KINETICS OF STABILITY , ACCELERATED STABILITY STUDY, AND ICH STABILITY GUIDELINES

CHEMICAL KINETICS
ORDER OF REACTION
DETERMINATION OF ORDER
SALIENT FEATURES OF ACCELERATED DRUG STABILITY
STABILITY METHOD
LIMITATIONS OF ACCELERATED DRUG STABILITY
ICH GUIDELINES ON STABILITY

1. KINETICS OF STABILITY , ACCELERATED STABILITY STUDY AND ICH STABILITY GUIDELINES PRESENTED BY : AKHILA A 1 st YEAR M PHARM PHARMACEUTICS NGSMIPS

2. CONTENTS INTRODUCTION CHEMICAL KINETICS ORDER OF REACTION DETERMINATION OF ORDER SALIENT FEATURES OF ACCELERATED DRUG STABILITY STABILITY METHOD LIMITATIONS OF ACCELERATED DRUG STABILITY ICH GUIDELINES ON STABILITY CONCLUSION REFERENCES

3. INTRODUCTION KINETICS OF DRUG STABILITY Chemical kinetics involves the study of the rate of a chemical reaction. The rate of a reaction means studying the time course of changes in the concentration According to law of mass action: rate of a chemical reaction is proportional to the product of molar concentration of reactant, each raised to a power usually equal to the number of molecules. In general terms, a chemical reaction can be written as : m A+ n B Products The rate equation can be written as: Rate = - = = = k m+n [A] m [B] n Kinetic principles have found application in pharmacy: drug stability, dissolution, drug release, pharmacokinetics, drug action.   1

4. Rate and order of a reaction RATE The speed or velocity of a reaction with which a reactant or reactants undergoes a change. ORDER OF REACTION The number of concentration terms on which the rate of a reaction depends when determined experimentally. 2

5. Types: ZERO ORDER REACTION PSEUDO ZERO ORDER FIRST ORDER REACTION PSEUDO FIRST ORDER REACTION It is a reaction in which the rates does not depend on the concentration terms of the reactants It is a reaction, which may be a first order, but behaves like a zero order, depending on the experimental conditions. It is a reaction in which the rates of reaction depends on the concentration of one reactant. It is a reaction which is originally a second order, but is made to behave like a first order reaction. SECOND ORDER REACTION It is a reaction in which the rate depends on the concentration terms of two reactants each raised to the power one. 3

6. Table 1: Rate expression for Zero-, First-, and Second-order reaction 4

7. ZERO ORDER REACTION: It is a reaction in which the rates does not depend on the concentration terms of the reactants. = k Mechanism: In zero order reaction, the rate must depend on some factor other than the concentration term. The rate-limiting factors are solubility as in suspension or absorption of light as in certain photo-chemical reactions. Examples: Oxidation of Vitamin A as in oily solution. Colour-loss of liquid multi sulphonamide preparation. Colour-loss is proportional to decrease in the concentrations Figure1: Zero order rate plots   5

8. APPARENT ZERO-ORDER REACTION: It is a reaction, which may be a first order, but behaves like a zero order, depending on the experimental conditions Example: In suspension- drug degradation is a chemical reaction and follows apparent zero-order reaction. The rate of degradation depends on solubility. The phenomenon of solubility-limited degradation explained with this diagram. Figure 2: Apparent zero order, suspensions 6

9. FIRST ORDER REACTION: It is a reaction in which the rates of reaction depends on the concentration of one reactant.  C  = k 1 c k 1 = Example: Decomposition of hydrogen peroxide catalysed by 0.02M potassium iodide. Figure 3: First order rate plots   7

10. PSEUDO FIRST ORDER REACTION: It is a reaction which is originally a second order, but is made to behave like a first order reaction. Example: Hydrolysis of sucrose to glucose and fructose in aqueous solution catalysed by acid. In second order reaction, the rate depends on the concentration terms in two reactants. Therefore, the rate equation would be : = k 2 [ A ][ B ] Where , A and B are the reactants in the reaction and K 2 is the second order rate constant. The reaction conditions are maintained in such a manner that one reactant (say B ) is present in large excess compared to the concentration of the other substance (say A ). Therefore, the concentration of ‘ B ’ does not change significantly during the course of the reaction. Then the above equation changes to; = k 2 [ A ][constant] =k 1 [A]. Thus the rate depends on the concentration of one reactant (on A ), i.e., first order reaction. This type of reaction is also termed as apparent first order.   8

11. SECOND-ORDER REACTION: It is a reaction in which the rate depends on the concentration terms of two reactants each raised to the power one. Example: Hydrolysis of chlorobutanol in presence of sodium hydroxide. If the concentration of the both reactants are same i.e., a=b, then the equation is; - k 2 t When a ≠ b , then the equation given as; log = k 2 Figure 4: Second order rate plots.   9

12. DETERMINATION OF ORDER 10

13. ACCELERATED STABILITY STUDIES The objective of accelerated stability studies is to predict the shelf life of a product by accelerating the rate of decompositions, preferably by increasing the temperature. SALIENT FEATURES: Many pharmaceutical preparations contain different adjuvants along with the drug. Ideally, drug degradation in the mixture has to be studied individually. But, it is time consuming and therefore, gross picture on the stability is evaluated. Some property of degradation, such as changes in the concentration of drug or the degraded substance, colour etc. should be decided. In case of physical stability, changes in viscosity (examples are suspensions and ointments) and number of globules (example is emulsion) are studied. Mechanism of the chemical reaction need not be explored, but such a study is always advantageous to predict stability. 11

14. A stability indicating assay method is essential. Establish an analytical method which estimates the drug, but degraded substance should not interfere. Degradation product can also be estimated provided starting material does not interfere. Some property of the degradation as a function of time should be estimated using stability indicating assay method. Conclusion obtained by accelerating stability studies should be corroborated by results obtained at normal stages (temperature) conditions. Suitable animal experiments are required to establish its efficacy, safety and toxicity. 12

15. STABILITY METHOD: Drug liquid preparations (solution dosage forms) are stored at elevated temperatures (50, 60, 70, 85, 100 and 121 o C). In addition, the samples should be studied at 40 o C, 75%RH and incubator During different time intervals, samples are withdrawn. The sampling may be done at: 3 month intervals during the first year. 6 month intervals during the second and yearly thereafter. Drug content determined by assay method after each sampling. 13

16. The drug content is estimates using a stability indicating assay: A plot is drawn by considering some function of concentration (examples are c or log c or x(c -x) against time. A straight line in a graph permits the estimation of k value at one temperature. Similarly experiments are conducted and graphs are drawn for different elevated temperatures. Linear relationships are obtained and these have different slopes. k value for each temperature is calculated. Arrhenius equation: K = Ae - Ea /RT log K= + log A   14

17. 3 . Log k values are then plotted against reciprocal of absolute temperatures. A linear relationship is desirable. The energy of activation can be calculated. The E a must be between 10-30 kcal/mol.    4. The straight line is extrapolated to temperatures (25 o C or 30 o C) or refrigerator temperature (4-8 o C) and the log k (or k 25 / k 4 ) value is read on y-axis. 15

18. LIMITATIONS: Accelerated stability studies are valid only when the breakdown depends on temperature. The result (shelf life) obtained for one set of conditions of a preparation cannot be applied to other preparations of the same drug. Not for thermolabile materials. Stability predication at elevated temperatures is of little use when the degradation is due to; diffusion, microbial contamination, photochemical reaction. 16

19. ICH STABILITY GUIDELINES ICH is the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use . ICH GUIDELINES TITLE Q1A Stability Testing of New Drug Substances and Products. Q1B Stability Testing: Photostability 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. 17

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21. ICH Q1A (R2)- STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS [1993] The following guideline is a revised version of the ICH Q1A guideline and defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC, Japan, and the United States. The guideline addresses the information to be submitted in registration applications for new molecular entities and associated drug products. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. The choice of test conditions defined in this guideline is based on an analysis of the effects of climatic conditions in the three regions of the EC, Japan and the United States. 19

22. Some important requirement of this guidelines are: General Stress testing Selection of batches Container Closure System Specifications Testing frequency Storage conditions Stability commitment Evaluation Statements/ Labelling 20

23. Drug substances: General Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation. Stress testing Stress testing of the drug substance can help identify degradation products. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved. Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance. Selection of Batches Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for, production batches 21

24. Container Closure System The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. Specification Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes. Testing Frequency At long term storage condition - every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed re-test period. At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. At the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12- month study is recommended. 22

25. Storage Conditions Stability Commitment When available long term stability data on primary batches do not cover the proposed re-test period granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the re-test period. Evaluation Any evaluation should cover not only the assay, but also the levels of degradation products and other appropriate attributes. Statements/Labelling. A storage statement should be established for the labelling in accordance with relevant national/regional requirements. The statement should be based on the stability evaluation of the drug substance. Where applicable, specific instructions should be provided, particularly for drug substances that cannot tolerate freezing. Terms such as “ambient conditions” or “room temperature” should be avoided.   23

26. ICH Q1B- STABILITY TESTING: PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS [1996] Approved in November 1996 A systematic approach to photostability testing is recommended covering, as appropriate, studies such as: Tests on the drug substance; Tests on the exposed drug product outside of the immediate pack; and if necessary; Tests on the drug product in the immediate pack; and if necessary; Tests on the drug product in the marketing pack 24

27. Light sources used for photostability testing: Option 1: Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp. D65 is the internationally recognized standard for outdoor daylight as defined in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight standard Option 2: For option 2 the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp. 1. A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993); and 2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm. 25

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29. ICH Q1C- STABILITY TESTING FOR NEW DOSAGE FORMS November 1996 A new dosage form has been defined in this document as “ a drug product which is different pharmaceutical product type, but contains the same active substance as included in the existing drug product approved by the pertinent regulatory authority”. Thus, new dosage form would include products of different administration route (e.g., oral to parenteral), new specific functionality delivery system (e.g., dispensable tablets to modified release tablets) and different dosage forms of the same administration route (e.g., capsules to tablet, solution to suspension). 27

30. I CH Q1D- BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS February 2002. Bracketing: As defined in the glossary to the parent guideline, bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. The use of a bracketing design would not be considered appropriate if it cannot be demonstrated that the strengths or container sizes and/or fills selected for testing are indeed the extremes 28

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32. Matrixing: Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations would be tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. 30

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34. ICH Q1E – EVALUATION FOR STABILITY DATA February 2003 The guidelines includes recommendations on: Data presentation Extrapolation Data evaluation for retest period or shelf life estimation for drug substances or drug products intended for room temperature storage; Data evaluation for re-test period or shelf-life estimation for drug substances or products intended for storage below room temperature; General statistical approaches. 32

35. ICH Q1F- STABILITY DATA PACKAGE FOR REGISTRATION APPLICATION IN CLIMATIC ZONES III AND IV February 2003 But some countries in climate zone IV expressed their wish to include a larger safety margin for medicinal products to be marketed in their region. In view to this, several countries revised their own stability testing guidelines, defining up to 30 o C/75% RH as the long term storage condition for hot and humid regions. Because of this divergence in global stability testing requirements, ICH Steering Committee decided to withdraw ICH Q1F and to leave the defining of storage conditions in climatic zones III and IV to the respective regions and WHO. 33

36. CONCLUSION The study of chemical kinetics is very crucial as it plays a significant role in drug stability, which has direct impact on storage and release characteristics of drugs. The scope of kinetics includes the rates and mechanisms of chemical reactions, diffusion and crystal growth. Stability tests should be carried out following proper scientific principles and after understanding of the current regulatory requirement as per the climate zones. 34

37. REFERENCES Subramanyam C.V.S. Textbook of Physical Pharmaceutics. 2 nd ed. Delhi: Vallabh Prakashan , 2000; P:17-37,71-76. Subramanyam C.V.S, Thimmasetty.J . Textbook of Industrial Pharmacy.1 st ed. Delhi: Vallabh Prakashan , 2013;P: 278-288, 338-343. Sharma P.P. Stability Studies of Pharmaceutical and Cosmetic Products. Delhi: Vandana Publications, 2014; P: 9-14 Subramanyam C.V.S, Thimmasetty J. Textbook of Pharmaceutical Regulatory Affairs. 1 st ed. Vallabh Prakashan , 2012; P:172-199. ICH website: www.ich.org Naga Raju Potnuri , Vykuntam U . Stability Studies of Pharmaceutical Products.World J.Pharm.Res.2019; 8(8):472-492. 35

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