.75 10.26 51.11 41.39 14.85 34.76 26.35 18.579
30 55.93 50.49 80.79 72.21 59.14 74.61 65.53 11.993
60 (200 rpm) 96.53 95.86 96.98 96.85 94.83 98.21 96.54 1.137
Table I36 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/65%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 7 Absorbance
10 0.0544] 0.0361] 0.0448] 0.0343] 0.0487] 0.0535
20 0.1267 I 0.0829] 0.0911] 0.0798] 0.1593] 0.1078
30 0.1815] 0.2162] 0.1349] 0.1465] 0.2442 L0.1572
%Dissolved
10 9.00 5.93 7.38 5.62 8.03 8.85 7.47 1.442
20 21.05 13.72 15.09 13.19 26.46 17.90 17.90 5.115
30 30.07 35.69 22.32 24.20 40.46 26.03 29.79 7.069
60 (200 rpm) 92.78 93.78 82.61 90.88 93.82 83.77 89.61 5.096
Table I37 Dissolution raw data of coated tablets stored for 5 months at 40°C/65%
Stirring time Number of trial '
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.0211 I 0.0282] 0.0324] 0.0269] 0.0237] 0.0112
20 0.0499] 0.1233] 0.1764] 0.1031] 0.0515] 0.0346
30 0.3496] 0.3614] 0.4286] 0.3249] 0.2828] 0.1780
% Dissolved 7
10 3.40 4.59 5.30 4.38 3.83 1.73 3.87 1.236
20 8.19 20.44 29.29 17.06 8.46 5.63 14.84 9.108
30 57.61 59.69 70.86 53.63 46.60 29.27 52.94 14.068
60 (200 rpm) 96.18 95.69 96.56 96.94 98.06 97.41 ' 96.81 0.856

 

213

 

 

Table I38 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.1214] 0.0843] 0.0635] 0.0993] 0.0944] 0.1030
20 0.2520] 0.2510] 0.1112] 0.1494] 0.3383] 0.1496
30 0.3812 0.3192] 0.1383] 0.1799] 0.4028I 0.1741
%Dissolved
10 20.27 14.03 10.52 16.56 15.72] 17.18 15.71 3.266
20 42.02 41.79 18.47 24.90 56.35] 24.94 34.75 14.333
30 63.33 53.04 22.94 29.92 66.99[ 28.98 44.20] 19.240
60 (200 rpm) 86.04 90.28 86.71 86.54 92.49] 86.62 88.11] 2.641
Table I39 Dissolution raw data of coated tablets stored for 5 months at 40°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance 7
10 0.0393] 0.0452] 0.036II 0.0295] 0.0322] 0.0245
20 0.0529] 0.0840] 0.0744] 0.0703] 0.0894] 0.0580
30 0.2300] 0.2899] 0.3953] 0.2483] 0.2583] 0.1112
%Dissolved
10 6.46 7.45 5.92 4.81 5.27 3.97 5.65 1.237
20 8.72 13.92 12.31 11.61 14.79 9.55 11.82 2.375
30 37.92 47.87 65.21 40.95 42.64 18.32 42.15 15.178
60 (200 rpm) 97.02 99.64 99.32 98.54 97.89 99.79 98.70 1.094
Table I40 Dissolution raw data of uncoated tablets stored for 5 months at 40°C/0%
Stirring time Number of trial
(minutCS) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.3704] 0.4120] 0.3998 I 0.3524] 0.3567] 0.3207
20 0.5617]0.5622| 0.5717] 0.5765] 0.5700] 0.5653
30 0.5757] 0.5750] 0.5817] 0.5875] 0.5760] 0.5788
% Dissolved
10 62.16 69.16 67.11 59.14 59.86 53.81 61.87 5.608
20 94.03 94.18 95.74 96.46 95.39 94.55 95.06 0.962
30 96.34 96.29 97.39 98.27 96.38 96.76 96.90 0.786
60 L200 rpm) 96.92 96.18 97.04 99.32 96.75 97.65 97.31 1.090
Table l4l Dissolution raw data of coated tablets stored for 5 months at 40°C/0%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance
10 0.0576] 0.0829] O.l888I 0.0593] 0.2550] 0.0938
20 0.5348] 0.5340] 0.5647] 0.5251] 0.5591] 0.5552
30 0.5796] 0.5751] 0.5780] 0.5691] 0.5755] 0.5816
%Dissolved I
10 9.54 13.80 31.61 9.82 42.75 15.62 20.52 13.575
20 89.02 88.93 94.22 87.41 93.40 92.48 90.91 2.802
30 96.41 95.71 96.41 94.66 96.10 96.83 96.02 0.762
60@0 rpm) 97.19 96.66 96.74 97.63 96.18 97.58 97.00 0.571

 

214

 

Table I42 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.5101] 0.5197] 0.5165] 0.4886] 0.5009] 0.5059
20 0.5618] 0.5640] 0.5615] 0.5582] 0.5510] 0.5534
30 0.5740] 0.5758] 0.5751L0.5744I 0.5656] 0.5666
%Dissolved
10 85.67 87.28 86.74 82.05 84.12 84.96 85.14 1.902
20 94.28 94.65 94.24 93.65 92.46 92.87 93.69 0.868
30 96.29 96.61 96.48 96.31 94.87 95.05 95.94 0.766
60 (200 rpm) 96.13 97.48 97.38 97.52 96.84 95.85 96.87 0.726
Table I43 Dissolution raw data of coated tablets stored for 5 months at 25°C/90%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance 7
10 0.5307] 0.5225] 0.5117] 0.5214] 0.5168] 0.5138
20 0.5643] 0.5724] 0.5655] 0.5580] 0.5692] 0.5533
30 0.5729] 0.5847] 0.5765] 0.5668] 0.5808] 0.5603
7 %Dissolved
10 89.13 87.75 85.93 87.56 86.80 86.29 87.24 1.161
20 94.73 96.06 94.89 93.66 95.52 92.86 94.62 1.181
30 96.15 98.08 96.71 95.12 97.43 94.02 96.25 1.501
60 (200 rpm) 96.46 98.30 96.76 96.53 97.56 94.99 96.77 1.122
Table I44 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/75%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance
10 0.5409] 0.5637] 0.5453] 0.5514] 0.5397] 0.5491
20 0.5749] 0.5716] 0.5700] 0.5687] 0.5794] 0.5750
30 0.5829] 0.5684] 0.5690 I 0.5659 I 0.5743] 0.5684
7 %Dissolved
10 90.84 94.68 91.58 92.61 90.65 92.23 92.10 1.475
20 96.50 96.00 95.71 95.49 97.25 96.54 96.25 0.646
30 97.83 95.47 95.53 95.03 96.42 95.45 95.96 1.027
60 (200 rpm) 96.24 95.39 95.38 95.05 96.67 95.61 95.72 0.611
Table I45 Dissolution raw data of coated tablets stored for 5 months at 25°C/75%
Stirring time Number of trial _
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance
10 0.4591] 0.3310] 0.4533] 0.3914] 0.1946] 0.0563
20 0.5739] 0.5699] 0.5715 I 0.5673] 0.5719] 0.5378
30 0.5887] 0.5809] 0.5831] 0.5814] 0.5864] 0.5846
%Dissolved
10 77.08 55.54 76.10 65.69 32.58 9.32 52.72 26.852
20 96.21 95.32 95.80 94.99 95.43 89.52 94.55 2.499
30 98.65 97.13 97.71 97.31 97.82 97.23 97.64 0.564
60(200 rpm) 98.35 97.53 98.13 97.44 98.25 98.99 98.12 0.573

 

215

 

 

 

 

 

Table I46 Dis
Stirring time
(minutes)

10

20

30

7 60 (200 mm

Table I47 Dis

Stirring timt
(minutes)

I] IIIH

 

IO

/

/

Stirring tlm

‘50 (200 n
Stirring tin
minmes)

T

[[Hs/

//"

l0

/./

IO
20
30

W

 

5‘
A
[O
O

O

Table I46 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7 7
10 0.4490 I 0.4452] 0.5333] 0.4894] 0.5205] 0.5255
20 0.5691] 0.5635] 0.5635] 0.5594] 0.5652] 0.5658
30 0.5754] 0.5727] 0.5703] 0.5709] 0.5685] 0.5793
%Dissolved
10 75.39 74.75 89.57 82.18 87.42 88.26 82.93 6.589
20 95.38 94.46 94.60 93.85 94.86 94.96 94.68 0.520
30 96.42 95.97 95.72 95.74 95.40 97.20 96.07 0.646
60 (200 rpm) 96.94 96.50 95.61 96.08 95.74 97.43 96.38 0.711
Table I47 Dissolution raw data of coated tablets stored for 5 months at 25°C/65%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance 7
10 0.2864] 0.1793] 0.0278] 0.0340] 0.0300] 0.0921
20 0.5634] 0.5573] 0.5209] 0.5370] 0.4480] 0.5393
30 0.5753] 0.5730] 0.5773] 0.5693] 0.5241 I 0.5676
7 I %Dissolved
10 48.04 30.01 4.52 5.56 4.89 15.34 18.06 17.673
20 94.16 92.96 86.65 89.28 74.52 89.82 87.90 7.087
30 96.13 95.56 95.95 94.67 87.06 94.48 93.98 3.454
60 (200 rpm) 97.26 96.26 97.18 95.88 96.79 95.99 96.56 0.602
Table I48 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance
10 0.5194] 0.5244] 0.5374] 0.5074] 0.4729] 0.5422
20 0.5613] 0.5613] 0.5732] 0.5697] 0.5702] 0.5718
30 0.5716] 0.5651] 0.5767] 0.5699] 0.5801] 0.5752
%Dissolved
10 87.23 88.07 90.27 85.21 79.41 91.06 86.87 4.221
20 94.22 94.21 96.22 95.59 95.62 795.99 95.31 0.879
30 95.90 94.84 96.80 95.62 97.25 96.55 96.16 0.878
60 (200 rpm) 96.53 94.78 96.00 95.46 96.85 96.61 96.04 0.791
Table I49 Dissolution raw data of coated tablets stored for 5 months at 25°C/50%
Stirring time Number of trial
(minutes) I ] 2 j 3 I 4 I 5 I 6 Average SD
7 7 Absorbance
10 0.2944] 0.2183] 0.2581] 0.1673] 0.4324] 0.0596
20 0.5717] 0.5559] 0.5637] 0.5172] 0.5619] 0.5527
30 0.5839] 0.5697] 0.5922] 0.5470] 0.5737] 0.5778
%Dissolved I 7
10 49.37 36.58 43.27 27.99 72.59 9.87 39.95 21.092
20 95.56 92.80 94.18 86.28 94.16 92.01 92.50 3.286
30 97.57 95.08 98.86 91.19 96.11 96.14 95.82 2.626
60 (200 rpm) 96.98 95.45 98.38 97.38 95.70 97.34 96.87 1.109

 

216

 

 

Table 150 Dissolution raw data of uncoated tablets stored for 5 months at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance
10 0.3814] 0.3752] 0.3464] 0.4219] 0.3543] 0.4328
20 0.5633] 0.5631] 0.5744] 0.5714] 0.5775] 0.5684
30 0.5789] 0.5724] 0.5880] 0.5761] 0.5882] 0.5761
% Dissolved
10 64.02 62.97 58.13 70.83 59.45 72.66 64.68 5.917
20 94.31 94.26 96.10 95.73 96.63 95.25 95.38 0.960
30 96.88 95.80 98.35 96.49 98.39 96.51 97.07 1.065
60Q00 rpm)
Table 151 Dissolution raw data of coated tablets stored for 5 months at 25°C/0%
Stirring time Number of trial
(minutCS) 1 I 2 I 3 I 4 I 5 I 6 Avegge so
Absorbance 7
10 0.1994] 0.1639] 0.0224] 0.3564] 0.0772] 0.0851
20 0.5558] 0.5690] 0.4960 I 0.5666] 0.5593] 0.5536
30 0.5722] 0.5907] 0.5634] 0.5776] 0.5710] 0.5718
* %Dissolved
10 33.39 27.42 3.61 59.81 12.84 14.16 25.21 20.053
20 92.76 94.89 82.49 94.81 93.13 92.19 91.71 4.649
30 95.46 98.47 93.62 96.63 95.06 95.20 95.74 1.647
60 (200 rpm) 96.29 99.04 97.42 96.99 95.54 96.79 97.01 1.184
Table 152 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/90%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Averaie SD
7 _ Absorbance
10 0.3347] 0.2884] 0.3440] 0.3078] 0.3352] 0.3098
20 0.4734] 0.4366] 0.4663] 0.448II 0.4543] 0.4419
30 0.5221] 0.4963] 0.5170] 0.5053] 0.4939] 0.4984
7 %Dissolved 7 7
10 56.15] 48.37] 57.67] 51.63] 56.23] 51.96 53.67 3.576
20 79.26] 73.05] 78.09] 74.99] 76.08] 73.97 75.91 2.401
30 87.29] 82.90] 86.45] 84.44] 82.60] 83.29 84.49 1.959
Table [53 Dissolution raw data of coated tablets stored for 6 months at 40°C/90%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 7 Absorbance 7 7
10 0.1348] 0.1542] 0.0612] 0.1260] 0.0711] 0.1083
20 0.3374] 0.3713] 0.2563] 0.3384] 0.2907] 0.3647
30 0.4468] 0.4617] 0.3676] 0.4414] 0.4100] 0.4606
7 7 %Dissolved 7 7
10 22.53] 25.79] 10.14] 21.05] 11.81] 18.06 18.23 6.169
20 56.27] 61.95] 42.63] 56.42] 48.38] 60.77 54.40 7.481
30 74.30] 76.85] 60.98] 73.40] 68.06] 76.58 71.70 6.132

 

217

 

 

 

Table 154 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I S I 6 Average SD
Absorbance 7
10 0.1017] 0.0601] 0.0776] 0.0484] 0.0594] 0.0615
20 0.3135] 0.1347] 0.2319 @2898] 0.2224] 0.1717
30 0.4731] 0.4144] 0.4340] 0.4404] 0.4380] 0.3719
%Dissolved
10 16.96] 9.97] 12.91] 7.99] 9.85] 10.20 11.31 3.185
20 52.23] 22.38] 38.60] 48.19] 36.99] 28.55 37.82 11.323
30 78.54] 68.50] 71.93] 73.03] 72.53] 61.56 71.02 5.651
Table 155 Dissolution raw data of coated tablets stored for 6 months at 40°C/75%
Stirring time Number of trial
(minutes) 1, I 2 I 3 I 4 I 5 I 6 Average so
Absorbance 7
10 0.0758] 0.0422 I 0.0359] 0.0580] 0.0646] 0.1022
20 0.2726] 0.1147] 0.1476] 0.2928] 0.4144] 0.4064
30 0.4926] 0.4421] 0.4625] 0.4955] 0.5439] 0.5229
%Dissolved I
10 12.59] 6.95] 5.89] 9.60] 10.72] 17.05 10.47 4.048
20 45.37] 19.03] 24.49] 48.72] 68.97] 67.70 45.71 20.959
30 8|.64I 73.00] 76.41] 82.14] 90.33] 86.92 81.74 6.410
Table 156 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/65%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance 7
10 0.0530] 0.0447] 0.0495] 0.0415] 0.0458] 0.0431
20 0.0768] 0.1287] 0.1030] 0.0809] 0.2143] 0.1109
30 0.1175] 0.1994] 0.1641] 0.1169] 0.3015] 0.1719
_ %Dissolved
10 8.77] 7.37] 8.18] 6.82] 7.55] 7.11 7.63 0.720
20 12.72] 21.35] 17.08] 13.38] 35.62] 18.39 19.76 8.407
30 19.44] 33.01] 27.16] 19.33] 49.99] 28.46 29.57 11.341
Table 157 Dissolution raw data of coated tablets stored for 6 months at 40°C/65%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance 7
10 0.0399] 0.0389] 0.0329] 0.0344] 0.0332] 0.0655
20 0.1236] 0.1937] 0.1261] 0.0744] 0.1581] 0.2740
30 0.3697] 0.3167] 0.3887] 0.3445] 0.3984] 0.4492
I %Dissolved
10 6.55] 6.39] 5.38] 5.64] 5.44] 10.88 6.71 2.098
20 20.50] 32.17] 20.90] 12.29] 26.23] 45.60 26.28 11.541
30 61.08] 52.45] 64.20] 56.84] 65.85] 74.48 62.48 7.651

 

 

 

 

 

218

 

 

 

Table 158 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
7 7 Absorbance
10 0.0843] 0.0880] 0.0816] 0.0944] 0.0593] 0.0831
20 0.2465] 0.1250] 0.1184] 0.1290] 0.0854] 0.1099
30 0.3242] 0.1664] 0.1493] 0.1633] 0.1201] 0.1382
I "/6 Dissolved
10 14.04] 14.66] 13.58] 15.73] 9.83] 13.83 13.61 2.005
20 41.04] 20.81] 19.71] 21.49] 14.18] 18.29 22.59 9.406
30 53.85] 27.64] 24.81] 27.15] 19.89] 22.97 29.39 12.321
Table 159 Dissolution raw data of coated tablets stored for 6 months at 40°C/50%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance
10 0.0503] 0.0339] 0.0276] 0.0523] 0.0372] 0.0390
20 0.0771] 0.0563] 0.0550] 0.2834] 0.1312] 0.0790
30 0.3111] 0.1203] 0.2171 I 0.4306] 0.3946] 0.1132
7 %Dissolved
10 8.31] 5.54] 4.50] 8.65] 6.11] 6.40 6.59 1.610
20 12.77] 9.28] 9.04] 47.14] 21.76] 13.07 18.84 14.610
30 51.36] 19.83] 35.78] 71.40] 65.19] 18.70 43.71 22.561
Table 160 Dissolution raw data of uncoated tablets stored for 6 months at 40°C/0%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance 7
10 0.3873] 0.3776] 0.4023] 0.3780] 0.3672] 0.4273
20 0.5724] 0.5753] 0.5689] 0.5738] 0.5646] 0.5769
30 0.5869] 0.5817] 0.5776] 0.5676] 0.5617] 0.5683
%Dissolved 7
.10 65.01] 63.37] 67.53 I 63.44] 61.63] 71.74 65.45 3.663
20 95.83] 96.31] 95.27] 96.05] 94.51] 96.65 95.77 0.772
30 98.23] 97.35] 96.70] 95.03] 94.03] 95.23 96.10 1.591
Table 161 Dissolution raw data of coated tablets stored for 6 months at 40°C/0%
Stirring time Number of trial
(minutes) 1 I 2 ] 3 I 4 | 5 I 6 Avagge so
7 7 Absorbance 7
10 0.2171] 0.0618] 0.0305] 0.1440] 0.0547] 0.2623
20 0.5796] 0.5100] 0.4086] 0.5668] 0.5646] 0.5718
30 0.5990] 0.5790] 0.5349] 0.5858] 0.5837] 0.5883
7 %Dissolved
10 36.37] 10.24] 4.98] 24.08] 9.06] 43.98 21.45 16.046
20 96.75] 84.89] 67.96] 94.49] 93.98] 95.52 88.93 11.108
30 99.95] 96.27] 88.78] 97.63] 97.13 I 98.24 96.34 3.900

 

 

 

 

 

219

 

 

 

Table 162 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 L 5 I 6 Aveggg SD
7 Absorbance 7
10 0.5153] 0.4968 I ~ 0.4961] 0.4942] 0.5027] 0.5231
20 0.5607] 0.5401] 0.5374] 0.5385] 0.5401] 0.5517
30 0.5643] 0.5470] 0.5494] 0.5514] 0.5548] 0.5596
%Dissolved 7
10 86.54] 83.44] 83.32] 82.99] 84.42] 87.86 84.76 1.992
20 94.10] 90.65] 90.19] 90.38] 90.65] 92.62 91.43 1.575
30 94.70] 91.78] 92.16] 923M 93.07] 93.92 93.02 1.110
Table 163 Dissolution raw data of coated tablets stored for 6 months at 25°C/90%
Stirring time Number Of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
7 Absorbance 7
10 0.5097] 0.4844] 0.5077] 0.4951] 0.5094] 0.5017
20 0.5465] 0.5360] 0.5422] 0.5449] 0.5501] 0.5519
30 0.5560] 0.5485] 0.5497] 0.5542] 0.5603 0.5601
7 %Dissolved I
10 85.59] 81.35] 85.27] 83.14] 85.55] 84.25 84.19 1.681
20 91.72] 89.93] 91.01] 91.44] 92.33] 92.61 91.51 0.966
30 93.29] 92.00] 92.24] 92.97] 94.11] 93.97 93.10 0.869
Table 164 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/75%
Stirring time Number of trial
(minuteS) 1 I 2 I 3 I 4 ] 5 I 6 Average so
Absorbance
10 0.5424] 0.5442] 0.5606] 0.5331] 0.5330] 0.5464
20 0.5671] 0.5660] 0.5710] 0.5587] 0.5609] 0.5661
30 0.5719] 0.5747] 0.5754] 0.5653] 0.5714] 0.5678
7 %Dissolved - 7
10 91.10] 91.41] 94.16] 89.54] 89.52] 91.77 91.25 1.714
20 95.22] 95.03] 95.90] 93.81] 94.16] 95.06 94.86 0.757
30 96.00] 96.46] 96.61] 94.88] 95.89] 95.33 95.86 0.661
Table 165 Dissolution raw data of coated tablets stored for 6 months at 25°C/75%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Averafl so
Absorbance 7
10 0.3641] 0.1156] 0.0580] 0.4667] 0.3046] 0.2065
20 0.5553] 0.5398] 0.526II 0.5611] 0.5548] 0.5154
30 0.5703] 0.5659] 0.5555] 0.5729] 0.5688] 0.5412
7 %Dissolved 7
10 61.10] 19.30] 9.60] 78.37] 51.09] 34.60 42.34 26.037
20 92.95] 89.96] 87.56] 94.08] 92.76] 86.03 90.56 3.248
30 95.42] 94.25] 92.41] 96.03] 95.07] 90.30 93.91 2.170

 

 

 

 

 

220

 

Table 166 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 I 6 Average so
Absorbance
10 0.4587] 0.5400] 0.5424] 0.5302] 0.5485] 0.5271
20 0.5789] 0.5680] 0.5714] 0.5734] 0.5763] 0.5799
30 0.5915] 0.5785] 0.5772] 0.5784] 0.5724] 0.5872
7 %Dissolved
10 77.02] 90.69] 91.09] 89.05] 92.12] 88.52 88.08 5.580
20 97.03] 95.37] 95.94] 96.25] 96.76] 97.33 96.44 0.732
30 99.12] 97.09] 96.88] 97.07] 96.11] 98.52 97.46 1.125
Table 167 Dissolution raw data of coated tablets stored for 6 months at 25°C/65%
Stirring time Number of trial
(minutes) 1 I 2 I 3 I 4 I 5 ] 6 Avgge so
7 Absorbance
10 0.2015] 0.1265] 0.1422] 0.1805] 0.0741] 0.3291
20 0.5582] 0.5608] 0.5592] 0.5781] 0.5590] 0.572
30 0.5781] 0.5831] 0.5750] 0.5893] 0.5921 I 0.5797
7 %Dissolved
10 33.75] 21.13] 23.77] 30.22] 12.32] 55.21 29.40 14.681
20 93.16] 93.47] 93.23] 96.43] 93.08] 95.69 94.18 1.483
30 96.43] 97.13] 95.83] 98.28] 98.53] 96.94 97.19 1.046
Table 168 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/50%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Avera e SD
Absorbance
10 0.5312] 0.5538] 0.4973] 0.5526] 0.5457] 0.5601
20 0.5860] 0.5768] 0.5689] 0.5807] 0.5853] 0.5704
30 0.5919] 0.5835] 0.5777] 0.5907] 0.5845] 0.5827
_7 %Dissolved
10 89.21] 93.01] 83.51] 92.81] 91.65] 94.07 90.71 3.900
20 98.34] 96.85 I 95.43] 97.50] 98.25] 95.80 97.03 1.227
30 99.31] 97.95] 96.88] 99.15] 98.12] 97.83 98.21 0.903
Table 169 Dissolution raw data of coated tablets stored for 6 months at 25°C/50%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.3376] 0.1986] 0.0906] 0.4570] 0.1840] 0.0793
20 0.5675] 0.5685] 0.5628] 0.5709] 0.5685] 0.5458
30 0.5820] 0.5813] 0.5775] 0.5848] 0.5868] 0.5762
%DiSsolved
10 56.65] 33.26] 15.09] 76.73] 30.80] 13.19 37.62 24.744
20 94.94] 94.87] 93.73] 95.70] 94.85] 90.89 94.16 1.722
30 97.32] 96.97] 96.16] 98.00] 97.87] 95.90 97.04 0.868

 

 

 

 

 

221

 

 

 

 

Table 170 Dissolution raw data of uncoated tablets stored for 6 months at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance 7
10 0.4190] 0.3749] 0.4070] 0.3796] 0.4671] 0.4535
20 0.5809] 0.5950] 0.5858] 0.5822] 0.5940] 0.5863
30 0.5914] 0.5940] 0.5910] 0.5889I 0.5940] 0.5940
7 % Dissolved I
10 70.33] 62.93] 68.33] 63.71] 78.43] 76.15 69.98 6.345
20 97.30] 99.58] 98.10] 97.46] 99.57] 98.25 98.38 0.996
30 99.04] 99.41] 98.96] 98.57] 99.57] 99.53 99.18 0.393
Table 171 Dissolution raw data of coated tablets stored for 6 months at 25°C/0%
Stirring time Number of trial
(minutes) I I 2 I 3 I 4 I 5 I 6 Average SD
Absorbance
10 0.2877] 0.3722] 0.3024] 0.2628] 0.2186] 0.3262
20 0.5811] 0.5758] 0.5873 I 0.5789] 0.5805] 0.5839
30 0.5909] 0.5845] 0.5933] 0.5893] 0.5908] 0.5925
%Dissolved
10 48.25] 62.47] 50.73] 44.06] 36.63] 54.72 49.48 8.874
20 97.12] 96.37] 98.17] 96.71] 96.90] 97.64 97.15 0.658
30 98.73] 97.80] 99.16] 98.43] 98.59] 99.07 98.63 0.492

 

222

 

2. Dissolution profiles of drug X uncoated tablets stored at 25°C

 

 

 

 

 

 

 

100% T -..-.- .._ ~— ~
75%
8
2 50°/
0 o
8
5
25%
0% . . - g
0 10 20 30 40

Stirring time (minutes)

I t==initial x t=l month 0 t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 86 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/90% RH (each point is average value for 6 tablets)

100% .

 

 

 

75%

 

50%

 

Dissolved

25%

 

 

 

0%

 

I] r 1

20 30 40
Stirring time (minutes)

I t=initial x t=l month 0 t=2 months + t=3 months 0 t=4 months A t=5 months * t=6 months

Figure 87 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/75% RH (each point is average value for 6 tablets)

223

100%

 

75%

 

 

50%

 

Dissolved

25%

 

 

 

0% r 1 1
O 1 0 20 30 4O

Stirring time (minutes)

 

I Finitial x t=l month I t=2 months + t=3 months 0 t=4 months I t=5 months * t=6 months

Figure 88 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/65% RH (each point is average value for 6 tablets)

 

 
 
 
    

 

 

 

 

 

 

100% ,,,,,,,,,,,,,,,,,,,

75%
8
z
o 50%
.3
O

25%

0% r T ,
o 10 20 . 30 4o

Stirring time (minutes)

I t=initia| x t=l month 0 i=2 months + F3 months 0 t=4 months I t=5 months * t=6 months

Figure 89 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/50% RH (each point is average value for 6 tablets)

224

1 00%

 

 

 

 

 

 

 

 

75%
‘8
2
g 50%
5

25% .

0% , T T
o 10 20 30 4o

Stirring time (minutes)

I Finitial x t=l month I F2 months + F3 months 9 t=4 months A t=5 months * t=6 months

Figure 90 Dissolution profiles of drug X uncoated tablets stored in open dishes for 6
months at 25°C/0% RH (each point is average value for 6 tablets)

225

3. Dissolution profiles of drug X coated tablets stored at 25°C

 

 

 

100% - ~ ~ ~~ A

 

 

75%

 

50%

Dissolved

 

25%

 

l r I

10 20 30 40
Stirring time (minutes)

0%

I Finitial x F] month I F2 months + F3 months 0 F4 months A F5 months * F6 months

Figure 91 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 25°C/90% RH (each point is average value for 6 tablets)

 

100%

75%

--. AJL. _ A---

50%

Dissolved

 

25%

 

r

0 10 20 30 40
Stirring time (minutes)

0%

I Finitial x Fl month I F2 months + F3 months 0 F4 months A F5 months * F6 months

Figure 92 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 25°C/75% RH (each point is average value for 6 tablets)

226

1 00%

 

 

 

75%

 

50%

Dissolved

25%

 

 

 

0%

 

r , I —1

0 10 20 30 40
Stirring time (minutes)

I Finitial x Fl month I F2 months + F3 months 0 F4 months A F5 months * F6 months

Figure 93 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 25°C/65% RH (each point is average value for 6 tablets)

 

 

 

100% ---—»-~-»—~——v—w-~ w. - ..--.----.-._-_ h __

75%

 

50%

 

Dissolved

 

25%

 

0%

 

!
i l T l

0 10 20 30 40
Stirring time (minutes)

I Finitial x Fl month I F2 months + F3 months 0 F4 months A F5 months * F6 months

Figure 94 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 25°C/50% RH (each point is average value for 6 tablets)

227

100% ~~ ~-—~

75%

 

50%

 

Dissolved

25%

 

 

 

0%

 

l’ T T j

0 10 20 30 40
Stirring time (minutes)

I Finitial x Fl month I F2 months + F3 months 0 F4 months I F5 months * F6 months

Figure 95 Dissolution profiles of drug X coated tablets stored in open dishes for 6
months at 25°C/0% RH (each point is average value for 6 tablets)

228

Appendix F

Dimensions (Swelling) and Raw Data

229

In order to explain the tablet swelling, the dimensions of tablets were measured at
each condition. Figures 96 and 97 show how the dimensions of drug X tablets increase
as a function of moisture content because excipients such as croscarmellose sodium in
tablets swell when they absorb moisture.

The thickness dimensions at 90% RH were increased at most about 0.17mm and
the diameter dimensions at 90% RH were increased at most about 0.15mm. Figure 96
shows the percent thickness increase and Figure 97 shows the percent diameter increase
as a function of relative humidity at 25°C and 40°C. When tablets were stored at higher
RH, they swelled quickly as they absorbed moisture. Afier the initial swelling, the
dimensions did not increase further as a function of storage time.

Drug X tablets are formulated with croscarmellose sodium that is a high swelling
material. The croscarmellose sodium swells to 4-8 times its original volume on contact
with water. The swollen croscarmellose reduce boundary strength among excipient
granules. Therefore, the tablets disintegrate quickly in a short time when they are

dropped into the dissolution medium.

230

 

 

 

 

 

 

 

5 i ‘‘‘‘‘‘‘‘‘‘ s “ E

4 i
E
a . g
5 3 ?
5 i
U ‘
“ ?
§ 2 ' .
i: x
E 1 e H I f
. i

0 ll . . a , . %

0 20 40 60 80 100

RH(%)

I uncoated at 40°C A coated at 40°C I uncoated at 25°C X coated at 25°C

Figure 96 Percent thickness dimension change of drug X tablets as a function of RH
(each point is average value for 5 tablets)

 

 

 

 

 

 

Q 2.0 u
2; .
2’ 1.5 x ,4
a i
5 ‘
z 2
g 1.0
.2 A
O
0.5 O 1
A . I
x ,
0,0 '— 1 T . r 7" i 1
0 20 40 60 80 100

RH(%)
O uncoated at 40°C A coated at 40°C I uncoated at 25°C X coated at 25°C

Figure 97 Percent diameter dimension change of drug X tablets as a function of RH
(each point is average value for 5 tablets)

231

Table 172 shows the dimensions of initial drug X tablets and Tables 173-202
show the dimensions of drug X tablets stored at 25/40°C, 0%, 50%, 65%, 75%, and 90%

RH for 6 months.

232

Table 172 Dimensions (mm) of initial tablets

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.01 9.07 4.09 9.22

2 4.04 9.04 4.11 9.11

3 4.01 9.06 4.10 9.12

4 4.01 9.04 4.10 9.18

5 4.01 9.03 4.09 9.10
Avg. 4.02 9.048 4.098 9.146
SD 0.013 0.016 0.008 0.052

 

Table 173 Dimensions (mm) of tablets stored for 20 days at 40°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.22 9.18 4.26 9.23

2 4.20 9.18 4.24 9.26
3 4.18 9.19 4.26 9.28

4 4.18 9.19 4.24 9.27

5 4.18 9.18 4.24 9.25
Avg. 4.192 9.184- 4.248 9.258
SD 0.018 0.005 0.01 1 0.019

 

Table 174 Dimensions (mm) of tablets stored for 20 days at 40°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter
1 4.12 9.12 4.14 9.19
2 4.12 9.14 4.15 9.19
3 4.13 9.11 4.14 9.19
4 4.12 9.12 4.14 9.20
5 4.12 9.11 4.14 9.20
Avg. 4.122 9.12 4.14 9.19
SD 0.004 0.012 0.004 0.005

 

Table 175 Dimensions (mm) of tablets stored for 20 days at 40°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.12 9.1 4.15 9.16
2 4.08 9.08 4.15 9.20

3 4.11 9.09 4.15 9.19
4 4.09 9.08 4.14 9.17
5 4.09 9.1 4.13 9.17
Avg. 4.098 9.09 4.14 9.18
SD 0.016 0.010 0.009 0.016

 

233

 

 

 

 

Table 176 Dimensions (mm) of tablets stored for 20 days at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.04 9.09 4.12 9.15

2 4.03 9.04 4.11 9.13

3 4.06 9.09 4.10 9.13

4 4.04 9.08 4.12 9.12

5 4.04 9.06 4.10 9.13
Avg. 4.042 9.072 4.1 l 9.13
SD 0.01 1 0.022 0.010 0.011

 

Table 177 Dimensions (mm) of tablets stored for 20 days at 40°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.03 9.05 4.09 9.15

2 4.02 9.06 4.05 9.08

3 4.00 9.04 4.10 9.14

4 4.00 9.02 4.10 9.12

5 4.00 9.04 4.10 9.12
Avg. 4.01 9.042 4.09 9.12
SD 0.014 0.015 0.022 0.027

 

Table 178 Dimensions (mm) of tablets stored for 20 days at 25°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.17 9.21 4.22 9.24

2 4.17 9.22 4.21 9.29

3 4.17 9.20 4.25 9.27

4 4.18 9.20 4.25 9.29

5 4.16 9.20 4.20 9.25
Avg. 4.17 9.206 4.226 9.268
SD 0.007 0.009 0.023 0.023

 

Table 179 Dimensions (mm) of tablets stored for 20 days at 25°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter
1 4.12 9.11 4.20 9.2
2 4.12 9.12 4.16 9.2
3 4.10 9.11 4.16 9.16
4 4.07 9.11 4.16 9.19
5 4.14 9.13 4.16 9.19
Avg. 4.11 9.116 4.17 9.19
SD 0.026 0.009 0.018 0.016

 

234

 

 

 

 

Table 180 Dimensions (mm) of tablets stored for 20 days at 25°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.07 9.09 4.16 9.16

2 4.11 9.11 4.14 9.18
3 4.11 9.08 4.18 9.18
4 4.09 9.08 4.16 9.18

5 4.09 9.09 4.12 9.15
Avg. 4.094 9.09 4.15 9.17
SD 0.017 0.012 0.023 0.014

 

Table 181 Dimensions (mm) of tablets stored for 20 days at 25°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 ' 4.05 9.06 4.08 9.15

2 4.04 9.06 4.09 9.12

3 4.05 9.07 4.11 9.15

4 4.05 9.05 4.10 9.15
5 4.05 9.05 4.16 9.16
Avg. 4.048 9.058 4.1 1 9.15
SD 0.004 0.008 0.031 0.015

 

Table 182 Dimensions (mm) of tablets stored for 20 days at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.01 9.05 4.06 9.1 1

2 4.02 9.02 4.11 9.1 l

3 4.01 9.03 4.10 9.11

4 4.02 9.03 4.10 9.1 l

5 4.02 9.02 4.10 9.1 1
Avg. 4.016 9.03 4.09 9.1 1
SD 0.005 0.012 0.019 0.000

 

Table 183 Dimensions (mm) of tablets stored for 70 days at 40°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.16 9.18 4.26 9.24

2 4.22 9.18 4.22 9.26

3 4.17 9.19 4.24 9.25
4 4.17 9.18 4.22 9.25

5 4.21 9.18 4.23 9.27
Avg. 4.186 9.182 4.234 9.254
SD 0.027 0.004 0.017 0.01 l

 

235

 

 

 

 

Table 184 Dimensions (mm) of tablets stored for 70 days at 40°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter
1 4.10 9.10 4.14 9.16
2 4.09 9.13 4.17 9.17
3 4.10 9.10 4.21 9.19
4 4.10 9.10 4.19 9.21
5 4.11 9.12 4.18 9.19
Avg. 4.10 9.11 4.18 9.18
SD 0.007 0.014 0.026 0.019

 

Table 185 Dimensions (mm) of tablets stored for 70 days at 40°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter
1 4.10 9.09 4.17 9.17
2 4.09 9.09 4.13 9.16
3 4.09 9.10 4.16 9.16
4 4.10 9.07 4.14 9.16
5 4.09 9.12 4.13 9.17
Avg. 4.094 9.094 4.15 9.16
SD 0.005 0.018 0.018 0.005

 

 

Table 186 Dimensions (mm) of tablets stored for 70 days at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter
1 4.04 9.04 4.12 9.13
2 4.04 9.05 4.12 9.10
3 4.03 9.05 4.09 9.10
4 4.02 9.03 4.09 9.12
5 4.05 9.04 4.07 9.1 1
Avg. 4.036 9.042 4.10 9.1 1
SD 0.01 1 0.008 0.022 0.013
Table 187 Dimensions (mm) of tablets stored for 70 days at 40°C/0%
Uncoated Coated
thickness diameter thickness diameter
1 4.00 9.02 4.08 9.12
2 4.01 9.01 4.08 9.12
3 4.01 9.02 4.04 9.07
4 4.02 9.01 4.06 9.09
5 3.98 9.01 4.07 9.12
Avg. 4.004 9.014 4.07 9.10
SD 0.015 0.005 0.017 0.023

 

 

 

 

 

 

236

 

 

 

 

Table 188 Dimensions (mm) of tablets stored for 70 days at 25°C/90%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.22 9.23 4.24 9.33

2 4.19 9.22 4.24 9.29

3 4.23 9.22 4.28 9.34

4 4.17 9.23 4.23 9.26

5 4.20 9.22 4.26 9.28
Avg. 4.202 9.224 4.25 9.30
SD 0.024 0.005 0.020 0.034

 

Table 189 Dimensions (mm) of tablets stored for 70 days at 25°C/75%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.10 ' 9.10 4.17 9.24
2 4.07 9.13 4.17 9.17
3 4.08 9.12 4.16 9.20

4 4.06 9.09 4.17 9.17

5 4.09 9.13 4.16 9.19
Avg. 4.08 9.114 4.17 9.19
SD 0.016 0.018 0.005 0.029

 

Table 190 Dimensions (mm) of tablets stored for 70 days at 25°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.04 9.07 4.13 9.16

2 4.08 9.07 4.17 9.17

3 4.06 9.07 4.13 9.15

4 4.09 9.09 4.13 9.17

5 4.08 9.07 4.17 9.18
Avg. 4.07 9.074 4.15 9.17
SD 0.020 0.009 0.022 0.01 l

 

Table 191 Dimensions (mm) of tablets stored for 70 days at 25°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.03 9.08 4.10 9.13

2 4.04 9.05 4.09 9.14

3 4.05 9.05 4.08 9.10

4 4.04 9.04 4.08 9.13

5 4.09 9.09 4.08 9.13
Avg. 4.05 9.062 4.09 9.13
SD 0.023 0.022 0.009 0.015

 

237

 

 

 

 

Table 192 Dimensions (mm) of tablets stored for 70 days at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter
1 4.00 9.00 4.09 9.12
2 4.00 9.01 4.08 9.10
3 4.00 9.01 4.04 9.09
4 4.00 9.01 4.07 9.09
5 4.03 9.02 4.10 9.11
Avg. 4.006 9.01 4.08 9.10
SD 0.013 0.007 0.023 0.013
Table 193 Dimensions (mm) of tablets stored for 180 days at 40°C/90%
Uncoated Coated
thickness diameter thickness diameter
1 4.20 9.21 4.20 9.24
2 4.19 9.20 4.24 9.26
3 4.16 9.19 4.26 9.25
4 4.21 9.20 4.23 9.27
5 4.16 9.18 4.23 9.26
Avg. 4.184 9.196 4.232 9.256
SD 0.023 0.011 0.022 0.01 1
Table 194 Dimensions (mm) of tablets stored for 180 days at 40°C/75%
Uncoated Coated
thickness diameter thickness diameter
1 4.11 9.10 4.19 9.22
2 4.12 9.10 4.17 9.22
3 4.09 9.10 4.22 9.20
4 4.10 9.10 4.20 9.20
5 4.10 9.l0 4.20 9.20
Avg. 4.104 9.10 4.20 9.21
SD 0.011 0.000 0.018 0.011
Table 195 Dimensions (mm) of tablets stored for 180 days at 40°C/65%
Uncoated Coated
thickness diameter thickness diameter
1 4.10 9.09 4.15 9.15
2 4.08 9.09 4.16 9.17
3 4.08 9.09 4.18 9.17
4 4.08 9.09 4.16 9.17
5 4.08 9.09 4.16 9.17
Avg. 4.084 9.09 4.16 9.17
SD 0.009 0.000 0.01 1 0.009

 

 

 

 

 

 

 

238

Table 196 Dimensions (mm) of tablets stored for 180 days at 40°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter
1 4.07 9.04 4.12 9.10
2 4.04 9.04 4.14 9.15
3 4.05 9.04 4.14 9.14
4 4.04 9.04 4.14 9.14
5 4.04 9.04 4.14 9.14
Av . 4.048 9.04 4.14 9.13
‘ so 0.013 0.000 0.009 0.019

 

Table 197 Dimensions (mm) of tablets stored for 180 days at 40°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter
. 1 4.00 9.00 4.13 9.12
2 4.00 9.00 4.09 9.12
3 4.00 9.00 4.10 9.12
4 4.00 9.00 4.09 9.12
5 4.00 9.00 4.09 9.12
M. 4.00 9.00 4.10 9.12
SD 0.000 0.000 0.017 0.000
Table 198 Dimensions (mm) of tablets stored for 180 days at 25°C/90%
Uncoated Coated
thickness diameter thickness diameter
1 4.21 9.22 4.25 9.29
2 4.21 9.24 4.24 9.28
3 4.21 9.22 4.25 9.28
4 4.22 9.22 4.25 9.28
5 4.22 9.22 4.25 9.28
, fig. 4.214 9.224 4.248 9.282
SD 0.005 0.009 0.004 0.004
Table 199 Dimensions (mm) of tablets stored for 180 days at 25°C/75%
Uncoated Coated
thickness diameter thickness diameter
1 4.06 9.07 4.16 9.19
2 4.04 9.06 4.20 9.20
3 4.07 9.07 4.16 9.17
4 4.06 9.08 4.17 9.19
5 4.07 9.08 4.17 9.19
ALg. 4.06 9.072 4.17 9.19
SD 0.012 0.008 0.016 0.01 1

 

239

 

 

 

 

Table 200 Dimensions (mm) of tablets stored for 180 days at 25°C/65%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.05 9.04 4.14 9.15

2 4.02 9.05 4.14 9.15

3 4.05 9.05 4.14 9.15

4 4.05 9.05 4.14 9.15
5 4.06 9.05 4.14 9.15
Avg. 4.046 9.048 4.14 9.15
SD 0.015 0.004 0.000 0.000

 

Table 201 Dimensions (mm) of tablets stored for 180 days at 25°C/50%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 4.02 9.05 4.09 9.10

2 4.02 9.06 4.10 9.09

3 3.99 9.05 4.07 9.09
4 4.02 9.05 4.06 9.10

5 4.02 9.05 4.11 9.09
Avg. 4.014 9.052 4.09 9.09
SD 0.013 0.004 0.021 0.005

 

Table 202 Dimensions (mm) of tablets stored for 180 days at 25°C/0%

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
thickness diameter thickness diameter

1 3.99 9.02 3.95 9.10

2 4.03 9.02 4.00 9.09

3 4.05 9.02 3.97 9.10
4 4.01 9.02 3.96 9.09

5 4.03 - 9.02 3.97 9.13
Avg. 4.022 9.02 3.97 9.10
SD 0.023 0.000 0.019 0.016

 

240

 

 

 

Appendix G

Hardness and Raw Data

241

In order to help explain the effect of intermolecular forces among ingredients in
tablets, the hardness of tablets was measured at each condition for 190 days. Table 203

shows the average hardness of tablets measured for 190 days.

Table 203 Average hardness of drug X uncoated and coated tablets
Hardness (kp)
Uncoated tablets
Storage time (da 8)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Temp (°C) RH (%) 0 6 18 70 100 130 170 190
90 8.9 2.2 1.6 1.6 1.7 1.9 1.7 1.8
75 8.9 5.9 6.5 7.0 7.3 7.6 6.8 6.8
25 65 8.9 6.9 7.4 8.3 8.5 8.7 8.4 8.1
50 8.9 7.2 7.5 7.8 7.8 8.1 7.8 8.2
0 8.9 7.4 7.1 7.4 7.1 7.3 7.1 7.1
90 8.9 2.5 2.6 2.6 3.0 2.7 3.0 3.1
75 8.9 6.7 7.4 7.5 7.4 7.8 8.1 7.7
40 65 8.9 8.0 8.5 8.9 8.8 8.9 9.7 9.5
50 8.9 8.0 8.8 9.4 9.2 9.8 10.1 10.1
0 8.9 7.1 7.5 7.4 7.2 7.3 7.0 7.4

 

 

 

 

 

 

 

 

Uncoated tablets
Stora e time (da 8)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Temj (°C) RH (%) 0 6 18 70 100 130 170 190
90 9.2 2.4 1.8 1.8 1.6 1.9 1.9 1.9
75 9.2 7.6 7.3 8.0 7.5 7.9 7.9 8.4
25 65 9.2 8.0 8.2 9.5 9.0 9.2 9.7 9.6
50 9.2 8.2 8.2 8.8 9.0 9.3 9.2 9.2
0 9.2 8.4 8.2 8.3 8.0 8.4 8.0 8.0
90 9.2 2.5 2.6 2.5 2.6 2.8 3.0 3.0
75 9.2 7.5 8.0 8.4 8.7 9.0 9.2 9.3
40 65 9.2 8.6 9.1 9.7 9.9 10.0 10.9 10.3
50 9.2 8.9 10.2 10.6 10.3 10.8 1 1.2 1 1.2
0 9.2 8.2 8.4 8.4 8.3 8.6 8.4 8.6

 

 

 

 

 

 

 

 

 

After 6 days storage time, the hardness of tablets obtained from all conditions

decreased. The hardness of coated and uncoated tablets stored at 90% decreased 3 lot;

242

around 2.2-2.5 kp (kilopond) from 8.9-9.2 kp initial hardness. The hardness of tablets
stored at 0% and 75% dropped to around 6-7 kp, then it increased a little as a function of
storage time as shown in Figures 98-101. The hardness of tablets stored at 50% and 65%
decreased a little (about 1-2 kp) from 9 kp to about 7-8 kp, then it increased as a function
of storage time to a value higher than the initial hardness. The hardness values at the

initial and 7 day storage times were analyzed statistically using t-tests (see Table 204).

Table 204 p-values from t-test between initial and 7 day aged tablet hardness

 

 

 

 

 

 

 

p-value p-value
40°C uncoated coated 25°C uncoated coated
90% 4.1E-19 3 .5E-20 90% 4.2E-19 2.3E-20
75% 1813-08 6.2E-O6 75% 1 .1 E-l l 2.7E-05
65% 6.4E-03 2.1E-02 65% 1.1E-05 2113-04
50% 3 .9E-04 9.0E-02 50% 6615-08 3. 1 E-03
0% 2.6E-08 2.5E-05 0% 5.2E-08 2.1 E-03

 

 

 

 

 

 

 

 

As shown in Table 204, the p-values are all less than 0.05 except for coated
tablets stored at 40°C/50%. Therefore, it could be concluded that all hardness values
from initial tablets to 6 day aged tablets changed significantly except for coated tablets
stored at 40°C/50%. The hardness of coated tablets stored for 7 days at 40°C/50% is not
significantly different statistically or visually in comparison with the hardness of initial
coated tablets. It can be concluded that the hardness at 50% RH was not changed
because it is close to the initial condition (42.6% RH).

Second, the hardness values from 7 days to 190 days were analyzed statistically

using ANOVA. Table 205 shows the p-values from ANOVA.

243

Table 205 p—values from AN OVA between 7 to 190 day aged tablet hardness

 

 

 

 

 

 

 

 

 

 

 

 

 

p-value p-value
40°C uncoated coated 25°C uncoated coated
90% l .1 E-03 1.0E-O9 90% 1 .4E-1 1 8.3E-20
75% 2.6E-05 6.1E-O4 75% 9.18-05 1.5E-02
65% 2.1 E-O8 8.1E-07 65% 5.3E-08 2.8E-O6
50% 1.2E-12 1.3E-1 1 50% 1.2E-O6 2.2E-05
0% 1.0E-02 3.2E-01 0% 2.8E-01 2.6E-01

 

25°C/0% are greater than 0.05. Therefore, they are not significantly different for 7 to 190
days. However, the hardness of tablets stored at other conditions is significantly different
for 7 to 190 days because the p-values are less than 0.05. This can also be recognized by

inspecting Figures 98-105.

also be explained by the swelling property. The swollen croscarmellose make boundary

strength among excipients weak. Therefore, the hardness of tablets decreases quickly at a

high relative humidity.

244

As shown in Table 205, p-values of coated/uncoated tablets stored at 40°C,

When tablets were stored at higher RH, the hardness decreased quickly. It can

 

10.0

 

 

 

 

 

8.0
2
g 6.0 ~ ‘ :
§ 4.0 «
I 1
I ;
2.0 _, v 4 :W i
1
0.0 r . 1 i
0 50 100 150 200
Storage time (days)

O90%RH I 75%RHA65%RHX50%RH*0%RH

Figure 98 Hardness of drug X uncoated tablets stored at 25°C as a function of storage
time (each point is average value for 10 tablets)

12.0 --.--.__-.._._,-_-,___._ ,,.

 

 

 

Hardness (kp)

 

2,0 1 f W
0.0

 

 

0 50 100 150 200
Storage time (days)

990%RH I 75%RHA65%RHX50%RH*0%RH

Figure 99 Hardness of drug X coated tablets stored at 25°C as a function of storage time
(each point is average value for 10 tablets)

245

1:! 0 ..., ~...........--i__._um_1“--....M,___...__.-..__...H.___F,_-_,,~-...a_..._.___--__.a._.-_.__-..
.

 

 

 

 

10.0 -
g 8.0 —
§ 6.0-
t:
E
a: 4.0 ~
I
2.0 .
0.0 1 1 1 1
0 50 100 150 200
Storage time (days)

990%RH I 75%RHA65%RH X50%RH7K0%RH

Figure 100 Hardness of drug X uncoated tablets stored at 40°C as a function of storage
time (each point is average value for 10 tablets)

 

 

Hardness (kp)

 

 

 

 

0.0

3

0 50 100 150 200
Storage time (days)

090%RH I 75%RHA65%RHX50%RH*O%RH

Figure 101 Hardness of drug X coated tablets stored at 40°C as a function of storage
time (each point is average value for 10 tablets)

246

Also, there is evidence for differences in tablet hardness at different temperatures.
Figures 102 and 104, and 103 anleS show the hardness values of tablets stored at 40°C
are higher than those of tablets stored at 25°C, and they also show the hardness increased

as a function of storage time, as concluded before. The tablets stored around 50-65% RH

have the greatest hardness.

120 - “we.--” ”_.-._...“mz_---_”--- ”_..._--L--- _ _MM . _ _-., _---..,-._-W.,,,- - _.-.. .. . - --fi- _MWH ..-

10.0 .

 

8.0 ~

6.0 ~

Hardness (kp)

4.0 -

 

2.0 4

 

0.0 T T 1 l 1
0 20 40 60 80 100

RH(%)

 

— initial tablets It = 6 days At = 18 days Xt = 70 days in = 100 days 0t = 130 days +t = 170 days .t =
190 days

Figure 102 Hardness of drug X uncoated tablets at 25°C as a function of RH (%) (each
point is average value for 10 tablets)

247

12.0 ~

10.0 «

 

 

 

8.0

6.0 «

Hardness (kp)

4.0 <

2.0 «

 

0.0 T i f
0 20 40 60 80 100

RH(%)

 

— initial tablets It = 6 days At = 18 days Xt = 70 days *t = 100 days 0t = 130 days +t = 170 days .t =
190 days

Figure 103 Hardness of drug X coated tablets at 25°C as a function of RH (%) (each
point is average value for 10 tablets)

10.0 «

  

 

 

8.0 «

6.0 ~

Hardness (kp)

4.0 4

2.0 4

 

0.0 . T , .
0 20 40 60 80 100

RH(%)

 

— initial tablets It = 6 days At = 18 days Xt = 70 days *t = 100 days 0t = 130 days +t = I70 days .t =
190 days

Figure 104 Hardness of drug X uncoated tablets at 40°C as a fimction of RH (%) (each
point is average value for 10 tablets)

248

Hardness (kp)

 

 

 

 

0.0

20

T

40

T

60

80

100

RH(%)

— initial tablets It=6days At= 18 days Xt= 70 days *t= 100 days Ot= 130 days +t= 170 days Ot=
190 days

Figure 105 Hardness of drug X coated tablets at 40°C as a fimction of RH (%) (each
point is average value for 10 tablets)

Inspection of Figures 102-105 shows that the hardness of tablets stored at 40°C

was greater than those stored at 25°C. Table 206 shows p-values from t-test analysis.

Table 206 p-values from t-test between hardness of tablets stored at 25’C and 40°C (p-
values greater than 0.05 are bold-faced)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

p-values from t-test
RH (%) l month 2 months 3 months 4 months 5 months 6 months
uncoated 1.3 308 4.05-07 1.75-09 4.6E-09 l . I E— 10 l .ZE- 10
90 coated 2.8E-08 1.25-12 5.2E-l 1 2613-1 1 3.85-12 2.0E-1 l
uncoated 1 08-02 1.7E—01 6.6E-01 3.7E-01 3 .3 E-03 2513-03
75 coated 1. l E-02 228-0| 2.4E-03 l .213-02 4.05-03 5.2 E-02
uncoated 1.8E-05 4.0E-03 2.3E-01 3.4E-01 2.2E-04 7.55-06
65 coated l .0E-O3 6.9E-01 l .9E-02 4.05-05 4.3 E-OZ 1.0E-01
uncoated 7.25-09 5.0Eo06 1.3E-05 l .4 132-07 8.3 E-i l 8.25-10
50 coated 5.05—06 8.0E-07 4.8E-06 3.0504 4.3 E-07 2.2E-08
uncoated 1.5E-01 9.5E-01 5.5E-01 7.4E-0l 3.1 E—Ol 7.8E-02
0 coated 7.8 E-02 4.1 E-01 2.7 E-01 4.2 E-01 6.3 E-02 5 .5 E-03

 

249

 

The hardness at 0% RH is not significantly different between 25°C and 40°C
because the p-values are greater than 0.05 during most of the storage time. The hardness
at 50% and 90% is significantly different between 25°C and 40°C because the p-values
are less than 0.05 at all storage times. Five p-values at 75% and four p-values at 65% are
greater than 0.05, but more p-values are less than 0.05. Figures 102-105 show that the
hardness of tablets stored at 40°C/75% and 65% is greater than hardness of those stored
at 25°C/75% and 65%. Therefore, it can be concluded that the hardness of tablets stored
at 40°C is greater than those stored at 25°C, except for 0% RH. This may explain why
the dissolution of tablets stored at 40°C decreased a lot more quickly than for tablets
stored at 25°C. See Chapter 4.4. Propgsed theog of dissolution retardation as a function
of relative humidity for a more detailed explanation.

The hardness of tablets is decreased by moisture absorption. The hardness at
25°C/90% and 40°C/90% changed to 2 kp from 9 kp. The tablets at those conditions are

still hard if they are squeezed as shown in Figure 106. However, if they are bent as

shown in Figure 107, they can be broken very easily in comparison to initial tablets.

250

 

\ \.
(a) Squeeze in the thickness direction (b) Squeeze in the diameter direction

Figure 106 Graphical representation of the tablet squeezing in the thickness and diameter
directions by fingers

I.' \'\ . .'
..i I ( ’ 3&8...” '.
/ (A ,I.\\
fiat" \Eiii'
// / . s

.\
.I '-
I
\ ‘

Figure 107 Graphical representation of the tablef breaking by fingers

Tablets will soften in a short time if they are packaged in PVC blisters and stored
at a high relative humidity. Therefore, pharmaceutical companies may not want to use
PVC blisters for solid dosage forms even if dissolution is high enough for a long time. It
must be determined whether 2 kp hardness is enough for use of blister packages or not.
Tablets obtained from the open dish study (0%, 50%, 65%, 75%, 90% at 25/40°C) were
packaged in PVC blisters by using a blister thermoform heat sealing machine. The
thickness of PVC film was 10 mil, and the thickness of the backing film (paper/Al

laminate) was 1.9 mil.

251

As shown in Table 207, some of the tablets from 90% RH were broken when the
blister packages were opened. Therefore, the hardness of tablets stored at 90% RH was
not enough for the blister packaging. Though the hardness also decreased at the other
conditions, the tablets were still hard enough to be used with the blisters since none of

them broke, as shown in Table 207.

Table 207 The results of PVC blister opening tests (the number of broken tablets/the
number of trials)

 

Temp. “11%)

 

0% 50% 65% 75% 90%

 

Hardness of uncoated tablets (kp) 7.12 7.51 7.43 6.48 1.59

 

25°C Opening test with PVC blisters 0/10 0/10 0/10 0/10 6/10

 

Hardness of coated tablets (kp) 8.18 8.19 8.16 7.25 1.83

 

Openingtest with PVC blisters 0/10 0/10 0/10 0/10 2/10

 

 

Hardness of uncoated tablets (kp) 7.51 8.81 8.45 7.44 2.63

 

40°C Opening test with PVC blisters 0/10 0/10 0/10 0/10 2/10

 

Hardness of coated tablets (kp) 8.44 10.17 9.1 8.02 2.6

 

 

 

 

 

 

 

Opening test with PVC blisters 0/10 0/10 0/10 0/10 0/10

 

Table 208 shows the hardness of the initial tablets and Tables 209-218 show the

hardness of tablets stored at 25/40°C, 0%, 50%, 65%, 75%, 90% RH for 190 days.

252

 

Table 208 Hardness (kp) of initial tablets

 

 

 

 

 

 

 

 

 

 

 

 

| [1 2 3 4 5 6 7 8 9 10|avg.|sol
[uncoated ] 9.8 9 9.2 8.4 8.6 8.7 8.9 9.5 8.6 8.3 | 8.9| 0.48|
[coated I 9.1 8.6 9.7 9.7 9.5 9.2 9.7 8.6 9.1 8.9 I 9.21 | 0.43 |

 

Table 209 Hardness (kp) of tablets stored at 40°C/90% as a function of storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated ' Coated .
7 21 70 100 130 170 190 7 21 70 100 I30 I70 190
l 2.8 2.8 2.9 2.8 2.8 2.7 2.9 2.5 2.7 2.4 2.6 2.7 3.2 2.8
2 2.5 2.6 2.5 2.6 2.8 2.7 2.6 2.4 2.9 2.6 2.5 2.7 2.9 3.4
3 2.5 2.8 3.2 2.7 2.9 2.9 3.1 2.7 2.9 2.5 2.8 2.8 3.2 2.9
4 2.4 3.3 2.8 3.0 2.9 2.8 3.2 2.5 2.8 2.7 3.0 2.9 2.9 3.1
5 2.5 2.5 2.8 2.7 2.5 3.0 2.7 2.6 2.6 2.6 2.5 2.7 3.0 2.8
6 2.5 2.5 3.2 3.2 2.6 3.1 3.1 2.2 2.4 2.6 2.6 2.8 3.2 2.8
7 2.4 2.4 2.0 3.5 2.5 3.0 3.1 2.6 2.6 2.4 2.8 2.9 3.2 3.1
8 2.5 2.5 2.8 2.8 2.8 2.7 3.3 2.6 2.3 2.5 2.6 2.9 3.1 3.1
9 2.6 2.7 2.0 2.7 2.4 3.5 3.4 2.7 2.6 2.5 2.6 2.4 2.8 3.0
10 2.3 2.2 2.8 3.2 3.0 2.9 2.8 2.5 2.2 2.4 2.2 3.0 2.7 3.3
M 2.5 2.6 2.6 3.0 2.7 3.0 3.1 2.5 2.6 2.5 2.6 2.8 3.0 3.0
SD 0.2 0.3 0.4 0.3 0.2 0.2 0.3 0.1 0.2 0.1 0.2 0.2 0.2 0.2

 

 

 

 

 

 

Table 210 Hardness (kp) of tablets stored at 40°C/75% as a function of storage time
Uncoated Coated
8 21 70 100 130 170 190 8 21 70 100 130 170 190
6.3 7.3 6.8 7.3 7.6 7.4 7.8 7.7 9.6 9.0 9.0 8.5 7.9 8.4

 

 

 

 

6.1 7.1 8.5 7.4 7.4 8.2 7.6 6.9 8.4 7.6 9.4 8.4 10.2 7.9

 

7.1 8.9 7.1 8.5 8.5 8.1 7.7 7.8 7.4 8.1 9.0 8.3 10.0 9.9

 

6.6 7.5 7.5 7.1 7.8 7.9 7.3 7.6 8.5 9.2 7.6 10.8 8.6 9.9

 

6.6 6.9 7.6 7.2 7.3 8.4 8.3 6.7 7.6 7.9 7.9 10.4 11.0 8.4

 

6.3 7.4 7.0 8.2 7.4 8.1 7.5 7.5 7.7 8.3 9.5 9.0 9.1 9.3

 

6.9 8.8 7.5 7.3 7.6 8.1 7.5 6.8 8.2 10.2 7.4 8.1 10.3 8.4

 

6.4 6.8 7.7 ' 7.2 7.8 7.0 7.6 7.1 7.8 7.4 8.7 8.5 8.4 9.3

 

8.0 6.8 7.5 6.9 8.3 9.9 7.4 9.0 7.2 7.6 9.9 8.1 8.0 10.5

 

OOQQOKM-wa—I

—

6.2 6.9 7.3 7.1 8.0 7.8 8.0 8.3 7.8 8.8 8.9 10.0 8.5 l 1.3
Avg. 6.7 7.4 7.5 7.4 7.8 8.1 7.7 7.5 8.0 8.4 8.7 9.0 9.2 9.3
SD 0.6 0.8 0.5 0.5 0.4 0.8 0.3 0.7 0.7 0.9 (1.8 I .0 1.1 1.1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

253

Table 211 Hardness (kp) of tablets stored at 40°C/65% as a function of storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
6 19 70 100 130 170 190 6 19 70 100 130 170 190
1 8.1 8.7 8.5 8.1 9.1 9.1 9.9 8.7 9.1 9.8 9.4 9.6 13.8 9.6
2 7.6 8.0 8.3 8.4 9.0 9.6 8.9 9.4 8.8 9.6 1 1.0 10.1 10.0 10.6
3 8.3 8.9 9.3 8.7 8.8 9.3 9.7 8.3 8.2 9.5 9.3 10.0 1 1.1 10.4
4 8.0 8.1 9.5 8.4 9.1 9.7 9.1 9.8 8.4 9.0 10.2 9.6 9.5 10.3
5 7.3 8.5 8.7 9.5 8.2 l 1.5 9.7 8.6 9.4 9.6 1 1.4 10.0 9.8 10.4
6 9.9 8.3 9.1 9.3 9.2 9.7 9.4 7.6 8.8 9.8 8.5 10.7 9.6 9.5
7 7.4 8.6 8.3 9.2 9.3 9.8 9.5 8.8 9.2 9.4 9.8 10.4 10.0 10.7
8 7.2 8.7 8.8 8.8 8.8 9.1 9.5 8.0 9.1 9.0 9.1 9.7 11.1 9.8
9 7.8 7.8 9.4 8.9 8.9 9.5 9.0 8.6 10.6 1 1.8 9.7 10.4 12.0 10.1
10 8.4 8.9 8.6 9.0 8.5 9.2 9.8 7.9 9.4 9.3 10.4 9.4 12.1 1 1.6
Avg. 8.0 8.5 8.9 8.8 8.9 9.7 9.5 8.6 9.1 9.7 9.9 10.0 10.9 10.3
so 0.8 0.4 0.4 0.4 0.3 0.7 0.3 0.7 0.7 0.8 0.9 0.4 1.4 0.6
Table 212 Hardness (kp) of tablets stored at 40°C/50% as a function of storage time
Uncoated Coated
6 19 70 100 130 170 190 6 19 70 100 130 170 190
l 8.2 8.4 9.4 8.1 9.4 10.5 10.0 9.0 9.3 9.7 10.0 9.9 1 1.4 l 1.0
2 7.2 8.7 10.4 10.3 9.4 10.8 9.1 9.0 10.6 11.2 10.5 12.4 12.4 11.6
3 7.8 9.0 9.9 8.9 10.2 9.6 10.4 8.3 9.8 10.0 10.6 1 1.6 l 1.1 1 1.0
4 7.1 9.2 9.0 9.2 9.4 10.6 10.4 9.2 10.4 10.9 10.1 10.5 10.7 10.9
5 8.6 8.8 10.0 9.4 9.8 9.8 10.4 8.4 10.4 10.5 9.6 10.3 10.5 1 1.3
6 8.2 8.8 9.5 10.0 9.8 10.0 10.3 9.5 10.5 1 1.4 10.2 1 1.4 10.8 1 1.1
7 8.1 8.4 8.6 9.1 10.0 10.0 10.4 8.6 9.2 10.9 10.7 10.2 12.4 1 1.4
8 8.2 8.8 9.0 8.8 10.4 10.0 9.5 8.8 9.9 10.1 10.1 10.8 1 1.3 10.7
9 7.7 9.4 9.4 9.4 9.3 9.1 10.5 8.7 12.1 1 1.2 10.3 1 1.2 l 1.6 10.8
10 8.4 8.6 8.5 9.2 10.6 10.2 9.9 9.3 9.5 10.2 10.7 9.5 10.2 12.2
Avg. 8.0 8.8 9.4 9.2 9.8 10.1 10.1 8.9 10.2 10.6 10.3 10.8 1 1.2 l 1.2
SD 0.5 0.3 0.6 0.6 0.5 0.5 0.5 0.4 0.8 0.6 0.4 0.9 0.7 0.4
Table 213 Hardness (kp) of tablets stored at 40°C/0% as a function of storage time
Uncoated Coated
5 18 70 100 130 170 190 5 18 70 100 130 170 190
1 6.8 7.4 7.8 7.1 6.9 7.1 7.6 7.9 8.7 8.8 7.5 8.5 8.1 8.0
2 7.9 7.1 7.2 7.8 7.2- 7.4 7.1 8.1 8.2 8.6 8.4 8.6 8.4 8.8
3 7.2 8.1 7.4 7.3 7.6 6.4 7.8 8.2 8.1 8.6 8.2 8.8 9.6 8.6
4 6.7 7.1 7.4 7.5 8.0 6.8 7.7 8.4 8.3 7.6 8.6 8.1 8.6 8.1
5 7.1 7.6 6.5 6.6 7.3 7.3 7.3 8.1 8.5 8.9 9.2 8.6 8.4 8.6
6 7.2 9.3 7.8 7.3 6.9 6.7 7.1 8.4 8.9 8.3 8.7 8.6 8.4 8.4
7 7.4 7.0 7.6 7.3 7.1 7.3 6.8 8.6 8.0 8.7 8.1 9.1 7.7 9.4
8 7.0 7.3 7.3 6.8 7.4 6.6 7.9 7.8 8.0 8.2 7.8 8.5 8.4 8.9
9 6.6 7.2 7.6 6.7 7.4 7.2 7.5 8.8 9.0 8.2 8.1 8.5 7.9 8.5
10 6.7 7.0 7.5 8.0 6.9 6.8 7.4 7.5 8.7 8.0 8.0 8.4 8.6 8.2
Avg. 7.1 7.5 7.4 7.2 7.3 7.0 7.4 8.2 8.4 8.4 8.3 8.6 8.4 8.6
SD 0.4 0.7 0.4 0.5 0.4 0.3 0.3 0.4 0.4 0.4 0.5 0.3 0.5 0.4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

254

 

 

 

Table 214 Hardness (kp) of tablets stored at 25°C/90% as a function of storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
7 20 70 100 130 170 190 7 20 70 100 130 170 190
1 2.2 1.7 1.5 1.6 1.9 1.9 1.5 2.4 1.9 1.8 1.6 2.0 1.9 1.9
2 2.1 1.5 1.7 2.1 1.9 1.6 1.7 2.6 1.9 1.8 1.5 1.8 1.8 2.0
3 2.6 1.4 1.6 1.7 1.8 1.6 1.9 2.2 1.9 1.8 1.7 1.7 2.0 1.7
4 2.5 1.9 1.8 1.8 1.6 1.6 1.8 2.3 1.8 1.6 1.8 1.9 1.9 1.6
5 2.4 1.8 1.6 1.6 2.0 1.7 1.6 2.4 1.8 1.8 1.6 2.0 1.9 1.9
6 2.1 1.5 1.8 1.7 1.8 1.8 1.8 2.5 2.0 1.9 1.5 1.9 2.1 1.9
7 2.2 1.5 1.6 1.8 2.1 2.0 2.0 2.5 1.8 1.9 1.6 2.0 1.9 1.8
8 2.1 1.5 1.5 1.5 1.9 1.5 1.9 2.5 1.8 1.8 1.5 1.8 1.7 2.1
9 2.1 1.6 1.7 1.8 2.0 1.5 1.7 2.2 1.8 1.8 1.5 1.9 1.7 1.8
10 2.0 1.5 1.4 1.5 2.0 1.5 1.8 2.2 1.6 1.8 1.5 1.8 1.8 1.8
Avg. 2.2 1.6 1.6 1.7 1.9 1.7 1.8 2.4 1.8 1.8 1.6 1.9 1.9 1.9
SD 0.2 0.2 0.1 0.2 0.1 0.2 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
Table 215 Hardness (kp) of tablets stored at 25°C/75% as a function of storage time
Uncoated Coated
7 20 70 100 130 170 190 7 20 70 100 130 170 190
1 5.6 5.8 7.0 9.1 7.6 8.9 7.2 8.4 7.1 7.5 7.7 8.0 7.7 8.9
2 6.6 6.4 7.1 6.8 7.3 6.4 7.5 7.6 7.5 8.2 6.8 7.3 7.8 8.6
3 6.3 5.8 7.2 6.7 7.6 6.5 6.4 8.0 6.9 7.8 7.7 8.7 7.1 9.6
4 5.6 6.0 6.0 6.6 7.4 6.6 6.9 8.0 6.8 7.6 8.3 ' 7.7 8.6 7.7
5 6.2 6.5 8.3 6.7 7.7 6.4 6.1 6.5 7.2 7.3 7.6 8.4 8.8 8.8
6 6.1 7.6 6.3 9.2 8.6 6.1 8.4 6.8 8.2 8.1 8.2 7.2 8.1 8.3
7 5.7 5.5 6.4 6.8 7.8 8.0 6.3 6.5 7.3 8.5 6.4 9.1 6.7 6.9
8 5.4 6.9 6.8 6.9 7.4 6.5 6.4 7.5 7.5 9.0 7.7 8.5 8.5 8.5
9 5.4 6.9 6.4 6.9 7.4 6.8 6.5 9.0 6.4 8.2 8.2 7.3 8.0 7.6
10 5.9 7.4 8.6 6.9 7.3 5.9 6.5 7.5 7.6 7.8 6.5 6.9 7.3 9.4
‘ _Avg 5.9 6.5 7.0 7.3 7.6 6.8 6.8 7.6 7.3 8.0 7.5 7.9 7.9 8.4
SD 0.4 0.7 0.9 1.0 0.4 0.9 0.7 0.8 0.5 0.5 0.7 0.7 0.7 0.8
Table 216 Hardness (kp) of tablets stored at 25°C/65% as a function of storage time
Uncoated Coated
5 19 70 100 130 170 190 5 19 70 100 130 170 190
l 6.9 6.8 7.8 8.2 8.4 9.5 8.5 7.7 7.7 9.0 8.7 9.4 10.2 8.3
2 6.5 8.0 8.2 8.9 8.6 8.3 8.1 8.0 8.6 8.5 8.8 9.4 9.3 8.5
3 7.1 7.5 8.6 7.2 8.0 7.9 8.2 7.6 8.1 8.9 8.6 9.0 l 1.0 10.5
4 6.5 7.3 8.2 8.2 7.8 8.4 7.7 9.4 7.8 8.7 9.6 8.9 8.5 12.0
5 6.5 7.6 8.3 8.0 8.9 8.3 6.8 8.3 8.7 9.8 8.7 9.4 8.4 10.0
6 6.7 7.8 7.9 10.4 8.8 8.1 7.6 8.9 8.2 10.5 9.2 9.0 8.6 9.6
7 6.3 7.2 8.4 8.3 8.8 8.5 8.2 7.3 8.0 8.5 8.6 9.2 10.0 9.1
8 6.4 7.9 7.8 8.1 9.1 8.5 8.6 7.3 7.9 9.6 10.0 9.4 9.4 9.8
9 9.4 7.3 8.7 9.0 9.2 7.9 8.8 8.1 8.7 1 1.1 8.6 9.1 10.7 9.5
10 7.1 6.9 8.7 8.3 9.4 8.8 8.5 7.4 7.9 10.6 9.6 9.2 1 1.0 9.0
Avg. 6.9 7.4 8.3 8.5 8.7 8.4 8.1 8.0 8.2 9.5 9.0 9.2 9.7 9.6
SD 0.9 0.4 0.3 0.8 0.5 0.5 0.6 0.7 0.4 0.9 0.5 0.2 1.0 1.1

 

255

 

 

 

Table 217 Hardness (kp) of tablets stored at 25°C/50% as a function of storage time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Uncoated Coated
5 19 70 100 130 170 190 5 19 70 100 130 170 190
1 7.3 7.3 8.5 7.9 8.4 7.7 8.3 9.7 7.4 8.2 8.7 10.2 8.8 8.6
2 6.7 7.3 7.2 7.7 7.2 8.0 8.1 7.0 7.7 8.6 8.5 9.9 9.2 8.9
3 7.5 7.9 7.5 7.9 8.5 7.5 7.7 8.1 7.7 9.6 9.4 8.7 9.4 8.4
4 7.0 7.6 8.0 8.0 8.2 7.7 8.1 8.0 8.7 8.4 8.9 8.8 8.7 8.8
5 7.0 7.7 7.4 7.1 8.6 7.5 8.3 7.7 7.9 8.1 10.1 9.4 8.7 9.5
6 8.0 7.4 7.5 8.5 7.7 8.0 8.4 8.8 8.2 8.5 8.6 9.1 9.3 10.0
7 6.9 7.7 7.9 7.8 7.4 8.1 8.0 8.4 8.6 9.2 8.7 9.1 9.3 9.4
8 7.3 7.4 8.1 7.8 8.4 7.7 8.3 7.5 8.8 9.1 8.4 8.6 9.1 9.1
9 7.4 7.7 7.7 7.3 8.2 7.7 8.4 8.0 8.5 9.4 9.5 10.0 9.1 9.8
10 7.0 7.1 8.5 8.4 8.2 7.7 8.3 9.1 8.4 8.8 9.0 9.3 10.1 9.2
.515: 7.2 7.5 7.8 7.8 8.1 7.8 8.2 8.2 8.2 8.8 9.0 9.3 9.2 9.2
SD 0.4 0.2 0.4 0.4 0.5 0.2 0.2 0.8 0.5 0.5 0.5 0.6 0.4 0.5
Table 218 Hardness (kp) of tablets stored at 25°C/0% as a fimction of storage time
Uncoated Coated
5 18 70 100 130 170 190 5 18 70 100 130 170 190
1 7.4 7.0 7.1 7.3 7.8 7.2 7.8 8.5 8.0 7.7 7.4 8.6 8.4 8.4
2 7.2 7.4 6.7 6.9 8.1 7.8 6.8 8.5 8.0 8.4 7.6 7.9 8.8 7.6
3 7.3 6.8 7.3 7.3 7.4 7.3 7.3 8.6 8.0 7.9 8.4 8.2 7.9 8.2
4 7.4 6.5 7.8 7.0 7.1 7.3 7.4 7.9 8.2 8.5 8.0 8.1 7.5 7.9
5 7.5 7.1 7.5 6.8 7.2 7.3 7.3 7.9 8.1 8.5 7.9 7.9 7.8 8.2
6 7.9 6.7 7.3 7.0 6.6 6.6 6.9 7.7 8.0 8.6 8.6 7.9 7.8 7.9
7 7.2 7.8 7.5 7.6 7.6 7.1 6.8 7.7 8.6 8.7 8.1 8.7 8.5 7.8
8 7.6 7.3 8.0 7.1 7.4 6.5 7.4 9.5 8.1 8.0 7.9 9.3 7.9 8.0
9 7.1 7.2 7.1 7.2 6.9 7.3 6.6 8.3 8.6 8.2 8.0 7.7 7.5 8.6
10 7.1 7.4 7.7 7.2 7.2 6.9 6.9 9.1 8.2 8.0 8.5 9.6 7.8 7.6
_A_vg. 7.4 7.1 7.4 7.1 7.3 7.1 7.1 8.4 8.2 8.3 8.0 8.4 8.0 8.0
SD 0.2 0.4 0.4 0.2 0.4 0.4 0.4 0.6 0.2 0.3 0.4 0.6 0.4 0.3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

256

 

 

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