Forced degradation studies of drug substances plays an important role in pharmaceutical development. It is conducted as part of the stability indicating impurity method development focusing on separating all of the degradants from the active pharmaceutical ingredient (API). The subsequent structural characterization of the main degradants provides the insight into the chemistry and stability of the drug. The knowledge from the study enables the proposal of plausible degradation pathways that are essential for regulatory filings as well as the development of formulation and package. Beclabuvir is an API which has been developed for the treatment of hepatitis C infection. The forced degradation study of Beclabuvir was conducted under stress conditions of solid exposed to 700C, solid exposed to HIL/UV, solution exposed to ambient light, oxidation, base and acid hydrolysis. Some key unknown degradants observed in the forced degradation profile were structurally characterized so as to establish the degradation pathways. It was unexpected that under photodegradation conditions, the tertiary amine on the piperazine ring of Beclabuvir was oxidized to form the hydroxyl and des-methyl analogs of the API while under oxidative condition using H2O2, the indole ring was more susceptible to oxidation to form a putative ring open degradant and two unexpected rearranged diastereomeric degradants. This presentation will discuss the workflow of the forced degradation study, the approaches to elucidate the structures of degradation products and proposal of the plausible degradation pathways.

Forced degradation and mechanistic study of beclabuvir

254th National Meeting (2017)

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