Accelerated stability studies

Accelerated stability studies of dosage form...
How a pharmaceutical dosage forms maintains its quality attributes over long period of time.

1. 1 ACCERELATED STABILITY STUDIES PRESENTED BY, SURIYAPRIYA .K, Ist M .PHARM , DEPARTMENT OF PHARMACEUTICAL ANALYSIS , KMCH COLLEGE OF PHARMACY, COIMBATORE.

2. CONTENT I ntroduction Stability studies Arrhenius equation Steps involved in prediction of shelf life Addition of Overages Conclusion References 2

3. INTRODUCTION OF STABILITY : DEFINITION : Ability of the pharmaceutical dosage form to maintain the physical , chemical, therapeutic and microbial properties during the time of storage and usage by the patient. 2. It is measured by the rate of changes that take place in the pharmaceutical dosage forms 3

4. STABILITY TEST USES : 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 . 4

5. Why Stability studies are necessary ? STUDIES EXPLANATION Quality The drug product varies with time . Shelf life Shelf life of the product is established . Storage Helps to determine the storage condition . Closure system Container closure suitability has been identified . Safety and efficiency Patients safety against drug product is analyzed . Chemical degradation Degradation leads to lowering the concentration that to be analyzed. Toxic product To be formed due to degradation , leaching, high stress etc… 5

6. TYPE CONDITION TO BE MAINTAINED Chemical Chemical Integrity and potency etc.. Physical Appearance ,Uniformity etc Microbiological Sterility Therapeutic Drug action remains unchanged Toxicological No increase in toxicity ACCORDING TO USP TYPES OF STABILITY : 6

7. GUIDELINE TITLE Q1A(R2) Stability Testing of New Drug Substances and Products Q1B Photo stability Testing of New Drug Substances and Products Q1C Stability Testing for New Dosage Forms Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E Evaluation of Stability Data Q1F  Stability Data Package for Registration Applications in Climatic Zones III and IV ICH GUIDELINES FOR STABILITY TESTING : 7

8. 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. 8

9. 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 9

10. TESTS AT ELEVATED TEMPERATURE Drug liquid preparation stored at 50, 60, 70,85,100 and 121˚c. study is performed at Relative Temperature and or refrigerator temperature . 3. Sampling: First year- 3 month interval Second year- 6 month interval 10

11. CLIMATE ZONE DEGREE Temperate zone 21˚c/45%RH Mediterranean zone 25˚c/60%RH Tropical zone 30˚c/70%RH Desert zone 30˚c/35%RH FOUR CLIMATIC ZONES TO BE CONTINUED…. 11

12. 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 the color change of drug to be examined. e.g. cycloprofen becomes very yellow after five days under 900 foot candles of light. 12

13. 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 13

14. TESTS AT HIGH RELATIVE HUMIDITY: Presence of moisture may cause hydrolysis and oxidation. These reactions may accelerated by exposing the drug to different relative humidifies. Control humidity by Lab desiccators . Closed desiccator are placed in an oven to provide constant temperature . 14

15. 15 SHELF LIFE The time required to reduced the concentration to 90% of its initial concentration. T90=0.105/k Stability of formulation can be determine by shelf life .

16. ORDER X axis Y axis HALF LIFE SHELFLIFE ZERO Time (a-x) a/2k 0.1Ao/ko 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 - CALCULATION OF SHELF LIFE 16

17. STEPS FOR PREDICATION OF SHELF LIFE 17

18. The Preparation is stored at different elevated temperatures T o accelerate the degradation  Samples are withdrawn at different time intervals The Order of the reaction is determined  plotting the concentration against time The straight line in the graph estimates the k value Similarly graphs are drawn for different elevated temperatures 18

19.   K value for each temperature are calculated  By using Arrhenius relationship Log k values are plotted against reciprocal of absolute temperature E nergy of activation can be calculated . Extrapolate the straight line to room temperature (k25) or refrigerated temperature Read the log k value on y-axis Substitute the k value in a equation to get the shelf life of the product . 19

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22. ARRHENIUS EQUATION Arrhenius equation gives "the dependence of the rate constant k of chemical reaction on the temperature T and activation energy Ea", as shown below , k = Ae^(-Ea/RT) where, k = specific rate constant A = A rrhenius factor Ea = activation energy R = ideal gas constant T = absolute temperature Take log on both sides, log k = log A – Ea /2.303RT  k = Ae^(-Ea/RT) 22

23.   Estimation of k 1. Reaction is conducted at several temperature . 2. Concentration is determined at different time period. 3 . Order of reaction is identified. 4. From slope of line k is calculated. 23

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25. 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 & units of kilojoules per mole. 25

26. 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. 26

27. ACCELERATED TESTS FOR MOISTURE ABSORPTION In this method, products are placed in an environment of high relative humidity and controlled temperature. i.e. the product is a placed in a small cabinets containing different saturated salt solution. Their physical and chemical stabilities are assessed. The results will indicate whether the product is susceptible to moisture or not and also whether the container needs to provide a high degree of protection. 27

28. ACCELERATED TESTS FOR SUSPENSION 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 . Freeze –thaw method : This cycling treatment promotes particle size, particle size distribution and crystal habit. 28

29. 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. 29

30. ADDITION OF OVERAGES: Excess amount of the drug can be added to the preparation to maintain 100% of 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. Mostly overages are added in multi vitamin preparations. 30

31. L IMITATIONS 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. 31

32. Conclusion : Knowledge of stability of a formulation is very important for three primary reasons: The product must appear fresh, elegant and professional for as long as it remains same. In multiple dose containers, uniformity of dose of the active ingredient must be ensured . The active ingredient must be available to the patient through out the expected shelf life . 32

33. REFERENCES International Stability Testing Drug stability- Cartensen C.V.S. Subrahmanyam 19 ICH guidelines of stability of drugs QAR2 33

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