Drug stability


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Drug stability

  1. 1. Rakesh Kumar Sharma 12/27/2013 1
  2. 2. The stability studies are important for the following reasons Assurance to the patient: This is the assurance given by the manufacturers that the patient would receive a uniform dose throughout the shelf life. Legal requirement: The drug control administrations insist on manufacturers on conducting the stability studies to prove the identity, strength, purity and quality of the drug in the conditions of normal storage. Rakesh Kumar Sharma 12/27/2013 2
  3. 3. The USP prescribes the following criteria for acceptable levels of stability. Type of stability Conditions to be maintained during the shelf life of the product. Chemical Retains its labelled chemical potency Physical Appearance, uniformity, dissolution etc are to be retained Microbiological Retain sterility, effectiveness of preservatives etc. Therapeutic Drug action remain unchanged Toxicologic No significant increase in toxicity Rakesh Kumar Sharma 12/27/2013 3
  4. 4. Physical degradation of Pharmaceutical products Loss of volatile constituents: Medicinal agents such as iodine, camphor, menthol, ethyl alcohol, chloroform have the tendency to evaporate from the product during the storage. Nitroglycerine tablets may loose its potency due to volatilization of medicament. The preventive measure includes keeping the product in well closed containers and store in cool place. Rakesh Kumar Sharma 12/27/2013 4
  5. 5. Loss of water: loss of water from the product leads to decrease in weight, rise in concentration of the drug and increased potency. Products such as emulsions exhibit cracking. The preventive measure includes keeping the product in well closed containers and store in cool place. Absorption of water: absorption of water from the atmosphere increases the weight of the product, dilute the dose and decrease the potency. Gelatin capsules will absorbs moisture and become soft and sticky. The preventive measure includes keeping the product in well closed containers. Rakesh Kumar Sharma 12/27/2013 5
  6. 6. Color change: color change indicates some kind of chemical decomposition of active ingredients. Aspirin tablets become pick and ascorbic acid tablets turns yellowish brown. Adrenaline on exposure to air becomes red. Protect the product from light and air. Crystal growth: fluctuations in the temperature of storage cause crystal growth. When the temperature is lowered the solution becomes supersaturated, precipitation crystal growth of drug is observed. Rakesh Kumar Sharma 12/27/2013 6
  7. 7. Chemical Decomposition of Drugs All medicinal agents are to be investigated for their decomposition before being marketed. A few important decomposition reactions are enumerated here. Hydrolysis: Drugs with ester or amide functional groups react with one molecule of water and undergoes hydrolysis. Reaction between ionic drugs proceeds faster than with neutral molecules. Further hydrolysis reactions are catalysed by H+ and OH- ions. Hydroxyl ions catalyzed hydrolysis by 100 to 1000 times more actively than hydrogen ions. Drugs that contain ester group include Aspirin, procaine, atropine etc while amide group containing drugs are chloramphenicol, ampicillin, barbiturates, cephalosporins etc. Rakesh Kumar Sharma 12/27/2013 7
  8. 8. Protection against hydrolysis: Hydrolysis reactions are known to occur in presence of moisture, catalytical species H+ and OH- ions. Buffers: Drugs may be stabilized by use of buffers. Type of buffer and optimum pH should be established. For example: pilocarpine is highly active in alkaline pH, because it occurs as unionized form. But at alkaline pH, it is highly irritating to the eye and also precipitates from the solution. Therefore to prevent hydrolysis acidic pH has to be selected. Boric acid buffer of a pH 5.0 with low buffer capacity is selected. A stronger buffer is not used since upon instillation into the eye; the pH of the solution is able to rise to that of tear secretions (pH7.4) with consequently formation of the more active basic form of the drug. Rakesh Kumar Sharma 12/27/2013 8
  9. 9. Complexation: Hydrolysis of Benzocaine in aqueous solution can be inhibited by the addition of caffeine. As a result of complexation the attack of catalytic species on benzocaine may be reduced. The rate of hydrolysis now will depends on the amount of uncomplexed free benzocaine present in the solution. Other drugs which may be stabilized by complexation are procaine, tetracaine etc. Rakesh Kumar Sharma 12/27/2013 9
  10. 10. Suppression of solubility: when the solubility of a drug decreases the concentration of drug in solution phase will be decreased. Hence the rate of hydrolysis is reduced. Additives: citrates, dextrose, sorbitol and gluconate, when combined with the drugs, the solubility of drugs will be suppressed, probably because of decreased hydration of drug molecules. Rakesh Kumar Sharma 12/27/2013 10
  11. 11. Salts: The degradation of penicillin can be prevented by using poorly soluble procaine penicillin in the dosage form. Derivatives: poorly water soluble derivatives such as esters of drugs can be used to reduced the tendency of hydrolysis. Example: erythromycin propionate, erythromycin stearate, chloramphenicol palmitate. Rakesh Kumar Sharma 12/27/2013 11
  12. 12. Choice of solvent: Non-aqueous solvents e.g alcohol and propylene glycol, have often been used to replace a portion, or all, of the water in a solution in order to reduce hydrolysis of a drug. For example an elixir of phenobarbitone sodium contains considerable quantities of glycerin and alcohol. Removal of water: Store the drug in dry form. When desire reconstitute the product. Example: streptomycin dry powder for injection. Other examples include ampicillin, amoxicillin dry powders for injection. Rakesh Kumar Sharma 12/27/2013 12
  13. 13. Oxidation: The general principals that govern an oxidation reaction may be as follows. Presence of atmospheric oxygen. Free radical mediated oxidation. Light provides the necessary energy to initiate the oxidation process. The presence of trace metals accelerates the rate of oxidation. Organic peroxides promote the chain reactions in oxidation process. Oxidation reactions are catalysed by H+ and OH- ions. Rakesh Kumar Sharma 12/27/2013 13
  14. 14. Factors affecting the rate of oxidation Dilution: Dilution of an oxidizable compound with an inert solvent will decrease the rate of oxidation. For example in oily vitamin solutions the vitamin is present in very low concentration. Temperature: The rate of oxidation of an organic compound is increased with increase in the temperature of storage. For example: the rate at which hydroperoxides break down in to aldehydes, ketones and fatty acids is accelerated at temperature in excess of 50oc. Rakesh Kumar Sharma 12/27/2013 14
  15. 15. The presences of pro-oxidants: The pro-oxidants accelerate the rate of autoxidation. The hydroperoxides formed during the auto oxidation are themselves pro-oxidants. The heavy metals for example copper and iron, also have a pro-oxidant effect. The degree of unsaturation of the organic compound: Highly unsaturated compounds are more susceptible to autoxidation and therefore oxidize at rates greater than compounds having a lower degree of unsaturation. For example linoleic acid is much more rapidly oxidized on exposure to air than oleic acid. Rakesh Kumar Sharma 12/27/2013 15
  16. 16. Protection against oxidation Antioxidants: Ideal antioxidant has the following properties effective in low concentrations soluble in the proposed vehicle Non-toxic, non irritant, odorless and tasteless. Stable and effective over wide range of pH . Should not react chemically with other constituents present. Rakesh Kumar Sharma 12/27/2013 16
  17. 17. Tocopherols are the naturally occurring antioxidants. Other examples are butylated hydroxyl anisole, butylated hydroxyl toluene, propyl gallate, ascorbyl palmitate. These are fat soluble antioxidants, acts by inhibiting the free radical chain reactions. Rakesh Kumar Sharma 12/27/2013 17
  18. 18. Water soluble antioxidants acts by preferentially undergoing oxidation instead of the drug itself. Examples are sodium metabisulphite, sodium formaldehyde sulphoxylate, thioglycolic acid, cysteine etc. Rakesh Kumar Sharma 12/27/2013 18
  19. 19. Chelating agent: addition of chelating agent to a product will be useful when traces of heavy metals catalyse the oxidation. Compounds such as EDTA, citric acid tartaric acid form complexes with heavy metals. Example addition of EDTA to the buffer system prevents the degradation of drugs such as dexamethasone sodium phosphate and ascorbic acid. Rakesh Kumar Sharma 12/27/2013 19
  20. 20. Micellar solubilisation: surfactants such as polysorbate 80 prevent the oxidation of ascorbic acid above critical micelle concentration. Buffers: buffers impart stability when the oxidation is catalysed by H+ and OH- ions. Choose a buffer with appropriate pH to maintain maximum stability of the product. Rakesh Kumar Sharma 12/27/2013 20
  21. 21. Environmental Control Measures Prevent the exposure to light: Morphine sulphate injection USP and ascorbic acid injection is protected from light by using amber color ampoules. Oxygen free environment: oxygen enhances oxidative degradation. Therefore, replace the air in the container (injection vials, ampoules) with inert gases such as nitrogen or carbon dioxide. Low temperature storage: since high temperature enhances the rate of reaction, store the product in a cool place. Rakesh Kumar Sharma 12/27/2013 21
  22. 22. Decarboxylation: These reactions are mainly observed when a parenteral solution contains sodium carbonate. During autoclaving, the carboxylic groups will be knocked off. To prevent this pass carbon dioxide gas into the solution for one minute. Seal the container prior to autoclave. Rakesh Kumar Sharma 12/27/2013 22
  23. 23. Absorption of carbon dioxide: Solutions absorb carbon dioxide from the atmosphere. Sodium hexabarbitone solution basic pH absorbs CO2 converts to acidic pH hexababitone precipitate. Solutions of potassium hydroxide, sodium hydroxide, calcium hydroxide and lead subacetate become turbid due to formation of insoluble carbonates. They are therefore stored in well-filled, well closed containers. Rakesh Kumar Sharma 12/27/2013 23
  24. 24. Volatile nasal decongestants, amphetamine and propylhexedrine also absorbs carbon dioxide from the atmosphere. The solution of hexobarbitone can absorb carbon dioxide and this result in precipitation of hexobarbitone. This is a serious problem in the preparation of intravenous solutions of soluble barbiturates. They are therefore distributed as sterile powders in vials with instructions to dissolve immediately before use in water for injection free from carbon dioxide. Rakesh Kumar Sharma 12/27/2013 24
  25. 25. Recemization: it is the inter conversion of dextro rotatry and leavo rotatry form of drugs. The conversion of (-) adrenaline greater biological activity to (±) adrenaline 50% reduction in biological activity. Epimerization: In this case the compound has more than one asymmetric carbon atoms. While one symmetric atom remains static the other carbon rotates to give epimer. Ergometrine solution converts to less active epimer ergometrinine. To prevent epimerization and racemisation, protect the product from light and heat. Maintain optimum pH. Rakesh Kumar Sharma 12/27/2013 25
  26. 26. Influence of Temperature on drug decomposition The speed of many reactions increases about two to three times with every 10o rise in temperature. Arrhenius equation explains the effect of temperature on rate of a reaction. k = A e- Ea/RT Where: k: specific rate constant A: frequency factor or Arrhenius factor Ea: energy of activation R: Ideal gas factor (1.987 cal/mol,deg) T: absolute temperature. Rakesh Kumar Sharma 12/27/2013 26
  27. 27. Energy of activation is defined as the minimum energy that a molecule should possess so that molecular collisions produce the product. Arrhenius factor is defined as frequency of collisions which can occur between molecule. A is the product of molecular collisions and probability factor of collisions which give a product. Take logarithms both sides log k = log A – Ea/2.303RT Rakesh Kumar Sharma 12/27/2013 27
  28. 28. Estimation of k: conduct the reaction at several temperatures. Determine the concentration of the reactant at different time periods at each temperature. Draw the graphs as per the principles of the different orders for each temperature. From the slopes of the lines, calculate the k value for each temperature. Rakesh Kumar Sharma 12/27/2013 28
  29. 29. Estimation of energy of activation: Draw the graph by taking log k on y-axis and 1/T on x-axis.the intercept will be log A and slope is equal to Ea/2.303R. To get a line we need the log k values at least at three temperatures. Rakesh Kumar Sharma 12/27/2013 29
  30. 30. Accelerated stability studies The objective of accelerated stability studies is to predict the shelf life of a product by accelerating the rate of decomposition, preferably by increasing the temperature. Method: Drug preparations are stored at elevated temperatures ranging from 400c to 900c. During different time intervals samples are withdrawn and the drug content is estimated using assay method. Rakesh Kumar Sharma 12/27/2013 30
  31. 31. Draw a plot by taking concentration undecomposed against time at different temperatures (from 400c to 900c). Estimate the value of k for each temperature Rakesh Kumar Sharma 12/27/2013 31
  32. 32. log k values are then plotted reciprocal of absolute temperature. A linear relationship is desirable. Energy of activation can be calculated. Rakesh Kumar Sharma 12/27/2013 32
  33. 33. Extrapolate the straight line to room temperature (250c) and read the log k25 value on Y-axis. Substitute the k25 value in the equation of an appropriate order to get shelf life of the product at room temperature. Rakesh Kumar Sharma 12/27/2013 33
  34. 34. Limitations: Accerlerated stability studies are valid only when the breakdown depends on temperature. Stability predictions at elevated temperatures are of little use when the degradation is due to microbial contamination, photochemical reaction. Stability studies are meaningless when the product looses its physical integrity at high temperature. For example: Coagulation of suspending agents ( methylcellulose) Denaturation of proteins Cracking of emulsion Loss of consistency of ointments. Rakesh Kumar Sharma 12/27/2013 34
  35. 35. Stability Testing of Pharmaceutical dosage forms The shelf life of the product depends on its storage temperature and for susceptible products, also on humidity. World is divided in to four climate zones, recognized by international conference on Harmonization (ICH). They are based on observed temperatures and relative humidity. Zone I Temperate Canada, New Zealand, 21oC 60%RH Northern Europe, Russia, UK Zone II Mediterranean and Subtropical Japan, south Europe, USA 26 oC 65%RH Zone III Tropical(dry) Middle east, Australia, 31 oC 60%RH 31 oC 70%RH Argentina Zone IV Tropical(wet) Indian subcontinent, china, brazil, Nigeria, philippines Rakesh Kumar Sharma 12/27/2013 35
  36. 36. The testing should cover those features susceptible to change during storage and likely to influence quality, safety and/or efficacy. Stress testing: Carry out in single batch, includes effect of temperature (100C increments above accelerated testing), humidity (75%RH or greater) and light. There must not be any significant change. Where significant change occurs test should be conducted under long term conditions. Rakesh Kumar Sharma 12/27/2013 36
  37. 37. Storage test conditions: The length of the studies and storage conditions should be sufficient to cover storage, shipment and subsequent use. Following test conditions are suggested. Study type Conditions Minimum Time period Long term Testing 300c ± 20c/ 65% RH 12 months ± 5% Accelerated testing 400c ± 20c/ 75% RH 6 month ± 5% Rakesh Kumar Sharma 12/27/2013 37
  38. 38. Where significant change occurs during storage under accelerated testing conditions at 400c ± 20c/ 75% RH ± 5%.The test should be conducted only under long term conditions. Significant change is defined as Loss of 5% or more potency from initial assay value of a batch. Failure to meet specifications for appearance, physical properties for example phase separation, caking, resuspendability, dose delivery per actuation etc. Failure to meet specification limit for pH Failure to meet specification limit for dissolution test for capsules or tablets. Rakesh Kumar Sharma 12/27/2013 38
  39. 39. Testing-Sampling frequency Long term studies: Every 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed retest period Accelerated: a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months) Rakesh Kumar Sharma 12/27/2013 39
  40. 40. Dosage form Test parameters Tablets Appearance, color, odor, assay, disintegration time, dissolution, hardness, moisture, friability Hard gelatin capsules Appearance, color, odor, assay, disintegration time, dissolution, moisture and microbiological limit Soft gelatin capsules Appearance, color, odor, assay, disintegration time, dissolution, moisture, microbiological limit, pH and leakage Emulsions Appearance including Phase separation, color odor, assay, pH, viscosity, wt loss, preservative contents, microbial limit. Suspensions Appearance, color, assay, pH, redispersibility, viscosity, particle size, wt loss, preservative contents, microbial limit Oral powders for reconstitution. Appearance, color, odor, moisture and reconstitution time. Small volume parenterals Appearance, color, assay, pH, particulate matter sterility, pyrogenicity Large volume parenterals Appearance, color, assay, pH, particulate matter sterility, pyrogenicity suppositories Appearance, color, assay, softening range, dissolution, microbial limit. Rakesh Kumar Sharma 12/27/2013 40
  41. 41. Rakesh Kumar Sharma 12/27/2013 41