In silico assessment of drug substances chemical stability

Abstract

The chemical stability of active pharmaceutical ingredients (API) can be studied by physico-chemical stress tests but the interpretation of the results is often not easy. We present here, how an in silico approach has been combined with chemical expertise to advise the pharmacists on the formulation of the drug product in order to prevent chemical degradation. Stability studies have shown that the vast majority of degradation reactions are either hydrolysis or radical oxidations by oxygen of air, also called autoxidation. So we have developed computational methods for both degradation reaction types. For hydrolysis, the method is based on the Fukui indices; and for oxidation by triplet oxygen, on the stabilities of hydrogen-abstracted radicals. The representation of the degradation susceptibilities has been the subject of special efforts in order to facilitate the communication between computational and experimental chemists.