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wjpmr, 2016,2(3), 99-103.

Review Article
WORLD JOURNAL OF PHARMACEUTICAL
World Journal of Pharmaceutical and Medical Research
ISSN 2455-3301
AND MEDICAL RESEARCH

Reddy et al.

WJPMR

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ACCELERATED STABILITY TESTING OF DOSAGE FORMS AS PER

INTERNATIONAL CONFERENCE OF HORMONIZATION (ICH) GUIDELINES
Dr A. Sambasivarao1, Dr. Chandra Sekhara Rao Baru2, M. Hareesh Reddy3*
1

Principal & Professor- Sri Indu College of Pharmacy- Hyderabad.

RGR Siddhanthi College of Pharmacy, Secunderabad, Telangana.
3
Associate professor Shadan College of Pharmacy Hyderabad.

*Corresponding Author: M. Hareesh Reddy

Associate professor Shadan College of Pharmacy Hyderabad.

Article Received on 01/04/2016

Article Revised on 20/04/2016

Article Accepted on 10/05/2016

ABSTRACT
Objectives of accelerated stability studies are linked to the establishment assurance of safety, quality and efficiency
of drug product from early phase development through the drug product. The stability data for the drug substance
are used to determine optimal storage and packaging conditions for bulk lots of material. In order to assess
stability, the appropriate physical, chemical, biological and microbiological testing must be performed.
Pharmaceutical companies estimate the shelf life (Expiration date) of a drug in order to determine the amount of
time the drug is at acceptable potency, color, etc., levels. The pharmaceutical company or the food and drug
administration set the acceptable levels. The process in which the shelf-life is determined is called a stability
analysis. During the shelf-life, a drug can stay on the shelf without degrading to unacceptable levels.
KEYWORDS: Accelerated stability, Shelf- life, Potency, Safety, Quality, Efficiency.

INTRODUCTION
The method of accelerated stability testing of
pharmaceutical products is based on the principles of
chemical kinetics, more specifically on the Arrhenius
plot. According to this technique, the k values for the
decomposition of the drug in solution at various elevated
temperatures are obtained, and the logarithms of these k
values are plotted against the reciprocals of the absolute
temperatures (in Kelvins). The resulting line is then
extrapolated to room temperature ( 5c
98 K). The
k 5 c is used to obtain a measure of the drug under
ordinary shelf conditions.[1-3]
Prediction of shelf life from accelerated stability data
Based on the principle of chemical kinetics demonstrated
by
1) Garret and Carper method
2) Free and Blythe method

If the slope of this line is determined from the results of

temperature by extrapolation, the k value obtained. And
this k value is substituted in appropriate order of reaction
allows the amount of decomposition after a given time.
Preliminary experiments are there for necessary to
determine this order.
K=Ae-Ea/RT
Log K=Log A - Ea/2.303*RT
Where, K= rate constant
R= gas constant =1.987 cal/mole
T = absolute temperature
A = frequency factor
Ea = energy of activation
T10% = (2.303/K)*(log100/90)
T90% = (2.303/K)*(log100/10)
GARRET AND CARPER METHOD
1.

Shelf Life Determination Based on Arrhenius Plot

(Garret and Carper method)
The mathematical prediction of shelf life is based on the
application of the Arrhenius equation, which indicates
the effect of temperature on the rate constant, k, of a
chemical reaction of thermodynamic temperature, 1/T, is
a straight line.

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2.

3.

Keep several samples of the drug product at least

three temperatures, such as 40 C, 50 C and 60 C.
Determine the drug content at all three storage
points by taking a number of samples and take the
mean drug content. We do this for a few weeks.
At each temperature we plot a graph between time
and log percent drug remaining. If the
decomposition is first order this gives a straight line.
If it is zero order, percent drug remaining versus
time will give a straight line.[4-6]

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Reddy et al.

4.

Next we take the log K or log of reaction constant

on axis and T x 0-3 on X axis and draw a best
fit line. This line is the Arrhenius Plot, extrapolate
this line to get k at 5 C and from this we calculate
the shelf-life.

Arrhenius plot for predicting drug stability at room

temp.
If the reaction is following zero-order Expiration date at
5 C Initial potency minimum potency / reaction rate
at 25C
tx =Yo - Yx/ Ko
If the reaction is following first order Expiration date at
5 C (tx)
Log initial potency log minimum
potency reaction rate at 5 C
tx =log Yo log Yx / K1
Where Yo = initial potency
Yx = final potency
Ko = zero order constant
K1 = first order constant
Pharmaceutical products can deteriorate with time,
through both chemical decomposition of the active
principles and excipients and sometimes also through
microbiologically induced degradation. Therefore, all
pharmaceutical products are required by law to display
an expiry date on the packaging. Stability testing is the
primary tool used to assess the expiration dating and
storage conditions for pharmaceutical products. Many
protocols have been used for stability testing, but most in
the industry are standardizing on the recommendations of
the international conference on Harmonization (ICH).[711]

Product changes in accelerated stability studies.

Physical changes- appearance, Melting point, Clarity
and color of solution, Moisture, Crystal Modification
(Polymorphism), particle size.
Chemical changes Increase in degradation, decrease
of assay.
Microbial changes.
ICH stands for international conference on
Harmonization of technical requirements for registration
of pharmaceuticals for human use.
Objectives of ICH
Harmonization of registration applications within the
three regions of the EU, Japan, and the
United states
ICH is a joint initiative program involving both
regulatory and industry as equal partners in the scientific
and technical discussions of the testing procedures which
required ensuring and assessing the safety, quality and
efficacy of medicines.[12-15]
Tripartite guideline in the stability testing of new drug
substance and product (Q1A) IN 1993 has become
standard for stability evaluation in Japan, US, Europe.

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World Journal of Pharmaceutical and Medical Research

ICH GuidelinesQuality guidelines Q (Chemical and Pharmaceutical

QA)
Safety guidelines S (In vitro and in vivo pre-clinical
studies)Covering carcinogenicity testing,
Genetic toxicity
testing, toxic kinetics and pharmacokinetics.
Efficiency guidelines E (Clinical studies in human
subject)Covering clinical safety, Dose response studies, good
clinical practices, Clinical evaluation.
Multidisciplinary guidelines M
Covering Medical Technology, electronic standards for
transmission of regulatory information.
Guideline M4-The common technical document.(CTD)
Accelerated stability studies
1. Storage condition of40 c and relative humidity of
75% has been recommended for all the four zones
for drug substances and drug products.
2. Studies carried out for 6 months
3. Accelerated storage conditions must be at least 5 c
above the expected actual storage temperature and
appropriate relative humidity.
Protection against hydrolysis:
Good packaging practices like moisture resistant
packing. Eg- Strip pack stored in controlled humidity
and temperature conditions, even using desiccant such as
silica gel.
Buffering agent for pH control.
Alteration of Dielectric constant.
Use of surfactants, Good refrigeration.
Addition of complexing agent like caffeine.
Protection against oxidation:
Incorporation of Antioxidants such as BHA, BHT,
Propyl gallate, tocopherol.
Chelating agents using EDTA, Citric acid, Tartaric acid.
Use of inert gases like nitrogen
Protection from light by use of amber colored container.
Storage at low temperature.
Type, size, No .of batches (ICH/WHO Guidelines)
At least 3 primary batches of drug product should be of
the same formulation, packed in same container as
proposed for marketing.
2 out of 3batches should be pilot scale batches.
Stability to be performed on each strength, container
size.
Long term stability studies
1. Stability is performed at 5 c 60% or 30 c 65%
2. Ideally 12 months date is to be generated, but 6
months date is also acceptable in circumstances for
submission of registration dossier, continued till end of
shelf-life.
3. For parenteral stability has to carried out at 2-8 c. For
drugs to be stored in freezer testing should be done at 0 c.

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Chemical properties
Assay
Degradation
Microbial properties
Container clouser system properties Functionality test.
Testing seep Liquid dosage forms for injections and
parenteral
Physical-chemical properties - PH
Loss of weight
Color & clarity of solution
Chemical properties
Assay
Degradation products
Degradation preservatives
Microbial properties Pyrogen testing
Container clouser system Functionality test
Leakage test
Testing seep for oral liquid form
Physical-chemical properties - PH
Viscosity
Color & clarity of solution
Particle size distribution (For oral suspension only)
Chemical properties Assay
Degradation products
Degradation preservatives
Antioxidants
Microbial properties
Testing seep for solid dosage forms
Physical-chemical properties Appearance, Elasticity,
Moisture, Hardness, Disintegration, Dissolution
Container clouser system
Functionality test.

Limitations of Accelerated stability study

1. Stability predictions are based on Arrhenius
equation, which has limitation for energy of
activation for validation of thermal decomposition,
which lies in the range of 10-30 Kcal/mole.
2. Functionality test
Testing seep for semisolid dosage form
Physical-chemical properties Appearance
Color
Homogeneity
Consistency
Loss of weight
Content uniformity
Viscosity
Chemical properties Assay
Degradation products
Degradation preservatives
Antioxidants.
Microbial properties
Container clouser system 3.

4.
5.

6.
7.

At accelerated conditions some new reactions may

take place, which usually do not take place at normal
storage conditions. Therefore, obtaining correct
information is difficult.
Order of reaction may also differ in some cases with
accelerated conditions.
Accelerated testing cannot be used for
microbiological decomposition and also for handling
during transport.
Thermolabile materials and products are not suitable
candidates for accelerated stability study.
Some products appear stable at higher temperature
than at normal storage conditions.
% of Relative humidity (RH) = Water-vapour
pressure in atmosphere/Saturated water-vapour
pressure x 100

ICH Summary of Stability Parameters

Study
General case
Long term
Intermediate
Accelerated
Refrigeration
Long term
Accelerated
Freezen
Long term

5
30
30
35

C (
C (
C (
C (

Storage conditions
C) at 60 % RH ( 5 %RH)
C) at 65 % RH ( 5 %RH)
C) at 65 % RH ( 5 %RH)
C) at 70 % RH ( 5 %RH)

5 C (3 C)
5 C ( C) at 60 % RH ( 5 %RH)

12 Months
6 Months

- 0 C ( 5 C)

12 Months

Product Characteristics Affecting Shelf-Life

Spoilage Microbial spoilage occurs in products that
provide an environment that supports microbial growth,
or are subjected to contamination during storage. The
leaching of chemicals, or similar reactions, promoted by

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Minimum time period

12 Months
12 Months
6 Months
6 Months

long- term contact with packaging materials leads to

chemical spoilage.
Flavors Off-flavors developed during storage are
often due to chemical reactions or microbial growth.

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World Journal of Pharmaceutical and Medical Research

Rancidity occurs as a result of oxidative reactions and

produces off-flavors. Texture Products containing
similar ingredients do not necessarily exhibit similar
textures. Water contributes greatly to a products texture.
Stalling, breakdown of gel structures, phase separation,
water activity, moisture migration and crystallization, all
contribute to textural changes during storage.

Functionality - A product is considered unacceptable and

unusable when it loses its functional properties such as a
vitamin-fortified product losing its potency.
Climatic zones for stability studies. Climatic conditions
prevalent in different countries, mentioning of ambient
temperature may be relevant here. For this purpose, four
climatic zones are proposed as listed here.

Appearance - An unacceptable appearance in colour

resulting in browning or fading is caused by fat and/or
moisture migration and chemical reactions. Other
processes affecting appearance making the product
undesirable during storage include surface crystal
formation, phase separation, syneresis and caking.

Temperate zone
Mediterranean
Tropical moist
Desert zone

C (45%RH)
5 C (60%RH)
30 C (70%RH)
30 C (35%RH)

Overview of storage conditions and storage period for solid, semisolid and liquid dosage forms.
Stability
investigation

Dosage form
Solid

Organoleptic and
photochemical
stability

Semisolid

Liquid
Photo stability
Chemical stability

All
Solid
Semisolid
Liquid

Storage condition
Storage in open container until equilibrium
at 5 C 60%,30 C 70%, 40 C 75%.
5C
>- 0 C
5 C -40 C Temperature cycle within 4
hrs.
5C
>- 0 C
Xenon lamp
40 C, 50 C, 60 C, 70 C.
30 C, 40 C, 50 C.
40 C, 50 C, 60 C, 70 C.

Addition of overages
1. Excess amount of the drug can be added to the
preparation to maintain 100% of the labeled amount
during the shelf-life of the product.
2. Overages are calculated from the accelerated
stability studies and added to the preparation at the
time of manufacture.
3. They should be within the limits compatible with the
therapeutic requirement.
4. Addition of overages doubles the shelf-life of the
product.
5. Overages are added in multi-vitamin preparations.
Freeze thaw stability testing
Freeze-thaw cycle testing is a part of stability testing that
allows you to determine if your formula will remain
stable under various conditions. This type of test puts
your sample through a series of extreme, rapid
temperature changes that it may encounter during normal
shipping and handling processes. Freeze-thaw stability
testing is highly recommended, especially for liquidbased cosmetics. These products may experience phase
separation that can negatively affect the intended
function. Freeze-thaw testing is conducted by exposing
the product to freezing temperatures (approximately 10C) for 24 hours, then allowing thawing at room
temperature for 24 hours. The sample is then placed in a
higher temperature (approximately 45C) for 24 hours,

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Storage
period
1-2 weeks
4 weeks
4 weeks
2 weeks
4 weeks
4 weeks
48 hrs
3 months
3 months
3 months

and then placed at room temperature again for 24 hours.

The sample is analyzed for significant changes. This
completes one cycle. If, after three cycles of freeze-thaw
testing, no significant changes are observed, you can be
confident that the stability of your product is sufficient
for transport.
CONCLUSION
Knowledge of stability of a formulation is very important
for three primary reasons.
1) A pharmaceutical product must appear fresh, elegant
and professional for as long as it remain on the shelf.
2) Since some products are dispensed in multiple dose
container uniformity dose of the active ingredient
over time must be ensured.
3) The active ingredient must be available to the patient
throughout the expected shelf-life of the preparation.
A break down in the physical system can lead to non
availability or of the medication to the patient.
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