This document discusses stability testing and shelf life prediction of pharmaceutical products. It defines stability as a product remaining within specifications over its shelf life under recommended storage conditions. Stability testing determines a product's shelf life and recommended storage. Types of stability studies discussed are long term, intermediate, and accelerated. The Arrhenius equation is used to predict shelf life from accelerated studies by determining reaction kinetics at different temperatures. Packaging selection, addition of overages, and limitations of shelf life prediction are also summarized.

1. GUIDED BY:
Dr. M. R. PATEL
Principale & HOD in
pharmaceutics
PRESENTEDE BY:
SAHILHUSEN I . JETHARA
M. PHARM – I (2013-14)
ROLL NO. - 02
DEPARTMENT OF PHARMACEUTICS
SHRI B. M. SHAH COLLEGE OF PHARMACEUTICAL EDUCATION AND REASERCH, MODASA-2013

2. contents
 Introduction
 Types of Stability studies
 Arrhenius equation
 Steps involved in prediction of shelf life
 Addition of Overages
 Conclusion
 References

3. INTRODUCTION
 Stability of a pharmaceutical preparation is the capability
of a formulation in a specific container-closure system to
remain within its physical, chemical, microbiological,
therapeutic and toxicological specifications throughout its
shelf life.
 The time during which the product retains the same
properties and characteristics that it possessed at the time
of manufacture.
 Stability testing is used to: Provide evidence as to how the
quality of the drug product varies with time.
 Establish shelf life for the drug product. Determine
recommended storage conditions. Determine container
closure system suitability. Introduction

4. OBJECTIVES
 To predict shelf life of product by accelerating rate of
decomposition preferably by increasing the
temperature.
 To serve a rapid means of quality control.
 To serve as a rapid means of selecting the best
formulation from amongst a series of similar
formulations of the product.
 To predict the expiry date of product

5. Why Stability studies are necessary ?
 Chemical degradation of the product leads to lowering of
the concentration of the drug in the dosage form.
 Toxic products may be formed , due to chemical
degradation of the active ingredient.
 Advantages of Stability studies Assurance to the patient
Economic considerations Legal requirement

6.  According to ICH guidelines, The ambient study for drug product
must be continued for a sufficient period of time beyond 12
months to cover the shelf life of the product.
 Intermediate storage condition data are required when a
significant change occurs prior to completion of study under the
accelerated storage condition. The accelerated storage condition
must be >15º C above the ambient storage conditions

7. Types of stability study
Study
Minimum time period
covered by data at
submission
Storage condition
Long term
25 C
30 C
2 C / 60%
2 C / 65%
5% r.h or
5% r.h.
12 months
Intermediate
30 C
2 C / 65%
5% r.h.
6 months
Accelerated
40 C
2 C / 75%
5% r.h.
6 months
7

8. LONG TERM STABILITY STUDIES
 Study is performed at 250C/60% or 300C/ 65%.
 Ideally 12 months data is to be generated but 6 months
data is also acceptable in circumstances for submission of
registration dossier, continued till end of shelf life.
 For parenterals stability has to carried out at 2-80 C for
drugs to be stored in freezer testing should be done at 200 C

9. ACCELERATED STABILITY STUDIES
 Storage condition of 400C and relative humidity of 75% has
been recommended for all the four zones for drug substances
and drug products.
 Studies carried out for 6 months.
 Accelerated storage conditions must be at least 150C above
the expected actual storage temperature and appropriate
relative humidity

10. Testing Frequency:
 For Long term testing: during first year sampling should
be done every three months, during second year, sampling
should be done every six months and after two years,
sampling should be done once a year.
 Accelerated testing : should be done atleast six months
and it suggests sampling points of 0, 3, 6 months.

11.  Accelerated Stability study to predict the shelf life of the product,
by accelerating the rate of decomposition, preferably by increasing
the temperature of reaction conditions.
 With the advancement in branch of kinetics, shelf life of a dosage
form can be predicted within months based on accelerated
stability reports Preparations are subjected to high stresses during
stability testing.
 Common high stresses include : Temperature Humidity Light

12. Arrhenius equation
 It explains the effect of temperature on rate of a reaction.
 According to Arrhenius, for every 10º rise in temperature,
the speed of reaction increases about 2-3 times.
 k = A e -Ea / RT
 Arrhenius factor Energy of activation Ideal gas constant
Log k = log A – Ea / 2.303 RT
 Arrhenius factor is the frequency of molecular collisions
occuring between the molecules.

13. Estimation of k value
 The reaction is conducted at several temperatures.
Concentration of reactants is determined.
 Appropriate graphs are drawn for the kinetic data. Data is
processed for all the orders. The order of the reaction is
identified.
 From the slopes of the lines, k values are calculated for all
temperatures.

14. Estimation of energy of activation
 A graph can be drawn by taking log k on y-axis and
reciprocal temperature (1/T) on x-axis.
 A straight line is obtained, the slope of the line is negative
and the magnitude is Ea / 2.303 R.
 The intercept corresponds to log A All the constants in the
Arrhenius equation can be obtained from the graph.
 Activation energy is the minimum energy that a molecule
should possess so that the molecular collisions produce the
product.

15. Steps involved in Accelerated Stability Testing
Steps involved in prediction of shelf life
 he Preparation is stored at different elevated temperatures,
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to accelerate the degradation Samples are withdrawn at
different time intervals
The Order of the reaction is determined by plotting the
appropriate function of concentration against time and
linear relationship is determined
Straight line in a graph permits the estimation of k value
from the slope Similarly graphs are drawn for different
elevated temperatures.
K value for each temperature are calculated.
By using Arrhenius relationship, Log k values are plotted
against reciprocal of absolute temperature, energy of
activation can be calculated.

16. Packaging material:in selecting packaging
material, the following has to be considerd :
Packaging material: in selecting packaging material, the following
has to be considerd Packaging materials permeable to water vapor
result in a falsification of the results for semisolid and liquid dosage
forms
if varying degrees of weight loss occur that leads to differences in
the active ingredient concentration or ion strength.
The use of inert standard packaging materials that are
impermeable to water vapor is important precondition for stress
tests that are evaluated in terms of reaction kinetics, and on the
results on which stability predictions are to be tested.

17. Most of the stress tests are carried out in standard
packaging material.The following standard
packaging materials are used:
•Most of the stress tests are carried out in standard packaging
material.
•The following standard packaging materials are used:
•Solid dosage forms: 50-mL glass container with twist-off
closure polypropylene tube
•Semisolid dosage forms: Standard tube, small volumetric flask,
Aluminum tube, inert internal lacquering
• Liquid dosage forms: 25mL volumetric flask with ground-glass
stopper However, furture investigations for the selection of the
final packaging are necessary.

18. •Selection of packaging material for solid dosage
forms. :
•On the basis of the results of the stress tests for solid dosage
forms, the sensitivity to moisture can be determined and
suitable packaging materials can be selected.
• As a rule, no interactions are to be expected.
•If the final packaging material has been selected and samples
packed in the final packaging material are available, the
investigation of photostability should be performed.
•Photostability :The samples with and without container are
irradiated with a Xenon lamp for 24 hours.

19. Selection of packaging material for semisolid
dosage forms
1. Selection of packaging material for semisolid dosage
forms. Packaging: Aluminum tube internally lacquered,
plastic tubes.
2. Problems: Corrosion , permeation, sorption. Tests
packaging material – dosage form: To test for corrosion
,the filled metal tubes are stored horizontally upright and
inverted at 400C, for 3 months and are then investigated.
3. To test for permeation and sorption the filled plastic
tubes are stored for 3 months at 500C, 400C, 300C/70%.
If the final packaging material has been selected, the
investigations on the photostability are performed.

20. Selection of packaging material for liquid dosage
forms :
 Selection of packaging material for liquid dosage forms
Packaging ampoule, injection vial with rubber stopper,
glass bottle or plastic bottle with screw closure.
 Problems: leakage. To test for permeation, and leakage,
the finale formulation solution is filled in the container,
and for desorption placebo solution is used.
 The samples are stored vertically and inverted under
500C, 400C, 300C/70% for up to 12 weeks.
 Tested intervals: 0, 1, 2, 3 months. If the final packaging
material has been selected the investigations on the
photostability are performed.

21. Accelerated Stability Testing in Emulsions
 An emulsion is stored at elevated temperature.
 This decreases viscosity of the continuous phase.
 If the emulsion withstands this stress it is assumed to be
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stable at normal conditions of storage.
Centrifugation Method: Creaming and flocculation are
slow processes.
Centrifugation accelerates rate of creaming and
flocculation in emulsions.
The emulsion is subjected to different centrifugal speeds
and separation of phases is observed at different time
periods.
Bad emulsion separates oil instantly. Good emulsion does
not exhibit detectable separation of oil phase until certain
time period.

22. Accelerated tests for Suspensions
 Cake formation is accelerated by centrifugation.
 High speed centrifugation is hence not preferred, low
speed centrifugation is used to study the physical
stability.
 A Freeze-Thaw cycling technique is one of the stress
testing .
 This cycling treatment promotes particle growth and
has primary importance for changes in absolute particle
size, particle size distribution and crystal habit.

23. Accelerated Tests for moisture
absorption
 In this method, products are placed in an environment of
high relative humidity and controlled temperature.
 Their physical and chemical stabilities are assessed. The
results will indicate whether the product is susceptible to
moisture and also whether the container needs to provide a
high degree of protection

24. Limitations
 Stability predictions based on Arrhenius equation are valid
only when the break down depends on temperature.
 The energy of activation obtained in the study should be
between 10 to 30 kcal/mole.
 When degradation is due to Microbial contamination
Photochemical reactions When the product looses its
physical integrity at higher temperatures.
 When the order changes at elevated temperatures. In case
of disperse systems, when temperature is elevated viscosity
is decreased and this may introduce errors in the
prediction of stability.

25. ADDITION OF OVERAGES
 Excess amount of the drug can be added to the preparation
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to maintain 100% of the labelled amount during the shelf
life of the product.
Overages are calculated from the accelerated stability
studies and added to the preparation at the time of
manufacture.
They should be within the limits compatible with the
therapeutic requirement.
Addition of overages doubles the shelf life of the product.
Overages are added in multi vitamin preparations
Addition of Overages

26. Conclusion
 Knowledge of stability of a formulation is very important
for three primary reasons: A Pharmaceutical product must
appear fresh, elegant and professional for as long as it
remains on the shelf.
 Since some products are dispensed in multiple dose
containers, uniformity of dose of the active ingredient over
time must be ensured .
 The active ingredient must be available to the patient
through out the expected shelf life of the preparation.
 A breakdown in the physical system can lead to non
availability or of the medication to the patient.

27. References :
 Martin’s Physical Pharmacy and Pharmaceutical Sciences.
 Theory and practice of Industrial Pharmacy - Lechman
 International Stability Testing Drug stability- Cartensen
 C.V.S Subramaniyam
 www.google.com