STABILITY STUDIES

stability studies of dosage form in pharmaceutics

1. Stability Testing of dosage forms Presented By- ROHIT R.K.S.D college of pharmacy, Kaithal ( Hry ) M.Pharma 1 st year (Pharmaceutics)

2. Contents Introduction Types of degradations Types of Stability studies Steps involved in prediction of shelf life Limitations

3. Introduction 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.

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. Types of degradations Chemical Physical Biological

6. Chemical Degradation 1- Hydrolysis: Hydrolysis means “splitting by water’’ 2- Oxidation: Oxidation of inorganic and organic compounds is explained by a loss of electrons and the loss of a molecule of hydrogen . 3-Photolysis

7. Physical Stability Physical stability implies that: The formulation is totally unchanged throughout its shelf life and has not suffered any changes by way of appearance, organoleptic properties, hardness, brittleness, particle size etc. It is significant as it affects: 1.pharmaceutical elegance 2.drug content uniformity 3.drug release rate.

8. Types of Stability Studies 1.Long-Term (Real-Time) Stability Testing Stability evaluation of the physical, chemical, biological and microbiological characteristics of a drug product duration of the shelf life Long –term stability testing Accelerated stability studies

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

10. Arrhenius equation

11. 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.

12. 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 prediction of shelf life

14. shelf life It is define as the time req. For the conc. Of the reactant to reduce to 90% of its initial conc. Units of shelf life : time/conc. t90= (a-0.9a)/k0 Where, a=initial conc. k0= specific rate constant for zero order reaction

15. 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 .

16. 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.

17. 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.

18. 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, future investigations for the selection of the final packaging are necessary.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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 .

25. Limitations Stability predictions based on Arrhenius equation are valid only when the break down depends on temperature. 2. The energy of activation obtained in the study should be between 10 to 30 kcal/mole. 3. When degradation is due to Microbial contamination Photochemical reactions 4. When the product looses its physical integrity at higher temperatures. 5. 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.