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

2. Stability protocol Study Storage condition Long Term 25º C ± 2º C
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
6 months
Accelerated
40º C ± 2º C
75%RH ± 5%

3. 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.

4. 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.

5. Accelerated 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

6. 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
Ideal gas constant
Arrhenius factor
Energy of activation
Arrhenius factor is the frequency of molecular collisions occuring between
the molecules.
Log k = log A – Ea / RT

7. 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.

8. 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 / 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.

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

11. 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.

12. 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.

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

14. Overview of storage conditions and storage period for solid, semisolid, and liquid dosage forms
Stability investigation
Organoleptic and physicochemical stability
Photostability
Chemical stability
Dosage form
Solid
Semisolid
Liquid
All
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)
≥ -10ºC
Xenon lamp
40ºC, 50ºC, 60ºC, 70ºC
30ºC, 40ºC, 50ºC
Storage period
1-2 weeks
4 weeks
2 weeks
3 months
4 Weeks
48 hrs

15. Bracketing system for Dosage forms
Dosages
1-2
3-4
>4
Samples tested
All
Highest Lowest
Highest Middle Lowest

16. 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:
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.
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 400C, for 3 months and are then investigated.
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
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 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 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

26. 110%
1 Year
2 years
100%
1 Year
90%

27. 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.
Conclusion

28. 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

29. THANK YOU -PHARMA STREET