1. Accelerated Stability Testing
of
dosage forms
……… A measure of how a pharmaceutical product
maintains its quality attributes over time
By
SUNILBOREDDY
Pharmaceutics

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

3. 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. 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

5. Study Storage condition
Minimum time period
covered by data at
submission
Long Term
(Ambient)
25º C ± 2º C
60%RH ± 5%
12 months
Intermediate
(controlled)
30º C ± 2º C
60%RH ± 5%
6 months
Accelerated 40º C ± 2º C
75%RH ± 5%
6 months

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. 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.

8. Accelerated Stability StudiesAccelerated Stability Studies
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

9. 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.

10. 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.

11. 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.

13. Steps involved in
Accelerated Stability Testing
Steps involved in
prediction of shelf life

14.  The Preparation is stored at different elevated temperatures, 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.

15.  Extrapolate the straight line to room temperature (k25) or
refrigerated temperature and read the log k value on y-axis.
 Substitute the k value in the appropriate equation to get the shelf
life of the product.

16. Arrhenius plot for predicting the rate constant at ambient
temperature(25ºC).

17. Stability
investigation
Organoleptic and
physicochemical
stability
Photostability
Chemical stability
Dosage form
Solid
Semisolid
Liquid
All
Solid
Semisolid
Liquid
Storage condition
Storage in open
container until
equilibrium is reached at
25ºC/60%,30ºC/70%,
40ºC/75%
5ºC
≥ - 10ºC
5ºC -40ºC Temperature
cycle within 24 hrs
40ºC(content uniformity)
5ºC
≥ -10ºC
Xenon lamp
40ºC, 50ºC, 60ºC, 70ºC
30ºC, 40ºC, 50ºC
40ºC, 50ºC, 60ºC, 70ºC
Storage period
1-2 weeks
4 weeks
4 weeks
2 weeks
3 months
4 Weeks
4 weeks
48 hrs
3 months
3 months
3 months

18. Dosages
1-2
3-4
>4
Samples tested
All
Highest Lowest
Highest Middle Lowest

19.  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.

20.  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.

21.  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.

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

23.  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 500
C, 400
C,
300
C/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.

24. 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 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.

25. 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.

26. 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.

27. 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.

28.  Excess amount of the drug can be added to the preparation 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

29. 110%
100%
90%
1 Year
1 Year
2 years

30. Conclusion
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.

31. References :
Patrick J.Sinko , Martin’s Physical Pharmacy and Pharmaceutical
Sciences.
Theory and practice of Industrial Pharmacy - Lachman
International Stability Testing
Drug stability- Cartensen
C.V.S Subrahmanyam
www.google.com

32. Thank You