Determination of potentially genotoxic impurities in crotamiton active pharmaceutical ingredient by gas chromatography.

In the recent years control of potentially genotoxic impurities have an increasing importance in the analysis of active pharmaceutical ingredients. Guidelines of different regulatory bodies specify very low limits for these impurities, in many cases the analytical development is challenging to comply with the requirements. In this paper potential genotoxic impurities of Crotamiton drug substance are investigated, a simple and robust gas chromatographic method is developed for the determination of genotoxic impurities in Crotamiton drug substance. One of the main benefits of this method is that it can quantify all potential genotoxic impurities that can be present in the entire synthesis pathway of Crotamiton drug substance. Crotamiton is synthesized from toluidine derivatives, in which the aromatic amine group represents genotoxic alert. In the method development toluidine isomers (o-, m-, p-toluidine), N-ethyl-toluidine isomers (o-, m-, N-ethyl-p-toluidine) and N-methyl-toluidine isomers (o-, m-, N-methyl-p-toluidine) were separated, and the developed gas chromatographic method is validated in accordance with the relevant guidelines at a specification limit of NMT 40 ppm.