Ah“... ..
E? m. awn»?

.521 :3
: iii”)

..
r

 

«.73

Am 3.
33...... m.

Ill

5:. 3 s. v
123.331.»:

with

n . v

.‘ :- t:

‘0: .1 .3.

3 01.23. M
3.1.

:1 «My
3.! . t.

 

21 $31.11
I. I n 3!
a: .a. .5 .
3.263.. hut.
@333... .
.3 .
|\ v ‘

.3...

g t «I...
(It!

«1:...

l» 3.. 4;?

 

 

3...... ill:lililllfllj’ifllllflyll

3

 

LIBR .3 mm.

Michigan State
University

 

 

This is to certify that the

thesis entitled

DISSOLUTION SHELF LIFE OF HYDROXYPROPYL
METHYL CELLULOSE COATED ASPIRIN TABLETS
AT I.C.H. TEMPERATURES AND VARIOUS
RELATIVE HUMIDITIES

presented by

SHANNON PATRICK ADAMS

has been accepted towards fulfillment
of the requirements for

_M_ASIEB_._degree in PACKAGING—

6'? MAW

Major professor

   

Date W

 

c.7539 Msunm- ‘ffin—M-‘w ‘ ' r, '3” .- ',lnstiruziou

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

 

DATE DUE DATE DUE DATE DUE

 

 

 

.3 ' W
.V'—\-.: ,3: . ..
‘. Petr-t t a?”
a g I A4
I ‘ ‘-

cEp 0 1 2000
U '5 1

JAN 1 2 2009

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1/98 WWW“

 

DISSOLUTION SHELF LIFE OF HYDROXYPROPYL
METHYL CELLULOSE COATED ASPIRIN TABLETS
AT I.C.H. TEMPERATURES AND VARIOUS
RELATIVE HUMIDITIES

By

Shannon Patrick Adams

A THESIS

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

MASTER OF SCIENCE

School of Packaging

1998

ABSTRACT
DISSOLUTION SHELF LIFE OF HYDROXYPROPYL
METHYL CELLULOSE COATED ASPIRIN TABLETS
AT I.C.H. TEMPERATURES AND VARIOUS
RELATIVE HUMIDITIES
By

Shannon Patrick Adams

This work constitutes a new approach to shelf life calculation for a dry solid oral
drug product based on the moisture content of such product which fails dissolution. The
dry solid oral hydroxypropyl methyl cellulose (HPMC) coated aspirin tablet used in this
approach was the Bayer 500 mg aspirin tablet. After determination of moisture sorption
isotherms for the product, the HPMC coated aspirin tablet was subjected to conditioning
for 90 days in three temperature chambers (25, 30, 40°C) each containing seven closely
monitored relative humidity vessels (12, 33, 50, 60, 75, 80, 90 %RH). The conditioning
temperatures are as specified by the International Conference on Harmonization (I.C.H.).
Once conditioning was complete, dissolution tests were conducted and the moisture
content of the product at physical and dissolution failure conditions were determined.
The water vapor transmission rate (WVTR) of the products bottle was also determined.
With the physical failure and dissolution failure conditions, the corresponding moisture
contents, and the WVTR of the products bottle known, a computer modeled shelf lifiz and
dissolution shelf life could be calculated. The computer model may also be used as an aid

in the process of selecting other candidate package systems for stability testing.

This thesis is dedicated to
my wife and family

Tracy “Boo”, Patrick, Carolyn, Todd, and Andrew Adams
Mike & Eileen Cooley - Gary Martiny & Marilyn Cooley
John & Amy Cavazos and Grandma Frances Waid

1N VIC TUS

Out of the night that covers me,
Black as the Pit from pole to pole
I thank whatever gods may be
For my unconquerable soul.

In the fell clutch of circumstance
I have not winced or cried aloud
Under the bludgeonings of chance
My head is bloody, but unbowed.

Beyond this place of wrath and tears
Looms but the Horror of the shade,
And yet the menace of the years
F inds, and shall find, me unaflaid

It matters not how strait the gate,
How charged with punishments the scroll
I am the master of my fate;

I am the captain of my soul.

~William Ernest Henley~

iii

ACKNOWLEDGMENTS

A wise man once said “it is not the destination, but the journey that matters”.
Now that I have finally reached my destination, I would like to thank the people who
made my academic journey matter.

I would like to thank Dr. Hugh E. Lockhart my major professor, for his open door,
his endless patience, and his trenchant mind - which has saved me on several occasions.
As one of the leading experts in the field of pharmaceutical packaging, Dr. Lockhart finds
himself wearing several hats: professor, author, researcher, industry lecturer, USP and
ASTM committee member, student organization faculty advisor, and many others too
lengthy to mention. Yet with the obvious time demand of such responsibilities his door
was always open to me, and his attitude was always one of motivation, challenge, and
support - all hallmarks of a great teacher.

I would also like to thank Dr. Susan Selke and Dr. Dennis Gilliland for serving on
my committee. AS with Dr. Lockhart, I always found an open door, and good advice.

In addition I would like to thank those members in our dissolution research group-
my fellow graduate students: Sheau-shya Wu, Xuemei Qian, Matt Thomas, and
Seung-Yil Yoon (resident computer genius).

I cannot forget my other friends in the department who helped me survive being a
student, teaching assistant, and research assistant, all at the same time: Chris Barr,

Laura Bix, Jay Chick, Jaemin Choi, Rosamari F eliu-Baez, Aaron Fitchko, Bill Green,
John Jackson, Young Suk Lee, Rujida Leepipattanawit, Paul Rearick, Jon Shaw,
David Singleton, Andres Soto, Delynne Vail, Jill Warnick and Jeff Wolford.

And of course my family, my Mom and Dad for their unconditional love and
support, my brother Todd for never letting me starve, and my little brother Andrew for
always putting family first.

And finally my wife “Boo”(Tracy). For all the nights she brought me dinner in the
lab and for calling me at 2 am. to ask “are you still there ?!?”.

For reminding me what really is important in life - that happiness is being married to your
best friend.

iv

TABLE OF CONTENTS

LIST OF TABLES ............................................................................................................. vii
LIST OF FIGURES ............................................................................................................ ix
CHAPTER 1 INTRODUCTION ........................................................................................ 1
CHAPTER 2 LITERATURE REVIEW ............................................................................. 3
2.1 Dissolution History and Methods ......................................................... 3

2.2 In Vitro Dissolution Testing ................................................................. 6

2.3 Stability Tests and Related Regulations ................................................ 7

2.4 Factors Influencing Tablet Dissolution Stability ................................. ll

2.4-1 Manufacturing Processes ..................................................... ll

2.4-2 Physiochemical Properties ................................................... 12

2.4-2a Solid-Phase Characteristics .................................... 12

2.4-2b Polymorphism ........................................................ 12

2.4-2c Particle Characteristics ........................................... 13

2.4-3 Formulation Variables ......................................................... 14

2.4-3a Excipients and Additives ....................................... 14

2.4-3b Binders and Disintegrants ....................................... 15

2.4-3c Compression Force ................................................. 15

2.4-4 Storage Conditions and Physical Aging ............................... 16
2.4-5 Packaging .............................................................................. 19

2.5 Dissolution of Tablet Products ............................................................ 23

2.6 Hydroxypropyl Methyl Cellulose ........................................................ 25

2.7 Data Treatment .................................................................................... 27
CHAPTER 3 MATERIALS AND METHODS - DATA AND RESULTS .................... 31
3.1 Moisture Sorption Equilibrium Determination .................................. 31
3.2 Moisture Content Determination ........................................................ 33
3.3 Moisture Sorption Isotherms ............................................................... 36
3.4 Dissolution .......................................................................................... 40

3.5 Determination of Moisture Content

( wet weight basis and dry weight basis )

-For Fresh Product

-At the First Physical Failure Condition

-At the First Dissolution Failure Condition ............................................... 53

3.6 Experimental Determination of Bayer Bottle WVTR
and Calculation of Permeability Constant ................................................ 57

3.7 Computer Modeled Determination of Shelf Life

and Dissolution Shelf Life ......................................................................... 63
CHAPTER 4 STATISTICAL ANALYSIS ...................................................................... 67
CHAPTER 5 CONCLUSIONS ........................................................................................ 74
APPENDIX A
Explanation of spread sheet calculation of dry weight basis from wet weight basis ......... 80
APPENDIX B
30 minutes dissolution values raw data and statistics ........................................................ 90
REFERENCES .................................................................................................................. 94

vi

Table 1.

Table 2.

Table 3.

Table 4.

Table 5.

Table 6.

Table 7.

Table 8.

Table 9.

Table 10.

Table l 1.

Table 12.

Table 13.

Table 14.

Table 15.

LIST OF TABLES

Bayer Aspirin moisture sorption to equilibrium.
Water weight gain - raw data ..................................................................... 31

Bayer Aspirin Day 16 moisture content (dry weight basis)

at 25°C and 12, 33, 50, 60, 75, 80, 9O %R.H. .......................................... 35
Bayer Aspirin Day 16 moisture content (dry weight basis)

at 30°C and 12, 33, 50, 60, 75, 80, 90 %R.H. .......................................... 35
Bayer Aspirin Day 16 moisture content (dry weight basis)

at 40°C and 12, 33, 50, 60, 75, 80, 9O %R.H. .......................................... 35
Bayer Aspirin dissolution testing storage plan .......................................... 49
Bayer Aspirin 30 minutes dissolution values for full storage plan ............ 50

Bayer Aspirin moisture content (wet weight basis) for tablets failing
dissolution .................................................................................................. 5 1

Physical nature of Bayer Aspirin tablets at the time of dissolution
testing ............ . ............................................................................................ 52

Bayer Aspirin initial and critical moisture contents (wet weight basis)....55

Calculated Bayer Aspirin initial moisture content, critical physical failure
moisture content, and critical dissolution failure moisture content

(dry weight basis) ....................................................................................... 56
Bayer Aspirin Bottle WVTR raw data - water weight gain ....................... 59
Bayer Aspirin Bottle WVTR - with regression data .................................. 61
Results of One way ANOVA test for the effect of time on

30 minute Bayer Aspirin dissolution values (p-values) ............................. 71
Bayer Aspirin Package WVTR - with regression data .............................. 79

Spread sheet table example - conversion of wet weight basis
to dry weight basis ..................................................................................... 82

vii

Table 16.

Table 17.

Table 18.

Table 19.

Table 20.

Table 21.

Table 22.

Table 23.

Table 24.

Table 25.

Spread sheet table example - with underlying formulas ............................ 83

Calculation of Bayer Aspirin Day 16 moisture content from wet weight
basis to dry weight basis at 25°C/ 12, 33, 50, 60, 75, 80, 9O % RH. ......84

Calculation of Bayer Aspirin Day 16 moisture content from wet weight
basis to dry weight basis at 30°C/ 12, 33, 50, 60, 75, 80, 90 % RH. ......85

Calculation of Bayer Aspirin Day 16 moisture content from wet weight
basis to dry weight basis at 40°C/ 12, 33, 50, 60, 75, 80, 90 % RH. ......86

Calculation of Bayer Aspirin initial moisture content from wet weight
basis to dry weight basis ............................................................................ 87

Calculation of Bayer Aspirin critical moisture content -
(physical failure) from wet weight basis to dry weight basis .................... 88

Calculation of Bayer Aspirin critical moisture content -
(dissolution failure) from wet weight basis to dry weight basis ................ 89

Bayer Aspirin 30 minutes dissolution value raw data, with sample
standard deviation and p-values at 25 °C ................................................... 91

Bayer Aspirin 30 minutes dissolution value raw data, with sample
standard deviation and p-values at 30°C ................................................... 92

Bayer Aspirin 30 minutes dissolution value raw data, with sample
standard deviation and p-values at 40°C ................................................... 93

viii

Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

Figure 1 1.

Figure 12.

Figure 13.

Figure 14.

Figure 15.

LIST OF FIGURES

U.S.P. Dissolution Method -- Apparatus 1, rotating basket ......................... 5
U.S.P. Dissolution Method -- Apparatus 2, rotating paddle ........................ 5
General dissolution profiles for tablets ...................................................... 24
Typical S-shaped dissolution profile of a tablet ........................................ 24
Chemical structure of 2-hydroxypropyl methyl cellulose .......................... 26
Representative 40°C Bayer Aspirin moisture gain vs. time
(to equilibrium) at 12, 33, 50, 60, 75, 80, 90 % R.H ............................... 32
Bayer Aspirin Day 16 Moisture Sorption Isotherms
at 25, 30 and 40°C ..................................................................................... 36
Bayer Aspirin Day 30 Physical Failure Sorption Isotherm at 30°C

. with supporting data table .......................................................................... 38
Bayer Aspirin Day 45 Dissolution Failure Sorption Isotherm at 30°C
with supporting data table .......................................................................... 39
Bayer Aspirin dissolution profile (fresh from the bottle) with bottle
storage conditions 22°C / 50 % R.H. ........................................................ 42
Bayer Aspirin dissolution profile (day 90 / 25 °C / 90 % R.H.) ................. 43

Bayer Aspirin dissolution profile (day 45 / 30°C / 90 % R.H.).
First dissolution failure at 30°C ................................................................. 44

Bayer Aspirin dissolution profile (day 75 / 40°C / 90 % R.H.).
First dissolution failure at 40°C ................................................................. 45

30 minutes dissolution isotherm of Bayer Aspirin stored at 25 °C
from 0 - 90 days ......................................................................................... 46

30 minutes dissolution isotherm of Bayer Aspirin stored at 30°C
from 0 - 90 days ......................................................................................... 47

ix

Figure 16.

Figure 17.
Figure 18.

Figure 19.

Figure 20.

Figure 21.

Figure 22.

30 minutes dissolution isotherm of Bayer Aspirin stored at 40°C

from 0 - 90 days ......................................................................................... 48
Bayer Aspirin Bottle weight gain vs. time ................................................. 60
Bayer Aspirin Bottle weight gain vs. time - linear fit ................................ 60

Effect of relative humidity on Bayer Aspirin 30 minutes dissolution
values at 25 °C ............................................................................................ 68

Effect of relative humidity on Bayer Aspirin 30 minutes dissolution
values at 30°C ............................................................................................ 69

Effect of relative humidity on Bayer Aspirin 30 minutes dissolution
values at 40°C ............................................................................................ 70

Fluctuation contributing to significant p-values for the 30 minutes .......... 72

Chapter 1

INTRODUCTION

“Dissolution stability is a critical parameter from the standpoint of quality control,
regulatory compliance, and impact on the bioavailability of the drug product. Significant
changes in the in vitro release profiles of a drug product during storage may alter its
bioavailability. Factors that affect the dissolution stability of a product during aging
include formulation components, processing factors, storage conditions, and packaging.
The role of each of these factors in promoting changes in dissolution in both immediate-
release and modified-release products is dependent on the product and has to be evaluated
on a case-by-case basis. Although data obtained under accelerated conditions of storage
are not useful in predicting the dissolution shelf—life of the product under ambient
conditions, they are of value in assessing the ‘ruggedness’ of the product and its ability to
withstand the varied climatic conditions during transport, shipping, and storage”

(Murthy and Ghebre-Sallassie, 1993).

Literature and previous research at the Center for Food and Pharmaceutical
Packaging Research support the existence of a failure in the rate of dissolution for solid
oral dosage forms, when such forms are subjected to high temperatures and relative
humidities over time. Failure in this case is defined as a reduction in the rate of

dissolution below that specified by the manufacturer.

Observations cited in literature also support a recognition that dissolution of the dosage
form is the rate limiting step in the bioavailability of the drug. (Savastano et al. 1995)

Thus, the identification of a critical time, temperature, relative humidity, and
moisture content at which the dosage form no longer performs at the specified rate of
dissolution can provide useful information in the design of a safe and cost effective
packaging system for that dosage form.

This research will focus on the determination of the critical data (time,
temperature, relative humidity, and product moisture content) at which the HPMC coated
aspirin product physically fails, and fails dissolution. This critical data, along with
experimentally determined WVTR data for the aspirin product’s bottle will then be used
to drive a computer modeled calculation of a shelf life and dissolution shelf life for the
product in its current bottle package.

The computer modeled shelf life based on the aspirin products physical failure
conditions can then be compared to the computer modeled dissolution shelf life based on
the aspirin products dissolution failure conditions.

The computer model driven by the critical data may also be used to screen other
candidate package systems, resulting in the selection of only the most promising

candidates for stability testing.

Chapter 2

LITERATURE REVIEW

2.1 Dissolution History and Methods

In the late 19605 deficiencies in the biological availability of drugs were brought
to the attention of regulatory agencies and compendial standards groups. During routine
investigation of identical competitive products by pharmaceutical manufacturers,
substantial differences in bioavailability were observed during in vivo testing of the two
items. According to all then-existing tests for physical properties, the two items should
have been pharrnaceutically identical. These observations presented a major problem with
regard to lifesaving drugs, especially those drugs with a narrow therapeutic index. The
need for a solution to this problem triggered the study of various dissolution test methods
(Banakar, 1992).

“Coordination of studies at this point was assigned to the director of the Drug
Standards Laboratories in Washington, which operated alongside the compendial groups.
Extensive and exhaustive evaluation of various methods was conducted and followed by
the selection of a new and official test procedure affecting all major disciplines in
pharmacy including medical professions, regulatory agencies, and drug manufacturers.

Each device was tested for its ability to discriminate between subtle variations in
dissolution characteristics, reproducibility from test to test, and its adaptability as

completely as possible to existing apparatus.

Dissolution research continued for over 10 years, during which time the variables
affecting consistent and repeatable results were studied” (Banakar, 1992).

It was in 1970 that the first dissolution test method (The USP Rotating basket)
was officially adopted. Dissolution tests were subsequently included in the monographs
in the National Formulary ( NF ) and U.S.P. (Qian, 1996). The historical progression of
test devices, leading to the dissolution device used in this shelf life approach are:

1) The Tumbling Method (1930)

2) The Beaker Method (1960)

3) The Rotating Disk Method (1962)

4) The Particle Size Method (1965)

S) The Oscillating Tube Method (1966)
6) The USP Rotating Basket (1969)

7) The Magnetic Basket Apparatus (1972)
8) The Modified USP Basket (1973)

9) The Rotating Filter Stationary Basket (1973,1974)
10) The USP Paddle Apparatus (1978)
(Banakar, 1992)

At this point in time there are now seven official dissolution methods, and each
method corresponds to seven different dissolution apparatuses (Qian, 1996). Apparatus 1
(Figure 1 next page) and Apparatus 2 (Figure 2 next page) are the most common and

widely accepted test apparatuses for immediate release dosage forms (Murthy and

Ghebre-Sallassie, 1993).

11

 

 

 

 

 

 

 

 

 

 

,_ Dosage form

Figure 1. U.S.P. Dissolution Method -- Apparatus 1, rotating basket.

11

 

 

 

 

 

 

 

 

\U_:
3!

 

Dosage form

Figure 2. U.S.P. Dissolution Method -- Apparatus 2. rotating paddle.

2.2 In Vitro Dissolution Testing

It has been known for many years that solid drugs ingested orally are not
immediately released to the biological system because normally the active ingredient in
such drugs are absorbed from solution. The in vitro dissolution test is used as a guide
during development of the dosage form in estimating the amount of drug released over
time in the dissolution medium. Other tests like in vitro disintegration are not as likely to
offer meaningful indications of physiological availability compared to in vitro dissolution
testing. This is because the dissolution of a dosage form is often the rate-limiting factor
determining the physiological availability of the drug. Based on this, current in vitro
dissolution testing seems to be the most sensitive and reliable predictor of in vivo
performance (Banakar, 1992).

Significant changes in the in-vitro dissolution profiles of a drug during its storage
may be an indication of changes in the bioavailability of the drug (Wu, 1996). This has
lead to the logical use of in vitro dissolution test specifications and requirements in the
individual monographs of various solid oral dosage forms. In the monographs, the
requirement is predicated as the minimum amount of drug to be in solution at a specific
time interval. Typically no less than 75% of the labeled amount of active ingredient
Should be dissolved in 45 minutes (typical range, 30-60 minutes). This specification is
based on the premise that bioequivalence problems are not observed when 75% of the
active ingredient dissolves in water in 45 minutes (Qian, 1996). In the case of the HPMC

coated aspirin tablet used in this study, a specific monograph currently does not exist.

In such case, the dissolution Specification is the responsibility of the product’s
manufacturer. Bayer Corporation, manufacturer of the HPMC coated aspirin tablet,
specifies that not less than 80% of acetylsalicylic acid (aspirin) must be in solution at 30
minutes. Other test parameters such as dissolution medium, medium temperature,
medium volume, apparatus type , paddle speed, and filter are also specified by the
manufacturer in the absence of a specific product monograph.

The dissolution profiles of an oral solid drug product can be an indicator of the
rate and the amount of active ingredient available for absorption, and therefore may be an
indication of the therapeutic efficacy of the product. When a product is stored as specified
on the label, it is expected that the product will maintain its initial dissolution profiles for
the balance of the shelf-life. A product which fails to meet dissolution specifications

during storage is one cause of drug product recalls (Murthy and Ghebre—Sellassie, 1993).

2.3 Stability Tests and Related Regulations

Long before a drug product can be sold on the open market, it must undergo
stability testing. Until recently, stability testing varied among drug manufacturers, due in
part to the purposely interpretable regulation governing such tests. With a myriad of
different drug formulations, and an equal amount of different environments in which the
drug must be packaged and distributed, it would be very difficult for the Food and Drug
Administration to require only one rigid formula for stability testing. The FDA attempts
to address the problem with 21 Code of Federal Regulations (CF R) 211.166, which

regulates as follows:

In such case, the dissolution specification is the responsibility of the product’s
manufacturer. Bayer Corporation, manufacturer of the HPMC coated aspirin tablet,
specifies that not less than 80% of acetylsalicylic acid (aspirin) must be in solution at 30
minutes. Other test parameters such as dissolution medium, medium temperature,
medium volume, apparatus type , paddle speed, and filter are also specified by the
manufacturer in the absence of a specific product monograph.

The dissolution profiles of an oral solid drug product can be an indicator of the
rate and the amount of active ingredient available for absorption, and therefore may be an
indication of the therapeutic efficacy of the product. When a product is stored as specified
on the label, it is expected that the product will maintain its initial dissolution profiles for
the balance of the shelf-life. A product which fails to meet dissolution specifications

during storage is one cause of drug product recalls (Murthy and Ghebre-Sellassie, 1993).

2.3 Stability Tests and Related Regulations

Long before a drug product can be sold on the open market, it must undergo
stability testing. Until recently, stability testing varied among drug manufacturers, due in
part to the purposely interpretable regulation governing such tests. With a myriad of
different drug formulations, and an equal amount of different environments in which the
drug must be packaged and distributed, it would be very difficult for the Food and Drug
Administration to require only one rigid formula for stability testing. The FDA attempts
to address the problem with 21 Code of Federal Regulations (CFR) 211.166, which

regulates as follows:

"There will be a written testing program designed to assess the stability
characteristics of drug products. The results of such stability testing shall be used to
determine proper storage conditions and expiration dates. The written program shall be
followed and shall include:

1) sample size and test intervals based on statistical criteria for each attribute
examined to assure valid estimates of stability;

2) storage conditions for samples retained for testing;
3) reliable, meaningful and specific test methods;

4) testing of the drug product in the same container-closure system as that which
the drug product is marketed;

5) testing of drug products for reconstitution at the time of dispensing. "

This arguably non-specific regulation was the FDA’S best attempt at the time to
mandate that drug manufacturers provide safe, “ reliable, meaningful and specific test
methods ” (CFR 211.166) for many different products, product package systems, and
distribution environments. Today, storage conditions for stability testing are more
uniform and standardized with the tripartite guideline, by the Expert Working Group
(Quality) of the International Conference on Harmonization.

The I.C.H. stability test conditions are:

Condition 'n'm m ' r' a m' ' n
Long-term testing .................................................... [2 months
(253:2°C)(60 i5%RH)

*A ccelerated testing ................................................. 6 months

(4032°C)(75 35% RH)

* If product fails accelerated testing, then:

Intermediate testing ................................................. 12 months

(30i2°C)(60 i5%RH)

Data from the first six months of intermediate testing may be submitted in place of
the failed accelerated testing data.

Because stability testing is very cost, labor, and time intensive, it is logical that
some form of estimation technique be developed to minimize experimentation. Attempts
have been made at estimation techniques in two areas.

The first involves estimating the dissolution shelf life of a product under ambient
storage conditions based on accelerated testing over a short period of time. This technique
has met with limited success. In many instances, a certain critical moisture and/or
temperature level of the product is usually required for the initiation of dissolution
changes. Attainment of this minimum level of moisture content is dependent on the time
of storage, the physio-chemical nature of the product, environmental conditions, and
packaging characteristics. Because of this, a general relationship is not available between
data obtained under accelerated conditions and those under ambient conditions
(Qian, 1996; Murthy and Ghebre-Sellassie, 1993).

The second and more realistic attempt at an estimation technique involves
simulation modeling. Simulation modeling considers the entire system and includes
expressions for product sensitivity, environmental severity, and packaging effectiveness
(Qian, 1996). To date only one model has been reported in the literature for predicting the
dissolution shelf life of a packaged drug product (Nakabayashi, 1981). However, the
model was not applied to drug products which required some minimum heat or moisture
level for initiation of dissolution changes (Qian, 1996).

Clearly there is a need, driven by the desire for stability test cost reduction, for a
simulation model which calculates a dissolution shelf life for moisture and/or temperature

sensitive drug products.

The literature supports the assertion that the dissolution rate of a solid oral dosage form is
a Motion of storage time, temperature, relative humidity, product moisture content,
packaging, and their interactions.

High relative humidities and/or high temperatures often cause large decreases in
the drug dissolution, but packaging may help maintain the dissolution stability by limiting
or slowing the moisture which enters the package.

In order to determine the needed protection from a package (and indeed the best
candidate packaging materials for stability testing) it is necessary to evaluate the effects
of storage time, temperature, relative humidity, and product moisture content on the
dissolution stability of the product by exposing it to these conditions without any
packaging protection.

Then, when the product’s dissolution failure conditions and moisture content are
known, the information can be substituted into a traditional computer shelf life model
which includes packaging parameters.

The end result should be a computer simulation model which:

1) produces reasonably accurate dissolution shelf life data for a given product.

2) quickly and cost-effectively screens candidate product package systems -

resulting in the selection of only the most promising candidates for stability

testing.

10

2.4 Factors Influencing Tablet Dissolution Stability
The factors and related subfactors influencing dissolution stability include:
Manufacturing processes
Physicochemical properties
- solid-phase characteristics
- polymorphism
- particle characteristics
F orrnulation variables
- excipients and additives
- binders and disintegrants
- compression force
Storage conditions and physical aging

Packaging

(Banakar, 1992; Murthy and Ghebre-Sellassie, 1993; Chowhan, 1994)

2.4-l Manufacturing Processes

In the literature a large number of studies report that the process of granulation
(manufacture) can significantly influence the dissolution rate of tablets. In addition to the
process of granulation the use of fillers and diluents such as microcrystalline cellulose,
spray-dried lactose, and starch, typically increases the hydrophilicity of the active
ingredients, which improves dissolution. With the invention of more modern tableting
materials and machines it becomes increasingly evident that the process of granulation is
less of a critical factor than once thought. The main factors affecting the dissolution
characteristics of tablets are their formulation, the sequence of mixing, and the timing of

the adding of their multiple ingredients (Banakar, 1992).

ll

2.4-2 Physicochemical Properties

“The physicochemical properties of the drug substance can assume a primary role
in controlling the drug’s dissolution. It is well known that the aqueous solubility of the
drug is one of the major factors that determines its dissolution rate” (Banakar, 1992).
“Under high humidity and temperature, the active component of a tablet product may
dissolve and recrystallize, resulting in altered dissolution profiles of the tablet. Fillers or
diluents in the formulations are normally considered as inert and noninteracting with the
active ingredients and other components. However, under accelerated storage conditions
specific interaction may occur between a filler and the active substance, resulting in a

decreased dissolution rate of the drug” (Qian, 1996).

2.4-2a Solid-phase Characteristics

Solid-phase characteristics such as the amorphicity and crystallinity of a drug
have been observed to have a significant effect on the dissolution rate. Several studies
considering the effect of solid-phase characteristics on the dissolution rates of drugs have
demonstrated that the amorphous form of a drug usually exhibits greater solubility and

higher dissolution rate than the crystalline form (Banakar, 1992).

2.4-2b Polymorphism
In the case of a solid oral tablet, polymorphism refers to the many possible
physical sizes and shapes of a tablet. The polymorphic forms or “shapes” of tablets and

other solid orals have been shown to influence changes in the dissolution rate of the drug

12

substance because of the forms effect on solubilizing characteristics. Several Studies have
demonstrated that polymorphism and the states of hydration, solvation, and complexation

may significantly influence the dissolution characteristics of a drug (Banakar 1992).

2.4-2c Particle Characteristics

The dissolution rate as measured by the release of active ingredient within a
tablet, is directly proportional to the surface area of the tablet according to Nernst-
Brunner theory. Since surface area increases with decreasing particle size, higher
dissolution rates may be achieved through the reduction of a tablet’s internal particle size
prior to tablet formation. The reduction in internal particle size improves dissolution by
enhancement of the solubility of the tablet’s active ingredient. Incorrectly one may
assume that the solubility of active ingredient is independent of particle size. However,
the solubility of a drug’s active ingredient and surface area of a tablet’s internal

component particles can be correlated by the 0stwald-Freundlich equation:

lnCs = pzadllt.._:_=_91f_

Where: C5 = solubility of the drug M = molecular weight
p = density )1 = interfacial tension
T = temperature R = gas constant

r = radius of the particle
This equation implies that solubility is inversely proportional to particle radius.
Despite the implication, unless a tablet’s internal particles are reduced to microlevels
prior to the tablet’s formation, there will be no appreciable effect on the solubility of the

tablets active ingredient (Banakar, 1992).

Particle characteristics which affect the rate of tablet dissolution other than particle size
include particle shape and particle density. These characteristics indirectly influence the
effective surface area by modifying the shear rate of fresh solvent that comes in contact

with the tablet (Banakar, 1992).

2.4-3 Formulation Variables

Several variables related to the formulation of a drug product can immediately
influence the dissolution rate of the active ingredient present within the product. When
these variables are studied and understood, one can use the information to design custom-
tailored drug dissolution profiles. This information can then be used to facilitate
development of optimally effective oral drug products. The effects of various formulation
variables on the dissolution rate and resulting bioavailability of the active ingredients
from solid oral drug products, such as tablets and capsules, have been well documented.
However, the significance of these effects must be determined on an individual basis for

each product (Banakar, 1992).

2.4-3a Excipients and Additives

For various design purposes most solid oral dosage forms will contain more than
one excipient along with the active ingredient within their formulation. It has been
demonstrated that when mixed with various adjuncts, the dissolution rate of a pure drug
can be significantly altered. Types of adjuncts include binders, diluents, disintegrants,

granulating agents, and lubricants.

Diluents and disintegrants which are common in industry’s preparation of tablets
have been studied. Examples include various grades of lactose and starch. Levy et a1.
noticed an approximate threefold increase in dissolution rate when studying the effect of
starch on the rate of dissolution of salicylic acid tablets manufactured by a dry, double-
compression process. This increase in dissolution rate was observed when the starch

content was increased from 5% to 20 % in the formulation (Banakar, 1992).

2.4-3b Binders and Disintegrants

Binders and disintegrants function oppositely in a tablet with regard to dissolution
rate. The binder is added to provide adhesion of the particles after tablet compression.
The disintegrant generally functions to increase surface area and deaggregate the tablet
once contact is made with the proper solvent. Both of these formulation components will

compete to decrease or increase the dissolution rate.

2.4—3c Compression Force

In 1953 Higuchi and co-workers demonstrated that in the tableting process,
compression force had an influence on factors such as density, disintegration time,
hardness, porosity, and average particle size of compressed tablets. The particles of a
tablet bonding, or in other cases cleaving or crushing, are two common effects resulting
from increased force of compression. In the case of bonding, dissolution rates tend to
diminish with increasing pressure. In the case of cleavage or crushing, dissolution rates

increased with an increase in the compressional force.

15

Different relationships between the dissolution rate and compressional force will be
, observed depending on which of the two effects (bonding or cleaving of tablet particles)

that dominates (Banakar, 1992).

2.4-4 Storage conditions and physical aging

Storage conditions are usually a combination of five factors: time, temperature,
relative humidity, atmosphere / oxidation, and UV / visible light. Solid oral drug efficacy
and dissolution rate may be affected by any combination or interaction of the five
variables. In this approach to dissolution shelf life calculation, the effects of oxidation
and UV / visible light were not studied. This decision was based on information from the
product’s manufacturer that the HPMC coated aspirin tablet and its active ingredient are
generally quite stable under normal atmospheric and UV / visible light conditions. The
remaining three factors, time, temperature, and relative humidity moisture, are a concern.

“Storage under less than optimal, if not adverse conditions of temperature and
humidity are not uncommon in many parts of the world. The packages used for
dispensing of medication are often less than adequate. These conditions may adversely
affect the quality of pharmaceutical preparations. It might be expected that the effect of
aging of tablets, capsules, and other solid dosage forms should always result in a decrease
in dissolution rate. However, work done in this area indicates that an increase in
dissolution rate may also be found”(Banakar, 1992). In some cases no effect is found at

all.

16

It is clear from the literature that the effects of storage conditions and physical
aging should be considered on a case by case basis - with careful statistical analysis to
address the problem of unknown combinations or interactions of storage condition
factors. Let us now consider in turn the two most typical deleterious storage conditions -
humidity and temperature.

With regard to the dissolution rate of a drug substance, humidity is usually a
factor of the storage environment. Hanson et al., Taborsky-Urdinola et al., and Gupta et
al. found that moisture influences the dissolution of many drugs in solid dosage forms.
“The environmental conditions to which the dosage forms are exposed, moisture content
in particular, should be rigorously assessed if reproducible and reliable dissolution data
are to be obtained” (Banakar, 1992).

The second storage condition of concern (temperature) is more commonly
associated with physical aging, especially with regard to drug coatings which often
behave as polymers. A significant amount of research has been conducted by Guo, Sinko,
and Amidon et al. at the University of Michigan on the effect of physical aging on the
dissolution rate of the enteric polymer hydroxypropyl methyl cellulose phthalate
(HPMCP). HPMCP is a functionally similar coating to HPMC. Both coatings are used
extensively by the pharmaceutical industry, and HPMCP is very similar to the HPMC
enteric coating used on the Bayer aspirin tablet. Guo, Sinko, and Amidon found HPMCP
to behave as an amorphous polymer. Guo defines physical aging in this class of enteric

coatings as follows:

“The phenomenon that amorphous polymers are not in thermodynamic equilibrium at
temperatures below their glass transition has been observed by several scientists

(Simon 1931, Kovacs 1963, Struik 1978). Because of the unstable non-equilibrium state,
the amorphous solids undergo slow processes which attempt to establish equilibrium,
indicating that even below Tg molecular mobility is not quite zero. This gradual approach
to equilibrium is termed as physical aging” (Guo, 1991).

Guo continues from the definition to link this phenomenon to the Free Volume
Theory of polymers, with some important implications for dissolution. “The free volume
concept states that the transport mobility of particles in a closely packed system primarily
depends on the degree of packing, or in other terms, on the free volume. When a polymer
is cooled to a temperature below Tg , the transport mobility will be small but not zero.”
The free volume will gradually decrease. “This contraction will be accompanied by a
decrease in the transport mobility” (Guo, 1991). Physical aging is temperature dependent,
and as temperature approaches Tg , the rate of physical aging will increase. “The majority
of oral controlled release systems rely on dissolution, diffusion, or a combination of both
mechanisms, to generate slow release of the drug to the gastrointestinal miliea”

(Guo, 1991).

This would indicate that temperature-induced physical aging would slow
dissolution of an enteric coating, or diffusion through it, due to reduced transport
mobility, which is caused by decreased free volume in the polymer coating. This was
confirmed by Guo, Sinko, and Amidon in dissolution studies carried out on HPMCP free

films, coated tablets, and coated granules. In all cases, the dissolution rate of HPMCP was

found to decrease with physical aging time after being quenched from above the glass
transition temperatures to sub-T8 temperatures.

“The gradual approach toward thermodynamic equilibrium during physical aging
decreases the free volume of the polymers. This decrease is accompanied by a decrease
in the transport mobility with concomitant changes in those properties of the polymer that
depend on it” (Guo, 1991).

Sinko reports the TB of the HPMCP used in their study to be 135 °C. He further
reports that the HPMCP was found to age in the 50-100°C range (by using creep
compliance techniques) and that changes in dissolution rates were observed only in
HPMCP films (initially above T8) quenched to annealing temperatures of 50°C, 80°C,
and 100°C.

It is important to note here that the highest temperature condition used in our
dissolution shelf life study of HPMC coated aspirin tablets is 40°C. If the 50°C
temperature reported by Sinko is the lowest temperature at which physical aging was
observed, and HPMCP and HPMC behave similarly, then physical aging may not be a
major factor in reduction of dissolution rate in our study. However, we will assume that
temperature and physical aging are factors until statistical analysis of our dissolution data

is completed.

2.4-5 Packaging
The function of packaging with regard to dissolution stability is to serve as a

barrier to moisture from the environment and to protect the product from the effects of

light and oxygen. Packaging ordinarily does not protect the product from the effects of
heat. “Packaging has been accorded a lower priority relative to the formulation activities
and storage conditions in the design and development of dosage forms. Although
packaging development is considered to lie outside the main stream of product
development, it is a key element that can control the result of dissolution stability during
storage and should be treated as an integral part of developing stable and effective
pharmaceutical products” (Murthy and Ghebre-Sellassie, 1993).

Several important considerations in the selection of a packaging material are the
ability of the material to maintain the identity, strength, quality, and purity of the given
drug product for the duration of its shelf life. Drug products are expected to retain their
dissolution characteristics during normal storage conditions. The use of proper packaging
materials usually provides an additional element of protection for the product. The degree
of additional protection achieved will depend on the attributes of the packaging material
used, including the permeation of the material, and the environment in which the package
is stored (Murthy and Ghebre-Sellassie, 1993).

The literature contains several studies on packaging and dissolution stability.
Those of particular interest follow, beginning with:

“The effect of packaging on the dissolution stability of a sustained-

release tablet product. Tablets were stored in three types of packages

and exposed to 37°C 75% RH for three months.

It turned out that the tablets stored in HDPE bottles and foil/foil

blisters were well protected, but samples packaged in laminated

PVC/PE/Saran blisters showed marked retardation in dissolution

rate. The moisture penneabilities of the packages were not reported.

The study showed the sensitivity of the in vitro release pattern of the

product to moisture effects and the moisture barrier properties of the
packages.

20

Khalil and co-workers (1991) studied the effects of package
type on in-vitro release and chemical stability of amoxycillin
capsules. A typical PVC/foil blister package and a nitrocellulose
lacquer/foil/PE laminated package were used for the study. The
product was stored both in, and outside the blister or laminated
packages at 76%, 80% and 92% RH at room temperature. Storage
at 92% RH without packaging protection resulted in a significant
loss of dissolution rate after 8 weeks, while only minor change
occurred in the dissolution rate of packaged capsules. The laminated-
type package afforded better protection compared with the PVC/foil
blister package in terms of amoxycillin potency.

The relationship between packaging variables and the
dissolution stability of model prednisone tablets was illustrated in
the studies by Taborsky-Urdinola and co-workers (1981). Two
types of multiple-unit vials and six types of unit-dose containers
were employed in the experiment. The multiple-unit vials were
PP vials and PS vials. The unit-dose containers were PS-MDPE/foil
strips, polyester/foil strips, PE bags, foil/foil strips, Bartuf/foil strips,
and PVC-Saran cup/foil. The packaged product was stored at
40°C/85% RH, 37°C/75% RH, and 22°C/75% RH for three to six
months. It was shown that, at 40°C/85% RH, the 30 minute
dissolution values of the tablets decreased with time, except those
packaged in the foil/foil strips which were impermeable to moisture
transmission. The rate of decrease depended on the moisture
permeation of the package. The higher the moisture transmission
rate, the greater was the decrease in the dissolution rate. When
stored at 22°C/75% RH, little change in the dissolution rate
occurred in any packaged tablets. It was concluded that packaging
and storage conditions affected tablet dissolution stability markedly.
The conditions of high heat and humidity caused the greatest change
in dissolution rate. At such conditions, the higher the moisture
transmission rate of the package and the longer the storage time,
the greater the loss of dissolution rate.

Hoblitzell and co-workers (1985) investigated the effect of

packaging on the dissolution stability of enteric-coated aspirin tablets.

The product was stored in five kinds of packages and exposed to

33°C/60% RH or 33°C/60% RH and 25°C/ 10% RH cyclic condition.

The packages were an Open petri dish, a two-ounce amber glass
bottle with child resistant closure, a U.S.P. class A strip pack, and
one of two U.S.P class B strip packs. It was indicated that there
were statistically significant differences in the dissolution among
packages, storage conditions, and storage periods. However, the

rate of decrease in dissolution rate did not correspond to the package
moisture-protection characteristics, which implied that temperature

21

was the primary factor. The dissolution stability also showed a

quadratic trend with time. It could be suggested that there were

interactions among storage conditions, storage times and packages

that were ignored in the statistical analysis” (Qian, 1996).

From these reported studies it could be concluded that, for a dosage form for
which the drug dissolution rate is greatly affected by moisture, packaging with low
moisture permeability can protect the product from the deleterious effect of humidity
and maintain the dissolution stability.

On the other hand, if the dissolution of a dosage form is only or mainly affected
by temperature rather than moisture, the role of packaging in maintaining the dissolution
stability is very small, since packaging cannot ordinarily shield the product from the

effects of heat. Therefore, it is necessary to characterize a product before determining

which type of package will function best to protect the product (Qian, 1996).

2.5 Dissolution of Tablet Products

“Compressed tablets still enjoy the status of being the most widely used dosage
form. Tablets are solid dosage forms of medicinal substance usually prepared with the aid
of suitable pharmaceutical adjuncts. Due to their very nature, the active ingredient is
uniformly dispersed within the contents of the formulation. Consequently, it stands to
reason that all factors that influence the physicochemical properties of the dosage form
will influence the dissolution performance of the drug from tablets.

There are primarily two pathways with which the drug entity is made available to

the dissolution medium.

The tablet either disintegrates, thereby exposing the drug contents to the medium, or the
dissolution process continues without the disintegration of the tablet. Thus for the
purpose of understanding the dissolution of tablets, they can be classified as either
disintegrating or nondisintegrating solids.

The surface area of the tablet will change during the dissolution process. The
change in surface area will alter the fluid flow dynamics involved in the dissolution rate
constant. Such an effect is more pronounced in disintegrating dosage forms than
nondisintegrating types. Nondisintegrating dosage forms gradually reduce their surface
area during the dissolution process.” (Banakar, 1992) The Bayer 500 mg aspirin tablet
produces dissolution profiles that place it in this category of nondisintegrating dosage
form. “Disintegrating forms, however, are subject to complicated disintegration and
deaggregation as they release particles of various sizes and specific gravities into the
solvent stream. The general dissolution process focusing on the change in surface area as

a function of time for both disintegrating and nondisintegrating tablets is show below.”

(Banakar, 1992)

(a) (b) (C)

 

 

 

 

Figure 3. General dissolution profiles for tablets. Ordinates:
concentration of ingredient dissolved; abscissas, time.
(a) Nondisintegrating tablet.
(b) Rapidly disintegrating tablet.
(c) slowly disintegrating tablet. (Banakar, 1992)

23

 

_ — _ _ — — —_ — — — -

l Occlusion

Onssotuuon

S Damn
"Cortconuuion
ot 0mg”

 

 

 

 

Figure 4. Typical S-shaped dissolution profile of a tablet. (Banakar, 1992)

2.6 Hydroxypropyl Methyl Cellulose (HPMC)

Hydroxypropyl methyl cellulose (HPMC) is a semisynthetic ether derivative of
cellulose. HPMC has been used by pharmaceutical companies since the early 19605.

Two of the more common uses of HPMC are as granulating agents for tablets, and as
film coatings for tablets, which function as hydrophilic matrices in oral controlled-release
dosage forms.

“Its popularity can be attributed to the polymer’s non-toxic nature, small influence
of processing variables on drug release, ease of compression, and its capacity to
accommodate high levels of drug loading” (Pham & Lee, 1984). The glass transition
temperature of HPMC has been determined to be 180°C.

“Mechanistically, solvent penetration is the first step leading to polymer
dissolution. The presence of solvent enhances the mobility of polymer chains and
gradually transforms a glassy matrix into a rubbery swollen gel. At the gel surface, the
polymer concentration has to reach a threshold disentanglement value before dissolution

actually takes place” (Pham & Lee, 1984).

24

Pham and associates investigated transient dynamic swelling and dissolution
behavior of HPMC using a flow-through cell capable of providing a well-defined
hydrodynamic condition. Based on the results of their study, Pham and associates believe

that true polymer dissolution does occur in HPMC matrices.

The chemical structure of 2-hydroxypropyl methyl cellulose -

CAS registry No. [9004-65-3] is shown below (Kirk-Othmer, 1979).

 

CHZOH H H OR
OR H
H
HOR O O
H
H H OH CHZOH H H
R = CHZCHZCHZOCH3
Figure 5. Chemical structure of 2-hydroxypropyl methyl cellulose.

25

2.7 Data Treatment
A literature review regarding the different treatments of dissolution data to

describe dissolution stability was conducted by Xuemei Qian in 1996. This review found

four methods of data analysis as follows:

1) “Present the dissolution profiles of a product before and after aging. Conclusions
were made based on the observed differences between the dissolution profiles.
No statistical analysis was performed in such studies.

2) “Choose a time point in the dissolution profile for dissolution value and compare
the values obtained under different storage conditions and periods. This second
approach was used in many studies. But again no statistical analysis was
performed for comparisons in these studies. Also, there have been no
mathematical relationships built between a single dissolution value and the
factors influencing the dissolution stability to predict the dissolution change.

3) “Determine a dissolution efficiency from a dissolution graph by expressing
the area under the experimentally determined dissolution curve as a percentage
of a defined rectangle. This method was employed in the dissolution stability
studies reported by Hoblitzell and co-workers (1985). An ANOVA indicated
significant differences in dissolution efficiencies among packages, temperature,
relative humidity, and storage periods. No quantitative relationships were given
between the dissolution efficiency and the above four factors for the purpose of

prediction.

26

 

4) “Establish a general mathematical expression for the entire dissolution curve in

terms of meaningful parameters and determine the effects of aging on these

parameters.

a. Log-normal type ln{C$/ ( Cs - Ct )} = k X t'
where:

t’ = dissolution time

C5 = the whole content of drug in a tablet

CI = the whole content of the drug at time t’ in the test solution

k = constant which is a function of storage time, moisture content

and temperature.

“According to Nakabayashi and his co-workers, the above equation fit the
dissolution curves in their study. They successfully developed, by a multiple regression
analysis, the mathematical relationship between the k value and the storage time (t)
moisture content (m) and storage temperature (T):

ln(k+ko)=-K><t

In K = 4.5241 + 3.4936 x In m - 4556.049 ><(1/T)

“Based on the above relationships, they predicted changes in the dissolution rate
of a packaged tablet kept under various temperature-humidity conditions. There were
good agreements between the predicted values and the observed data. However, the log-
normal expression can only describe a few dissolution curves (Nakabayashi et al., 1981).

b. Weibull distribution

log[-ln(1-C+C,,)]=blog(t-T,)-blogTd

27

[Hm

Where:
C ' = the concentration in solution at time t

C- = the concentration in solution at time t,

t = dissolution time
b = shape parameter which characterize the curve
Ti = location parameter representing time lag before the onset of the

dissolution process

Td = the time interval necessary to dissolve 63.2% of the material

“The equation was considered to be able to describe all common types of
dissolution curves (Langenbucher 1976). The expression was employed by Rubino and
co-workers for their dissolution stability studies (1985). An ANOVA indicated that C,
was significantly affected by the excipient to drug ratio, humidity, storage time and the
interaction between the later two factors. T,l was significantly affected by excipient to
drug ratio and the interaction between the type of excipient and storage time. However,
no mathematical relationships were developed to calculate the values of those parameters
under different storage conditions.

“There are some difficulties in using this expression. Of the four parameters, b
and Td can be obtained in a straightforward linearized manner, but Ti and C, have to be
determined by trial-and-error. This requires many data points and an enormous amount of
work. Possibly this is one of the reasons why the expression has not been widely used”

(Qian, 1996).

28

Chapter 3
MATERIALS AND METHODS
DATA AND RESULTS

3.1 Moisture Sorption Equilibrium Determination

Purpose

To determine the amount of time necessary for HPMC coated aspirin tablets to
reach moisture sorption equilibrium at each of seven different relative humidities
(12, 33, 50, 60, 75, 80, 90) and three different temperatures (25, 30, 40°C).

Materials

- Controlled temperature chambers (25, 30, 40°C) - Saturated salt solutions

- Twenty one five gallon buckets - Mettler AB 160 gram scale
- Bayer 500 mg HPMC Aspirin Tablets ' Twenty one Petri Dishes
Methods

Three tablets were placed in each petri dish at each temperature (25, 30, 40°C)
and relative humidity (12, 33, 50. 60, 75, 80, 90) and weighed every two days until all
tablets had reached moisture sorption equilibrium.

Data and Results

Table 1. Bayer Aspirin moisture sorption to equilibrium.
Water weight gain - raw data.

 

29

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

l_—“ _“"-° ‘uhuh-Kuo’n'mi. __ "__ ‘ T T _ _—i;im_ 0an in; " _ ‘4" _
OOCIIR$RH dOC/IJ‘RH
“ _ -_ ”T" r--- -—-——-— — -— '--~ - ~4— — ———~
A X‘ A
0' O
s 3.. IH~—-.— -- --_.- _.
\ t,
ii /P ‘ 1 ; "-’/
‘ "// " ’ "4" “' ‘Tt
~ \

L _— _-_- _ —.' — 4 ——~——- ~———--—~»———»—a—~——H—~ —- —.3 .__4
O 2 ‘ . . '0 ‘2 M ‘0 0 2 G 0 T .6 10 12 I. 16
Tm‘OQ] m‘ "j
“Manitoulin-o ’ WM".TIIM
OOCISO‘RN COCIIO‘RH

. —— ._
l
.5 a .
-3 3» ._.__.a - m, - .2... - 1
s. / I S ,1} - ‘h‘--— ~-———-———.——QI
£1 3 i - l
31/
. 1 z
I _ ; ~-«-w~~—— —— -~« -—————.—~#
0 2 . . . ‘0 ‘2 H '0 0 2 4 O I 10 12 N ‘6
Tm‘m, Yin-(day)
{ Mama‘sn.flmo Wmmnmfl
ICC/75%RH lOCIOO%RH

 

W19)
I
VIN-emu _

-. _ ._ _ U--. . . _ __ .___ .. ..__.._—__—J _ _______—. _._..____..._.._.__
o 2 a e a to 12 u to o 2 d o o to 12 u 16
into-y) tmloayi

 

 

 

 

 

 

 

 

 

 

aocnosan
i /
i r
‘/
o"-— 2 a o a 335—32 "In 16
Tun-I «11
Figure 6. Representative 40°C Bayer Aspirin moisture gain vs. Time

(to equilibrium) at 12, 33, 50, 60, 75, 80, 90 % R.H.

The Bayer 500 mg aspirin tablet reaches moisture sorption equilibrium at or before
16 days at all three temperatures (25, 30 40°C) and all seven relative humidities
(12, 33, 50, 60, 75, 8O 9O % RH).

30

3.2 Moisture Content Determination
Purpose

To determine the moisture content of the HPMC coated aspirin tablets at each
temperature (25, 30, 40°C) and relative humidity (12, 33, 50, 60, 75, 80, 90). These
conditions include the tripartite guideline test conditions as published by the International
Conference on Harmonization.
Materials

- Controlled temperature chambers (25, 30, 40°C)

0 Twenty one five gallon buckets

- Saturated salt solutions

- Twenty one Pyrex Petri Dishes

- Mettler AB 160 gram scale

0 Brinkmann Titration Unit

- Hydranal Composite 5

Karl Fischer Reagent

- Methanol solvent

- Morter & pestle

- Borosilicate test tubes

0 Bayer 500 mg HPMC Aspirin Tablets
Methods

Three tablets at each test condition were removed from the humidity bucket and
each tablet pulverized with the mortar and pestle and placed in a separately labeled test
tube, and sealed with paraffin film.

The contents of each test tube were inserted into the Brinkmann Titration vessel,

and a 60 second Karl Fischer titration was performed to determine percent moisture

content by weight, of each tablet.

31

 

Calculations

The following terms, calculations, and conversion, refer to the spread sheet data in
appendix A. They serve only as a summary of such operations performed on the data
presented in the data and results portion of this section.

 

Condition Average Water Weight (g) = CAWW

CAWW = (Avr. Moisture + 100) X Avr. Sample wt.

 

Condition Average Dry Product Weight (g) = CADPW

CADPW = (l - (Avr. Moisture + 100)) X Avr. Sample wt.

 

100 (g) Factor = (100 / CADPW)

This is the number by which the two condition weights
(wet weight) are multiplied to derive the dry weight
of H20 in grams per 100 grams of DRY product.

 

Conversion of Dry Weight to Wet Weight:

Percent Dry weight = X where X = Wet Weight
100 - X

 

Conversion of Wet Weight to Dry Weight:

Percent Wet weight = X where X = Dry Weight
100 + X

 

Note: The pharmaceutical industry uses wet weight basis for calculation purposes.
The Brinkmann Titrator (set for Karl Fischer titration) displays moisture per weight
of sample (or percent moisture) which is moisture content on a wet weight basis.
The food and packaging industry often use moisture content for moisture sorption
isotherms. The Y axis of such isotherms traditionally use moisture content on a

dry weight basis, which necessitates the conversion set forth above.

Additional explanation of data and calculations can be found in appendix A.

32

Data and Results

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 2. Bayer Aspirin Day 16 moisture content (dry weight basis)
at 25°C and 12, 33, 50, 60, 75, 80, 90 % RH.
25 °C
% RH. 12 33 50 60 75 80 90
M01510“? 0.7963 1.1054 1.4473 1.7432 2.8348 3.6556 4.5078
content
(gHzO/
1008 417)
Table 3. Bayer Aspirin Day 16 moisture content (dry weight basis)
at 30°C and 12, 33, 50, 60, 75, 80, 90 % R.H.
30°C
% RH. 12 33 50 60 75 80 90
Moi-“Ute 0.7489 1.0918 1.3925 1.6777 2.5045 2.9760 4.1233
content
(gHZO/
I00g dry)
Table 4. Bayer Aspirin Day 16 moisture content (dry weight basis)
at 40°C and 12, 33, 50, 60, 75, 80, 90 % R.H.
40°C
% RH. 12 33 50 60 75 80 90
MOiSmfe 0.6813 1.0645 1.3342 1.5366 2.1277 2.5676 3.6520
content
(gl-IZO/
IOOg dry)

 

 

 

 

 

 

 

 

 

 

'1

I m a

T

3.3 Moisture Sorption Isotherms
Purpose

To construct moisture sorption isotherms for each test temperature (25, 30, 40°C).
Materials

- Controlled temperature chambers (25, 30, 40°C) - Mortar & pestle

- Twenty one five gallon buckets - Brinkmann Titration Unit

- Saturated salt solutions - Hydranal Composite 5

- Twenty one Pyrex Petri Dishes Karl Fischer Reagent

- Mettler AB 160 gram scale ' Methanol solvent

- Bayer 500 mg HPMC Aspirin Tablets - Borosilicate test tubes
Methods

The percent moisture by weight of each tablet was converted to g H20/ 100 g dry
product and plotted vs. relative humidity at each test temperature (25, 30, 40°C).
Data and Results

Figure 7. Bayer Aspirin Day 16 Moisture Sorption lsotherrns at 25, 30, and 40°C.

 

 

 

 

 

512.0

D}

.3100

5 8.0

‘i‘

3 6.0

33' 4.0

8 2.0

9

.3 0.0.!
g 010 20 30 40 50 60 70 80 90100

RH °/o

34

After completion of dissolution testing, and subsequent moisture content analysis
of failing tablets, it was discovered that the Day 16 Moisture Sorption Isotherms did not
include the physical or the dissolution failure point moisture contents as was initially
expected.

The problem with the Day 16 Moisture Sorption Isotherms was that aspirin tablets
resumed moisture sorption after what appeared to be the moisture sorption equilibrium
point on day 16. Irrespective of the reason for additional moisture gain in the aspirin
tablet, the additional gain necessitated the development of two additional isotherms. One
at physical failure conditions and the other at dissolution failure conditions.

The Day 30 Physical Failure Sorption Isotherm, and The Day 45 Dissolution
Failure Sorption Isotherm used in calculation of shelf life and dissolution shelf life are

illustrated in Figure 8 and Figure 9 which follow respectively.

35

Figure 8. Bayer Aspirin Day 30 Physical Failure Sorption Isotherm at 30°C
with supporting data table.

 

12.0
10.0
8.0
6.0
4.0
2.0
0.0

 

 

 

 

Moisture content ( 9 H20 I 100 9 Dry )

O 10 20 30 4O 50 60 70 80 90 100
RH°/o

uzoitoo Dry

 

36

Figure 9. Bayer Aspirin Day 45 Dissolution Failure Sorption Isotherm at 30°C
with supporting data table.

12.0
10.0
8.0
6.0
4.0
2.0
0.0

 

 

 

 

Moisture content ( 9 H20 I 100 9 Dry )

O 10 20 30 40 50 60 70 80 90 100
RH%

 

37

3.4 Dissolution
Purpose

To determine a critical time, temperature, and relative humidity at which the
dosage form no longer performs at the Specified rate of dissolution by the manufacturer
(80 % of 500 mg at 30 minutes).
Materials

- Controlled temperature chambers (25, 30, 40°C)

0 Twenty one five gallon buckets

- Saturated salt solutions

- 108 Pyrex Petri Dishes

- VanKel VK6010 six vessel dissolution deck

- Perkin-Elmer 3B Spectrophotometer

0 Brinkmann Titration Unit

- Hydranal Composite 5

Karl Fischer Reagent
- Methanol solvent
- Morter & pestle

- 3,888 Borosilicate test tubes
0 432 Bayer 500 mg Aspirin Tablets

Methods

Dissolution testing followed the procedure for the test as outlined by Bayer
Corporation for their Bayer Plus, 500 mg Caplet. This is an HPMC coated capsule shaped
tablet used in this research. A sample of dissolution medium (*buffer + sample) was
removed from the vessel at time intervals of 5, 10, 20, 30, 40 and 50 minutes. The
sample was removed from the vessel using a 5 ml plastic syringe attached to plastic
tubing. A cotton filter within the syringe end of the tubing removes undissolved large

particulate matter from the medium. (*buffer: 17.94g sodium acetate trihydrate, 9.96g

glacial acetic acid, 6L deionized dearated water with a pH of 4.5)

38

Approximately 3 ml of solution was removed at each time interval, from which
1.0 ml was measured via a calibrated Pipetman. The 1.0 ml sample was transferred to a
glass tube and the remaining sample medium replaced in the vessel.

Assay of sample solution:

The 1.0 ml sample of solution medium was diluted to produce appropriate and
useable absorbance values in the calculation of percent dissolution and was determined
by finding a dilution coefficient which produced absorbance values within the range of
the reference standard calibration curve for the pure product (aspirin). Purity of the
reference standard product has been verified by Bayer Corporation.

Once a suitable dilution coefficient was isolated, the absorbance of each sample
medium was measured at 265 nm on a Perkin-Elmer 3B spectrophotometer within one
hour of sampling.

The data was converted to percent dissolved as follows:
% dissolved = (Absorbance / s) X n X V / (W x 100)
Where: 3 = slope of reference standard calibration curve
n = dilution coefficient
V = volume of dissolution medium in vessel
(500 ml)

W = amount of aspirin in each tablet
(500 mg)

39

Data and Results

 

 

 

   
 

 

 

 

120

10° .. + 109.53
..\° 80 ..
c 4»
.9. 60 .
2
o 0
.3 40 -
o 4»

20 ,

0 3 i 3 i 3 3 3 i
o 10 20 30 40 50
TIME (min)

+ tab~1 + tab-2+ tab-3

Figure 10. Bayer Aspirin dissolution profile (fresh from the bottle)
with bottle storage conditions of 22°C / 50 % RH.

40

120

 

m
o
r .

Dissolution ( °/o )
8

8

 

Figure l l.

 

 

  

 

A l
I Y T v '

10 20 30 40 50
TIME ( min )

 

qu-

—.-.. tab-1+ tab-2+ tab—3

Bayer Aspirin dissolution profile (day 90/ 25°C / 90 % R.H.).

The initiation of a trend towards dissolution failure begins. However,
no failure is observed.

Note: The sample # 3 value at 30 minutes is 80.13 % dissolved. This

exceeds the Bayer specification of 80 % dissolved at or before
30 minutes.

41

120

 

100 41-

 

a)
o
l .

 

 

Dissolution ( °/o )

 

       

0 10 20 30 40
TIME (min )

l
I

.1.

+ tab-1...— tab-2+ tab-3

Figure 12. Bayer Aspirin dissolution profile (day 45 / 30°C / 90 % R.H.).

First dissolution failure at 30°C.

42

 

50

 

 

 

Dissolution ( % )
8

 

 

 

 

40
20 q
0 s i : + 3 i 3 4 4.
0 10 20 3O 4O 50
TIME ( min )

+ tab-1 + tab-2+ tab-3

Figure 13. Bayer Aspirin dissolution profile (day 75 / 40°C / 90 % R.H.).
First dissolution failure at 40°C.

43

 

 

 

 

£120 ‘

ӣ100 3- W

.9 ..

§ 8° " W

8 0 ISSOUIOD BIUfe cm or f Ll

m di-

5 60 0

a 40 ..

‘2' ..

5 2° 1’

8 0 ¢ : § c t t i 4

0 20 40 60 80 100
Relative Humidity ( % )
—aa— Day 6 + Day 30+ Day 60—.— Day 90

Figure 14. 30 minutes dissolution isotherm of Bayer Aspirin stored at 25 °C

from 0 - 90 days.

44

N
O

 

 

on
O

 

 

DissoluIIon FaIIure PoInI For Product

#0)
OO

30 Minutes Dissolutiory %J
N
o

 

 

O
I.

 

20 4O 60 80 100
Relative Humidity ( % )

O

 

—ea— Day 6 —.— Day 30—-— Day 45+ Day 60—.— Day 75+ Day 90

Figure 15. 30 minutes dissolution isotherm of Bayer Aspirin stored at 30°C
from O - 90 days.

45

 

 

 

 

 

$120

”6100 .. g

.9 ..

g 80 T lSSOUIOfl aIure om 01' f U

.9 60 ..

O o

a 40 -.

E 201“

8 0 i #3 ,L c § ; 4 t
0 20 40 60 80 100

Relative Humidity ( % )

—ea— Day 6 + Day 30—-— Day 45+ Day 60+ Day 75—a— Day 90

Figure 16. 30 minutes dissolution isotherm of Bayer Aspirin stored at 40°C
from 0 - 90 days.

46

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Temp Time RH ( % )
0C Day 12 33 50 6O 75 8O 90
6 X X X X X X X
30 X X X X X X X
45 X X X X
25 °C 60 X X X X x X X
75 X X X X
90 X X X X X X X
6 X X X X X X X
30 X X X X X X X
45 X X X X
30°C 60 X X X X X X X
75 X X X X
90 X X X X X X X
6 X X X X X X X
30 X X X X X X X
45 X X X X
40°C 60 X X X X X X X
75 X X X X
90 X X X X X X X

Table 5. Bayer Aspirin dissolution testing storage plan.

47

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Temp Time RH ( % )
0C Day 12 33 50 6O 75 8O 90
6 103.31 107.01 101.79 103.08 106.45 104.20 106.56
30 101.46 103.53 102.18 104.71 103.87 104.82 105.33
45 101.28 104.71 105.44 106.78
25°C 60 106.28 101.91 111.67 104.88 99.83 105.04 101.68
75 104.65 102.97 104.09 95.17
90 102.75 105.16 103.64 105.27 106.95 103.25 90.46
6 102.47 104.60 101.51 103.42 102.41 102.02 107.07
30 103.64 104.26 104.49 104.09 102.30 104.43 89.78
45 105.61 105.39 102.75 77.60
30°C 60 102.29 103.31 103.31 104.99 99.43 97.24 45.79
75 104.54 106.28 102.46 56.11
90 102.58 101.40 100.84 105.21 103.59 103.70 46.63
6 103.53 104.32
30 103.14 104.71 102.86 104.43 106.50 105.61 101.34
45 103.92 103.53 103.03 93.99
40°C 60 103.14 101.74 102.74 101.73 ' 106.90 107.12 87.98
75 103.81 97.13 95.78 78.61
90 101.12 99.83 101.00 104.26 105.72 92.86 71.99
Table 6. Bayer Aspirin 30 minutes dissolution values for full storage plan.

48

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Temp Time RH ( % )
0C Day 12 33 50 6O 75 8O 90

6
30
45

25°C 60
75 ?
90 X
6
30 X
45 9.63

30°C 60 9.98
75 9.88
90 10.18
6
30
45 * ' ?

40°C 60 X
75 ? 5.48
90 ? 5.77

Table 7. Bayer Aspirin moisture content (wet weight basis) for tablets failing

dissolution.

? - Indicates the 30 minutes dissolution value is 95 °/o dissolved or less,
and the begining of a possible trend toward dissolution failure.

X- Indicates the 30 minutes dissolution value is 90 % dissolved or less,
and the continuation of a possible trend toward dissolution failure.

49

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

50

Temp Time RH ( % )
0C Day 12 33 50 6O 75 80 90

6
3O
45

25 °C 60
75 yellowing
90 yellowing yellowing
6
30 pastey cracked
45 YCllOWlng pastey cracked

30°C 60 yellowing pastey pastey cracked
75 yellOWlng pastey cracked

» 90 yellOWlng pastey cracked

6
30 pastey cracked
45 yellOWlng pastey cracked

40°C 60 yellOWlng pastey cracked
75 yellowing pastey cracked cracked
9O YCllOWing pastey cracked cracked

Table 8. Physical nature of Bayer Aspirin tablets at the time of dissolution testing.

 

3.5 Determination of Moisture Content (wet weight and dry weight basis)

-For Fresh Product

-At the First Physical Failure Condition

-At the First Dissolution Failure Condition
Purpose

To determine the moisture content of the Bayer 500 mg tablet when the tablet is
fresh from the manufacture’s bottle, and to determine the moisture content at first
physical (day 30 / 30°C / 9O %R.H.) and first dissolution (day 45 / 30°C / 90 %R.H.)
failure conditions on both a wet and dry basis.
Materials

- Brinkmann Titration Unit

- Hydranal composite 5 Karl Fischer Reagent

- Methanol solvent

- Mortar & pestle

- Borosilicate test tubes

0 36 Bayer 500 mg HPMC coated aspirin tablets

- Controlled temperature chambers (25, 30 , 40°C)

- Two 5 gallon humidity buckets (90 % RH.)

- Saturated salt solutions

0 Three 100 mm Pyrex Petri Dishes
Methods

The moisture content values used in shelf life calculation are all based on the
average of 12 Bayer Aspirin tablets. The initial product moisture content was determined
by pulverizing 12 Bayer tablets obtained from their original factory induction sealed
bottle which had been stored at controlled room temperature and 50 % relative humidity.

The 60 second Karl Fischer test was performed for moisture content on each tablet

using the automated Brinkmann Titration Unit. The moisture content was reported by the

unit in percent weight of water per weight of tablet product.

51

Physical failure moisture content was determined in the same manner, with the exception
that the 12 tablets were first subjected to conditioning of 30 days / 30°C / 90 % R.H.
Dissolution failure moisture content was also determined in like manner, with the
exception in this case that the 12 tablets were first subjected to conditioning of

45 days / 30°C / 90 % RH.

52

Data and Results

Table 9. Bayer Aspirin initial and critical moisture contents (wet weight basis).

that is water

is water

 

Table 10. Calculated Bayer Aspirin initial moisture content, critical physical failure
moisture content, and critical dissolution failure moisture content

 

 

 

 

(dry weight basis).
Moisture content g H20 / 100 g dry product
Initial 0.9082
Critical physical failure 8.5305
Critical dissolution failure 10.6562

 

 

 

 

54

3.6 Experimental Determination of Bayer Bottle WVTR and Calculation of
Permeability Constant.

Purpose

To determine the water vapor transmission rate (WVTR) of the Bayer Aspirin
Package at three different temperatures (25, 30, 40°C) each at 90 % relative humidity, by
gravimetric analysis.
Materials

0 Controlled temperature chambers (25, 30, 40°C)

- Three five gallon buckets (9O % RH.)

- Saturated salt solutions

- Mettler AB 160 gram scale

- Enercon LM2534-2 Induction Sealer

- 38-400 “Quali-Top” MJ-469 Induction seal closures

- 21 Bayer Aspirin Packages

- Drierite desiccant (samples)

- Pyrex glass beads (controls)
Methods

The WVTR test was conducted on 21 induction sealed Bayer Aspirin bottles at
three temperatures (25, 30 , 40°C) each at 90 % relative humidity. For each temperature,
seven samples were placed in the humidity buckets. Five sample bottles were filled with
approximately 115 grams of desiccant. Two control bottles were filled with
approximately 115 grams of Pyrex beads. The weight of each sample and control was

recorded every two days for one month. Once all data was collected, the control values

were subtracted and the adjusted data graphed.

55

The slope (WVTR) was determined by linear regression for all three
temperatures. The WVTR of the bottle will be used to calculate the permeability constant
of the bottles packaging material at all three temperatures. For the purpose of shelf life
and dissolution shelf life calculation the permeability constant for the most demanding

temperature (30°C) will be used.

56

Data and Results

Table 11. Bayer Aspirin Bottle WVTR raw data - water weight gain.

 

57

Figure 17.

Bayer Aspirin Bottle weight gain vs. time.

 

 

 

 

 

 

 

 

 

 

 

115.5
A1151! .. - ; .4. - ; ; ; j‘ #—
E f!—
2 D
315-3-0-
‘3 .
31152.. W
.9 i
8
115-0 ‘ 1 4 1 l i l l i i l 1 l 4
b é A 681012141618202'22426
Time(Day)
+250+300+40C
Figure 18. Bayer Aspirin Bottle weight gain vs. time - linear fit.
115.5
A115'4 ail- ‘ A ; I; ; ; ; #—
E if ; é ; '; ; — _
‘2
3115.3“
2 ..
.9:
3115.2“
2 ‘P
g
m115.1.g
1.
115-0 . 1 1 1 . l l i l 4. i 4. l i
23 68101214161820222426
Time(Day)

+ 25 C (Linear Fit)..— 30 C (Linear Fit)..— 40 C (Linear Fit)

58

 

 

 

Table 12. Bayer Aspirin Bottle WVTR - with regression data.
fiRegression filtput:
Constant 1 15.2268
Std Err of Y Est 0.0059534
R Squared 0.7967
No. of Observations 13
Degrees of Freedom 11

 

 

X Coefficient(s) 0.00 449 gram/day
Std Err of Coef. 0.000221 25-
Regression Output:

Constant 115.19648
Std Err of Y Est 0.0061083
R Squared 0.8123423
No. of Observations 13
Degrees of Freedom 11

 

 

X Coefficient(s)
Std Err of Coef.

 

X Coefficient(s) 0.00156 gram/day
Std Err of Coef. 0.000226 30-C
Regressiorfiutput:

Constant 1 15.36868
Std Err of Y Est 0.0051509
R Squared 0.8910566
No. of Observations 13
Degrees of Freedom 11

 

 

0.00 811 gram/day
0.000191 40-

 

59

Calculation of Permeability Constant

WE
25°C = 0.001449 g/day

30°C = 0.001562 g/day
40°C = 0.001811 g/day

mmHg
25°C = 23.756 mmHg ° 0.9 = 21.380 mml-Ig

30°C = 31.824 mmI-Ig - 0.9 = 28.642 mmHg
40°C = 55.324 mmHg - 0.9 = 49.792 mmHg

Benneanse
25°C = 0.001449 g/day / 21.380 mmHg = 6.77E-05 g/day - mmHg

30°C = 0.001562 g/day / 28.642 mmHg = 5.45E-05 g/day ° mmI-Ig
40°C =0.001811 g/day/ 49.792 mmHg = 3.64E-05 g/day ° mmHg

E l l. .
Thickness = 50 mil

Exposed surface area = 0.01229 m2

(Exposed surface area is for bottle only, because the bottle is induction sealed with foil)

E l 'l‘ t
25°C = (6.77E-05 g/day - mmHg) - 50 mil / 0.01229 m2 = 0.28 g ' mil / day - m2 - mmHg
30°C = (5.45E—05 g/day - mmHg) - 50 mil / 0.01229 m2 = 0.22 g - mil / day - m2 ° mmHg
40°C = (3.64E-05 g/day - mmHg) - 50 mil / 0.01229 m2 = 0.15 g - mil / day - m2 °mmHg

60

3.7 Computer Modeled Determination of Shelf Life and Dissolution Shelf Life
Purpose
To determine using a computer model, the shelf life and the dissolution shelf life
of the HPMC coated Bayer 500 mg aspirin tablet based on aspects of the package system
such as package permeability, surface area, and thickness, and based on the critical
moisture content of tablets with first physical failure and first dissolution failure.
Materials
- Michigan State University School of Packaging Computer Shelf Life
Program. (Downes and Lee, 1982)
Updated for windows ( Downes, Lee, and Yoon, 1998)
Methods
The computer program requires various input data which can be obtained from

actual physical and experimental analysis of the package system. The program makes use

of the following formula:

t = {4.3 -1°w log LRHEXTflmltimes-t

P-A-p,°b ( RHEXT - RH,NT ) time - 0
Where:

t = time for relative humidity inside the package to reach the critical
moisture level.

1 = package wall thickness

P = permeability constant of packaging material

A = surface area of the package

ps = saturation vapor pressure of water at temperature of test

b = slope of linear region of sorption isotherm of product at temperature of
test

w = weight of product packaged

RHEXT = external relative humidity
RI-I,NT = internal relative humidity

(Packaging Course 815, 1998)

61

The variable (b) in the formula is the slope of the linear region of the moisture
sorption isotherm of the product at the temperature of the test. However, not every
product will conveniently produce initial moisture and critical moisture content points on
the linear portion of a normally sigmoidal moisture sorption isotherm. The computer
program can accept information from a product with critical moisture points that fall on
the non-linear portion of the moisture sorption isotherm. This is the case with the Bayer
500mg aspirin tablet. The program (in non-linear mode) accepts up to seven points on the
product’s moisture isotherm and integrates a best fit trinomial (sigmoidal) curve based on
the seven points. The formula then makes use of point values along the trinomial curve

function rather than using point values calculated from a simple linear slope (b).

62

Data and Results
“5115' If!!! . $1 [“132 :

The shelf life of the Bayer package was calculated using the computer program’s non-
linear model and the physical failure sorption isotherm.
The program query and inputs are as follows:

 

Enter seven points along the products isotherm.

 

RH % 12 33 50 60 75 I 80 90

 

 

 

 

 

 

 

 

WWW 1.99 2.45 2.71 3.14 5.03 I 5.86 8.53

 

 

Enter the temperature in Celsius under which the product’s sorption isotherm is studied.
30°C

Enter the moisture content of the product in grams of water per 100 grams of solids when
the product is fresh.

0.91 g

Enter the equilibrium relative humidity in % for the above product.

4.4 %

Enter the moisture content of the product in grams of water per 100 grams of solids when
the product is about to spoil.

8.53 g

Enter the equilibrium relative humidity in % for the above product.

90 %

Enter the weight in grams of the product in the package.

52.2 g '

Enter the permeability constant of the packaging material in

(gram * mil / day *m2 * mmHg).

0.22 g - mil / day - rn2 - mmHg

Enter the thickness of the packaging material in mil.

50 mil

Enter the area of the packaging material used in the packaging in (inz).

19.05 in2

Enter the relative humidity for the environment where the packaged product is stored.
91 %

 

The program output:
The maximum shelf life of the product is 1,588 days.

1,588 days = 4.35 years = 4 years, 4 months, 8 days.

63

“5115' It!!! . SIIEI'EE r ,

The Dissolution shelf life of the Bayer package was calculated using the computer
program’s non-linear model and the dissolution failure sorption isotherm.
The program query and inputs are as follows:

 

Enter seven points along the products isotherm.

 

RH % 12 33 I 50 60 75 80 90

 

 

 

 

 

 

 

 

WWW 2.00 2.64 j 2.89 3.36 5.97 7.26 10.66

 

 

Enter the temperature in Celsius under which the product’s sorption isotherm is studied.
30°C

Enter the moisture content of the product in grams of water per 100 grams of solids when
the product is fresh.

0.91 g

Enter the equilibrium relative humidity in % for the above product.

4.4 °/o

Enter the moisture content of the product in grams of water per 100 grams of solids when
the product is about to spoil.

10.66 g

Enter the equilibrium relative humidity in % for the above product.

90 %

Enter the weight in grams of the product in the package.

52.2 g

Enter the permeability constant of the packaging material in

(gram *mil / day ’mz * mmHg).

0.22 g - mill day . m2 - mmHg

Enter the thickness of the packaging material in mil.

50 mil

Enter the area of the packaging material used in the packaging in (inz).

19.05 in2

Enter the relative humidity for the environment where the packaged product is stored.
91 %

 

The program output:
The maximum shelf life of the product is 2,068 days.

2,068 days = 5.67 years = 5 years, 8 months, 3 day.

64

4.0 Statistical Analysis
The experimental design for dissolution testing involved three factors:
1. Temperature (three levels-25, 30, 40°C)
2. Relative humidity (seven levels-12, 33, 50, 60, 75, 80, 90 % R.H.)

3. Time (four levels-6, 30, 60, 90 days)

For each combination, three tablets were measured for dissolution at 30 minutes
(3 x 7 x 4 x 3 = 252). This produced a total of two hundred and fifty two, 30 minute
dissolution values - three values, on each of 84 treatments.

The experimental design was very similar to a split-split-plot design.
Temperature at three levels was assigned to the three whole plots (chambers); each whole
plot was divided into seven subplots (R.H. buckets); each of these further divided into
four sub-subplots (time periods). There is no replication of whole plots. Therefore, an
ordinary ANOVA for the split-split-plot design will not provide statistical tests for
temperature and relative humidity effects.

It is possible however, to plot the 30 minute data, and graphically depict the effect
of TIME on the 30 minute dissolution data as a function of temperature and relative
humidity. It is also possible to perform a one-way ANOVA test for the effect of time at

each temperature and relative humidity condition.

65

When the 30 minutedissolution data is plotted as a function of relative humidity
at the 25 °C temperature, at no time does the average 30 minute dissolution value fall
below 95 % dissolved. The product is specified to meet or exceed 80 % dissolved at 30
minutes dissolution. This suggests that there is no failure effect of time on the 30 minute
dissolution value within the zero to ninety day storage and test interval, irrespective of

relative humidity at 25 °C. I?"

Figure 19. Effect of relative humidity on Bayer Aspirin 30 minutes dissolution
values at 25 °C.

 

115

 

12%

A

 

1° 33 %

/
1

l

11
It

\1

111‘
l

+ i

A __ 50 %

60 %

 

75%

(O
0'!

 

80%

 

 

 

90 . 1 L L . 1 n I n
I i l r j l r r V 90 %
0 20 40 60 80 1 00
Time ( days )

When the 30 minute dissolution data is plotted as a function of relative humidity
at the 30°C temperature, at no time does the average 30 minute dissolution value fall
below 95 % dissolved for relative humidities below 80 % R.H. However at 90 % R.H.
there is a drastic reduction in the 30 minute dissolution value, which drops to 89 %
dissolved at day 30, and drops further to 45 % dissolved and 46 % dissolved on day 60
and 90 respectively. The 30°C temperature appears to have an even more deleterious

effect on 30 minutes dissolution values than the 40°C temperature.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 20. Effect of relative humidity on Bayer Aspirin 30 minutes dissolution
values at 30°C.
110 ‘9‘
g 12 %
100 —a—
3 33 %
99° +
c
.93 “ 50 %
280
3 +
5'" 0 60 9
O o
9 7O
:3 +
.E "
E60 75 %
o
°° «» +
50 \ J 80 %
0 1’ r w —a—
4 1 i 1 1 1
I r l ' l I l V 90 O/
0 20 40 60 80 100 °
Time ( days )

67

When the 30 minute dissolution data is plotted as a function of relative humidity
at the 40°C temperature, at no time does the average 30 minute dissolution value fall
below 95 % dissolved for relative humidities below 80 % R.H. The highest relative
humidity, 90 % R.H., does produce a reduction in the 30 minute dissolution value, which

drops to 87 % dissolved at day 60, and drops further to 72 % dissolved on day 90.

Figure 21. Effect of relative humidity on Bayer Aspirin 30 minutes dissolution
values at 40°C.

110

.. _ + 12 %

00 H— 7"
.. \ 33 %

2. +
‘l \ 50 %

 

 

-§

 

CD
0

 

 

 

 

30 Minute Dlssolgtion Value
0

 

 

 

 

70 " - 60 %
.1 +
60 75 %
.. +
40 L +
0 20 4O 60 80 100 90 %
Time ( days )

68

 

This would indicate that the Bayer aspirin tablet is very robust with regard to
maintaining dissolution stability. The Bayer Corporation specifies that 80 % of the aspirin
tablets active ingredient must be in solution at or before 30 minutes, for the tablet to pass
dissolution testing. Based on this definition of dissolution failure, only tablets stored
without packaging protection, at temperatures above 30°C and relative humidities above
90 % R.H., will produce a dissolution failure before ninety days.

The results of the one-way ANOVA test for the effect of time (p-values)

supports the above conclusion with some explanation.

Table 13. Results of One way AN OVA test for the effect of time on
30 minute Bayer Aspirin dissolution values (p-values).

 

 

 

 

 

 

 

 

 

One-way ANOVA test for the effect of Time ( p-values )

RH. % 25°C 30°C 40°C
12 0.045 0.615 0.449
33 0.076 0.174 0.073
50 0.004 0.091 0.655
60 0.492 0.371 0.406
75 0.028 0.100 0.054
80 0.593 0.006 0.019
90 0.014 1.1E-05 2.6E-06

 

 

 

 

 

 

Summary of significant p-values:

25°C - 12 %, 50%, 75 %, and 90%R.H.
30°C - 80 % and 90 % R.H.
40°C - 80 % and 90 % RH.

69

The significant p-values for all relative humidities below 90 % can be explained
by visual inspection of a plot containing only the significant p-value 30 minute

dissolution data.

It is illustrated from the plots of the conditions with significant p-values that for
relative humidities below 90 %, the 30 minute dissolution value may fluctuate up and

down enough to produce a significant result in the p-value.

Figure 22. Fluctuation contributing to significant p-values for the 30 minutes
dissolution data below 90 % RH.

115

 

.5.
250 - 12 %
+
250 - 50 %
+
25C - 75 %
+
300 - 80 °/o

40C - 80 °/o

0 20 , 40 60 80 100
Time (days )

 

 

 

 

 

30 Minute Dissolution Value
0
01

 

 

95

 

However it is important to note that this fluctuation (producing the significant p-

value result in all cases below 90 % R.H.) takes place ABOVE the 95 % dissolved level.

70

 

Therefore 25°C (12 %, 50 %, 75 % RH.) and both the 30°C and 40°C (80 % R.H.)
do significantly affect dissolution with regard to time but never below 95 % dissolved

and therefore never any closer than 15 % dissolved of the dissolution failure point.

71

5.0 Conclusions

(Section 3.1) Moisture Sorption Equilibrium Determination: The Bayer 500 mg
aspirin tablet appears to reach moisture sorption equilibrium within 16 days, at all three
temperatures (25, 30 40°C) and all seven relative humidities (12, 33, 50, 60, 75, 80 90 %
R.H.)

However, it was discovered after completion of dissolution studies that the
product resumes moisture sorption at some time afier day 16, and continues sorption up
until the 90th day for all three temperatures. This suggests that true moisture sorption
equilibrium exists for this product beyond the dissolution failure moisture content, and
beyond the 90th (last) day of testing. The reason for resumed moisture sorption is
unknown but one possible contribution is discussed in conclusion section 3.3.

(Section 3.2) Moisture Content Determination: The moisture content of aspirin
tablets at moisture sorption equilibrium, for all conditions, was determined by Karl
Fischer testing on a Brinkmann titration unit. The resulting wet weight moisture contents
were converted to dry weight moisture content values.

(Section 3.3) Moisture Sorption Isotherms: As a traditional first step in shelf life
calculation, the dry weight moisture content values (reported in gram HZO/ 100 gram Dry
Product) were used to construct Moisture Sorption lsothenns for each of the three
temperatures. After completion of dissolution testing, and subsequent moisture content
analysis of failing tablets, it was discovered that the Day 16 Isotherms did not include the

physical or the dissolution failure point moisture contents as was initially expected.

72

The problem with the Day 16 lsothenns as explained previously, was that the aspirin

tablets resumed moisture sorption after the equilibrium point on day 16. This may be due
to a physicochemical reaction between the active ingredient - acetylsalicylic acid, and the
invading moisture into the tablets. One possible reason for this additional tablet moisture

gain is worth mention. This hypothesis on additional tablet moisture gain is based on two

points:

1) Bayer corporation specifies sodium acetate trihydrate and glacial acetic acid
in its dissolution buffer, no doubt to maintain the active ingredient
(acetylsalicylic acid) in solution for dissolution assay.

2) A white crystalline substance (probably salicylic acid) was found to
de-aggregate the tablet matrix and crack the tablet coating in tablets exposed to

30°C / 90 % RH. and 40°C / 80 and 90 % R.H.

The hypothesis starts with the industrial chemical reaction that produces the active

ingredient in aspirin, acetylsalicylic acid, which is as follows:

0
II
on O 0 OCCH.
H II 8...... O
+ CH3C— O — CCH, —’—l—' + CH3C02H
C 02 H acetic anhydride C O; H acetic acid

acetylsalicylic acid

salicylic acid
(aspirin)

73

As H20 slowly enters the tablet, perhaps due to the observed cracking or even due to
undetected micro-cracking of the tablet’s coating after day 16, a conversion of
acetylsalicylic acid to salicylic acid, and acetic acid, may take place as water attacks the

bridging oxygen of the ester.

 

0
ll
OCCH; OH
heat
+ H20 ; + CHICO!“
H’ . acid
C0111 CO;H m
acetylsalicylic acid salicylic acid
(aspirin)

Because this reaction with water is known to be spontaneous in the forward direction,
additional water may be drawn into the tablet to feed the reaction via Le Chatelier’s
principle. The destroyed water involved in this reaction would not contribute to the
additional moisture as detected by Karl Fischer titration. However, additional moisture
drawn in by the reaction which does not, or can not react with the acetylsalicylic acid may
be absorbed by binder or other inert additives. Absorption of moisture by the additives
would increase moisture content. This may not be unreasonable given the total moisture
gain from initial product moisture content (0.009 g H20) to critical dissolution failure
moisture content (0.0963 g H20) on a per tablet basis is 8.73 x 10‘2 grams of H20 - based
on a typical 1 gram tablet.

Irrespective of the reason for additional moisture gain in the aspirin tablet, the
additional gain necessitated the development of two additional isotherms, one at physical
failure conditions and the other at dissolution failure conditions. The Physical Failure
Sorption Isothenn, and Dissolution Failure Sorption Isotherm used in calculation of shelf

life and dissolution shelf life are presented and explained in section 3.3.

74

(Section 3.4) Dissolution: Representative dissolution profiles are presented in this
section. The average 30 minute dissolution value “fresh from the bottle” was found to be
103 % of active ingredient in solution.

At 25 °C mild physical discoloration (yellowing) was observed on day 75 at 90 %
RH. and on day 90 at 80 % and 90 % R.H. However, at this temperature, no dissolution
failure occurred at any relative humidity.

At 30°C physical failure (tablet cracking) occurred on day 30 at 90 % RH, and
dissolution failure occurred soon after, on day 45 at 90 % R.H. Because these conditions
represent the first physical and dissolution failures of tablets with regard to storage time -
it is the moisture content of these tablets which is used in shelf life and dissolution shelf
life calculation.

At 40°C physical failure (tablet cracking) occurred on day 30 at 90 % RH, and
dissolution failure occurred on day 75 at 90 % R.H. All failure points for 30 minute
dissolution can be observed graphically on the 30 Minutes Dissolution Isotherms at the
end of section 3.4.

(Section 3.5) Determination of Moisture Content (wet weight basis and dry
weight basis), For Fresh Product and at the First Physical Failure Condition and at the
First Dissolution Failure Condition: Based on 12 tablets obtained from their original
factory induction sealed bottle stored at controlled room temperature and 50 % R.H., the
initial moisture content of tablets “fresh from the bottle” is 0.90 g HZO (wet weight basis)

and 0.91 g H20 / 100 g Dry product (dry weight basis).

75

Based on 12 tablets subjected to conditioning of 30 days / 30°C / 90 % R.H.,
the critical moisture content of tablets at physical failure is 7.86 g H20 (wet weight basis)
and 8.53 g 1120/ 100 g Dry product (dry weight basis).

Based on 12 tablets subjected to conditioning of 45 days / 30°C / 90 % R.H.,
the critical moisture content of tablets at dissolution failure is 9.63 g H20 (wet weight
basis) and 10.66 g H20/ 100 g Dry product (dry weight basis).

The Physical Failure Sorption Isotherm and the Dissolution Failure Isotherm
which are based on this data, can be observed graphically at the end of section 3.3.
(Note: due to space limitations in the humidity buckets, all points other than critical
moisture content, on both isotherms, are based on only 4 tablets - rather than 12)

(Section 3.6) Experimental Determination of Bayer Bottle WVTR and Calculation
of Permeability Constant: The WVTR for the Bayer Package was experimentally
determined to be 0.001562 grams / day - at the 30°C test condition, and the permeability
constant at 30°C was calculated to be 0.22 g - mil / day ° m2 - mmHg.

Because this is the WVTR value at the most demanding test condition, the
permeability constant derived from it will be used in the computer modeled shelf life
calculation.

(Section 3.7) Computer Modeled Shelf Life and Dissolution Shelf Life
Determination: The Computer Modeled Shelf Life was calculated to be:

1,588 days or 4 years, 4 months, and 8 days.
The Computer Modeled Dissolution Shelf Life was calculated to be:

2,068 days or 5 years, 8 months, 3 days.

76

 

Table 14. Shelf Life Summary Table:

 

 

 

 

Computer modeled 1,588 days 2,068 days
Shelf life difference 480 days
Percent difference 23.21 %

 

 

 

With regard to Shelf Life and Dissolution Shelf Life, the computer modeled
values have a percent difference of 23.21 %. This is significant in that the product fails
physically some 23 % earlier than it fails dissolution. This suggests that the Bayer 500 mg
tablet is quite stable with regard to dissolution, stable to the point that it cracks and
discolors prior to dissolution failure. The consumer would no doubt find this offensive

and hopefully discard the product.

With the information provided in this study, the computer model may now be
used to quickly screen subsequent new package systems for the Bayer 500 mg aspirin
tablet in order to select only the most promising candidate package systems for stability

testing.

77

APPENDIX A
Explanation of spread sheet calculation
of dry weight basis from wet weight basis

including:

Calculation of dry weight basis from wet weight basis
for raw data - section 3.2

Calculation of dry weight basis from wet weight basis
for raw data - section 3.5

78

Explanation of Moisture Content Spread Sheet

In the ideal case where we have 3 tablets each weighing 1 gram and only 1% of that
1 gram tablet weight is water then:

Average Moisture is 1% or 0.01 of the 1 gram sample weight.
Average Sample Weight is 1 gram.

The percent moisture at this point is on a WET WEIGHT basis because if we were
to multiply average sample weight times 100 we would have 100 grams of product
of which 1 gram or 1% is water. '

The important thing to realize here is that the 1 gram of water is included in the
total weight, or in other words, we have 1 gram of water and 99 grams of DRY
product.

We need to know how many grams of water per 100 grams of DR Y product, or we
need to know the percent moisture on a DRY WEIGHT basis.
Now we crunch some numbers:

100 gram dry ( desired ) / 0.99 % Dry ( WET WEIGHT basis ) = 101010101 repeating

101.010101 is now our 100 gram DRY factor because:

0.99 ( gram of DRY product - WET WEIGHT basis ) X 101.010101 ( 100 grams DRY factor) =
100 grams of dry product

We can also use the same factor to find the weight of water in excess of the 100
grams of DRY product in the sample.

0.01 ( gram water in product - WET WEIGHT basis ) X 101.010101 ( 100 grams DRY factor) =
1.0101 grams of water for every 100 grams of DRY product.

Thus there are 1.0101 grams of water for every 100 grams of dry product in this

sample.
Or:
1.0101 g H20/ 100 g dry product

(the units required for the Y axis of a moisture sorption isotherm)

79

Spread sheet table example - conversion of wet weight basis to dry weight basis.

15.

2me 5995 “was...

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

_ . .. Solo 828131
_ 29:69:36.2
. o; A m 2: v
Heaven an
r . . l: _ oeoofimvoe
a. A 9 2925 .2626 .o. . . . § 2925
>5 cameo? Loam; ommao><
coztfico cocficob.
.ov . .o 5:8: 9:86.: ..>
cone; is oEEm .m> ._ .8. .oSEOE £15.
0000.? cc;
0084 ooe
. ooooe 8.?
8V is 29:91? manic—2 oxo

 

 

 

80

mama £995 62,.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Spread sheet table example - with underlying formulas.

Table 16.

m ANA .9 V 3668:8134:

_ Emucob 9353—2 0?

” A A of . A68: 9

. 8285 A5 3

_ 2

. AA: 9: _ Leon“. A 98? NA

. :

Am .202 o v: 52992885 . -V .2 . v A9 ago; 2
>5 ommao? Loam; ommoo>< m
5:68 8:65p m
.oEmO... c0309: 0.556;. .._>< N
Am a .E oasn .6? A8: v ><. .ooaeoeosée. o
A A m
A F o
l P F m
A9 .3, anmm 6556.2 oxr N
m o o m A

81

Table 17. Calculation of Bayer Aspirin Day 16 moisture content from wet weight basis
to dry weight basis at 25°C/ 12, 33, 50, 60, 75, 80, 90 % R.H.

 

82

Table 18. Calculation of Bayer Aspirin Day 16 moisture content from wet weight basis
to dry weight basis at 30°C/ 12, 33, 50, 60, 75, 80, 90 % R.H.

 

83

Table 19. Calculation of Bayer Aspirin Day 16 moisture content from wet weight basis
to dry weight basis at 40°C/ 12, 33, 50, 60, 75, 80, 90 % R.H.

 

84

Table 20. Calculation of Bayer Aspirin initial moisture content from wet weight basis
to dry weight basis.

on avr.
1 2 tablets and
avr. product

100

H20/100

 

85

Table 21. Calculation of Bayer Aspirin critical moisture content -
(physical failure) from wet weight basis to dry weight basis.

on aw.
12 tablets and
avr. product wt.

100

 

HZOI 100

86

Table 22. Calculation of Bayer Aspirin critical moisture content -
(dissolution failure) from wet weight basis to dry weight basis.

on avr.
12 tablets and
avr. product wt.

 

100

 

H20/100

87

APPENDIX B

30 minutes dissolution values raw data
and statistics

 

88

Table 23. Bayer Aspirin 30 minutes dissolution value raw data, with sample
standard deviation and p-values at 25°C.

 

89

Table 24. Bayer Aspirin 30 minutes dissolution value raw data, with sample
standard deviation and p-values at 30°C.

P-value
4

 

90

Table 25. Bayer Aspirin 30 minutes dissolution value raw data, with sample
standard deviation and p-values at 40°C.

 

9l

 

REFERENCES

Abdou, HM. 1996. Remington 's Pharmaceutical Sciences, 17th ed., 653-666, Mack
Publishing, Easton, Pa.

Al-Meshal, M.A., Al-Angary, A.A., Hammad, A.A., Mahrous, G.M., Molokhia, A.M.
1989. Storage Related Physico-chemical Changes in Aspirin and Phenylbutazone Tablets
Compressed with Different Initial Moisture Content. Drug Dev. Ind. Pharm.
15:2709-2719.

', Banakar, U.V. 1992. Pharmaceutical Dissolution Testing, 53-55, 133-142, 156-161, 180,

./

272-276, Marcel Dekker, Inc., NYNY.
Bremer, P.O., Kolstad B., and F inholt, P. 1969. Medd. Norslc Farm. Selsk. 31:67.
Broadbent, J.F., Mitchell, A.G., and O’Reilly, W.J. 1966. J.Pharm., 471846, S92.

Chowhan, Z.T. 1994. Factors Affecting Dissolution of Drugs and Their Stability Upon
Aging in Solid Dosage Forms. Pharm. Techno]. 60-73, September.

Cox, D. C., Douglas, C. C., Furrnan, W. B., Kirchhoefer, R. D., Myrick, J. W., and Wells,
C. E. 1978. Pharm. Techonol., 2:41.

Downes, T. and Lee, J. 1982. Michigan State University School of Packaging Computer
Shelf Life Program, School of Packaging, East Lansing, Michigan.

Downes, T. Lee, J. and Yoon, S. 1998. Michigan State University School of Packaging
Computer Shelf Life Program (for windows), School of Packaging, East Lansing,
Michigan.

Edmundson,1. C. and Lees, K. A. 1965. .l. Pharm. Pharmacol, 17:193.

Gouda, H. W., Moustafa, M. A., and Al-Shora, H. A. 1984. Int. J. Pharm., 18:213.
Gouda, H. W., Moustafa, M. A., and Molokhia, A. M. 1980. Int. J. Pharm., 5:345.
Guo, J. H. and Amidon, G.L. 1991. Investigating the Properties of Polymers for
Pharmaceutical Controlled Release Applications, Doctoral Dissertation, University of

Michigan.

Gupta, V. D. and Gupta, A. 1981. Am. J. Hosp. Pharm., 38:1539.

92

 

/"/Hanson, W. A. 1992. Dissolution: Past, Present, and Future. Talk Delivered to FDA
Workshop, Cincinnati, Ohio, April 14.

Hanson, W. 1982. Handbook of Dissolution Testing. 6, Pharmaceutical Technology
Publications Springfield, Oreg.

Hanson, W. and Hanson, R. 1979. Pharm. Technol., 3(3):42.
Haringer, G., Poulsen, B. J ., and Havemeyer, R. N. 1973. J. Pharm. Sci, 62:130.
Hoblitzell, J. R., Thakker, K. D., Rhodes, C. T. 1985. Effects of Moderate Stress
Storage Conditions on the Dissolution Profile of Enteric-Coated Asprin Tablets. Pharm.
Acta. Helv., 60:28-32.

/ Khalil, s. A. 11., Barakat, N. s., and Boraic, N. A. 1991. Effects of Package Type on In
Vitro Release and Chemical Stability of Amoxycillin in Capsules. Pharm. 1nd,
53:698-701.

Kirk-0thmer Enclycolpedia of Chemical Technology 1979. 5: 144-161, John Wiley &
Sons, Inc., USA.

Kovacs, A. J ., Stratton, R. A., and Ferry, J. D. 1963. Dynamic Mechanical Pr0perties of
Polyvinyl Acetate in Shear in the Glass Transition Range. J. Phys. Chem. 67:152.

Langenbucher, F. 1976. Parametric Representation of Dissoluton-Rate Curves by the
RRSBW Distribution. Pharm. 1nd. 38(5):472-477.

Lee, P. 1. and Peppas, N. A. 1987. Prediciton of Polymer Dissolution in Swellable
Controlled-Release System. J. Control. Rel. 6:207-215.

Lees, K. A. 1963. Pharm. Pharmacol. 15:143T.

Levy, G., Antlkowiak, J., Proknal, J., and White, D. J. 1963. Pharm. Sci, 52:1047.
Levy, G. and Hayes, B. A. 1960. N. Engl. J. Med, 262:1053.

Levy, G. and Sahli, B. A. 1962. J. Pharm. Sci, 51:58.

Marlow, E. and Shangraw, R. F. 1967. J. Pharm. Sci, 56:498.

Morrison, A. B. and Campbell, J. A. 1965. J. Pharm. Sci, 54:1.

93

‘31.???“ 1"”

Murthy, K. S. and Ghebre-Sellassie, 1. 1993. Current Perspectives on the Dissoluton
Stability of Solid Oral Dosage F orms. J. Pharm. Sci, 82:113-126.

McCrum, N. G., Buckley, C. P., and Bucknall, C. B. 1988. Principles of Polymer
Engineering. 45. Oxford University Press: Oxford and New York.

FUN TEL" 'P1 {Q- (”"11” 1‘0 if; 1 In?

Nakabayashi, K., Shimanoto, T., and Mirna, 11., 1981. Stability of Packaged Solid
Dosage Forms. IV. Shelf Life Prediciton of Packaged Prednisolone Tablets in Relation to
Dissolution Properties. Chem. Pharm. Bull., 29:2057-2061.

Packaging Course 815, 1998. Formula used by Michigan State University School of
Packaging Computer Shelf Life Program.

Pham, A. T. and Lee, P. I. 1984. Probing the Mechanisms of Drug Release from
Hydroxypropylmethyl Cellulose Matrices. Pharmaceutical Research 11(10):]379-1383.

Qian, X. 1996. Dissolution Stability for Packaging Application. MS. Thesis, Michigan
State University.

Richter, A., Myhre, B., and Khauna, S. C. 1969. J. Pharm. Pharmacol. Suppl., 2124095.
Rubino, J. T., Halterlein, L. M., and Blanchard J. 1985. Int. J. Pharm., 26:165.
Sakelariou, P., Rowe, R. C., and White, B. F.T. 1985. The Therrnomechanical Properties
in Glass Transition Temperatures of Some Cellulose Derivatives Used in Film Coating.
Int. J. Pharm. 27:267-277.

Sandell, E., Ericksson, K., and Mellstrom, G. 1971. Farm. Notisbl., 80:118.

Savastano, L., Leuenberger, H., and Merkle, H. P. 1995. Membrane Modulated
Dissolution of Oral Drug Delivery Systems. Pharmaceutica Acta Helvetiae 70:117-124.

Shah, A. C., Peot, C. B, and Ochs, J. F. 1973. J. Pharm. Sci, 62:671.

Shah, A. C. and Ochs, J. F. 1974. J. Pharm. Sci, 63:110.

Shepherd, R. E., Price, J. C., and Luzzi, L. A. 1972. J. Pharm. Sci, 6121152.

Simon, F. Z. 1931. Anorg. Allgem. Chem. 203:219.

Sinko, K. M. and Amidon, G. L. 1989. An Investigation into the Relaxation Behavior of 1

Pharmaceutical Film Coatings. Doctoral Dissertation, University of Michgian.

94

Struik, L.C.E. 1980. Polymer. 21:962.

Taborsky-Urdinola, C. J ., Gray, V. A., and Grady, L. T. 1981. Am. J. Hosp. Pharm.,
38:1322.

Toronto, University of. 1994. Faculty of Pharmacy, Toronto, Ontario M58 282, Canada.

Toronto, University of. 1994. Department of Chemical Engineering and Applied
Chemistry, Toronto, Ontario MSS 1A4, Canada.

Wruble, W. S. 1930. Am. J. Pharm. 102:368.

Wu, S. 1996. Dissolution Shelf Life of Unpackaged Solid Oral Drug Products.
MS. Thesis, Michigan State University.

95