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1 DRUG STABILITY Physical Pharmacy (Attwood C3 ) ( Loftsson Drug Stability for Pharmaceutical Scientists)

Chemical Breakdown of Drugs:

Chemical Breakdown of Drugs Hydrolysis Oxidation Isomerization Photochemical decomposition Polymerization


Hydrolysis Drugs containing ester, amide, lactam, imide or carbamate groups are susceptible to hydrolysis Solutions can be stabilized by formulating at the pH of maximum stability or, in some cases, by altering the dielectric constant by the addition of non-aqueous solvents


Oxidation Oxidation involves the removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or radical Oxidative degradation can occur by auto-oxidation, in which reaction is uncatalyzed and proceeds quite slowly under the influence of molecular oxygen, or may involve chain processes consisting of 3 concurrent reactions: initiation, propagation and termination


Oxidation Examples of drugs that are susceptible to oxidation include steroids and sterols, polyunsaturated fatty acids, phenothiazines , and drugs such as simvastatin and polyene antibiotics that contain conjugated double bonds


Oxidation Various precautions should be taken during manufacture and storage to minimize oxidation The oxygen in pharmaceutical containers should be replaced with nitrogen or carbon dioxide Contact of the drug with heavy-metal ions such as iron, cobalt or nickel, which catalyze oxidation, should be avoided Storage should be at reduced temperatures Antioxidants should be included in the formulation


Isomerization The process of conversion of a drug into its optical or geometric isomers, which are often of lower therapeutic activity

Photochemical Decomposition:

Photochemical Decomposition Examples of drugs that degrade when exposed to light include phenothiazines , hydrocortisone, prednisolone, riboflavin, ascorbic acid and folic acid Photodecomposition may occur not only during storage, but also during use of the product. For example, sunlight is able to penetrate the skin to a depth sufficient to cause photodegredation of drugs circulating in the surface capillaries or in the eyes of patients receiving the drug

Photochemical Decomposition:

Photochemical Decomposition Pharmaceutical products can be adequately protected from photo-induced decomposition by the use of colored-glass containers (amber glass excludes light of wavelength < 470 nm) and storage in the dark Coating tablets with a polymer film containing ultraviolet absorbers has been suggested as an additional method for protection from light


Polymerization Polymerization is the process by which 2 or more identical drug molecules combine together to form a complex molecule Examples of drugs that polymerize include amino- penicillins , such as ampicillin sodium in aqueous solution, and also formaldehyde

Factors Influencing Drug Stability of Liquid Dosage Forms:

Factors Influencing Drug Stability of Liquid Dosage Forms pH Temperature Ionic strength Solvent effects Oxygen Light


pH Has a significant influence on the rate of decomposition of drugs that are hydrolyzed in solution F ormulating at the pH of maximum stability using buffers minimizes this decomposition


Temperature Increase in temperature usually causes a very pronounced increase in the hydrolysis rate of drugs in solution This effect is used as the basis for drug stability testing If drug formulation is particularly unstable at room temperature, for example, injections of penicillin, insulin, oxytocin and vasopressin, it should be labelled with instructions to store in a cool place


Oxygen The susceptibility of a drug to the presence of oxygen can be tested by comparing its stability in ampoules purged with oxygen to that when it is stored under nitrogen Drugs which have a higher rate of decomposition when exposed to oxygen can be stabilized by replacing the oxygen in the storage container with nitrogen or carbon dioxide. These drugs should also be kept out of contact with heavy metals and should be stabilized with antioxidants


Light The susceptibility of a drug to light can be tested by comparing its stability when exposed to light to that when stored in the dark Photolabile drugs should be stored in containers of amber glass and, as an added precaution, should be kept in the dark

Factors Influencing Drug Stability of Solid Dosage Forms:

Factors Influencing Drug Stability of Solid Dosage Forms Moisture Excipients Temperature Light and Oxygen


Moisture Water-soluble drugs in the solid dosage form will dissolve in any moisture layer which forms on the solid surface. The drug will now be in an aqueous environment and will be affected by many of the same factors as for liquid dosage forms It is important to select packaging that will exclude moisture during storage


Excipients Excipients such as starch and povidone have high water contents and affect stability by increasing the water content of the formulation Chemical interactions between the excipients and the drug can sometimes occur and these lead to a decrease of stability. For example, stearate salts used as tablet lubricants can cause base-catalyzed hydrolysis; polyoxyethlene glycols used as suppository bases can cause degradation of aspirin


Temperature The effect of temperature on stability can sometimes be described by the Arrhenius equation, but complications arise if dosage form melts on temperature increase (e.g. suppositories) or if the drug or one of the excipients changes its polymorphic form

Light and Oxygen:

Light and Oxygen Solid dosage formulations containing photolabile drugs or drugs susceptible to oxidation should be stored in the same was as described for liquid dosage forms to protect from light and oxygen Note also that moisture contains dissolved oxygen and hence the preparations should be sored in dry conditions

Stress Testing:

Stress Testing Expiry date The date up until which the manufacturer guarantees the full safety and potency of the drug product Stress testing Performed in drug substances, excipients, and drug products that is used to identify degradation pathways and degradation products (potential impurities), as well as intrinsic stability of the compounds under various conditions

Stress Testing:

Stress Testing May include the following Degradation studies in an aqueous HCl acid Degradation studies in an aqueous NaOH solution Degradation studies in the presence of h ydrogen peroxide Photostability studies (e.g., in sunlight or under a UV light) Evaluation of stability during sterilization (e.g., during heating in an autoclave

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