Understanding unconventional routes to impurities from drugs in hydrolytic conditions

Abstract

Abstract: Introduction: Hydrolytic degradation is the most common cause of formation of impurities or degradation products in drugs during different stages of drug product development and/or shelf life of the drug/product. Degradation products formed by hydrolysis of ester, amide, urethane, sulfonamide, sulfonate and ether linkages, and of nitrile, hydroxyl and amino groups in drugs can be conveniently predicted and identified. Many drugs are known to degrade to such expected conventional hydrolytic degradation products, and the mechanisms of such degradations are also well known and reported. However, many drugs are reported to degrade under hydrolytic conditions to products, which cannot be justified by the conventional hydrolytic reactions. Objectives: Though structures of such unconventional hydrolytic products can be characterized through different spectral techniques, but there is a need to understand the mechanisms of such unconventional hydrolytic reactions in order to help in establishing intrinsic stability characteristics of a drug. Methodology: In the present review, we have studied and critically analysed all possible reports on hydrolytic degradation of various dugs to provide a thorough insight into unconventional routes of hydrolytic degradations of drugs. The various unconventional hydrolytic reactions found responsible for degradation of drugs are classified as oxidation, dehydrogenation, coupling/condensation, N-alkylation, C-C bond cleavage, C-N bond cleavage, dehalogenation, cyclization, decarboxylation and hydroxylation. Discussion: Varied types of reactions under hydrolytic conditions are triggered/controlled by the nature of substituent(s) across or around the susceptible bonds/groups. The mechanisms for such unconventional hydrolytic reactions have been discussed or proposed with support from the standard literature. The contents are expected to enable an analyst and a drug formulator to predict various possible as well as seemingly improbable hydrolytic degradation products of a drug well ahead of systematic forced degradation studies. Key words: Forced degradation, Impurities, Hydrolysis, Conventional, Unconventional, Mechanisms.