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UNIT-V DRUG STABILITY

UNIT-V DRUG STABILITY. By: Ms. Santoshi Naik Department of Pharmaceutics YPCRC. Introduction. Reaction kinetics/ Chemical kinetics

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UNIT-V DRUG STABILITY

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  1. UNIT-V DRUG STABILITY By: Ms. Santoshi NaikDepartment of PharmaceuticsYPCRC

  2. Introduction Reaction kinetics/ Chemical kinetics Is the branch of Physical Chemistry which deals with the rate of reaction including rate laws, external factors such as temperature, time, pressure, concentration, characteristics and also includes mechanism of the reactionor sequence of steps involved.

  3. Law of mass action: • Given by Norwegian Chemist Guldberg and Wage. • It states that for any given reaction the rate is directly proportional to molar concentration of the reacting species when the temperature condition is kept fixed. A + B  C + D Rate of reaction ∝ Concentration of reactants R = K [A]m [B]n

  4. Rate of Reaction: It is defined as the speed at which the reaction takes place. Reacting molecule A  Product B Rate constant Rate constant Δ[A] = change in concentration of A over time period Δt Δ[B] = change in concentration of B over time period Δt Because [A] decreases with time, Δ[A] is negative. Because [B] increases with time, Δ[B] is positive

  5. Order of Reaction: • It is defined as the sum of the powers of the concentration of reactants in the given rate law. • m A + n B --- mn [AB] • Rate of reaction ∝ [A]m [B]n • Thus order of reaction is m + n • Range of the order of reaction varies from 0 to 3. Eg: Rate = K [N2O5] Order is 1 Rate = K [H2] [O2] Order is 2 Rate = K [H2] [NO2]2 Order is 3

  6. Molecularity of the reaction: • Number of reacting molecules undergoing simultaneous collision in a given chemical reaction. • They are classified as: • Elementary reaction • Complex reaction • They are also classified as: • Unimolecular • Bimolecular • Termolecular

  7. TYPES OF ORDER OF REACTION

  8. Pseudo-order reaction Are the reactions in which one of the reacting species is in excess showing the order different from the actual order. CH3COOC2H5 + H2O  CH3COOH + C2H5OH • Original order of the reaction is 2 • But actual order is 1

  9. Pseudo Zero order reaction: Is a reaction which may be a first order, but behaves like a zero order reaction depending on the experimental conditions. Eg: drug degradation in suspension • Pseudo First order reaction: Is a reaction which may be a second order, but behaves like a first order reaction depending on the experimental conditions. Eg: acid hydrolysis of methyl acetate

  10. Zero order reaction • It is defined as a reaction in which the rate does not depend on the concentration terms of the reactants. • Mathematically expressed as: • Where ko is the specific rate constant for zero order • Unit of zero order reaction is moles/litre. Sec. • Eg: Colourloss of liquid multisulfonamide preparation, oxidation of vitamin A in oily solution.

  11. Half life of zero order reaction: • It is the time required for the concentration of the reactant to reduce to half of its initial concentration in a reaction. c = a/2 at t = t ½ • Unit is sec/conc. or min/conc. or hour/conc. t 1/2

  12. Shelf life of zero order reaction: • It is defined as the time required for the concentration of the reactant to reduce 90% of its initial conc. c = 90a/100 at t = t 90 • Unit is sec/conc. or min/conc. or hour/conc. t 90

  13. First order reaction • It is defined as the reaction in which the rate of reaction depends on the conc. of one reactant. • Mathematically expressed as: • Where k1 is the specific rate constant for first order • Unit of first order reaction min-1 or hour-1 or sec-1. • Eg: Acid hydrolysis of ester, inversion of sugar, disintegration of radioactive elements.

  14. t 1/2 Half life of first order reaction: Shelf life of first order reaction: t 90

  15. Second Order Reaction • It is defined as the reaction in which the rate of reaction depends on the conc. of two reactants. • Eg: A + B  Products • The rate equation can be written as: [A]1[B]2 • Unit of second order rate constant is litre/ mole /min • Eg: alkaline hydrolysis of esters such as methylacetate or ethylacetate, hydrolysis of chlorbutanol in presence of NaOH

  16. Half life of second order reaction: • Shelf life of second order reaction: t 1/2 t 90%

  17. Determination of order of reaction • Graphical method • Substitution method • Half life method

  18. Graphical method • Most reliable method of determination of order of reaction. • A straight line that gives better fit is identified.

  19. Substitution method • Data is substituted in the integral equations of zero, first and second order reactions to get k value and the one that gives constant k value is identified.

  20. Half life method • The average k value is calculated and then t1/2 values are calculated.

  21. Physical and Chemical Factors Influencing Degradation of Pharmaceutical Products

  22. Influence of solvent • The more polar solvent (nitrobenzene & ethanol) accelerate the formation of more polar products or retards the formation of less polar products. • Less polar solvent (hexane) accelerates the formation of less polar products or retards the formation of more polar products. C2H5OH + (CH3CO)2O CH3COOC2H5 + CH3COOH LESS POLAR MORE POLAR

  23. Influence of pH • Most of the drugs degrade at extreme pHs. ie. At high H+ and OH- because they are the catalytic species and accelerate the rate of reaction. • Ionic species degrade at a faster rate than the neutral/ unionized species because the ionic species are more water soluble & prone to chemical reaction. • The optimum pH for maximum stability is 3.5 to 5.0

  24. Influence of Buffers • The vehicle of dosage form is adjusted to defined pH using buffers – which resist the changes in pH of the solution. • Eg. of buffers are acetate, citrate, lactate, phosphate and ascorbate. • Buffers participate in the formation or breakdown of activated complexes. • The catalytic species are referred as General acid base catalysts and Specific acid base catalysts.

  25. General acid-base catalysts: It refers to any acid or base we add to the solution will affect the rate of reaction. • Specific acid-base catalysts: It refers to the fact that just one acid or base from the solvent (specifically H+ or OH- ions) will affect the rate of reaction.

  26. Influence of Ionic strength • Drug degradation involves drug-ion or ion-ion species interaction. • The rate is affected by presence of other ions (sodium chloride) in solution, but in presence of buffers the effect of ions is nullified. • As ionic strength increases, the rate of reaction between ions of opposite charges decreases, whereas between ions of similar charges increases.

  27. Influence of dielectric constant • The rate constant depends on the dielectric constant of the solvent.

  28. Influence of excipients • Excipients may act directly or indirectly in drug degradation. • Direct – by acting as reactant or as catalyst. • Indirect – moisture present in excipients accelerates the drug degradation by changing melting behaviour or pH or functional groups. • Eg: Mg stearate accelerates discolouration of tablets containing amines and lactose, sugars enhance hydrolytic degradation of thiamine hydrochloride.

  29. Influence of temperature • The rate of reaction increases about 2 or 3 times with every 10° rise in temperature. • Arrhenius equation explains the effect of temperature on the rate of reaction. k = Ae –Ea/RT

  30. Taking log on both sides, ln k = ln A – Ea/ RT ln e Converting to log base 10 log k = log A -

  31. Energy of activation (Ea)- is the minimum energy that the molecule should possess so that molecular collisions produce the product. • Arrhenius factor (A)- is the frequency of collisions between the reacting molecules in a reaction.

  32. Mechanism: Collision theory postulates • Collisions must occur between reactant molecules for the reaction to proceed. • The colliding molecules must possess certain energy for reaction to take place. At any temperature molecules possess certain energy, but as temp. rises more molecules absorb energy and get activated which results in increased rate of reaction.

  33. Influence of light • Drugs undergoing light induced chemical degradation is called Photolabile (photosensitive) drugs. • The light induced chemical degradation – Photolytic degradation • The energy unit of radiation is photon. • Photon is directly proportional to frequency or inversely proportional to wavelength of the radiation.

  34. Photodegradation is usually hydrolysis and oxidation. • Photodegrdation is mediated by free radicals to produce dark or light coloured products. • Eg: Riboflavin, ciprofloxacin, chlorpromazine, tetracycline. Photolytic degradation may induce following changes: • Degradation of substance • Retention or transfer of energy • Conversion to heat • Emission of light at a new wavelength

  35. Prevention of photolytic degradation: • It can be inhibited with additives like antioxidants which interrupt degradation processes. e.g: derivatives of aniline. • It can be inhibited by using UV absorbers which capture the photon and convert it to heat in case creams, ointments & liquid d.feg: hydroxy-substituted benzophenones.

  36. It can be prevented by use of opacifying and coating agents in various dosage forms. e.g.. of opacifiers are yellow, red & black iron oxides & e.g.. of coating agents includes film coating, use of opaque blisters and capsules.

  37. Protection of drug from light can be achieved by the use of an opaque or amber coloured container. • The pharmacopoeia prescribe conditions for containers (eg: light resistant) and storage (eg: protected from light) for photosensitive drugs and formulations.

  38. Complex formation between photosensitive drug and complexing agent is a method of stabilization of drugs. Eg: caffeine as complexing agent for photostabilization of drug riboflavin.

  39. Influence of oxygen • Chemical degradation under the influence of oxygen is called Photo-oxidation. • Oxidation is loss of electrons from a molecule. • The reaction between compounds and molecular oxygen is called auto-oxidation which proceeds in presence of O2, light and traces of heavy metals. • Eg: Riboflavin, morphine, prednisolone, epinephrine, arachis oil, clove oil, ascorbic acid.

  40. OXIDATION OF ASCORBIC ACID

  41. General principles: • Atmospheric oxygen promotes the rate of oxidation. • Light provides the necessary energy to initiate the oxidation process. • The presence of trace heavy metals also accelerate the rate of oxidation. • Organic peroxides also promote the oxidation reaction. • Oxidation reaction between ionic species proceeds faster compared to neutral molecules. • Oxidation reactions are catalysed by H+ and OH- ions. The hydroxyl ions catalyse oxidation faster than hydrogen ions.

  42. Protection against Oxidation • Antioxidants – eg. tocopherols, BHA, BHT, ascorbic acid. • Chelating agents – eg. EDTA, citric and tartaric acid. • Vehicles – replacing water with other solvents taking into consideration solubility, ionic strength, polarity and dielectric constant of the solvent. • Micellar solubilization–surfactants protect the drug above its CMC by entrapping drugs into micelles.

  43. Buffers – will impart stability to drug when oxidation is catalyzed by H+ or OH- ions. • Environmental control measures: • Preventing the exposure to light – amber coloured containers or secondary packaging. • Oxygen free environment – replacing air with inert gases such as Nitrogen or CO2. • Low temperature storage – store the product in a cool place.

  44. Influence of moisture • Water is a critical reactant and degradation catalyzed by moisture is called hydrolysis. • Mechanism of hydrolysis: • Acts as a reactant or as a catalyst (H+ or OH- ions). • Hydration • Isomerization • Alters the physical state by adsorbing on the surface of the solid • Solubilizing the drugs in the solvent

  45. Eg. of drugs which decompose by hydrolytic pathway are esters like Aspirin, Procaine, atropineand amides like Chloramphenicol, ampicillin, cephalosporins, barbituric acid. • Drugs with ester and amide groups react with one molecules of water and undergo hydrolysis. • Esters undergo hydrolysis to give acids and alcohols. • Esters undergo hydrolysis at a faster rate than amides.

  46. Hydrolysis of Aspirin:

  47. Protection against Hydrolysis • Buffers: are added to maintain the optimum pH to 3.5-5. Eg: Pilocarpine is highly active at alkaline pH so acidic buffer (boric acid buffer) is selected for maximum stability. • Complexation: Hydrolysis can also be inhibited by addition of complexing agent. Eg: Hydrolysis of benzocaine can be inhibited by addition of caffeine as complexing agent.

  48. c) Suppression of solubility:when the solubility of drug decreases the rate of hydrolysis is reduced because conc. of drug in solution phase will be decreased. Solubility can be suppressed by: • Addition of additives like citrates, dextrose, sorbitol and gluconates. • Using salt form of drug which is poorly soluble eg: procaine penicillin. • Using poorly water soluble derivatives like esters of drugs (chloramphenicol palmitate)

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