Development and validation of a sensitive method for alkyl sulfonate genotoxic impurities determination in drug substances using gas chromatography coupled to triple quadrupole mass spectrometry.

Alkyl sulfonate esters have been widely concerned as genotoxic impurities (GTIs). A gas chromatography triple-quadrupole mass spectrometry (GC-MS/MS) method has been developed for trace determination of 9 commonly encountered sulfonate esters in drug substances. Three different solvents of acetonitrile (ACN), dichloromethane (DCM) and ethyl acetate (EtOAc) were evaluated as diluents to accommodate different solubilities of test articles and multiple reactions monitoring (MRM) mode was applied for quantitation of these 9 GTIs. The method was validated in terms of linearity, sensitivity, injection precision, accuracy and solution stability. The limit of quantitation (LOQ) for the 9 commonly encountered sulfonate esters in drug substances was within 0.10-1.05 ng mL, which was much lower than the reported LOQs in other methods (2.5-1500 ng mL). It is indicated that the method gave extremely high sensitivity for all the target analytes. The correlation coefficient (r) values of 9 GTIs were no less than 0.9993 in the range of 2.0-100 ng mL. Recoveries of all the target analytes at 10, 20, 50 ng mL (equivalent to 2, 4, 10 ppm relative to 5 mg mL API samples) in two different drug substance (capecitabine and imatinib methanesulfonate) were within 75%˜120%. All alkyl sulfonates were stable in these three solvents up to 36 h. This method has been successfully used for determination of these alkyl sulfonates in capecitabine and imatinib methanesulfonate and can be further applied to other drug substances.