Trace determination of genotoxic impurity p‐toluene sulfonate alkyl esters in four active pharmaceutical ingredients by using on‐line column switching liquid chromatography

Abstract

Sulfonate esters, one of the genetic impurities, have gained significant attention in recent years due to their potential to cause genetic mutations and cancer. In this study, we reported a novel on‐line column‐switching liquid chromatography method for the quantitative analysis of three p‐toluene sulfonate alkyl esters in active pharmaceutical ingredients (APIs). The sensitivity was improved by large‐volume injection. A diluting modulation‐based sampling procedure was specifically devised to mitigate the impact of solvent effects and resolve the poor stability of isopropyl p‐toluene sulfonate alkyl ester. The established method was validated in terms of linearity, sensitivity, accuracy, stability, and robustness. The limit of quantitation level was determined to be 1 ng/mL (equivalent to 1 ppm relative to 1 mg/mL API samples). Besides, the method was applied for four APIs Tosuloxacin toluene sulfonate, Lapatinib toluene sulfonate, Nirapalib toluene sulfonate, and Capecitabine. The recoveries of all target analytes in the four‐drug substances were within 89%–110%. The expanded uncertainties of the measurements ranged from 6.8% to 8.4% at a coverage level of k = 2 and a confidence level of approximately 95%. The method described in this paper was compared with other published literature, demonstrating its simplicity and ease of standardization which could be further applied in the quality control and safety assessment of drug substances.