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Drug stability consideration and degradation

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Mini Presentation on Drug Stability

Publié dans : Santé & Médecine

Drug stability consideration and degradation

  1. 1. A Glimpse on Drug Stability Consideration and Degradation of Drugs School of Pharmacy World University of Bangladesh Dhaka-1205, Bangladesh Prepared by: Jalal Uddin Jr. Lecturer
  2. 2. Drug Stability: The capacity or capability of a particular drug formulation in a specific container to remain within a particular chemical, microbiological, therapeutically, physical & toxicological specification in a specified period of time. The United States Pharmacopoeia define the drug stability as extent to which a particular drug product retains intake within a specified limit throughout its storage and use i.e. shelf life. Drug Instability: The incapacity or incapability of a particular formulation in a specific container to remain within a particular chemical, microbiological, therapeutically, physical & toxicological specification.
  3. 3. Shelf life: Shelf life may be defined as the time required to degrade a pharmaceutical product to 10% which is pharmaceutically acceptable. It is indicated as t90 and the unit is time/conc. Where, a = initial concentration of drug product . ko = specific rate constant for zero order reaction.
  4. 4. Factors effecting drug stability: Factors effecting the drug stability are as under  PH  Temperature  Moisture  Humidity  Light  Storage closure and containers  Oxygen  Particle size (suspension and emulsion)  Additives  Molecular binding  Diffusion of drugs and excipients .
  5. 5. Objective of the drug stability  To determine maximum expiration date/ shelf life.  To provide better safety to the patients.  To prevent the drug product from different kind of instability.  To provide better storage condition.  To determine the packaging components.  To gather information during preformulation stage to produce a stable product.
  7. 7. TYPES OF STABILITY THAT MUST BE CONSIDERED FOR ANY DRUG  CHEMICAL Each active ingredient retains its chemical integrity and labeled potency within the specified limit.  PHYSICAL The physical stability properties includes appearance, palatability ,uniformity ,dissolution and suspendability are retained.  MICROBIOLOGICAL Sterility or resistance to microbial growth is retained according to specified requirement.  THERAPEUTIC Therapeutic activity remains unchanged .  TOXICOLOGIC No significant increase in toxicity occurs.
  8. 8. TYPES OF DRUG INSTABILITY: Drug instability can be divided into two major types- 1. Physical degradation 2. Chemical degradation Physical degradation: “Degradation, which results into the change of physical nature of the drug.” Types: Types of physical degradation are as under 1. Loss of volatile components 2. Loss of H2O 3. Absorption of H2O 4. Crystal growth 5. Polymorphic changes 6. Color changes
  9. 9. 1. Loss of Volatile Components: Volatile components such as Alcohol ether, Iodine, volatile oils, Camphor, menthol etc. escape from the formulations. Examples: a. Aromatic waters b. Elixirs c. Spirits d. Some types of tablets which contain aromatic water (Nitroglycerin tablets) 2. Loss of H2O: This tendency depends on temperature and humidity of surrounding environment. a. Saturated solution: by loss of water they become supersaturated and precipitate as crystals is formed b. Emulsions: Loss of water lead to separation of the two phases and change to other type c. Creams: especially oil/water, they become dry by loss of water d. Pastes e. Ointments: especially aqueous base ointments Humectant is added to the previous dosage forms which defined as hydrophilic substances added to aqueous phase to absorb water from atmosphere and prevent its loss from the dosage forms. Examples: Glycerin
  10. 10. 3. Absorption of H2O: Hygroscopic drugs absorb the water from external atmosphere causing the physical degradation. Depends on temperature and humidity of surrounding environment. This phenomena can be seen in the following pharmaceutical forms: a. Powders: Liquification and degradation may occur as a result of absorption of water b. Suppositories which base made from hydrophilic substances as Glycerin, Gelatin, poly ethylene glycol. c. Some deliquescent salts calcium chloride, potassium citrate. The consistency of these forms becomes jelly-like appearance 4. Crystal Growth:  In solutions after super saturation crystal growth occurs. Reason may be the fall in temp and a consequent decrease in solubility of solute. E.g. Injection of calcium glucconate.  In suspensions crystals settle down and caking occurs and suspension becomes unstable. e.g. Ophthalmic preparations.
  11. 11. 5. Polymorphic Changes: In polymorphic changes crystal forms are changed. A stable crystal form loosens. This may cause alteration in solubility and possibly crystalline growth in aqueous suspensions. CHEMICAL DEGRADATION: Change in the physical nature of the drug is called as chemical degradation. Chemical degradation of a dosage form occurs through several pathways like – hydrolysis ,oxidation , decarboxylation , photolysis , racemization .which may lead to lowering of therapeutic agent in the dosage form ,formation of toxic product , decreased bioavailability etc. HYDROLYSIS: It is defined as the reaction of a compound with water.  Most important in systems containing water such as emulsion , suspension , solutions , etc.  Also for drugs which are affected by moisture (water vapor) from atmosphere.  It is usually catalyzed by hydrogen ion(acid) or hydroxyl ion(base).  In this active drug is decomposed with solvent.  Usually solvent is water some time reaction may involve pharmaceutical co solvents such as ethyl alcohol or poly ethylene glycol  Main classes of drugs that undergo hydrolysis are the Esters ,Amide ,Alkali, Acid.
  12. 12. ESTER HYDROLYSIS involve acyl – acid cleavage. Example of drugs: aspirin ,atropine , physostigmine , procaine. R-COOR (ester) + H2O  R-COOH (acid) + R-OH(alcohol) AMIDE HYDROLYSIS is more stable than ester , susceptible to specific and general acid base hydrolysis. It involves cleavage of amide linkage to give an amine instead of alcohol as in case of esters. Example of drugs : chloramphenicol , barbiturates . RCONHR(amide) + H2O  RCOOH + R-NH2(AMINE) f
  13. 13. Types of Hydrolysis: It has two types · Ionic hydrolysis · Molecular hydrolysis Ionic hydrolysis: Hydrolysis, which occur when the salts of the weak acids & bases interact with water to give either alkaline or acidic solutions” e.g. CH3COOK gives alkaline while codeine phosphate gives acidic Sol when interact with water. Molecular Hydrolysis: Hydrolysis, which involve the cleavage of drug molecule. It is much slower and irreversible process. It is catalyzed by hydrogen or hydroxyl ion and specifically acid or base catalyzed. Rate of decomposition depends on the pH of the system. e.g. the local anesthetics, amethocain and benzocaine.
  14. 14. PROTECTION AGAINST HYDROLYSIS:  Avoiding contact with moisture at time of manufacture.  Packaging in suitable moisture resistant packs such as strip packs and storage in controlled humidity and temperature.  In liquid dosage form since , hydrolysis is acid or base catalyzed , an optimum PH for max stability should be selected and the formulation should be stabilized at this PH by inclusion of proper buffering agents.  Hydrolysis of certain drugs such as benzocaine and procaine can be decreased by the addition of specific complexing agent like caffeine to the drug solutions .  Hydrolysis susceptible drugs such as penicillin and derivatives can be prevented by formulating them in the dry powder form for reconstitution or dispersible tablets instead of a liquid dosage form such as solutions or suspensions.
  15. 15. Preventive Measures for Hydrolysis: Adjustment of pH: Rate of decomposition is critically dependent upon pH. In the case of acid-base catalyzed hydrolysis at minimum pH the drug stability is maximum. This can be shown by plotting a relationship b/w log of the reaction velocity constant for decomposition and pH Maximum stability for different drugs at dif. pH Atropine sulphate 3.8, Procaine 3.6, Benzocaine 4.9 Choice of solvent:  More we go away from the water hydrolysis- e.g. Aspirin is unstable in aq. Sol. So it is formulated in alcohol i.e. propylene glycol.  In some cases non-aq. Solvent increases the instability of product e.g. Cyclamic acid in aq. sol. Hydrolyze in slow rate while in alcohol high rate. Addition of surfactants: Addition of surface-active agents results into significant improvement of drug stability. This occurs due to the micelles formation. Surface active agents are of two types cationic and anionic. Anionic micelles are more effective.
  16. 16. Production of insoluble form of drug: Hydrolysis occur only with that portion of drug which is in aq. Sol. Hydrolysis can be minimized by · By making suspensions · By pH adjustment of the aq. Vehicle. · By preparing insoluble salt of the drug. E.g. insoluble procaine salt of benzyl penicillin. · By preparing “transient derivatives” of the drug. Modification of chemical structure: Change of chemical structure of a chemical drug may prevent the hydrolysis. e.g. Alkyl to alkyl chain. Presence of complexing agent: By the presence of a compound, which would form water, soluble complex with drug the rate of decomposition may be decreased. e.g. caffeine decrease the rate of decomposition of local anesthetics such as benzocaine, procaine & amethocaine.  f
  17. 17. 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.  Occurs when exposed to atmospheric oxygen.  Either the addition of oxygen or removal of hydrogen .  Oxidation is the loss of electrons while reduction is the gain of electrons. Types: Oxidation has two types · Auto-oxidation · Photo-oxidation  Auto-oxidation: Oxidation in which the oxygen present in the air is involved. This process proceeds slowly under the influence of atmospheric oxygen e.g. Oil, fats & unsaturated compound can undergo auto- oxidation.  The reaction between the compounds and molecular oxygen is required for initiating the chain reaction is called autoxidation .  Free radicals produced during initial reaction are highly reactive and further catalyze the reaction produced additional free radicals and causing a chain reaction.  Heavy metals such as copper , iron , cobalt , and nickel have been known to catalyze the oxidative degradation .Heat and light further influence the kinetics of oxidative degradation processes.
  18. 18. Photo-oxidation: Oxidation in which removal of the electron is involved without presence of O2.” This type is less frequently encountered e.g. It occurs in adrenaline, riboflavin & ascorbic acid etc. STEPS INVOLVED OXIDATION REACTION:  INITIATION : Formation of free radicals is taken place . R--H  R. + [H. ]  PROPOGATION : here the free radical is regenerated and react with more oxygen . R. + O2  R.—O2 R.O2 + RH  ROOH + R.  HYDROPEROXIDE DECOMPOSITION ROOH  RO. + OH.  TERMINATION : free radicals react with each other resulting in inactive products. R.--O2 + X  Inactive product RO2 + RO2  Inactive product EXAMPLE OF DRUGS DECOMPOSED BY OXIDATION PATHWAYS Archis oil , clove oil , ethyl oleate ,Heparin , Ascorbic acid , Morphine ,Vitamin A , Vitamin B12 , etc.
  19. 19. PROTECTION AGAINST OXIDATION  USE OF ANTIOXIDANTS : antioxidants are Mainly of 3 types : 1. The first group probably inhibits the oxidation by reacting with free radicals. Example – tocopheral , butylated hydroxyl anisole (BHA) , butylated hydroxyl toluene's (BHT). Concentration 0.001 – 0.1%. 2. The second group comprising the reducing agents , have a lower redox potential than the drug or other substance that they should protect and are therefore more readily oxidized. Example –ascorbic acid and iso ascorbic acid , potassium or sodium salts of metabisulfite. 3. The third group, little antioxidant effect themselelf but enhance the action of true antioxidant Example -- Citric acid , tartaric acid , disodium edetate and lecithin .  USE OF CHELATING AGENT: when heavy metals catalyze oxidation . Example -- EDTA , citric acid , tartaric acid form complexes.  The presence of reducing agent: Oxidation of pharmaceutical products can be retarded by the addition of reducing agents they are equally effective against oxidizing agents and atmospheric oxygen. e.g. · potassium metabisulphites · sodium metabisulphites
  20. 20. Removal of oxygen: By limiting the contact of drug with the atmosphere, those oxidative decompositions dependent upon atmospheric oxygen may be often minimized. The presence of surface active agent: Oxidizable materials such as oil soluble vitamins essential oils and unsaturated oils have been formulated as solubilized and emulsified products Adjustment of pH: Many of those oxidative decompositions involving a reversible oxidation reduction process are influenced by the hydrogen ion concentration of the system.  m n m n
  21. 21. PHOTOLYSIS  Exposure to light cause substantial degradation of drug molecule. • When molecules are exposed to electromagnetic radiation they absorb light (photons) at characteristic wavelength which cause increase in energy which can :  Cause decomposition.  Retained or transferred.  Be converted to heat .  Result in light emission at a new wavelength (fluorescence , phosphorescence). • Natural sun light lies in wavelength range (290– 780nm) of which only higher energy (UV) range (290 --320) cause photo degradation of drugs.
  22. 22. Example of phototoxic drugs: Furosemide , acetazolamide , cynocobalamine . EXAMPLE Sodium nitropruside in aqueous solution (which is administered by IV infusion for management of acute hypertension ). 1. If protected from light it is stable to at least 1yr. 2. If exposed to normal room light it has a shelf life of 4 hrs. PROTECTION 1. Use of amber colored bottles . 2. Storing the product in dark , packaging in cartons also act as physical barrier to light. 3. Coating of tablets with polymer films. bb
  23. 23. Decarboxilation: Elimination of CO2 from a compound. e.g. · When sol. Of NaHCO3 is autoclaved. · autoclaving the tuberculostatic agent sodium aminosalicylate Isomerization: Conversion of an active drug into a less active or inactive isomer having same structural formula but different stereochemical configuration. Types: · Optical isomerization · Geometrical isomerization Polymerization: Combination of two or more identical molecules to form a much larger and more complex molecule. e.g. Degradation of antiseptic formulations and aldehydes is due to polymerization. mm