Determination of genotoxic impurities monomethyl sulfate and dimethyl sulfate in active pharmaceutical ingredients

Abstract

Dimethyl sulfate (DMS) and monomethyl sulfate (MMS) are potential genotoxic impurities created during synthesis of some active pharmaceutical ingredients. While there are a few methods to determine the genotoxic compound DMS, the determination of MMS has not been reported. Novel and sensitive methods to rapidly, simply and efficiently quantify both MMS and DMS impurities in API-salts to determine if patients could potentially meet the threshold of toxicological concern (TTC 1.5 μg per day) were developed and validated according to ICH guidelines. The extremely polar and charged analyte MMS was determined using LC-MS/MS based on reversed-phase ion-pair chromatography with no sample extraction required, and a 5 minute method run time. DMS was determined using liquid–liquid extraction using MTBE and analysed by GC-MS with a 6 minute method run time. These methods provide good recovery, accuracy, and precision over a wide concentration range (2 to 64 μg mL⁻¹ for MMS and 0.1 to 20 μg mL⁻¹ for DMS), which adequately cover the current threshold of toxicological concern.