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This is to certify that the

thesis entitled

DISSOLUTION SHELF LIFE
OF PACKAGED PHARMACEUTICAL TABLET
BY PREDICTION AND EXPERIMENT

presented by

Jurmkwan Suemag

has been accepted towards fulfillment
of the requirements for

EASIER—.— degree in WING

2M flow/«f

I

Major professor

Date MAY 15, 2001

0-7639

MS U is an Affirmative Action/Equal Opportunity Institution

 

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DATE DUE

DATE DUE

DATE DUE

 

JAN 0 9 2007

 

Q11 OATS

 

 

 

 

 

 

 

 

 

 

 

 

6/01 CJCIRC/DatoDUOpGS-DJS

 

 

DISSOLUTION SHELF LIFE OF PACKAGED PHARMACEUTICAL TABLET
BY PREDICTION AND EXPERIMENT
By

J urmkwan Suemag

AN ABSTRACT OF A DISSERTATION
Submitted to
Michigan State University
In partial fulfillment of the requirements
For the degree of

MASTER OF SCIENCE

School of Packaging
2001

Professor Hugh E. Lockhart

ABSTRACT

DISSOLUTION SHELF LIFE OF PACKAGED PHARMACEUTICAL TABLET
BY PREDICTION AND EXPERIMENT

By

Jurmkwan Suemag

This research was designed to predict shelf life of packaged pharmaceutical
tablets by using dissolution as a function of moisture content and storage time. Shelf life
was predicted by the amount of time required for the moisture content of the
pharmaceutical product to increase until it reached equilibrium (permeation time) plus the
time that the product could tolerate that storage condition (exposure time) in an open dish
study. Permeation time can be calculated by using information from a sorption isotherm,
WVTR and other parameters, including product dry weight, storage conditions, initial
and critical moisture content.

In this study, prednisone, a moisture sensitive uncoated tablet, was stored in an
Open dish at 75%RH at 25°, 30° and 40°C to determine exposure time. To prove the
validity of the calculation, the actual permeation time was determined by measuring the
moisture content of prednisone packaged in PVC and PVC/0.6 mil Aclar blisters at
certain intervals. The calculation provided an error of less than 10%. Therefore, this
calculation is useful to select the packaging material that provides enough moisture
barrier to the products for the stability test. The actual dissolution shelf life was
determined by using as critical point a 10% reduction in dissolution. The shelf life
predicted and the actual shelf life were compared. Predicted shelf life was from 8 to 44

percent less than the experimental result.

ACKNOWLEDGEMENT

My work could not have been done without Dr. Hugh Lockhart, my major
advisor. I would like to thank him for his never-ending patience. He always smiles and
welcomes me to his office to talk. I will always remember him as an outstanding mentor
whom I hope to emulate someday. I also would like to thank Dr. Susan Selke and Dr.
Robert Worden, my committee, for their guidance.

I’d like to thank Matt Thomas and the people at the Eli Lilly Company Laboratory
for blister packaging along with those at the Pharmacia & Upjohn Company for the
product. I really appreciate all my friends did for me. Seung-yil Yoon gave me
suggestions, drove me to Indianapolis and helped me out throughout my experiment.
Krittika Tanprasert always answered my questions. Cengiz Caner worked beside me to
keep me from feeling lonely during holidays or at night. Pornchai Rachtanapun gave me
helpful comments on my presentation. Yongseong Ha always made me laugh out loud. I
would also like to thank my other packaging friends and my roommate, Stacy Hung. I
cannot forget my friends, Sopacha Apichartvorasilp, Viphop Tatiyamaneekul, Nalinee
Tuntivanich and Katkate Bunnag who stood beside me and supported me during hard
times, along with my dearest friend, Chattavom Sangsuwan who picked me up when I
was down. Finally, I would like to thank my Dad, Mom, Sister and Brother for their
unconditional love. What I have become is because of you. You are the main part of my

life.

iii

TABLE OF CONTENT

LIST OF TABLES .................................................................................. v
LIST OF FIGURES ............................................................................... xii
CHAPTER 1 INTRODUCTION ................................................................ 1
CHAPTER 2 LITERATURE REVIEW AND PREVIOUS WORK ..................... 4
CHAPTER 3 MATERIALS AND METHODS ............................................. 17
CHAPTER 4 RESULTS ......................................................................... 27
CHAPTER 5 CONCLUSIONS AND FUTURE WORK ................................. 63
APPENDIX A

Sorption Isotherm, WVTR and Moisture Content Raw Data ............................ 66
APPENDIX B

Dissolution Raw Data ............................................................................. 76
APPENDIX C

Calculation .......................................................................................... 118
BIBLIOGRAPHY ................................................................................ 121

iv

LIST OF TABLES

Table 1 Saturated Salt Solutions Provide Relative Humidities at 25°, 30° and 40°C

Table 2 P Required to Attain the Desired Shelf Life

Table 3 Time Interval for Determining Water Vapor Transmission Rate of PVC and
PVC/0.6 mil Aclar at 3 Storage Temperatures

Table 4 Comparison of Required P Calculated and P of Material Chosen
Table 5 Sampling Plan of Moisture Content Determination of Prednisone in Open Dish

Table 6 Sampling Plan of Moisture Content Determination of Prednisone in PVC Blister
Packaging

Table 7 Sampling Plan of Moisture Content Determination of Prednisone in PVC/0.6 mil
Aclar Blister Packaging

Table 8 Sampling Plan of Dissolution Determination of Prednisone in Open Dish
Storage

Table 9 Sampling Plan of Dissolution Determination of Prednisone in PVC Blister
Packaging

Table 10 Sampling Plan of Dissolution Determination of Prednisone in PVC/0.6 mil
Aclar Blister Packaging

Table 11 Relative Humidity and Equilibrium Moisture Content (Dry Basis) at 25°, 30°
and 40°C for Prednisone Tablets

Table 12 Total Weight Gained vs Time of Desiccant Tablets in a 2x5 (10 cavities) PVC
Blister Cards at 25°, 30° and 40°C

Table 13 Total Weight Gained vs Time of Desiccant Tablets in a 2x5 (10 cavities)
PVC/0.6 mil Aclar Blister Cards at 25°, 30° and 40°C

Table 14 Water Vapor Transmission Rate (WVTR) and Permeance (P ) of PVC Blister
Cavity

Table 15 Water Vapor Transmission Rate (WVTR) and Permeance (P ) of PVC/0.6 mil
Aclar Blister Cavity

Table 16 Initial Moisture Content of Prednisone

Table 17 Moisture Content of Prednisoen in Open Dish

Table 18 Moisture Content of Prednisoen in PVC Blister

Table 19 Moisture Content of Prednisoen in PVC/0.6 mil Aclar Blister at 25°C
Table 20 Moisture Content of Prednisoen in PVC/0.6 mil Aclar Blister at 30°C
Table 21 Moisture Content of Prednisoen in PVC/0.6 mil Aclar Blister at 40°C

Table 22 Time to Achieve Equilibrium Moisture Content of Prednisone from the
Experiment

Table 23 Slopes of the Plots of Dissolution and versus Time

Table 24 Summary of Failure of Prednisone in Open Dish stored at 75%RH, 25°, 30° and
40°C

Table 25 Summary of Failure of Prednisone Packaged in PVC Blister and Stored at
75%RH, 25°, 30° and 40°C

Table 26 Summary of Failure of Prednisone Packaged in PVC/0.6 mil Aclar Blister and
Stored at 75%RH, 25°, 30° and 40°C

Table 27 The First Day that Failure was Found

Table 28 Standard Deviation of Dissolution at 30 minute Stirring Time of Prednisone in
Open Dish after Aging

Table 29 Standard Deviation of Dissolution at 30 minute Stirring Time of Prednisone
Packaged in PVC Blister after Aging

Table 30 Standard Deviation of Dissolution at 30 minute Stirring Time of Prednisone
Packaged in PVC/0.6 mil Aclar Blister after Aging

Table 31 Time to Achieve Equilibrium Moisture Content of Prednisone by Prediction
and Experiment

Table 32 Shelf Life Prediction by Using a 10% Decrease in Dissolution as a Critical
Point

Table 33 Shelf Life by Prediction and Experiment by Using a 10% Decrease in
Dissolution as a Critical Point

Table 34 Shelf Life Prediction by Using the Dissolution of Less Than 80% as a Critical
Point

vi

Table 35 Shelf Life by Prediction and Experiment by Using the Dissolution of Less Than
80% as a Critical Point

Table 1A Raw Data of Sorption Isotherm of Prednisone at 25°C

Table 2A Raw Data of Sorption Isotherm of Prednisone at 30°C

Table 3A Raw Data of Sorption Isotherm of Prednisone at 40°C

Table 4A Raw Data of Weight of PVC Blister vs Time at 25°C

Table 5A Raw Data of Weight of PVC Blister vs Time at 30°C

Table 6A Raw Data of Weight of PVC Blister vs Time at 40°C

Table 7A Raw Data of Weight of PVC/0.6 mil Aclar Blister vs Time at 25°C
Table 8A Raw Data of Weight of PVC/0.6 mil Aclar Blister vs Time at 30°C
Table 9A Raw Data of Weight of PVC/0.6 mil Aclar Blister vs Time at 40°C

Table 10A Raw Data of Moisture Content of Prednisone in Open Dish Stored at 25°C,
75%RH

Table 11A Raw Data of Moisture Content of Prednisone in Open Dish Stored at 30°C,
75%RH

Table 12A Raw Data of Moisture Content of Prednisone in Open Dish Stored at 40°C,
7 5%RH

Table 13A Raw Data of Moisture Content of Prednisone in PVC Blister Stored at 25°C,
75%RH

Table 14A Raw Data of Moisture Content of Prednisone in PVC Blister Stored at 30°C,
75%RH

Table 15A Raw Data of Moisture Content of Prednisone in PVC Blister Stored at 40°C,
75%RH

Table 16A Raw Data of Moisture Content of Prednisone in PVC/0.6 mil Aclar Blister
Stored at 25°C, 75%RH

Table 17A Raw Data of Moisture Content of Prednisone in PVC/0.6 mil Aclar Blister
Stored at 30°C, 75%RH

vii

Table 18A Raw Data of Moisture Content of Prednisone in PVC/0.6 mil Aclar Blister
Stored at 40°C, 75%RH

Table 1B Dissolution of Prednisone Fresh from the Bottle

Table ZB Dissolution of Prednisone in Open Dish at 25°C, Day 6
Table 3B Dissolution of Prednisone in Open Dish at 25°C, Day 12
Table 4B Dissolution of Prednisone in Open Dish at 25°C, Day 18
Table 5B Dissolution of Prednisone in Open Dish at 25°C, Day 24
Table 6B Dissolution of Prednisone in Open Dish at 25°C, Day 30
Table 7B Dissolution of Prednisone in Open Dish at 25°C, Day 36
Table 8B Dissolution of Prednisone in Open Dish at 25°C, Day 42
Table 9B Dissolution of Prednisone in Open Dish at 30°C, Day 6
Table IOB Dissolution of Prednisone in Open Dish at 30°C, Day 12
Table 11B Dissolution of Prednisone in Open Dish at 30°C, Day 18
Table 12B Dissolution of Prednisone in Open Dish at 30°C, Day 24
Table 13B Dissolution of Prednisone in Open Dish at 30°C, Day 30
Table 14B Dissolution of Prednisone in Open Dish at 40°C, Day 6
Table 15B Dissolution of Prednisone in Open Dish at 40°C, Day 12
Table 16B Dissolution of Prednisone in Open Dish at 40°C, Day 18
Table 178 Dissolution of Prednisone in Open Dish at 40°C, Day 24
Table 183 Dissolution of Prednisone in Open Dish at 40°C, Day 30
Table 19B Dissolution of Prednisone in Open Dish at 40°C, Day 36
Table 20B Dissolution of Prednisone in PVC at 25°C, Day 8

Table 21B Dissolution of Prednisone in PVC at 25°C, Day 14

Table 228 Dissolution of Prednisone in PVC at 25°C, Day 20

viii

Table 238 Dissolution of Prednisone in PVC at 25°C, Day 26
Table 24B Dissolution of Prednisone in PVC at 25°C, Day 32
Table 25B Dissolution of Prednisone in PVC at 25°C, Day 38
Table 26B Dissolution of Prednisone in PVC at 25°C, Day 44
Table 278 Dissolution of Prednisone in PVC at 25°C, Day 50
Table 28B Dissolution of Prednisone in PVC at 25°C, Day 56
Table 29B Dissolution of Prednisone in PVC at 25°C, Day 62
Table 30B Dissolution of Prednisone in PVC at 30°C, Day 7

Table 31B Dissolution of Prednisone in PVC at 30°C, Day 13
Table 32B Dissolution of Prednisone in PVC at 30°C, Day 19
Table 338 Dissolution of Prednisone in PVC at 30°C, Day 25
Table 348 Dissolution of Prednisone in PVC at 30°C, Day 31
Table 35B Dissolution of Prednisone in PVC at 30°C, Day 37
Table 36B Dissolution of Prednisone in PVC at 30°C, Day 43
Table 378 Dissolution of Prednisone in PVC at 30°C, Day 49
Table 38B Dissolution of Prednisone in PVC at 40°C, Day 6

Table 39B Dissolution of Prednisone in PVC at 40°C, Day 12
Table 408 Dissolution of Prednisone in PVC at 40°C, Day 18
Table 41B Dissolution of Prednisone in PVC at 40°C, Day 24
Table 42B Dissolution of Prednisone in PVC at 40°C, Day 30
Table 43B Dissolution of Prednisone in PVC at 40°C, Day 36
Table 44B Dissolution of Prednisone in PVC at 40°C, Day 42

Table 45B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 10

ix

Table 46B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 20
Table 47B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 30
Table 48B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 40
Table 49B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 50
Table 50B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 60
Table SIB Dissolution of Prednisone in PVC/Aclar at 25°C, Day 65
Table 52B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 71
Table 53B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 77
Table 548 Dissolution of Prednisone in PVC/Aclar at 25°C, Day 83
Table 55B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 89
Table 56B Dissolution of Prednisone in PVC/Aclar at 25°C, Day 95
Table 57B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 5

Table 58B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 10
Table 593 Dissolution of Prednisone in PVC/Aclar at 30°C, Day 15
Table 60B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 20
Table 61B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 25
Table 62B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 31
Table 633 Dissolution of Prednisone in PVC/Aclar at 30°C, Day 37
Table 64B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 43
Table 65B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 49
Table 66B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 55
Table 678 Dissolution of Prednisone in PVC/Aclar at 30°C, Day 61

Table 68B Dissolution of Prednisone in PVC/Aclar at 30°C, Day 67

Table 693 Dissolution of Prednisone in PVC/Aclar at 40°C, Day 3
Table 708 Dissolution of Prednisone in PVC/Aclar at 40°C, Day 6
Table 718 Dissolution of Prednisone in PVC/Aclar at 40°C, Day 9
Table 72B Dissolution of Prednisone in PVC/Aclar at 40°C, Day 14
Table 73B Dissolution of Prednisone in PVC/Aclar at 40°C, Day 20
Table 74B Dissolution of Prednisone in PVC/Aclar at 40°C, Day 26
Table 75B Dissolution of Prednisone in PVC/Aclar at 40°C, Day 32
Table 763 Dissolution of Prednisone in PVC/Aclar at 40°C, Day 38

Table 77B Dissolution of Prednisone in PVC/Aclar at 40°C, Day 44

xi

LIST OF FIGURES

Figure 1 Dissolution Profiles of Enteric-coated Aspirin Tablets Packaged in a Two-sided
Wrap USP Class B Strip Pak and Stored at 33°C, 60%RH (Hoblitzell et a1 1985)

Figure 2 Structural Formula of Deltasone Tablet

Figure 3 Dissolution Standard Curve of Prednisone (Thomas 2000)
Figure 4 Sorption Isotherm of Prednisone at 25°, 30° and 40°C
Figure 5 Sorption Isotherm of Prednisone at 25°C

Figure 6 Sorption Isotherm of Prednisone at 30°C

Figure 7 Sorption Isotherm of Prednisone at 40°C

Figure 8 Total Weight Gained vs Time of Desiccant Tablets in a 2x5 (10 cavities) PVC
Blister Cards at 25°, 30° and 40°C

Figure 9 Total Weight Gained vs Time of Desiccant Tablets in a 2x5 (10 cavities)
PVC/0.6 mil Aclar Blister Cards at 25°, 30° and 40°C

Figure 10 Dissolution Profiles of Prednisone Fresh from the Bottle

Figure 11 Dissolution Profiles of Prednisone in Open Dish after Storage at 30°C,
75%RH

Figure 12 Dissolution Profiles of Prednisone in PVC/0.6 mil Aclar after Storage at 25°C,
Day 30

Figure 13 Dissolution Profiles of Prednisone in PVC/0.6 mil Aclar after Storage at 25°C,
Day 65

Figure 14 Dissolution at 5, 10, 20 and 30 Minute Stirring Time vs Storage Time of
Prednisone in Open Dish and Stored at 30°C

Figure 15 Dissolution at 5, 10, 20 and 30 Minute Stirring Time vs Storage Time of
Prednisone Packaged in PVC and Stored at 30°C

Figure 16 Dissolution at 5, 10, 20 and 30 Minute Stirring Time vs Storage Time of
Prednisone Packaged in PVC/0.6 mil Aclar and Stored at 30°C

xii

Figure 17 Dissolution Profiles of Prednisone in Open Dish afier Storage at 25°, 30° and
40°C, 75%RH at Day 6

Figure 18 Moisture Content vs Storage Time

xiii

CHAPTER 1

INTRODUCTION

Shelf life is the time lapse from manufacturing to the specified expiration date
during which the characteristics of a drug product will remain within the approved
specifications (Chow and Shao 1991; USP 23 <1151>). Expiration dating on the label
indicates the shelf life of the pharmaceutical product'. Shelf life depends on product
properties, package properties and storage condition. Two methods used to identify the
shelf life of pharmaceutical products are stability testing and prediction or calculation by
equation sets. Stability testing is designed to assess the stability characteristics or the
shelf life of the drug products. For stability testing, the product is packaged in the market
package and stored for a period of time until failure, or lack of it, can be identified.
Stability testing is required for Food and Drug Administration (FDA) permission to
introduce a new drug to market (USP 23 <1077>). Another way to study the shelf life of
a pharmaceutical product is prediction or calculation by mathematical model. The model
can be represented by a computer program which is a tool to provide convenient
calculation of shelf life, or of the barrier required to attain a specified shelf life. The
computer program is based on the equation sets which include equations for permeation
of packages and the moisture equilibrium isotherm for the product. Although prediction
of the shelf life of the pharmaceutical product by these equation sets can not be used in
place of stability testing, this prediction is very useful for calculating the barrier required

to achieve a desired shelf life by selecting the appropriate packaging material. Study of

 

1 Expiration date as defined on page 4

the product in package can be done in this way to minimize the trial and error process in
package selection. The choice of barrier is then validated using the stability test.

Dissolution is one of the physical properties of pharmaceutical products that are
listed as criteria for acceptable levels of stability in the United States Pharmacopoeia
monograph for every product. In many researches, dissolution has been found to be
susceptible to change during storage (Nakabayashi et a1 1981; Chowhan 1994; Qian
1996; Wu 1996; Kokitkar 1997; Rohrs et a1 1999 and Yoon 2000). Therefore, dissolution
can define the shelf life of the products. Other physical properties are appearance,
palatability, uniformity and suspendability (USP <1191>). Acceptability in appearance,
for example, turning yellow in tablet, stickiness in capsule or cracking in coated tablets
can be determined easily by patients. Failure to meet these limits can result in recall of
the product (Murthy and Ghebre-Sellassie 1993).

In the School of Packaging, Michigan State University, pharmaceutical product
packaging is studied by using dissolution as one of the indicators to determine shelf life.
These researches are done using the open dish method. The open dish method of
exposure to heat and humidity is a way to study behavior of product which is not
packaged. Product will absorb moisture until it reaches equilibrium with the environment,
and many researchers have reported that the dissolution is affected by moisture content.
(Taborsky-Urdinola et a1 1981, Akbuga et a1 1984 and Rohrs et a1 1999)

A product in open dish will meet the dissolution requirements for some time after
its moisture content reaches equilibrium with the environment. Therefore, the open dish
method can tell us how long the product can tolerate a specific condition after the

moisture content reached equilibrium. But the moisture content of a packaged product

takes longer to reach equilibrium than the product in open dish. Equations (1) to (6),
chapter 2, page 10-12, can be used to calculate the time for the product in the package to
reach a moisture content in equilibrium with the storage condition. The hypothesis has
been raised that shelf life can be predicted as the time during which the product in the
package gains moisture until it reaches a specific condition (permeation time) plus the
time that the product can tolerate such specific condition (exposure time). This portion is
determined during the open dish study.

This research was designed to prove the prediction and compare the shelf life by
prediction to the actual shelf life of the product in the package. In addition, the physical
deterioration and dissolution of the product in the package were observed to determine
whether they follow the same course as the product in open dish study. In this research,
failure of prednisone in open dish and stored at 75%RH, 25°, 30° and 40°C was found at
day 30, 12 and 18 respectively. Failure of prednisone tablets packaged in PVC at the
same storage conditions was found at day 38, 25 and 24 and for those packaged in
PVC/0.6 mil Aclar was found at day 65, 37 and 32 respectively. No physical

deterioration was found before product failed dissolution.

Objective; of the Research

 

1. To determine whether the dissolution failure and physical failure of the drug in
package follows the result from open dish study.

2. To demonstrate that the correct moisture barrier package can be chosen by
calculation, using results of open dish studies and measured permeation values of
packages.

3. To prove that the hypothesis predicts correctly the failure point (shelf life) under
prescribed conditions.

CHAPTER 2

LITERATURE REVIEW AND PREVIOUS WORK

2.1 Stability Testing

“Stability refers to the chemical and physical integrity of the drug dosage unit
and/or the ability of the dosage unit to maintain protection against microbial
contamination” (USP 23 <1151>). In this reference, the stability parameters are listed as:

I Drug ingredient; therapeutically active or inactive

Particle size, pH, the properties of water and other solvents employed

I Environmental conditions of storage; temperature, light, air, humidity

Packaging

Other chemicals resulting from contamination or from the intentional
mixing of different products.
This research focuses only on environmental condition and packaging.

“The purpose of stability testing is to provide evidence on how the quality of a
drug substance or drug product varies with time under the influence of a variety of
environmental factors such as temperature, humidity and light. The result of such stability
testing shall be used in determining appropriate storage conditions and expiration date.
Expiration date is the date placed on the container/labels of a drug product designating
the time during which a batch of the product is expected to remain within the approved
shelf life specification if stored under defined conditions, and after which it must not be
used” (USP 23 <1196>). Furthermore, stability studies are intended to match the

packaging performance with the needed protection by using optimal packaging material

(Murthy and Ghebre-Sellassie 1993). Stability testing is required by FDA for
qualification of packaged drugs for marketing.
The storage test conditions for stability studies are as follows. These are standard

conditions agreed to by the International Committee for Harmonization (ICH).

Conditions Minimum Time Period at Submission
Long-term testing 25 i 2° / 60 i 5%RH 12 months

Intermediate Accelerated 30 3: 2° / 60 i 5%RH 6 or 12 months

Accelerated testing 40 i 2° / 75 i 5%RH 6 months

For long-term testing, the time period will continue after 12 months for the
expected lifetime of the product. For intermediate accelerated condition, it must be a 12
month study but data from first 6 months can be submitted in place of accelerated data.
Accelerated data is required to submit with long-term data.

Prediction of shelf life at the ambient condition by conducting the experiment
only at accelerated condition is not accurate because the diffusion of moisture into the
product and permeability of the package are not always linearly related to temperature
and humidity at higher temperatures and humidities. “Although data obtained under
accelerated conditions are not usefiil in predicting the dissolution shelf life of the product
under ambient condition, they are of value for assessing the ruggedness of the product
and its ability to withstand the varied climate conditions during transport, shipping and

storage” (Murthy and Ghebre-Sellassie 1993).

2.2 Dissolution

Dissolution stability is the maintenance of the dissolution characteristics of the
product, within specified limits, from the time of manufacture up to the expiration date
(Grimm, W. et al 1985). During storage, the pharmaceutical product will change in
properties that may affect the bioavailability of the dosage form ((Murthy and Ghebre-
Sellassie 1993). In vivo bioavailabilities of several drugs in solid dosage form are closely
related to their in vitro dissolution rate (Fraser 1973). Therefore, dissolution testing is
used to evaluate the performance of the pharmaceutical product. The purpose of
dissolution testing is to determine compliance with the USP dissolution requirements
where stated in the individual monograph for a tablet or capsule dosage form, except

where the label states that the tablets are to be chewed (USP 23 <71 1>).

2.2.1 Factors Influencing Dissolution Stability
One or a combination of factors that affect the dissolution stability of a product
during aging include (Murthy and Ghebre-Sellassie 1993; Chowhan 1994).

' Formulation: particle-size distribution of drug substance, ratio of the
active ingredient and excipients, coating materials, composite solubility
and hygroscopicity, type and concentration of the disintegrant, binder and
lubricant.

' Manufacturing method: “directly compacted tablets and direct-blend
capsules in general are less prone to the deleterious effects on dissolution

after aging” (Chowhan 1994).

I Processing factors: time and speed of mixing, granulation, the type and
amount of granulating solvent, granulation moisture content before
compaction, blending time with lubricant and tablet crushing strength.

I Storage conditions: “The condition of high heat and humidity caused the
greatest change in dissolution rate” (Taborsky-Urdinola et a1 1981).
Dissolution of many tablets is affected by moisture; for example,
dissolutions of Delavirdine Mesylate 200 mg tablets and Phenytoin
Sodium tablets were dramatically decreased afier storage at high relative
humidity (Akbuga et a1 1984 and Rohrs 1999).

I Packaging: Tablet dissolution is affected by action of moisture (Rohrs et a1
1999). One of the factors controlling the permeation of the water into the
pharmaceutical products is the barrier property of packaging material.
Prednisone tablets stored in higher barrier packaging material dissolved
more than those in lower barrier packaging material (Taborsky-Urdinola et
a1 1981).

Of the five factors presented in the literature, storage conditions and packaging

were selected for study in this research.

2.2.2 Effect of Packaging on Dissolution

One of the functions of packaging is to protect the product from elements of the
external environment such as moisture, oxygen and light depending on the properties of
the packaging material. The packaging that has a higher moisture barrier characteristic

retains the stability in term of dissolution better than the packaging that has lower

moisture barrier characteristic. A prime factor that causes sensitivity of drug products to
moisture is excipients (Taborsky-Urdinola et a1 1981). Water up-take causes the
development of intermolecular hydrogen bonding among excipients. The stronger the
hydrogen bond, the less the rate of dissolution. The amount of crystallinity of an active
ingredient, which has an inverse relationship with dissolution, varies according to the
moisture content. (Hirasawa et a1 1998). “Tablets exposed to excess moisture can either
harden or sofien and then crumble, depending on excipients and the drug” (Taborsky-
Urdinola et a1 1981).

Blister packaging made from PVC and PVC/0.6 mil Aclar was used for this
experiment. “PVC is the most widely used blister material because of its good
thermoforming properties, enabling high speed production. Although PVC does possess
water vapor barrier properties, the water vapor transmission rate of this material is
considered to be too high for moisture sensitive products” (Guise 1984). The moisture
barrier property of PVC is improved by lamination with Aclar
(polychlorotrifluoroethylene). Aclar film provides an excellent moisture barrier and
clarity which has an attractive cost/performance ratio for pharmaceutical products. It is
also heat sealable. There are 4 types of Aclar; homopolymer, Aclar RX series,

copolymers Aclar 22A and 33C and Aclar NT (AlliedSignal Specialty Films 1998).

2.2.3 Dissolution of Tablet Products
A dissolution test requirement has been included in the product monographs in the
National Formulary (N F) and USP (Hanson 1992). There are many dissolution methods

and apparati but the most common methods for immediate release dosage forms are the

rotating basket apparatus and the rotating paddle apparatus. Water is recommended for
dissolution medium for prednisone. The volume of water is not less than three times the
volume required for a saturated solution of pharmaceutical products (Murthy and Ghebre-
Sellassie 1993). A standard dissolution test procedure is published by USP as <71 1>
Dissolution. This is the method used here.

The dissolution profiles, the plot of dissolution versus stirring time, can be
obtained fi'om the dissolution test. The profile of dry fresh tablets will lie above those for
tablets that have aged. As product is exposed to high temperature and relative humidity,

the profiles shift downward (Figure 1).

100

80'

60*

%Dissolved

40'

20

 

 

 

10 20 30 45

Time, minutes

 

o=Day0,I=Day10,A=Day20,o=Day42

 

 

 

Figure l. Dissolution Profiles of Enteric-coated Aspirin Tablets Packaged in a Two-
sided Wrap USP Class B Strip Pak and Stored at 33°C, 60%RH
(Hoblitzell et a1 1985)

Disintegration occurs when the solvent penetrates through the pores of the tablets.
Because the pores of tablets are very small, the amount of solvent that penetrates into the
tablet matrix does not affect tablet disintegration and disaggregation. “For this reason,
disintegrants are added to effect swelling of the granules, followed by increased strain
inside the tablet boundaries and this finally leads to the tablet rupture and rapid
disintegration. After deaggregation and dislodgement occurs, more drug particles become
exposed to the solvent and dissolution proceeds effectively. Therefore, close correlation

can exist between disintegration and dissolution” (Abdou 1989).

2.3 Mathematical Model for Shelf Life

Shelf life can be calculated by using linear, piecewise or non-linear models
depending on the shape of the isotherm between the initial point which is the condition of
the fresh product and the critical point which is the condition of the product when it is
about to spoil (Hernandez 2000). If the line is linear, choosing a linear model is
preferable. On the other hand, if it is not linear, choosing either the piecewise or the non-
linear model is more accurate.

For a linear model, if the portion of the sorption isotherm between initial and
critical point is a straight line, there will be only one slope. Only 2 pairs of moisture
content and relative humidity data points are enough for calculation. The general

equation used to calculate shelf life for the linear model (Rudolph 1986) is

 

t

= IWDfl 1n[Aw0 —Aw,=0] (1)

PApS Aw0 — Awm

The following definitions of terms apply to both equations (1) above and (2) on

the next page.

10

t = Time during which the product in the package gains moisture until it

reaches equilibrium
1 = Thickness of packaging material, mils (see note below)
W D = Product dry weight, grams

P = Permeability constant, gram-mil/mz-mmHg-day (see note below)

A = Area, m2 (see note below)
p, = Saturation partial pressure, mmHg

,6 = Slope of sorption isotherm

 

. . . . RH
Aw0 = Water act1v1ty of storage condition = 100"

RH o = Relative humidity of storage condition
Aw,=0 = Water activity of product when it is fresh

Aw,=, = Water activity of product when it is about to spoil

For the piecewise model, when the sorption isotherm is not linear between the two
points, it may be divided into several ranges, each of which has an individual linear slope.
This is an approximation of non-linear curves. In some cases, this works well. The
number of ranges depends on the data pairs from the experiment. If we get 5 pairs of
moisture content and water activity, the sorption isotherm can be divided into 4 ranges
and also provides 4 slopes. The equation used for a piecewise model (Rudolph 1986) is

t= 1WD 2 ,Biln Awo—Aw,=,. (2)
‘12/1173 i=1 [ITVb _- 14““

=i+l

 

 

Note: For any package, it may be more convenient to measure P , the permeance, for

the whole package, closed or sealed. When this is done, the following is true.

l a 1 for calculation of equation (1) or (2)

A E 1 for calculation of equation (1) or (2)

This leads to Equations (3) and (4) which show

 

 

 

W A - A

t = i In w" w,=0 (linear model) (3)
Pp: AWO —AWI=I
W " - -

I = ,D '3’, ln Aw“ Aw,=, (piecewise model) (4)
PP, i=1 Awo - Awr=i+l

Where P' = Permeance of the package, gram/package-mmHg-day
The rest of the parameters of the equations are defined as above for Equations
(1) and (2).

Equation (5) show the relationship between WVTR and t.

 

 

P'= —R and MW = f‘fl
P.
Therefore, P' = R
AAw'pr
And I = W 1n , Aw" ' Aw'=° (linear model) (5)
W VTR AwO — Aw,___,

The non-linear model (G.A.lB. Model) is a three-parameter equation which fits
data very well up to 0.9Aw in many cases (Bizot 1991). Equation (6) is the non-linear

model (Diosady et a1 1996).

M, —M,+—2E/l(—:—ln (II+C)M, —2W,,,C (6)
(n+C) (l'I+C)M,. —2W,,,C

 

1
"m

 

1*

2
where,IT= W" -C— 2+ "' ~C-C —4+4C
Me Me

12

R

 

 

= morn-p,
WD-l-(2)-K-(1—C)

 

M = Moisture content, g of water/ g of dry product
C = Guggenheim constant
k = A factor correcting properties of the multi-layer molecules with

respect to the bulk liquid

Wm = Water content corresponding to saturation of all primary adsorption
site by one water molecule

Each model does not fit all products. Root mean square can be used to determine
if the model fits the product. A low root mean square value would show that the model
fits the product.

The result calculated from the equation sets may not be exactly the same as that
from the actual test condition because of limitations of the program. For example, the
calculation assumes constant storage temperature and relative humidity. Therefore, it may
not account for the fluctuation of the actual storage condition which always occurs, even
in a controlled storage chamber. The storage conditions must be managed so as to keep

fluctuations at an acceptable minimum, and so provide a useful approximation.

2.4 Computer Solution of Equations

A computer program has been developed for the purpose of time saving and ease of
use in a variety of applications (Yoon 2000). The computer program contains the
equations (1), (2) and (6) for users to select depending on the shape of the sorption

isotherm of each product. The computer program can calculate

l3

I Shelf life when given a barrier package.
I The barrier required when given a shelf life expectation.

Data necessary to calculate the shelf life are

I Sorption Isotherm of the product.
I Moisture content at initial point and at critical point.
I Package properties: Permeability constant, Area and thickness of walls.

For blister packaging, permeance (P') is the appropriate term to
show the package properties. The amount of water permeated into
the blister cavity can be reported in gram or milligram of water per
blister cavity without reference to the area and thickness of the
material to make the blister cavity.

I Storage conditions: temperature and relative humidity.

2.5 Prednisone

Deltasone tablets contain prednisone which is a glucocorticoid. Glucocorticoids
are adrenocortical steroids which are readily absorbed from the gastrointestinal tract.
Prednisone is a white, odorless, crystalline powder. The chemical name for prednisone is
pregna-1,4-diene-3,11,20—tn'one, 17,21-dihydroxy- and its molecular weight is 358.43.
The structural formula is represented below.

61130“

00
--OH

  

Figure 2 Structural Formula of Deltasone Tablet

l4

Prednisone is used as replacement therapy in adrenocortical deficiency states.
Their synthetic analogs are primarily used for their potent anti-inflammatory effects in
disorders of many organ systems.

A 5 mg Deltasone tablet contains 5 mg of active ingredient plus the excipients,
calcium stearate, corn starch, lactose, mineral oil, sorbic acid and sucrose
(Pharmacia&Upjohn).

From official monographs of prednisone, prednisone tablets must contain 90.0 to
110.0 percent of the labeled amount of C21H2605. Not less than 80% of the labeled
amount of C21H2505 is dissolved in 30 minutes (USP official monographs for
prednisone).

From previous data, prednisone passed dissolution after storage in open dish at
65% relative humidity but failed dissolution afier stored at 75% (Thomas 2000). This
means the product failed at relative humidity somewhere between 66 to 75%. Therefore,
75% relative humidity was selected to be a storage condition for this experiment to make
sure that the storage condition used is not below the failure point of the product. Storage
the product at the relative humidity lower than critical relative humidity resulted in the
product will not be deteriorated by that storage condition.

Reference standard curve is a plot of Absorbance vs %Dilution. It is necessary to
construct a standard curve in order to convert the absorbance from dissolution testing
procedure into dissolution percentage. For the whole research, dissolution percentages are

calculated from the average of three equations obtained by the following standard curve

below.

15

 

 

Absorbance (AU)

Dissolution Standard Curve of Prednisone

 

 

   
   
  

 

 

0. 5
y = 0.4568x + 0.001
0. 4 “ R2 = 0.9998
0. 3 - .4596x - 0.001
R2 = 0.9999
0- 2 J y = 0.4564x - 0.002
0. 1 - R2 = 0.9993
0 i T i m
0% 20% 40% 60% 80%
%Dilution

100%

Figure 3 Dissolution Standard Curve of Prednisone (Thomas 2000)

16

 

CHAPTER 3

MATERIALS AND METHODS

MATERIALS AND EQUIPMENT

1.

2.

10.

11.

12.

13.

14.

15.

16.

Prednisone, 5 mg, from Upjohn Lot 92DUW, Exp. 10/2004
Environmental chamber 25°, 30° and 40°C (Nor Lake Scientific and Lab-line
instruments Inc.) in which temperature and relative humidity are controlled

automatically

Saturated salt solutions for 13, 34, 51, 75, 80, 96%RH

Aluminum weighing pans

Plastic petri dishes

Polyethylene buckets

Humidity sensors (Newport Scientific Inc., accuracy i1%)

Mettler balance (Model no. AB 160, Mettler Inc.)

Metrohm Karl Fischer Titrator with Brinkman Polytron® Homogenizer (720 KFS
Titlino, 703 Ti Stand)

Dissolution apparatus (V ankel VK6010)

UVN IS spectrophotometer (Lambda 20, Perkin Elmer Corporation)
Thermometer (-1 to 51°C, 1/ 10, Fisher Scientific)

5 m1 plastic syringes (Becton Dickinson and Company)

Filter (0.45 pm, MILLEX®-HV)

Disposable culture tubes (12 x 75 mm, VWR Scientific®)

Parafilm 4 in x 125 ft roll

17

17. F isherbrand latex examination gloves

18. Kim-wipe

19. Computer program “Shelf life 2000” developed by Seung-yil Yoon, School of

Packaging, Michigan State University

20. Blister packaging fabricated from

- 7.5 mil Polyvinyl chloride (PVC) film Lot#EA901

- Lamination of 0.6 mil Aclar RX 160/2 mil Polyetheylene/7.5 mil Pentapharm clear

PVC Lot#EA886

- Lidding: 0.8 mil foil/1 .2#C133/3.5# C1 1551 heat seal coating

21. Molecular sieve desiccant tablets for permeation

METHODS

3.1 Determination of Moisture Sorption Isotherm of Prednisone at 25°, 30° and 40°C.

3.1.1 Prepare the saturated salt solutions to provide relative humidities as follows.

Table 1 Saturated Salt Solutions Provide Relative Humidities at 25°, 30° and 40°C

 

 

 

 

 

 

 

 

%Relative %Relative %Relative
Saturated Salt _ _ . .
Bucket no. Humidity at Hum1dlty at Hum1dlty at
Solution of

25°C 30°C 40°C

1 Lithium Chloride ~13 ~13 ~13
2 Magnesium Chloride ~34 ~33 ~33
3 Magnesium Nitrate ~51 ~51 ~51
4 Sodium Chloride ~75 ~74 ~74
5 Ammonium Sulfate ~80 ~79 ~78
6 Potassium Nitrate ~96 ~89 ~87

 

 

 

 

 

l8

 

3.1.2 Weigh the product before storage in each bucket and reweigh after storage

for a period of time until no change in weight.
3.1.3 Determine %IMC by Metrohm Karl Fischer Titrator with Brinkman
Polytron® Homogenizer (720 KFS Titrino, 703 Ti Stand).

3.1.4 Calculate the Equilibrium Moisture Content (EMC) by following equation.
%EMC = {Bil—((1 + IMC):| — l}x100 (7)
1

Where, Wf = final weight of the samples, g
Wi = initial weight of the samples, g
IMC = initial moisture content of the samples, g water/ g dry product

3.1.5 Moisture Sorption Isotherm is the plot of %EMC vs %RH

3.2 Selection Packaging Material

3.2.1 Calculation Barrier Required to Provide the Specific Time to Achieve
Equilibrium Moisture Content

In order to choose packaging, it is necessary to solve equation (3) for P' and

choose the packaging material that provides P matched with calculation. Samples of 1"
required to attain the desired time to achieve equilibrium moisture content, t, for the

Prednisone used in this experiment are shown in Table 2.

l9

Table 2 P' Required to Attain the Desired Shelf Life

 

 

 

 

 

Shelf life Temperature P Required,
g/day-mmHg-package
65 days 25°C 3.2061E-06
20 days 30°C 9.1615E-06
9 days 40°C 6.5856E-06

 

 

 

Note: Parameters used to calculate P in the table above based on experimental
data of Prednisone in this study.
PVC and PVC/0.6 mil Aclar were selected to form blister packaging for this
experiment because they provide convenient time periods for permeation of moisture into
the blister cavity until moisture content of tablets reached equilibrium. From experience,

we know that the PVC is poor barrier while PVC/0.6 mil Aclar is better.

3.2.2 Determination of Water Vapor Transmission Rate (WVT R) of Blister
Packaging

WVTR was determined according to USP <671> Container Permeation for
Single-Unit Container and Unit-Dose Containers for Capsules and Tablets, with certain
changes, as follows.

3.2.2.1 Two types of blister packaging; PVC and PVC/Aclar were filled with
molecular sieve and sealed at the Packaging Laboratory, Eli Lilly.

3.2.2.2 Empty blister packs were used as a blank.

3.2.2.3 Packages were stored at 25°C, 75%RH, 30°C, 75%RH and 40°C, 75%RH.

3.2.2.4 The weight gained was measured at time intervals described in Table 3.

20

 

Table 3 Time Interval for Determining Water Vapor Transmission Rate of PVC and

PVC/0.6 mil Aclar at 3 Storage Temperatures

 

 

 

 

 

Blister Packaging Storage Temperature Time Interval
PVC 25°, 30°C 24 hours
40°C 12 hours
PVC/0.6 mil Aclar 25°, 30° and 40°C 3 days

 

 

 

3.2.2.5 Weighing continued at each time interval until at least 3 data points were
available to establish the slope.
3.2.2.6 Calculate weight gain by the following equation.
Weight gain, g = (Wf — Wi) - (Cf — Ci) (8)
Where, (Wf — W i) = The difference, in mg, between the final and initial
weights of each test pack
(Cf — Ci) = The average of the difference, in mg, between the final
and initial weights of the control packs (blanks)
3.2.2.7 Plot weight gain versus time. The slope of this plot can be used to
calculate WVTR in gram/day-package. This WVTR can be used to calculate P' which
was used to calculate time, t, by equation (3). This time is not a shelf life of the
pharmaceutical product but time for the moisture uptake to reach equilibrium moisture

content. Shelf life is this time plus time that the product can tolerate this moisture content

in the open dish study.

21

 

3.2.3 Compare Calculated P with Actual P
Table 4 shows the comparison between calculated P from 3.2.1 and actual P
from 3.2.2. The actual P must be no greater than the required P . An actual P less than

required P is preferred.

Table 4 Comparison of Required P Calculated and P of Material Chosen

 

 

 

 

 

Time to
. P Required, Actual P' of PVC/0.6 mil
achleve Temperature
, , , g/day-mmHgopackage Aclar, g/day-mmHg-package
equlllbrlum

65 days 25°C 3.2061E-06 3.1156E-O6

20 days 30°C 9.1615E-06 7.1208E-06

9 days 40°C 6.5856E-06 6.7636E-06

 

 

 

 

3.3 Determination of Moisture Content

Determine moisture content of

- Prednisone in Open Dish at 75%RH, 25°, 30° and 40°C

- Prednisone in PVC and PVC/0.6 mil Aclar at 75%RH, 25°, 30° and 40°C
By Metrohm Karl Fischer Titrator with Brinkman Polytron® Homogenizer (720 KFS
Titrino, 703 Ti Stand)
Note: Moisture content determined by Karl Fischer Titrator is reported on wet basis. The
equation below is the conversion of moisture content from wet basis to dry basis.

Moisture Content (Dry Basis) = Moisture Content (Wet Basis) (9)
1 - Moisture Content (Wet Basis)

22

 

Table 5 Sampling Plan of Moisture Content Determination of Prednisone in Open
Dish

 

 

 

 

Day 0 1 2 3
Prednisone in Open Dish @25°C x x x x
Prednisone in Open Dish @30°C x x x x
Prednisone in Open Dish @40°C x x x x

 

 

 

 

 

 

 

Numbers of specimens for determining moisture content of Prednisone in open dish are 3

tablets for each point or 36 tablets for total.

Table 6 Sampling Plan of Moisture Content Determination of Prednisone in PVC

 

 

 

 

Blister Packaging
Day 0 1 2 3 4
Prednisone in PVC @25°C x x x x x
Prednisone in PVC @30°C x x x x x
Prednisone in PVC @40°C x x . x x x

 

 

 

 

 

 

 

 

Numbers of specimens for determining moisture content of Prednisone in PVC blister are

4 tablets for each point or 60 tablets for total.

Table 7 Sampling Plan of Moisture Content Determination of Prednisone in
PVC/0.6 mil Aclar Blister Packaging

 

 

 

 

Day 0 3 5 6 9 10 14 15 20 25 30 40 50 60 65 70 76
250C x x x x x x x x x x
300C x x x x x x x
400C x x x x x x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

23

Numbers of specimens for determining moisture content of Prednisone in PVC/0.6 mil

Aclar are 4 tablets for each point or 92 tablets for total.

3.4 Determination of Dissolution

Dissolution test was done by using Vankel VK6010 dissolution tester with
rotating paddle by Vankel Industries, Inc, Edison, NJ. Dissolution test was performed
according to USP <711>Dissolution and Official monographs of prednisone as follows.

3.4.1 Deaerate the deionized water by boiling the water for an hour.

3.4.2 Place 500 ml of dissolution medium (deaerated deionized-water) into the
controlled temperature dissolution vessel.

3.4.3 Equilibrate the dissolution medium to 37 i 0.5°C.

3.4.4 Place one tablet into each vessel and operate the apparatus at the rate
specified, 50 rpm., in the individual monograph.

3.4.5 Withdraw the solution at 5, 10, 20 and 30 minutes from the zone midway
between the surface of the dissolution medium and the top of the blade, not less than 1
cm from the vessel wall.

3.4.6 Filter the solution by inert filter, 0.45 pm, MILLEX®-HV for Prednisone
that does not cause adsorption of active ingredient.

3.4.7 Measure absorbance by using UV/V IS spectrophotometer Lambda 20,
Perkin Elmer Corporation, at the wavelength specified, 242 nm for Prednisone, in the
individual monograph.

3.4.8 Convert absorbance value reading from the spectrophotometer to

%dissolution by using dissolution standard curve of prednisone.

24

Table 8 Sampling Plan of Dissolution Determination of Prednisone in Open Dish

 

Day 0 6 12 18 24 30 36 42

 

Prednisone in Open Dish @25°C x x x x x x x x

 

Prednisone in Open Dish @30°C x x x x x x x

 

Prednisone in Open Dish @40°C x x x x x x x

 

 

 

 

 

 

 

 

 

 

 

Numbers of specimens for determining dissolution of Prednisone in open dish are 6

tablets for each point or 126 tablets for total.

25

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26

CHAPTER 4

RESULTS

4.1 Sorption Isotherm of Prednisone at 25°, 30° and 40°C

The purpose of the sorption isotherm study is to understand the product behavior.
Each product has its individual behavior in absorption of water. The tablets gain weight
when exposed to a humid environment because water molecules diffuse into the tablets.
Once tablets reach equilibrium with the environment, the weight remains constant.

The sorption isotherm is a plot of equilibrium moisture content versus relative
humidity at each temperature. From data in Table 1 1, as the relative humidity increases,
the weight or moisture content increases until equilibrium with the environment is
reached.

In general, the sorption isotherm at higher temperature lies below that of the lower
temperature because the water holding capacity decreases as temperature increases.
However, in Figure 4, sorption isotherms of prednisone at the three temperatures
appeared not to be separated from each other, but this was a result of the vertical scale
used. The water holding capacities of prednisone at 25°, 30° and 40°C tended to be lower

with increasing temperature, but the differences may be negligible (Table 11).

27

Table 11 Relative Humidity and Equilibrium Moisture Content (Dry Basis) at 25°,
30° and 40°C for Prednisone Tablets

 

 

 

 

 

 

 

 

 

25°C 30°C 40°C
%Equilibrium %Equilibrium %Equilibrium
%Relative Moisture %Relative Moisture %Relative Moisture
Humidity Content Humidity Content Humidity Content
(dry basis) (dry basis) (dry basis)

13 5.40 13 5.43 13 5.50

34 5.64 33 5.56 33 5.60

51 5.80 51 5.80 51 5.78

75 6.15 74 6.03 74 5.94

80 6.27 79 6.44 78 6.05

96 11.47 89 8.58 87 6.62

 

 

 

 

 

 

Figure 4 shows the shape of the whole isotherms of prednisone from the relative

humidity of 13% up to almost 100% at 25°, 30° and 40°C. Because the failure of

prednisone was at 75% relative humidity, it was unnecessary to utilize the whole

isotherm. The regions of 13% to 80% relative humidity in the sorption isotherms were of

interest because the initial points and critical points were within this range. The useful

regions of sorption isotherms of prednisone at three temperatures were straight lines.

Therefore, the linear model or equation (3) was appropriate to be used to calculate the

time to reach equilibrium moisture content, t.

28

 

 

 

Sorption Isotherm of Prednisone at 25°, 30° and 40°C

 

 

‘f

 

 

Wait—

 

 

 

 

 

2
'5 a 10.00
g a:

t. 8.00
a
.g e. 6.00
g g 4.00
E 5 2.00 ~
g 0.00

l

20

40 60
% Relative Humidity

T

80 100

+25Cl

+30C
+4ocl.

 

 

 

 

J

Figure 4 Sorption Isotherm of Prednisone at 25°, 30° and 40°C

Figures 5, 6 and 7 show linear trend lines and their equations of isotherms at 25°,

30° and 40°C respectively. From the relation between X (%relative humidity) and Y

(%moisture content) in equations in Figures 5, 6 and 7, %relative humidity could be

predicted from %moisture content. Since the initial moisture content in dry basis of fresh

prednisone was 5.45% (more detail in 4.3.1 page 37), the relative humidity of prednisone

inside the bottle was 19% at 25°C. Because the isotherms were so close, the relative

humidity inside the bottle was probably around 19% throughout this range of

temperature.

The equilibrium moisture content of prednisone at 75%RH was 6.15%, 6.04% and

5.94% at 25°, 30° and 40°C respectively. Since the difference of initial and equilibrium

moisture content was small (less than 1%), the time it took to achieve equilibrium

moisture content, t, was short.

29

The slope of each sorption isotherm was necessary to calculate the time needed to

achieve equilibrium moisture content, t, for each storage condition (calculation shown in

appendix C).

 

 

 

Sorption Isotherm of Prednisone at 25°C

y= -
R = 0.9883

 

 

%Equilibrium Moisture
Content (Dry Basrs)
.O t" E" S" P S" F" >1 9°

0 2 0 40 60 80 1 00
%Relative Humidity

 

 

 

 

Figure 5 Sorption Isotherm of Prednisone at 25°C

30

 

 

 

 

 

 

 

Sorption Isotherm of Prednisone at 30°C
3 8 00
A o = +

it a mo y

O a .

g a: 6.00

a t‘ 5.00

.3 e 4. 00

’3 g 3.00

'5 *5 2.00

55 1. 00

,\° 0. 00

' 0 20 40 60 80 100
%Relative Humidity

Figure 6 Sorption Isotherm of Prednisone at 30°C

 

Sorption Isotherm of Prednisone at 40°C l

 

 

 

 

 

 

 

 

 

 

 

0
E a; 3- 00 y=0.0082x+5.3647 l
:5 a 7'00 R2=0.9754 " ‘
2 a: 6.00 - +h___
a r: 5.00 ———~€:Ze‘—.o .,———~e———=£e¢r ",,,,.,—--~
.g e 4. 00 0 ~———~-——~-~——A ~—-———
g E 3. 00 ‘”"_*' g“ E_¥ _"‘— “W“
'5 ‘5 2. 00 ‘T"—* __ —“c—“ mm"
55 1.00 fig -
°\° O. 00 . m m f
i 0 20 40 60 80 100
%Relative Humidity
.0

 

 

Figure 7 Sorption Isotherm of Prednisone at 40°C

31

 

4.2 Water Vapor Transmission Rate (WVTR) Determination

In Tables 12 and 13, as time passed by, the weight of desiccant increased. When

the desiccant was ahnost saturated with water, the rate of weight gain decreased. Those

data points were disregarded and do not show in Tables 12, 13, or in Figures 8 and 9.

Because of the limitation of the balance, it was necessary to weigh the card of 2x5

blisters (10 cavities) and then divide that weight by ten to get the weight gained for each

cavity or tablet. The total weight gained values shown in Tables 12, 13, Figures 8 and 9

are the total weight gained of a card of 2x5 blisters. Therefore, the slopes in Figures 8 and

9 are WVTR of a 2x5 blister card. However, Tables 14 and 15 show WVTR and the

permeance of each cavity of PVC and PVC/0.6 mil Aclar blister which are 1/ 10 of the

values calculated per blister card. The values in these tables will be used to calculate the

time required to achieve equilibrium moisture content, I.

4.2.1 Water Vapor Transmission Rate of 7.5 mil Polyvinyl Chloride (PVC)

Table 12 Total Weight Gained vs Time of Desiccant Tablets in a 2x5 (10 Cavities)
PVC Blister Card at 25°, 30° and 40°C

 

 

 

 

 

 

 

 

25°C 30°C 40°C
Total Total Total
Time, day Weight Time, day Weight Time, day Weight
Gained, g Gained, g Gained, g

0 0 0 0 0 0

1 0.0102 1 0.0141 0.5 0.0142

2 0.022 2 0.0316 1 0.0273

3 0.0347 3 0.0485 1.5 0.075

4 0.0466 4 0.0627

 

 

 

 

 

 

32

 

 

Total Weight Gained vs Time of PVC Blister '

0.08

 

 
   
    

y = 1.5787E-02x
= 25900302,, R2 = 9.9830E-01

2 = 9.9326E-O

0.06

 

0.04

 
  
 

y = 1.149OE-02x

 

 

 

Total Weight Gained, g

0.02 2
R = 9.9777E-01
O l I i
0 1 2 3 4 5
Time, Day

 

 

 

Figure 8 Total Weight Gained vs Time of Desiccant Tablets in a 2x5 (10 Cavities)

PVC Blister Card at 25°, 30° and 40°C

33

4.2.2 Water Vapor Transmission Rate of PVC/0.6 mil Aclar

Table 13 Total Weight Gained vs Time of Desiccant Tablets in a 2x5 (10 Cavities)
PVC/0.6 mil Aclar Blister Card at 25°, 30° and 40°C

 

 

 

 

 

 

 

 

 

 

 

 

25°C 30°C 40°C
Total Total Total
Time, day Weight Time, day Weight Time, day Weight
Gained, g Gained, g Gained, g

0 0 O 0 O 0

3 0.0017 3 0.0035 3 0.0071

6 0.0029 6 0.0083 6 0.0162

9 0.0047 9 0.0133 9 0.0250

12 0.0065 12 0.0191 12 0.0336

15 0.0080 15 0.0223 15 0.0412

21 0.0115 21 0.0355 21 0.0601

24 0.0135 24 0.0431

27 0.0154 27 0.0476

 

 

 

 

 

 

34

 

 

 

 

    
  
 

 

 

 

 

Tatal Weight gained vs Time of PVC/0.6 mil Aclar Blister

an
'6 0.08
g y = 1.6996E-03x
5 0.06 - y = 2.8064E-03x R2 = 9.8725E—Ol
ill 2 = -
a) 0.04 _ R 9.983013 01
.5 = 5.5515E-04x

' 3 0.02 9 9729 -01
To
a: o .

i 0 10 20 30

Time, days

 

ezsc§

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A403

 

__l

 

Figure 9 Total Weight Gained vs Time of Desiccant Tablets in a 2x5 (10 Cavities)

PVC/0.6 mil Aclar Blister Card at 25°, 30° and 40°C

From equation (5), the higher the WVTR, the less the time to reach equilibrium

moisture content and the shorter the shelf life. From WVTR shown in Table 14 and 15,

PVC/0.6 mil Aclar has low WVTR compared with PVC at all 3 temperatures. This means

Aclar allowed permeation of water at a slower rate than PVC. As a result, it provided

better protection to the Prednisone than PVC.

35

Table 14 Water Vapor Transmission Rate (WVT R) and Permeance (P ) of PVC

 

 

 

 

 

Blister Cavity
Temperature WVTR (g/day-cavity) P' (g/day-cavity-mmHg)
25°C 1.1489E-3 6.4483E—5
30°C 1.5787E-3 6.6143E-5
40°C 2.5900E-3 6.2420E-5

 

 

 

Table 15 Water Vapor Transmission Rate (WVT R) and Permeance (P') of
PVC/0.6 mil Aclar Blister Cavity

 

 

 

 

 

Temperature WVTR (g/day-cavity) P ' (g/day'cavity-mmHg)
25°C 5.5515E-5 3.1158E-6
30°C 1 .6996E-4 7.1208E-6
40°C 2.8064E-4 6.7636E-6

 

 

 

36

 

 

4.3 Moisture Content

4.3.1 Initial Moisture Content

Initial moisture content is the moisture content of tablets fresh from the bottle. It
shows the initial condition of the product. Relative humidity inside the bottle, which is
necessary to calculate the time required to achieve equilibrium moisture content, can be
determined by projecting from the initial moisture content in the isotherm. Karl Fisher
equipment reports the percent of moisture content in wet basis. It is necessary to convert
to moisture content in dry basis by using equation (9) to be compatible with the result of

equilibrium moisture content in the sorption isotherm.

Table 16 Initial Moisture Content of Prednisone

 

 

 

 

 

 

 

 

Sample Moisture Content from Equipment in Moisture Content in Dry Basis,
No. Wet Basis, g water/ 100 g wet product g water/ 100 g dry product
1 5.18 5.46
2 5.23 5.52
3 5.25 5.54
4 5.02 ‘ 5.29
Average 5. 1 7 5.45
STDEV 0.104 0.1 14

 

 

 

4.3.2 Moisture Content of Prednisone in Open Dish
Table 17 shows the moisture content of the prednisone in open dish at 25°, 30°
and 40°C at the three time intervals chosen for measurement. From the sorption isotherm,

we learned that the equilibrium moisture content of prednisone at 75%RH, 25°, 30° and

37

 

40°C was about 6.15%, 6.03% and 5.94% respectively. The moisture content of
prednisone in the open dish achieved equilibrium within a day. After the moisture content

of tablets reached equilibrium, it varied around the mean as shown in Table 17.

Table 17 Moisture Content of Prednisone in Open Dish

 

 

 

 

 

Day 0 1 2 3

Moisture Content (Dry Basis) at ZSTC 5.45 6.13 6.00 5.95
Moisture Content (Dry Basis) at 30°C 5.45 6.00 6.10 6.00
Moisture Content (Dry Basis) at 40°C 5.45 5.94 6.03 5.95

 

 

 

 

 

4.3.3 Moisture Content of Prednisone in PVC and PVC/0.6 mil Aclar Blister

Tables 18 to 21 show the moisture content of the prednisone in PVC and PVC/0.6
mil Aclar at 25°, 30° and 40°C at the time intervals chosen for measurement. In Table 22,
times to achieve equilibrium moisture content of prednisone packaged in PVC/0.6 mil
Aclar were longer than those in PVC at the same temperature. Therefore, the higher the
barrier of packaging material, the longer time to reach equilibrium moisture content at the
same storage condition. Regardless of the packaging material, as the temperature

increased, the time to reach equilibrium decreased.

38

 

Table 18 Moisture Content of Prednisone in PVC Blister

 

 

 

 

 

 

 

 

 

Day 0 1 2 3 4

Moisture Content (Dry Basis) at 25°C 5.45 5.82 6.04 6.11 6.05
Moisture Content (Dry Basis) at 30°C 5.45 5.86 6.02 6.02 6.00
Moisture Content (Dry Basis) at 40°C 5.45 6.04 5.99 6.14 6.02

 

 

 

Table 19 Moisture Content of Prednisone in PVC/0.6 mil Aclar Blister at 25°C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Day 0 10 20 3O 40 50 60 65 70 76
Moisture Content
(Dry Basis) 5.45 5.40 5.71 5.88 5.97 5.98 6.01 6.15 6.11 6.14
Table 20 Moisture Content of Prednisone in PVC/0.6 mil Aclar Blister at 30°C

I Day 0 5 10 15 25 31

I Moisture Content (Dry Basis) I 5.45 5.61 5.67 5.78 6.04 6.04 6.10 I
Table 21 Moisture Content of Prednisone in PVC/0.6 mil Aclar Blister at 40°C

I Day I 3 6 9 14

I Moisture Content (Dry Basis) j 5.45 5.62 5.81 5.94 5.94 I

 

 

 

 

 

Table 22 Time to Achieve Equilibrium Moisture Content of Prednisone from the

 

 

 

 

Experiment
Temperature 25°C 30°C 40T C
Open dish 1 day 1 day 1 day
PVC 3 days 2 days 1 day
PVC/0.6 mil Aclar 65 days 20 days 9 days

 

 

 

 

 

 

39

4.4 Dissolution
4.4.1 Dissolution Profiles of Prednisone Fresh from the Bottle

The dissolution profile shows the dissolution characteristic of an individual
product. Profiles changes, as described on page 9, under the conditions of heat, moisture
and aging.

Figure 10 shows the dissolution profiles of prednisone tablets fresh from the
bottle. The profiles for six tablets were nearly superimposed one upon the other. The
standard deviations of dissolution values of six tablets at 5, 10, 20 and 30 minutes stirring
time were small. The average dissolution value of the prednisone fresh from the bottle at
30 minutes was 93.0%. The standard deviation of dissolution value at 30 minute stirring

time of six tablets was 0.972.

40

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41

4.4.2 Dissolution Profiles of Prednisone after Aging

Dissolution of prednisone changed considerably after aging at all storage
conditions. Figure 11 shows dissolution profiles of prednisone in open dish after storage
at 30°C, 75%RH. As time passed, the dissolution curve shifted well below that of fresh
prednisone. Even though the tablets meet the monograph requirement of 80% dissolved
at 30 minutes stirring time, the profile has moved steadily downward. Profiles of
prednisone packaged in PVC and PVC/0.6 mil Aclar shifted in the same way as those in
open dish. Figures 12 and 13 show dissolution profiles of prednisone tablets in PVC/0.6
mil Aclar stored at 25°C, 75%RH at day 30 and 65 respectively. Compared with the
profiles of 6 tablets of prednisone fresh from the bottle (Figure 10), the gaps between
profiles of six tablets at day 30 and 65 were wider than the closely packed profiles of
fresh prednisone. Therefore, the variability of profiles which got greater as time went on
was an early warning of deterioration of tablets, so increased standard deviation can be

used as an early warning indication.

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Dissolution of prednisone at 5, 10, 20 and 30 minute stirring time decreased as
storage time increased. Figures 14 to 16 depict the trend in decreasing dissolution of
prednisone in open dish, prednisone packaged in PVC blister and prednisone packaged in
PVC/0.6 mil Aclar blister and stored at 30°C. Negative slope, the rate of decreasing
dissolution, of the plot of dissolution versus storage time demonstrates the degree of
deterioration at each storage condition. Prednisone in open dish had the highest slope
(Figure 14) while prednisone in PVC/0.6 mil Aclar had the lowest slope (Figure 16). In
conclusion, the rate of decrease in dissolution or deterioration of prednisone in open dish
(without packaging) was greatest while that of prednisone in the best barrier packaging
was smallest. Table 23 shows the slopes of the plots of dissolution versus storage time for
prednisone in open dish, prednisone in PVC and prednisone in PVC/0.6 mil Aclar stored
at 25°, 30° and 40°C. Slopes of prednisone in open dish at 40°C were very close to those
of prednisone packaged in PVC at 40°C especially at 5 and 10 minutes stirring time
because PVC at 40°C did not provide the protection to the product. The moisture content
of prednisone packaged in PVC at 40°C reached equilibrium within a day of that in open
dish.

In Figures 14 to 16, since the R2 of linear trend lines were not high, linear

equations should not be used to calculate storage time at 80% dissolution.

46

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Table 23 Slopes of the Plots of Dissolution versus Storage Time

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Temperature Stirrihg Time, Open Dish PVC PVC/0.6 mil
mmutes Aclar
5 minutes 0.383 0.186 0.123
0 10 minutes 0.489 0.254 0.163
25 C 20 minutes 0.313 0.117 0.096
30 minutes 0.134 0.080 0.044
5 minutes 0.466 0.331 0.222
30°C 10 minutes 0.587 0.412 0.286
20 minutes 0.284 0.190 0.153
30 minutes 0.174 0.099 0.111
5 minutes 0.428 0.432 0.318
o 10 minutes 0.543 0.524 0.393
40 C 20 minutes 0.264 0.335 0.156
30 minutes 0.144 0.212 0.076

 

 

 

 

 

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51

4.4.3 Failure of Prednisone

According to its USP monograph, prednisone that dissolves less than 80% at 30
minutes stirring time is unacceptable. In order to detect the failure point as early as
possible, a 10% reduction in dissolution was designated to be a failure point for this
research. For this prednisone product, a dissolution at 10% decrease from initial
dissolution was 93.0 x 0.90 = 83.7%. At each time interval, six tablets of prednisone were
sampled to measure the dissolution. If one or more tablets dissolved less than 83.7%, this
indicated the dissolution failure.

Tables 24 to 26 show the failure of prednisone in open dish, PVC and PVC/0.6
mil Aclar at 25°, 30° and 40°C. The dissolution test was done on the days shown in the
tables. These days were chosen as the test dates because they represented the number of
days of added shelf life as provided by the barrier. The dissolution of prednisone in open
dish was tested in six day intervals. We learned that the moisture content of prednisone in
open dish reached equilibrium within a day. Packaged prednisone tablets took a longer
period of time to reach equilibrium moisture content. Since the permeation time of the
PVC at 25°C was 3 days (2 days more than open dish), the first test date of prednisone in
PVC was day 8 at 25°C and then every six days from day 8.

In Table 25, dissolution change of more than 5% of three out of six tablets was
used to point out the failure of prednisone in PVC blister stored at 40°C at day 24 instead
of 10% change in dissolution of a single tablet. The failure on the following days also
showed signs of deterioration.

Table 27 summarizes the first day that failure was found after storage. The

deterioration or 10% change in dissolution of prednisone at all three temperatures can be

52

found earlier in open dish than that in PVC and PVC/0.6 mil Aclar because of the
protection provided by the package. Since PVC/0.6 mil Aclar provided better moisture
protection than PVC, the failure of Prednisone packaged in PVC/0.6 mil Aclar occured
later than that in PVC. Prednisone in open dish at 30°C failed earlier than that at 40°C
because not only heat causes the failure of prednisone but also moisture content. Moisture
content of the tablets at 30°C is higher than at 40°C. Therefore, the combination of heat
and moisture content might have caused the prednisone stored at 30°C to fail earlier than
at 40°C. This was also found in aspirin tablets in a previous study; first dissolution failure

of aspirin found on day 45 at 30°C but not until day 75 at 40°C (Adams 1998).

53

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Table 27 The First Day that Failure was Found

 

Prednisone in

The first day that failure was found

 

 

 

 

 

25°C 30°C 40°C
Open Dish 30 12 18
PVC blister 38 25 24
PVC/0.6 mil Aclar 65 37 32
blister

 

 

 

 

High standard deviation of dissolution values at 30 minutes stirring time is

another indicator to point out the dramatic change of the tablets. Tables 28 to 30 show

standard deviations of dissolution values at 30 minutes for prednisone in open dish,

prednisone packaged in PVC blister and prednisone packaged in PVC/0.6 mil Aclar

blister. The bold numbers in the tables show the high standard deviation values that

occurred on the same day that 10% decrease in dissolution was found.

Table 28 Standard Deviation of Dissolution at 30 Minute Stirring Time of

Prednisone in Open Dish after Aging

 

 

 

 

 

 

 

25°C Day 0 6 12 18 24 30
STDEV 0.972 1.053 1.755 1.673 3.197 4.380
0 en Da 0 6 12
p 30°C y
dish STDEV 0.972 1 .710 4.387
Day 0 6 12 18
40°C
STDEV 0.972 3.611 2.501 4.715

 

 

 

 

 

 

 

 

 

57

 

 

Table 29 Standard Deviation of Dissolution at 30 Minute Stirring Time of

Prednisone Packaged in PVC Blister after Aging

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

25°C Day 0 8 14 20 26 32 38
STDEV 0.972 1.223 1.026 2.824 3.568 2.731 4.764
Day 0 7 13 19 25
PVC 30°C
STDEV 0.972 1.604 0.688 1.168 3.027
Day 0 6 12 18 24
40°C
STDEV 0.972 1.740 0.609 2.888 2.395
Table 30 Standard Deviation of Dissolution at 30 Minute Stirring Time of
Prednisone Packaged in PVC/0.6 mil Aclar Blister after Aging
25°C Day 0 10 20 30 40 50 60 65
PVC/ STDEV 0.972 2.263 2.53 2.594 1.776 1.940 2.695 5.402
0.6 30°C Day 0 5 10 15 20 25 31 37
mil STDEV 0.972 1.060 1.317 1.346 2.384 0.979 2.789 2.864
Aclar 40°C Day 0 3 6 9 14 20 26 32
STDEV 0.972 1.427 1.926 1.345 2.268 1.733 2.539 4.500

 

 

 

 

 

 

 

 

 

 

 

58

 

 

4.5 Verification of Calculation
4.5.1 Moisture Content

Table 31 shows the results of using equation (3) to predict the time to achieve
equilibrium moisture content. Predicted moisture contents were compared with the actual
moisture contents of the Prednisone tablets from the experiment. The only difference
between actual and predicted time to achieve equilibrium moisture content was found in
prednisone packaged in PVC/0.6 mil Aclar and stored at 30°C which was 20 days instead

of 22, less than 10% difference.

Table 31 Time to Achieve Equilibrium Moisture Content of Prednisone by

Prediction and Experiment

 

 

 

 

 

 

 

 

 

 

 

 

Packaging Storage Condition Prediction Experiment

25°C 3 days 3 days

PVC 30°C 2 days 2 days

40°C 1 day 1 day
25°C 65 days 65 days
PVC/0.6 mil Aclar 30°C 22 days 20 days
4W5C 9 days 9 days

4.5.2 Shelf Life

Table 32 shows the predicted shelf life or failure time resulting from calculation
of permeation time plus exposure time. Exposure time is the time required to produce

10% change in dissolution of prednisone as found in the open dish study.

59

 

Table 32 Shelf Life Prediction by Using a 10% Decrease in Dissolution as a Critical

 

 

 

 

 

 

 

 

Point
. _ Time to 10% change
Blister Storage Permeation Predicted failure
. . . . in dissolution from
Packaging Condition time, day _ time, day
open dish, day
25°C 3 30 33
PVC 30°C 2 12 14
406C 1 18 19
25TC 65 30 95
PVC/0.6 mil
30°C 22 12 34
Aclar
40°C 9 18 27

 

 

 

 

 

In Table 33, predicted failure times were less than the actual failure times for

prednisone packaged in PVC stored at all 3 temperatures and PVC/0.6 mil Aclar at 300

and 40°C. Therefore, it was safe to use this prediction for the packaging that provided

low barrier. For higher barrier packaging, the time to achieve the equilibrium moisture

content was long. The permeation time shown in table 33 of prednisone packaged in

PVC/0.6 mil Aclar was 65 days. The mechanism of failure was in fact operating before

equilibrium moisture content was established.

60

 

Table 33 Shelf life by Prediction and Experiment by Using a 10% Decrease in

Dissolution as a Critical Point

 

Predicted failure

Actual failure time,

 

 

 

 

 

 

 

Blister Packaging Storage Condition
time, day day
25°C 33 38
PVC 30°C 14 25
40°C 19 24
25°C 95 65
PVC/0.6 mil Aclar 30°C 34 37
40°C 27 32

 

 

 

 

Since the experiment was continued after the 10% change in dissolution was

found, we have an additional result of failure by using the dissolution of less than 80%,

according to individual monograph of prednisone, as a failure point. The predicted shelf

lives were shown in Table 34. Table 35 shows a comparison of the predicted and the

actual failure time. The validity of prediction agreed with those using a 10% change in

dissolution as a failure point. The prediction reasonably correctly predicted the failure of

prednisone packaged in PVC. Prednisone in PVC/0.6 mil Aclar failed earlier at 25°C than

predicted using both criteria as the failure points. Failure at the other two temperatures

was about the same as or later than predicted.

61

 

Table 34 Shelf Life Prediction by Using the Dissolution of Less Than 80% as a

 

 

 

 

 

 

 

 

Critical Point
Time to the
Blister Storage Permeation dissolution of less Predicted failure
Packaging Condition time, day than 80% was found time, day
in open dish on day
25°C 3 42 45
PVC 30°C 2 30 32
40°C 1 36 37
25“C 65 42 107
PVC/0.6 mil
30°C 22 30 52
Aclar
40°C 9 36 45

 

 

 

 

 

Table 35 Shelf life by Prediction and Experiment by Using the Dissolution of Less
Than 80% as a Critical Point

 

 

 

 

 

 

 

 

Blister Packaging Storage Condition Predicted failure Actual failure time,
time, day day
25°C 45 62
PVC 30°C 32 49
40°C 37 42
25°C 107 95
PVC/0.6 mil Aclar 30°C 52 67
40°C 45 44

 

 

 

 

62

 

 

CHAPTER 5

CONCLUSIONS AND FUTURE WORK

In sections 4.1 to 4.3, since the difference of initial and critical moisture content
of prednisone was small (less than 1%), the time it took to achieve equilibrium moisture
content was short. PVC did not provide enough moisture protection to a moisture
sensitive tablet such as prednisone which has a narrow range of initial and critical
moisture content. However, PVC might be suitable for other products which have a broad
range of initial and critical moisture content. Equation (3) reasonably accurately predicted
the time it took to achieve equilibrium moisture content with an error less than 10%. It is
useful to apply this equation in order to select the packaging material that provides an
adequate moisture barrier for pharmaceutical products.

In section 4.4, dissolution decreased as temperature increased or storage time
passed. In plotting dissolution versus storage time, the slope indicated the rate of
deterioration. The decrease in dissolution of prednisone in an open dish was highest while
that of prednisone packaged in PVC/0.6 mil Aclar was lowest.

In order to use this testing and calculation for finding packaging for drugs, we
needed to consider that the shelf life ended when there was an important change, not
necessarily the complete failure of the drug. The critical point for the drug was something
that occurred sooner than actual failure. It was appropriate to show specific changes such
as high standard deviation, greater variability of dissolution profiles or a 10% change

from initial dissolution, which is 83.7%, to indicate the failure.

63

In section 4.5, the hypothesis predicted correctly the shelf life of prednisone
packaged in low barrier packaging such as PVC that provided a short permeation time.
For prednisone packaged in PVC/0.6 mil Aclar and stored at 25°C, the experimental shelf
life was shorter than the predicted shelf life. Because the permeation time was a long
term, dissolution deterioration may have begun before tablets even reached equilibrium
moisture content; permeation was slow enough to lag behind the dissolution rate change.
However, the permeation times at higher temperature (300 and 40°C) were shorter, this
caused the predicted shelf life of prednisone packaged in PVC/0.6 mil Aclar to be
acceptable.

However, the prediction is useful to avoid the trial and error process to select the
barrier for the stability test. The barrier that provided calculated shelf life less than

whatever shelf life we want can be discarded immediately.

Future Work

The prediction of shelf life by using permeation time plus exposure time should
be correct if there is no deterioration that occurs during the permeation time. The
deterioration must start after the moisture content reaches equilibrium, as did prednisone
in the open dish. For the high barrier packaging in this experiment, permeation time was
long. Deterioration had begun before the moisture content had reached equilibrium.
Therefore, the predicted shelf life was longer than the actual shelf life. From Figure 18,
prediction by counting the shelf life from day “X” in which the percent moisture
increased from the initial to “Y” might be more accurate. Experiments should be done by

using high barrier packaging to package prednisone and collect enough data on actual

64

shelf life. Then, evaluate which value of “Y” will provide the most accurate “X” as a
starting point to count for the shelf life. After getting the “Y” value which predicts most
accurately the shelf life, the next experiment should determine if this method can be used

consistently with other pharmaceutical products.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Moistune Content vs Storage Time T
H Critical
:1
8
t:
8
0 Y
I-
3
.2
e
5.
e\
Initial
. X .
1 Storage Time, days
Note: Y is a percent moisture content increased from the initial moisture content that

causes the dissolution change.
X is a starting date to count for shelf life.

Figure 18 Mositure Content vs Storage Time

65

APPENDIX A

Sorption Isotherm Raw Data
Water Vapor Transmission Rate Raw Data

Moisture Content Raw Data

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APPENDIX B

Dissolution Raw Data

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117

APPENDIX C

Calculation

118

Initial Moisture Content (IMC) of Prednisone

Average Initial Moisture Content in Wet Basis Determined by Karl Fischer with
Homogenizer is 5.17 g of water/ 100 g of wet product

Moisture Content in Dry Basis = Moisture Content in Wet Basis

1 - Moisture Content in Wet Basis

= 0.0517

1- .0517

0.0545 g of water/g of dry product

5.45 g of water/ 100 g of dry product

5.45%(Dry Basis)

Product Dry Weight (WD) Calculation
Average Weight of Prednisone Tablet = 0.0988 g.

_ WI
D 1+ IMC

 

Where, WD = Product Dry Weight, g
W, = Product Wet Weight, g

IMC = Initial Moisture Content of Prednisone in Dry Basis, g of water/g

of dry product

0.0988

= _— = 0.0937
D 1+ 0.0545 g

119

Shelf Life Calculation

From equation (3),

t: W01; 1n [Awo —Aw,=0]

 

P'ps Awo —Awt=t
p: m ..d W: a
Ps
P'= n I M
AAw.pS

t:

 

WDflAAw 1n Aw0 —Aw,=0
WVTR' Aw0 —Aw,=,

Time to reach equilibrium moisture content of Prednisone packaged in PVC/0.6

mil Aclar at 25°C, two,”

W D = 0.0937 g (from calculation above)
[3 = 0.0127 (from figure )

AAw= Aw

outside

- Aw.

Inside

= 0.75 — 0 = 0.75
WVTR = 5.5515E-05 g/day.cavity

Awo = 0.75

Awm = 0.19 (from equation in figure )

Aw,=, = 0.74 (critical point in figure )

 

t = (0.0937)(0.0127)(0.75) In [0.75 — 0.19]
”W” (5.551513 - 05) 0,75 _ 0,74

(Adam, = 64.7 days

120

 

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Akbuga, J ., Ari-Ulubelen, A. and Bayraktar-Alpmen, 6., “Effect of Relative Humidity on
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Diosady, L.L., Rizvi, S.S.H., Cai W. and Jagdeo, DJ, “Moisture Sorption Isotherms of
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