Determination of trace methanesulfonates in drug matrix using derivatization and headspace single drop microextraction followed by high-performance liquid chromatography with ultraviolet detection

Abstract The selective and sensitive determination of potential genotoxic methanesulfonate impurities in drug substances is highly challenging. A new method is reported for testing of methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS) and isopropyl methanesulfonate (IPMS) in active pharmaceutical ingredients (APIs). Headspace single drop microextraction (HS-SDME) with room-temperature ionic liquid (RTIL) as extractant was employed to preconcentrate analytes and eliminate the drug matrix simultaneously. In order to increase volatilities for HS extraction and to improve their reactivity of the further derivatization at the same time, sodium iodide (NaI) was added to the sample to derivatize methanesulfonates to the corresponding iodoalkanes. The iodoalkanes in the extract were derivatized with N , N -diethyldithiocarbamate (DDTC) after HS-SDME, followed by separation and detection with high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Several important parameters, including reaction temperature, reaction time and concentration of NaI, sample volume, microdrop volume, stirring rate, salt addition, extraction time, concentration, reaction time and reaction temperature of DDTC were investigated. Under the optimal conditions, LODs and LOQs of all methanesulfonates were 15 ng mL −1 and 40 ng mL −1 , respectively. Linearity (correlation coefficient values r > 0.999) and precision (the relative standard deviations were 1.0–4.6%) of six repeated injections were obtained. The recoveries at three spiked concentration levels were all in the range of 86.2–107.5% with the relative standard deviations