Identification of Novel Impurity of Ziprasidone

Abstract

Ziprasidone hydrochloride is a second-generation antipsychotic drug employed for the treatment of schizophrenia and acute mania or mixed episodes associated with bipolar disorder. During the scale-up of ziprasidone hydrochloride, an unknown impurity was observed in the batches ranging from 0.10% to 0.15% by HPLC-UV analysis. The structure of an unknown impurity was proposed as 3,3'-methylenebis(5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one) which is named as methylene ziprasidone dimer (MZD impurity). It was isolated from an enriched sample by preparative HPLC, and its structure was elucidated by comprehensive analysis of HRMS, 1D NMR (¹H, ¹³C), DEPT-135, 2D NMR (COSY, HSQC, HMBC) spectroscopy. A plausible mechanism for the formation of isolated impurity is proposed.

Keywords: Antipsychotic drug; ICH; Impurities; Methylene ziprasidone dimer; Ziprasidone.