Accelerated Stability Testing of dosage forms ……… A measure of how a pharmaceutical product

maintains its quality attributes over time

BySUNILBOREDDY

Pharmaceutics

Contents

Introduction

Types of Stability studies

Arrhenius equation

Steps involved in prediction of shelf life

Addition of Overages

Conclusion

References

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

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

Study Storage conditionMinimum 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

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.

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.

Accelerated Stability Studies 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

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 factorEnergy 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.

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.

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.

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

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.

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.

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

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

Dosages

1-2

3-4

>4

Samples tested

All

Highest Lowest

Highest Middle Lowest

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

110%

100%

90%

1 Year

1 Year

2 years

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.

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

Thank You