drug stability

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AIMST UNIVERSITY

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welcome

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CONTENTS Identify those classes of drugs that are particularly susceptible to chemical breakdown and examine some of the precautions that can be taken to minimize the loss of activity. Look at how reactions can be classified into various orders, and how we can calculate the rate constant for a reaction under a given set of environmental conditions. Look at some of the factors that influence drug stability. Examine methods for accelerating drug breakdown using elevated temperatures and see how to estimate drug stability at the required storage conditions from these measurements.

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KEY WORD Drugs may break down in solution and also in the solid state (for example, in tablet or powder form).It is often possible to predict which drugs are likely to decompose by looking for specific chemical groups in their structures. The most common causes of decomposition are hydrolysis and oxidation, but loss of therapeutic activity can also result from isomerisation, photochemical decomposition and polymerization of drugs. It is possible to minimize breakdown by optimizing the formulation and storing under carefully controlled conditions.

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THE CHEMICAL BREAKDOWN OF DRUGS The main ways in which drugs break down are as follows: Drugs containing ester, amide, lactam, imide or carbamate groups are susceptible to hydrolysis. Hydrolysis can be catalyzed by hydrogen ions (specific acid catalysis) or hydroxyl ions (specific base catalysis). 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. HYDROLYSIS:

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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 uncatalysed and proceeds quite slowly under the influence of molecular oxygen, or may involve chain processes consisting of three concurrent reactions: initiation, propagation and termination. 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.

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Con… 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

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ISOMERISATION: Isomerisation is the process of conversion of a drug into its optical or geometric isomers, which are often of lower therapeutic activity. Examples of drugs that undergo isomerisation include adrenaline (epinephrine: racemisation in acidic solution), tetracyclines ( epimerisation in acid solution), cephalosporins (base- catalysed isomerisation) and vitamin A ( cis –trans isomerisation).

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

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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 photodegradation of drugs circulating in the surface capillaries or in the eyes of patients receiving the drug.

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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 suffi - cient to cause photodegradation of drugs circulating in the surface capillaries or in the eyes of patients receiving the drug. Pharmaceutical products can be adequately protected from photo-induced decomposition by the use of coloured 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.

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PREVENTION OF OXIDATION,HYDROLYSIS AND PHOTOCHEMICAL DECOMPOSITION Theoretically speaking, we have to choose for every drug product an antioxidant which can undergo oxidation faster than the drug itself, i.e. based on the difference in redox potential. But practically what pre-formulation scientists do is, after selecting the antioxidant, the drug is placed together with the antioxidant and they are subjected to standard oxidative conditions. The products are periodically assayed both for the drug content and the antioxidant content. Based on this type of practical studies a suitable antioxidant is fixed for the formulation. The effectiveness of antioxidants can be enhanced through the use of synergists such as chelating agents. LIMITATION: ANTIOXIDANTS

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Chelating agents form complexes with heavy metal ions and prevent them from catalyzing oxidative decomposition. Some good examples of chelating agents are ethylenediamine tetracetic acid derivatives and salts, dihydroxyethyl glycine , citric acid and tartaric acid. Chelating Agents

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Light sensitive materials are stored in amber coloured bottles. LIGHT Packing materials are so chosen (usually glass and plastic) to prevent exposure of drug products to high humid condition. Humidity

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For different drug products the pH of optimum stability is determined and maintained by the addition of buffering solutions. pH By the addition of a suitable solvent hydrolysis rate may be decreased. Modification of chemical structure of the drug moiety and the use of salts and esters of the drug which have lesser solubility are also methods used to reduce hydrolytic decomposition. Solvents LIMITATION But these methods have the very big limitation that they alter the physiological activity of the drug molecule or bio-availability of the drug molecule.Thus drug products are designed in a way that minimizes decomposition. Then they are stored under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality and purity of the drug products are not affected.

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Kinetics of chemical decomposition in solution Zero-order reactions: The decomposition proceeds at a constant rate and is independent of the concentrations of any of the reactants. The rate equation is: d x / dt = k0 Integration of the rate equation gives: x = k0 t A plot of the amount decomposed (as ordinate) against time (as abscissa) is linear with a slope of k0 (Figure ). The units of k0 are concentration time-1. Many decomposition reactions in the solid phase or in suspensions apparently follow zero-order kinetics. Plot of the amount decomposed against time for a zero-order reaction.

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First-order reactions: The rate depends on the concentration of one reactant. The rate equation is: Integration of the rate equation gives: Rearrangement into a linear equation gives: A plot of time (as ordinate) against the logarithm of the amount remaining (as abscissa) is linear with a slope = –2.303/ k1 (Figure ). The units of k1 are time–1. If there are two reactants and one is in large excess, the reaction may still follow first-order kinetics because the change in concentration of the excess reactant is negligible. This type of reaction is a pseudo first-order reaction. The half-life of a first-order reaction is t0.5 = 0.693/k1. The half-life is therefore independent of the initial concentration of reactants. d x / dt = k1(a – x)

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SECOND-ORDER REACTIONS: The rate depends on the concentration of two reacting species A and B. For the usual case where the initial concentrations of A and B are different, the rate equation is: where a and b are the initial concentrations of reactants A and B, respectively. The integrated rate equation is: d x / dt = k2(a – x)(b – x) Rearrangement into a linear equation gives: A plot of time (as ordinate) against the logarithm of [( a – x)/(b – x)] (as abscissa) is linear with a slope = 2.303/ k2(a – b) (Figure). The units of k2 are concentration–1 time–1. The half-life of a second-order reaction depends on the initial concentration of reactants and it is not possible to derive a simple expression to calculate it .

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