TRACE QUANTIFICATION OF EPICHLOROHYDRIN AS A POTENTIAL GENOTOXIC IMPURITY IN ACEBUTOLOL HYDROCHLORIDE DRUG SUBSTANCE BY ADVANCED GAS CHROMATOGRAPHY TECHNIQUE.

Abstract

Epichlorohydrin is a potentially genotoxic impurity widely used as an intermediate in the synthesis of
several pharmaceutical active ingredients. Due to its mutagenic and carcinogenic potential, its presence
in drug substances must be controlled at trace levels in accordance with regulatory requirements. The
present study describes the development and validation of a sensitive, accurate, and reliable headspace
gas chromatographic method coupled with flame ionization detection (HS-GC-FID) for the
determination of epichlorohydrin in Acebutolol Hydrochloride API. Chromatographic separation was
achieved using an Rtx-1301 capillary column under optimized headspace and gas chromatographic
conditions. The developed method was validated according to ICH guidelines for specificity, system
precision, method precision, accuracy, linearity, limit of detection (LOD), limit of quantification (LOQ),
and intermediate precision. The method exhibited excellent specificity with no interference at the
retention time of epichlorohydrin. Precision studies demonstrated satisfactory reproducibility with
%RSD values well within acceptance limits. Accuracy studies showed recoveries ranging from 93% to
112%, confirming the reliability of the method. The method was linear over the studied concentration
range with a correlation coefficient of 0.981. The LOD and LOQ values were found to be 0.7 ppm and
1.5 ppm, respectively, indicating adequate sensitivity for trace-level determination. The validated HS-
GC-FID method is simple, precise, accurate, and suitable for routine quality control monitoring of
epichlorohydrin in Acebutolol Hydrochloride API.