Low level determination of p-toluenesulfonate and benzenesulfonate esters in drug substance by high performance liquid chromatography/mass spectrometry

GC/FID and HPLC/MS single ion monitoring methods have been evaluated for the determination of trace levels of methyl, ethyl and isopropyl esters of p-toluenesulfonic acid and methyl, ethyl, isopropyl and n-butyl esters of benzenesulfonic acid in drug substances. These sulfonate esters have been highlighted as potential genotoxins. HPLC/MS was found to be more promising and limits of quantification were between 2.5 and 5 ng/mL, which enabled detection limits in drug substance at 0.01-0.1 ppm for a 50 mg/mL solution. For one drug substance excellent recoveries of 94-95% were obtained at the 1.0 ppm level, however, with a second drug substance, a besylate salt. recoveries ranged from 86% to 100% and were dependant on the sample preparation. Limited stability of the sulfonate esters ill various potential sample solutions indicated that samples may need to be prepared immediately before injection. (c) 2005 Elsevier B.V. All rights reserved.