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ACCELERATED STABILITY STUDY

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CONTENTS Introduction Activation energy Arrhenius equation Accelerated stability testing Limitations of accelerated stability testing ICH guidelines References

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INTRODUCTION Stability:

Stability of pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, therapeutic and toxicological specification.

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Need for stability testing:

1. Provide evidence as to how the quality of the

drug product varies with time.

2. Establish shelf life for the drug product.

3. Determine recommended storage conditions.

4. Determine container closure system suitability.

5. Safety point of view of patient.

6. Prevention of economical repercussion.

7. Essential quality attribute.

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ACCORDING TO USP TYPES OF STABILITY

Type Condition to be maintained

1.Chemical : Chemical integrity & lebelled potency

2.Physical: Appearance, palatability, uniformality.

3.Microbiological

Sterility

4.Therapeutic: Drug action remains unchanged

5.Toxicological: No increase in toxicity

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ACTIVATION ENERGY:It is defined as the energy that must be overcome in order for a chemical reaction to occur. Activation energy may also be defined as the minimum energy required to start a chemical reaction.

The activation energy of a reaction is usually denoted by Ea, and given in units of kilojoules per mole.

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ARRHENIUS EQUATION :Arrhenius equation gives "the dependence of the rate constant k of chemical reaction on the temperature T (in absolute temperature, such as Kelvin or degrees Rankine) and activation energy Ea", as shown below:

Where k=specific rate constantA=frequency factorEa= activation energyR=ideal gas constantT=absolute temperature

Take log on both sides,ln k = ln A –Ea/RT ln e (2)

Converting eq. 2 to log 10log k = log A – Ea/2.303RT

(1)

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Estimation of k:1.Reaction is conducted at several temp.2.Conc. is determined at different time period.3.Order of reaction is identified.4.From slope of line k is calculated.

Fig. Estimation

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ESTIMATION OF ACTIVATION ENERGY: 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.

Fig. estimation of activation energy

Calculation of shelf life:ORDER X axis Y axis HALF

LIFESHELF LIFE

ZERO Time (a-x) a/2k 0.1A0/K0

FIRST Time log(a-x) 0.693/k 0.105/K1

SECOND(a=b)

Time 1/(a-x) 1/ka -

SECOND(a≠b)

Time Log b(a-x)/a (b-x)

1/ka -

THIRD Time 1/(a-x)2 3/2ka2 -

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TYPES OF STABILITY TESTS: Long term stability tests Field test Accelerated stability tests

Accelerated stability studies:Studies designed to increase the rate of chemical degradation or physical change of an active substance or drug product by using exaggerated storage conditions as part of the formal, definitive storage programme.

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TESTS AT ELEVATED TEMPERATURE:

Drug liquid preparation stored at 50, 60, 70,85,100 and 121˚c.

Also study performed at R.T. and or refrigerator temp.

Sampling:First year- 3 month intervalSecond year- 6 month interval

Four climatic zones:Temperate zone 21˚c/45%RH

Mediterranean zone 25˚c/60%RH

Tropical zone 30˚c/70%RH

Desert zone 30˚c/35%RH

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TESTS AT HIGH INTENSITY OF LIGHT: Drug substances fade or darken on exposing to light, can be

controlled by using amber glass or opaque container.

By exposing drug substance to 400 & 900 (FC)of illumination for 4 & 2 weeks to light and another sample examined protected from light .

Results found on appearance and chemical loss may be

recorded.

Comparing color or using diffused reflectance spectroscopy for examination.

e.g. cycloprofen becomes very yellow after five days under 900 foot candles of light.

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TESTS AT HIGH PARTIAL PRESSURE OF OXYGEN:

Sensitivity of the drugs to atmospheric oxygen

must be evaluated from which it should be

packed in inert atmospheric condition with

antioxidants is decided .

Here, high oxygen tension plays important role

to investigate stability Usually ,40% of oxygen

atmosphere allows for rapid evaluation.

Results were correlated with inert & without

inert condition .

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TESTS AT HIGH RELATIVE HUMIDITY: Presence of moisture may cause hydrolysis

and oxidation.

These reactions may accelerated by exposing

the drug to different relative humidities.

Control humidity by Lab desiccators

Closed dessicator are placed in an oven to

provide constant temperature.

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LIMITATIONS OF ACCELERATED STABILITY TESTING 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. It is not useful when degradation is due to:

• Microbial contamination• Photochemical reactions• Diffusion• Excessive agitation

When the product looses its physical integrity at higher temperatures.

When the order changes at elevated temperatures.

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STABILITY PROTOCOL: Containers and closures Container orientation Sampling interval Type, size and number of batches Plan of sampling Storage conditions Test methodology Acceptance criteria

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ICH GUIDELINES ON STRESS TESTING:

Standard Title and reference

ICH Q1A(R2) Stability Testing of New Drug Substances and Products (the parent guideline)

ICH Q1B Photostability Testing of New Drug Substances and Products

ICH Q C Stability testing of new dosage forms

ICH D Bracketing and matrixing designs

ICH Q E Evaluation of stability data

ICH Q F Stability data package for registration applications in climatic zone I and IV

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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.ich.org

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THANK YOU…

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