Trace determination of mutagenic alkyl toluenesulfonate impurities via derivatization headspace-GC/MS in an active pharmaceutical ingredient of a candidate drug

Abstract

This study aims to optimize sodium iodide (NaI) derivatization headspace-GC/MS described in European Pharmacopoeia by using vitamin C as an alternative antioxidant for the determination of mutagenic alkyl toluenesulfonate impurities in an active pharmaceutical ingredient (API) of a candidate drug with an artemisinin derivative. Alkyl toluenesulfonates are transformed into their corresponding alkyl iodides (methyl iodide, ethyl iodide, propyl iodide, and isopropyl iodide) by utilizing the derivatization reagent NaI. Results show that the MS response of methyl iodide is a critical indicator of method robustness because of the deteriorating effects of methyl iodide on stability when sodium thiosulfate is used as an antioxidant originally described in the pharmacopoeia. With vitamin C as a newly developed antioxidant, the robustness of this method is improved significantly. The optimized method is further validated and applied successfully for the quality control and safety of the API of an artemisinin derivative.

Keywords: Alkyl toluenesulfonate; Derivatization; GC/MS; Headspace; Mutagenic impurities.