Abstract

Reaction Mechanisms under Different Forced Degradation Conditions

R Nageswara Rao, Chief Scientist/Head, Analytical Chemistry, Indian Institute of Chemical Technology

One of the major challenges in drug development is identifying the mechanisms of degradation responsible for the instability of active pharmaceutical ingredients under different storage conditions. Generally, two basic mechanisms viz., chemical and physical degradation are largely responsible for product instability. Chemical degradation involves processes leading to break or formation of new cova¬lent bonds which ultimately generate new chemical entities. Alternatively physical degradation involves changes in the physical state such as aggregation or phase transition without altering the chemi¬cal composition. Although the two major mechanisms of degradation are distinct, they are often interrelated with well-known connections between chemical degradation reactions and the induction of physi¬cal changes. Forced degradation is as an integral part of the drug development process which helps us in generation of all possible degradation products that may form under different conditions. It is an important tool that is used to predict stability problems, develop analytical methods, and identify degradation products/pathways. The chemical instability of the drug substance under the conditions of heat, humidity, solvent, pH, and light encountered during manufacture, isolation, puri?cation, drying, storage, transportation, and/or formulation is main cause of its degradation. The major routes of degradation of any drug substance include hydrolysis, oxidation, heat and photolysis. In this lecture, the major mechanisms of chemical decomposition of pharmaceuticals including hydrolysis/dehydration, oxidation, isomerization/epimerization, decarboxylation, rearrangements, dimerization/polymerization, and photolysis and transformation products involving reactions with excipients/salt forms will be examined. The use of advanced analytical techniques in proposing/predicting the reaction mechanisms of pharmaceutical degradations will also be discussed.