stability of dosage form

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DRUG STABILITY:

1 DRUG STABILITY Presented by Mr.Bhosale Gajanan M.Pharm.(Pharmaceutics) ( semester-1) Prof.Sagar Kadam Sir( M.Pharm ) H.S.B.P.V.T’s,Groups Of Institutions College Of Pharmacy,Kashti Hon.Shri.Babanrao Pachpute Vichardhara Trust’s,Groups Of Institutions,College Of Pharmacy,Kashti Guided by

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2 CONTENTS Introduction Pathways of Drug degradation Stability study Stability study of solid dosage form Stability study of semisolid dosage form Testing frequency Packaging/container ICH Guidelines Summary References

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3 Introduction Stability is defined as the time lapse during which the drug product retains the same property and characteristics that it possessed at the time of manufacture. It can be expressed as expiry period or shelf life which is valuable quality attribute for all pharmaceutical dosage forms. Adequate stability data should be available to support the expiration period and storage conditions. No drug may be sold after 5 years from date of manufacturing .

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4 Need of Stability to avoid following Problem:- Instability Ineffective Concentration Toxic Product Change in Physical appearance

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5 Types of stability Chemical Physical Microbiological Therapeutic Toxicological

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6 Causes of instability in drug/drug product Physical degradation Chemical degradation Influence of light Influence of Temperature

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7 Loss of volatile constituents e.g. Nitroglycerine tablet Loss of water e.g. Efflorescent substance( caffeine , qunidine etc.) Absorption of water e.g. Deliquescent substance (calcium chloride , gelatin capsule etc.) Crystal growth e.g. 10% w/v calcium gluconate Polymorphism e.g. Cortisone acetate Colour change e.g. Tartrazine , Indigo carmine Physical degradation

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8 Hydrolysis e.g. Aspirin, chloramphenicol etc. Oxidation e.g. ascorbic acid Optical isomerisation e.g. (l)Adrenaline (dl) Adrenaline Epimerization e.g. Ergometrine Ergometrinine Chemical degradation

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9 Geometric isomerisation e.g. Vitamin A palmitate Polymerisation e.g. Dextrose injection 5- hydroxymethyl furfural Absorption of carbon dioxide e.g. sodium hexobarbitone i.v injection Decarboxylation e.g. PAS Straw coloured solution Autoclaving acidic pH polymerise

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10 Influence of light on drug decomposition Light can affect drugs, causing chemical changes ICH Q1B guidance spells out how to do photostability tests Light sources Combination of visible and UV light Procedure Samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter Standards given identical exposure, but protected by light barrier such as aluminum foil.

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11 Influence of temperature It can be explained by the Arrhenius equation

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Stability studies Objectives :- The purpose of stability testing is to provide evidence on how the quality of a drug substance [API] or drug product [FPP] varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light. To establish a re-test period for the API or a shelf life for the FPP To recommend storage conditions. 12

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General Phases for Stability Study Phase 1 - Initial Test Create a new stability study Create and assign the initial sample Initial test for the stability study: Inspection lot for initial test with flexible selection/change of specifications Process initial test: results recording, unplanned characteristics Complete initial test: decision whether or not to continue the study 13

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Phase 2 - Stability Planning Define different storage conditions Define inspection periods for each storage condition e.g ., after 3, 6, 9, 12, 18, 24, 36, 48, 60, 72 months Define inspection specifications for each storage condition Inspection plan for each storage condition Calculation of sample quantities Print storage list and sample labels Store samples for storage conditions Start date for stability study 14

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Phase 3 Stability Protocol and Report Batches tested General information Container/closure system Literature and supporting data Stability-indicating analytical methods Testing plan Test parameters Test results Other requirements (post-approval commitments) Conclusions Result sheets must bear date and responsible person signature / QA approval 15

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16 Types of Stability Study Long term stability studies :- ICH guidelines Q1A(R2) defines long term studies as stability under the recommended storage conditions for the retest period or shelf life proposed or approved for labeling. Or WHO guideline on stability study defines long term testing as the stability testing during and beyond expected shelf life under storage condition in the intended market. WHO guideline also refers to these studies as real time studies.

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17 Climatic zones Recommended conditions for long term stability studies in general case I and II III and IV Temperature ( ◦C) Relative humidity(%) 25±2◦C 60±2% 30±2◦C 65±2% Table:- Recommended conditions for long term stability studies

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18 Accelerated stability studies Objectives of accelerated stability study analysis To serve as a rapid means of selecting the best formulation from amongst a series of similar formulations of the product formulation of the product. To predict the shelf life of the product. To serve as a rapid means of quality control. Common high stresses during stability testing Temperature:- Vant hoff equation In k = ∆H/RT + constant Humidity:- Light :-

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19 Prediction of shelf life The prediction of shelf life is based on applying arrhenius equation which gives the effect of temperature on rate constant k of a chemical reaction. The stability of any active component in pharmaceutical preparation can be evaluated by determining some property of degradation such as decreases in active constituent or increase in degradation product under accelerated storage as function of time. If this function is found to be linear with respect to any of the chemical kinetic reaction order, temperature dependency of the degradation can be obtained with the help of arrhenius equation.

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20 Various steps involving in the prediction of the shelf life Divide preparation in various portion and store at different elevated temperature such as 40,50,60,70 ◦C Sample withdrawing Determine order of reaction by suitable method Determation of k at room temp. Calculate the degraded amount of drug Calculate the amount of overage to be added

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21 Limitation of accelerated stability analysis Valid only when the energy of activation for the thermal decomposition lies within range of 10 to 30 kcal/mol The order of reaction may differ in normal condition and stressed condition. Some reaction are occur at high temperature only hence actual data is not getting. Decomposition due to freezed condition, micro-organism is not determined. Products like protein,cellulose,ointment,suppositories are not suitable for accelerated stability study. Emulsions are more stable at elevated temperature which may be the case at normal storage condition.

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22 Stability of Solid dosage form The decomposition of drug in solid dosage form is more complex than that of occuring in pure drug. Situation is more complex in multi-drug dosage form. Following are the factor which affect the stability in solid dosage form Temperature Moisture Chemical Interaction

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23 Stability study of semisolid dosage form Stability depend up on the nature of ointment or cream base used in the formulation. Cream bases are more prone to decomposition of drug Dilution of cream or ointment by user with untested diluent can further lead to instability. Incorporation of drug into gel structure leads to change in their stability Some example Coconut oil used as diluent for cream or ointment Instability of betamethsone valerate Increased degradation of penicillin G in hydrogels of various natural and semisynthetic polymer.

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24 Testing frequency long term storage condition . Every three month over the first year . Every six month over the second year . Annually through the proposed shelf life. Accelerated stability condition:- Minimum of three points including initial and final time point(e.g. 0,3,6), from six month study is recommanded. To decrease the testing frequency reduced designs can be applied, if justified.

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25 Packaging /container Stability studies should be carried out in the final packaging proposed for marketing. Additional testing of unprotected finished product can form useful part of the stress testing and pack evaluation. Studies carried out in other related packaging material in supporting .

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26 ICH guide lines to carry out stability testing:- ICH Q1A(R2) Stability Testing of New Drug Substances and Products (second revision) ICH Q3A(R) Impurities in New Drug Substances ICH Q1B Photostability Testing of New Drug Substances and Products ICH Q2B Validation of Analytical Procedures: Methodology ICH Q3B(R) Impurities in New Drug Products

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27 ICHQC stability testing for new dosage form ICHQD Braceting and matrixing Design for stability testing of drug substance and product ICHQ Evaluation of stability data ICHQF stability data package for registration application in climatic zones III and IV.

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28 Climatic zone Climatic zone Dfination Criteria Mean annual temperature measured in the open air / Mean annual partial water vapour pressure Testing condition [◦C/%RH] Zone I Temperature ≤15 ◦C / ≤11hPa 21/45 Zone II Subtropical with possible high humidity >15 to 22 ◦C /11to18hPa 25/60 Zone III Hot,dry >22 ◦C / ≤15hPa 30/35 Zone IV Hot and humid >22 ◦C /> 15hPa 30/70

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29 Summary Stability studies should be planned on the basis of pharmaceutical R+D and regulatory requirements. Forced degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date. The shelf life (expiry date) of FPPs is derived from Accelerated stability studies. Variability and time trends of stability data must be evaluated by the manufacturer in order to propose a retest date or expiry date.

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30 References Jens T. Cartensen , C. T. Rhodes, Drug stability principle and Practice, Third edition, Volume 107 Marcel Deccker series. Leon Lachman , Herbert A. Lierberman,Joseph L. Kaing , The theory and practice of industrial pharmacy,third edition,Varghese publising house hind rajasthan building Dadar Bombay. Martins,Physical pharmacy and pharmaceutical sciences,fifth edition,Indian edition,Lippincott Williams and Wilkins. Loyed V.Allen,Jr . Nicholas G.Popovich Howard C.Ansel Pharmaceutical dosage forms and drug delivery systems,eighth edition, Lippincott Williams and Wilkins.

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31 ICH Q2A (R) (1995) Guideline for industry, text on validation of analytical procedures. ICH Q2B (R) (1996) Guideline on validation of analytical procedures: methodology. Reynolds DW, Facchine KL, Mullaney JF, Alsante KM, Hatajik TD, Motto MG (2002) Available guidance and best practices for conducting forced degradation studies. Pharm Technol 26:48–56. Sprangler M, Mularz E (2001) A validated, stability-indicating method for the assay of dexamethasone in drug substance and drug product analyses, and the assay of preservatives in drug product. Chromatographia 54:329–334.

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32 C.V.S. Subrahmanyam , Text book of Physical Pharmaceutics, second edition ,2000, Page no 51-84 L. J. Edwards, The hydrolysis of aspirin: A determination of the thermcdynamic dissociation constant and a study of the reaction kinetics by ultraviolet spectrophotometry , Trans. Faraday Soc. 46,723-735 (1950). Sprangler M, Mularz E (2001) A validated, stability-indicating method for the assay of dexamethasone in drug substance and drug product analyses, and the assay of preservatives in drug product. Chromatographia 54:329–334.

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33 THANK YOU

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