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Drug stability


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Mpharm overview of drug stability

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Drug stability

  1. 1. 19/11/2016 1 A Seminar On “DRUG STABILITY” SUBMITTED TO MUMBAI UNIVERSITY By Ms. Swati S. Bharati (F.Y.M.Pharm) Under the Guidance of Dr. BHUSHAN RANE HOD (Pharmaceutics) SHRI. D.D. Vispute College of Pharmacy & Research Center PANVEL (2016-2017)
  2. 2. CONTENTS... Introduction Importance And Need Of Stability Testing Degradation Pathways Kinetic Stability Solution Stability Solid State Stability pH Stability Profile Conclusion Reference 19/11/2016 2
  3. 3. INTRODUCTION STABILITY: USP defines stability of pharmaceutical product as, “extent to which a product retains with in specified limits and throughout its period of storage and use (i.e. shelf life). The capacity or the capability of a particular formulation in a specific container to remain with in particular chemical , microbiological , therapeutically , and toxicological specifications. 19/11/2016 3
  4. 4. Drug stability is defined as the 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. The purpose of stability studies is to provide evidence on how the quality of the active substance or pharmaceutical product varies with time under the influence of a variety of environmental factor such as temperature, humidity and light DRUG STABILITY 19/11/2016 4
  5. 5. IMPORTANCE Chemical and physical degradation of drug substances may change their pharmacological effects, which is then affecting on their therapeutic and toxicological effect. Pharmaceuticals products are used therapeutically based on their efficacy and safety, they should be stable. Maintenance of quality until the time of usage or until their expiration date. The quality should be maintained under the various conditions that pharmaceuticals encounter, during production, storage in warehouses, transportation and storage in hospitals as well as in the home. 19/11/2016 5
  6. 6. NEED 19/11/2016 6
  7. 7. Where stability studies takes place....... Drug discovery development 19/11/2016 7
  8. 8. Types of stability • 19/11/2016 8
  9. 9. TYPES OF STABILITY TESTING • Stability condition Study SR. NO . STUDY STORAGE CONDITION TESTING TIMING (MONTH) Minimum Time Period Covered By Data At Submission 1 LONG TERM (Ambient) 25º C ± 2º C 60%RH ± 5% 0, 3, 6, 9, 12, 18, 24, 36, 48, 60. 12 months 2 INTERMEDIATE (controlled) 30º C ± 2º C 60%RH ± 5% 0, 3, 6, 9, 12. 6 months 3 ACCELERATED (Short term) 40º C ± 2º C 75%RH ± 5% 0,1, 2, 3, 6, 9. 6 months 19/11/2016 9
  10. 10. DEGRADATION PATHWAYS Degradation of active drug leads to lowering of quantity of the therapeutic agent in the dosage form A toxic product formation may takes place due to decomposition instability of drug product can lead to a decrease in its BIOAVAILABILITY. Changes in PHYSICAL APPEARANCE of given dosage form may takes place. Degradation may increase or decrease the POTENCY of drug. 19/11/2016 10
  11. 11. TYPES OF DEGRADATION PATHWAYS 19/11/2016 11
  13. 13. LOSS OF VOLATILE COMPOUNDS Some of volatile components alcohol, ether, Iodine, volatile oils, Camphor menthol etc escape from the formulations exposé them degraded. EXAMPLE: Some types of tablets (Nitroglycerine tablets) Aromatic water PREVENTION: Such product should be placed in well closed container. Temperature should be proper. 19/11/2016 13
  14. 14. LOSS OF WATER Water loss from liquid preparation (o/w emulsion) leads to changes in stability. It causes crystallization of drug product . which may lead to increase in potency , and decrease in weight. EXAMPLE : Water evaporates from na2so4 .BORAX. Creams: especially oil/water, they become dry by loss of water. PREVENTION: Products should be placed in well-closed container. 19/11/2016 14
  15. 15. ABSORPTION OF WATER Hygroscopic drugs absorb the water from external atmosphere causing the physical degradation. Effervescent powders and tablets will deteriorate if stored in a moist atmosphere. EXAMPLE: Powders: Liquification and degradation may occur as a result of absorption of water Suppositories which base made from hydrophilic substances as Glycerin, Gelatin, and polyethylene glycol. The consistency of these forms becomes jelly-like appearance. PREVENTION: Products should be placed in well-closed container and in dry place. 19/11/2016 15
  16. 16. Drugs when loose water, become saturated and crystal growth occurs. Crystallization is enhanced in porous tablets.In solutions after super saturation crystal growth occurs. EXAMPLE: Injection of calcium glucconate In suspensions crystals settle down and caking occurs and suspension becomes unstable. Ophthalmic preparations. PREVENTION: SOLUTIONS-Stabilizers are added SUSPENSION- ·Incorporation of surface active agent ·By increasing viscosity of suspending material CRYSTAL GROWTH 19/11/2016 16
  17. 17. Polymorphs show significant differences in important physiochemical properties such as solubility, dissolution rate and melting point. In polymorphic changes crystal forms are changed. This may cause change in solubility and possibly crystalline growth in aqueous suspension. EXAMPLE: Cortisone acetate suspension. • PREVENTION: suspension –suspending agent like methyl cellulose & ethyl cellulose POLYMORPHISMS 19/11/2016 17
  18. 18. When molecules are exposed to electromagnetic radiation they absorb light (photons) at characteristic wavelength which cause increase in energy which can cause decomposition. EXAMPLE: Sodium nitropruside in aqueous solution (which is administered by IV infusion for management of acute hypertension). Iodine PREVENTION: Use of amber colored bottles. Storing the product in dark, packaging in cartons also act as physical barrier to light. PHOTOLYSIS 19/11/2016 18
  19. 19. Colour changes indicate chemical or photochemical decomposition of the active ingredients, dyes or other ingredients. Colour changes are of two types. 1) Loss of colour 2) Development of colour EXAMPLE: Phenolphthalein color changes as the PH changes. It is colorless in acidic solution and pink in basic. ascorbic acid tablet turn yellowish brown. • PREVENTION: • Protect the product from light and air • Avoid the using reducing substances as additives. COLOUR CHANGES 19/11/2016 19
  20. 20. CHEMICAL DEGRADATION 19/11/2016 20
  21. 21. 2 HYDROLYSIS 19/11/2016 21
  22. 22. - Involve Acyl – Acid Cleavage. EXAMPLE : aspirin ,atropine, physostigmine & procaine.. REACTION: 19/11/2016 22
  23. 23. • Amide bonds are less susceptible to hydrolysis than ester bonds. • The leaving group, an amine, is a poorer leaving group. It involves cleavage of amide linkage to give an amine instead of alcohol as in case of esters. EXAMPLE: Chloramphenicol , Barbiturates REACTION: RCONHR(amide) + H2O  RCOOH + NH2-R(AMINE) 19/11/2016 23
  24. 24. • Barbiturates, hydantoins, and imides contain functional groups related to amides but have a tendency to be more reactive. • Barbituric acids such as barbital, phenobarbital and amobarbital, undergo ring-opening hydrolysis. REACTION: 19/11/2016 24
  25. 25. • Benzodiazepines such as diazepam, oxazepam, and nitrazepam undergo ring opening due to reversible hydrolysis of the amide and azomethine bonds. • Benzodiazepinoxazoles(oxazole-condensed benzodiazepines) such as oxazolam, flutazolam, haloxazolam, and cloxazolam are undergo ring opening due to hydrolysis. REACTION: 19/11/2016 25
  26. 26. 19/11/2016 26
  27. 27. ISOMERIZATION 19/11/2016 27
  28. 28. RACEMIZATION Racemization refers to partial conversion of one enantiomer into another. It involves the optically active form of a drug into its enantiomorph. 19/11/2016 28
  29. 29. EPIMERIZATION It occurs with the compound having more than one asymetric carbon atom in the molecule. At equilibrium, both epimers are present, but not in equal proportion. EXAMPLE: Under prolonged storage solution containing ergometrine is decomposed by hydrolysis and isomerized to ergometrinine 19/11/2016 29
  30. 30. DECARBOXYLATION Elimination of CO2 from compound. Drug substances having a carboxylic acid group is sometimes susceptible to decarboxylation, EXAMPLE: 4-Aminosalicylic acid procain 19/11/2016 30
  31. 31. ELIMINATION In elimination, reaction some groups of the substance is eliminated. EXAMPLE: Trimelamol eliminates its hydroxymethyl groups and forms formaldehyde. 19/11/2016 31
  32. 32. OXIDATION Removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or radical. Oxidation is controlled by environment i.e., light, trace elements, oxygen and oxidizing agent. 19/11/2016 32
  33. 33. TYPES of OXIDATION • Oxidation in which the oxygen presents in the air is involved. This process proceeds slowly under the influence of atmospheric oxygen. • Oxidation in which removal of the electron is involved without presence of O2. 19/11/2016 33
  34. 34. PREVENTION Chelating agent Antioxidant agent 19/11/2016 34
  35. 35. MICROBIAL DEGRADATION Contamination of a product may sometimes cause a lot of damage and sometimes may not be anything at all. -Thus it is dependent on the type of microbe and its level of toxicity it may produces. -If parenterals or ophthalmic formulations are contaminated, it may cause serious harm. 19/11/2016 35
  36. 36. Source of microbial contamination Water & air Container & closure Raw material 19/11/2016 36
  37. 37. PREVENTION Suitably designing the containers Usually using single dose containers Sticking to proper storage conditions Adding an antimicrobial substance as preservative 19/11/2016 37
  38. 38. THERAPEUTIC DEGRADATION Therapeutic effect must be changed due to hydrolysis, isomerisation or epimerization . Example: Adrenaline 19/11/2016 38
  39. 39. Toxicological degradation 19/11/2016 39
  40. 40. Kinetic stability Kinetics deals with the study of the rate at which processes occur and mechanism of chemical reactions It involves the study of rate of change and the way in which this rate is influenced by the concentration of reactants, products, and other chemical species that may be present, and by factors such as solvents, pressure, and temperature. Kinetics applies to: Stability Incompatibility Dissolution Absorption Distribution Drug action at molecular level Elimination processes 19/11/2016 40
  41. 41. Rate & order of reaction • The speed or velocity of a reaction with which a reactant or reactants undergoes a change. • It is determined by the change in the concentration of the reactants or products as a function of time. Rate • The number of concentrations that determine rate. • The way in which the concentration of the reactant influences the rate. Order of reaction 19/11/2016 41
  42. 42. Types of order of reaction • Rate is constant and is independent of the concentration of any of the reactants. Zero order of reaction • The reaction rate of change is proportional to drug concentration. First order of reaction • Rate depends on the product of two concentration terms. When you have two components reacting with each other or one component reacting with itself. Second order of reaction • For some reactions, the rate of the reaction may be independent of the concentration of one or more of the reacting species over a wide range of reactions. Pseudo order of reaction 19/11/2016 42
  43. 43. Overall order of reaction 19/11/2016 43
  44. 44. Shelf life It is defined as the time required for the concentration of the reactant to reduce to 90% of its initial concentration . Represented as t90 the units of time /conc. t90 = (a-0.9a)/ ko = 0.1 a/ ko Where, a = initial concentration. ko = specific rate constant for zero order reaction. 19/11/2016 44
  45. 45. Shelf life 19/11/2016 45
  46. 46. SOLUTION STABILITY The main purpose of solution stability is identification of conditions necessary to form a stable solution Study. Includes – effects of pH, Ionic strength, Co-solvent, light , temperature and oxygen Interested experiments at extremes conditions of pH and temperature (0.01N HCl , water ,0.01N, NaOH all at 90°C). Aq. Buffers are used to provide wide range with constant levels of drug, co solvent and ionic strength Compatible with physiological media 19/11/2016 46
  47. 47. SOLID STATE STABILITY The purpose of solid state stability is identifications of stable storage conditions for drug in the solid state and identification of compatible excipients for a formulations. Affected by change in purity and crystallinity Initial bulk lots and newer lots– to be studied Solid state is slower and difficult to interpret than solution state TLC, UV-Vis, fluorescence Polymorphic changes – DSC, IR or appearance changes like oxidation – surface discoloration 19/11/2016 47
  48. 48. pH STABILITY STUDIES The pH-stability profile is essential for understanding how the compound behaves in different environments and informs formulation development, process development, drug product stability and the route of administration of the molecule. To develop a pH-stability profile, it is important to develop stability-indicating assays for the intact drug at the various pH values to be studied. 19/11/2016 48
  49. 49. pH-stability studies 19/11/2016 49
  50. 50. CONCLUSION Pharmaceutical products are assigned a shelf life which determines the time when a product is considered to be safe and effective under storage condition. Stability studies should be based on the basis of pharmaceutical R&D and regulatory requirements. Degradation studies reveal the intrinsic chemical properties of the API while formal stability studies establish the retest date. The shelf life is derived from stability studies 19/11/2016 50
  51. 51. REFERENCE date15/10/2016 C.V.S Subrahmanyam “Textbook of Physical Pharmaceutics” vallabh prakashan, second edition, reprint 2007, page no: 13-50, 51-84. techniques. On date 19/10/2016 radation%202015.pdf. On date 21/10/2016 products on date 19/10/2016 Drug-Stability.pdf. Cartensen J, Marcel Dekker “ Drug Stability Principles and Practises ”Informa healthcare, third edition,vol 107, 1990, page no: 19/11/2016 51
  52. 52. 19/11/2016 52