Identification of a Novel Process Impurity, Root Cause Investigation, and Its Control Strategy in Process Chemistry of Nevirapine API

Abstract

An impurity eluting at RRT of 6.4 was observed during the HPLC testing of nevirapine (1) API for related substances. By using a strategy that combines LC-PDA/UV-MSⁿ with NMR studies, the impurity was identified as 8-n-propyl nevirapine (2), a novel impurity that has not been reported in the literature. This impurity was sometime above 0.10% and difficult to be purged in the downstream of the existing manufacturing process of nevirapine, most likely due to its structural similarity to the API. Hence, this impurity should be controlled from the source of its generation in the process chemistry of nevirapine. During the early stage of the root cause investigation, two critical precursors to the impurity (2), (E)- and (Z)-N-propylidenecyclopropanamine (10 and 10′), were detected along with other relevant impurities, and based upon that, a probable formation mechanism of the impurity was proposed. In the late stage of the investigation, guided by the proposed mechanism, the process parameters of nevirapine manufacturing are optimized, under which the level of the impurity is reduced to 0.02% or below, while the yield of nevirapine is improved by 16%.