Summary

• The most common cause of degradation of drugs in aqueous systems is hydrolysis and the most susceptible drugs are those containing ester, amide, lactone, lactam, imide or carbamate groups. Hydrolysis can be controlled by adjusting the pH to that of maximum stability or in some cases by the addition of nonaqueous solvents.

• Oxidative degradation is a problem with drugs possessing carbon-carbon double bonds such as the steroids, polyunsaturated fatty acids and polyene antibiotics. Such drugs can be stabilised by replacing the oxygen in the system with inert gases such as nitrogen; by avoiding contact with metals such as iron, cobalt and nickel, and by adding antioxidants or reducing agents to the solution. Some oxidative degradations are pH-dependent and can be stabilised by buffering the system.

• Loss of activity of solutions of some drugs such as the tetracyclines can occur because of epimerisation of the drug molecule, while others such as vitamin A lose activity because of geometrical isomerisation.

• Photochemical decomposition can be a problem with drugs such as the pheno-thiazine tranquillisers and can cause discoloration of the solution and loss of activity. Such systems have to be stored in amber glass containers, which remove the ultraviolet components of light.

• Reactions can be classified according to their order of reaction; the breakdown of drugs in the majority of preparations in which the drug is dissolved in aqueous solution follows first-order or pseudo firstorder kinetics. There are, however, many cases of drugs in which decomposition occurs simultaneously by two or more pathways (parallel reactions), or involves a sequence of decomposition steps (consecutive reactions) or a reversible reaction.

• The hydrolysis rate of drugs in liquid dosage forms is strongly influenced by the pH of the solution and can be catalysed not only by H + and OH- ions (specific acid-base catalysis) but also by the components of the buffer used (general acid-base catalysis). We have looked at the ways in which the effect of the buffer components can be removed so that the pH of maximum stability of the solution can be determined from the pH-rate profile and the rate constants for specific acid-base catalysis can be calculated.

• Temperature increase usually causes a pronounced increase of hydrolytic degradation. We have seen how to calculate the hydrolytic rate constant at room temperature from data at elevated temperatures using the Arrhenius equation.

• The addition of electrolyte can increase the hydrolysis rate if the reaction involves the interaction of the drug ion with an ion of similar charge. Similarly, a change of solvent to one of lower dielectric constant will stabilise only this type of system but not one involving the reaction between ions of opposite sign.

• In solid dosage forms containing drugs that are susceptible to hydrolysis, decomposition of the drug can occur if moisture is allowed to adsorb on the surface of the dosage form. Careful selection of packaging is important to reduce this possibility. Drug which dissolves in this surface layer will be affected by many of the factors which

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