Simultaneous Determination of 15 Sulfonate Ester Impurities in Phentolamine Mesylate, Amlodipine Besylate, and Tosufloxacin Tosylate by LC-APCI-MS/MS

Abstract

Sulfonate esters have been recognized as potential genotoxic impurities (PGIs) in pharmaceuticals. An LC-MS/MS method was developed and validated for the simultaneous determination of 15 sulfonate esters, including methyl, ethyl, propyl, isopropyl, and n-butyl esters of methanesulfonate, benzenesulfonate, and p-toluenesulfonate in drug products. The method utilized atmospheric pressure chemical ionization (APCI) in multiple reaction monitoring (MRM) mode for the quantitation of impurities. The method employed an ODS column as the stationary phase and water-acetonitrile as the solvents for gradient elution without derivatization steps. The method was specific, linear, accurate, precise, and robust. Recoveries of the sulfonic esters from three drug matrices were observed in the range of 91.6∼109.0% with an RSD of not greater than 17.9% at the concentration of the LOQ and in the range of 90.4%∼105.2% with an RSD of not greater than 7.1% at the concentration of 50 ng/mL for the methanesulfonates and 10 ng/mL for the benzenesulfonates and p-toluenesulfonates. The LOD was not greater than 15 ng/mL, 2 ng/mL, and 1 ng/mL for the methanesulfonate, benzenesulfonate, and p-toluenesulfonate esters, respectively. This method was sufficiently sensitive to detect the 15 PGIs in the phentolamine mesylate tablet, amlodipine besylate tablet, and tosufloxacin tosylate tablet. This analytical method is a direct, specific, rapid, and accurate quality control tool for the determination of the 15 sulfonate esters that are most likely to exist in drug products.

Liquid chromatography-tandem mass spectrometric method for trace quantification of ethyl methanesulfonate: a genotoxic impurity in dapoxetine hydrochloride

“…No interference was observed in the MRM transition chromatograms of blank and DAPO at m/z of 125.1(Q1)/79.1(Q3) at the retention time of EMS, indicating that the developed method is specific and selective for EMS. LOQ value found to be lower or equal to the reported LC-MS/MS methods [14,16,17]. F cal values from the linear regression analysis were found to be significantly greater than their corresponding F crit at 5% level of significance, suggesting that the regression model is significant.…”

“…While the GC methods involving derivatization of EMS can suffer from false-positive results due to the possibility of residual alcohols present in the drug substances also undergoing derivitization. The mass spectrometric methods reported [14][15][16][17] for the determination of EMS in different drug substances were found to have either higher injection volume or higher LOQ or narrow linearity ranges.…”

A Primer for Pharmaceutical Process Development Chemists and Analysts in Relation to Impurities Perceived to Be Mutagenic or “Genotoxic”

“…Another feature of such articles is that there is nearly always no attempt to apply the analytical method to actual drug substance or drug product samples. The 2019 publication by Jin et al is an exception, and it is noteworthy that no alkyl sulfonate impurities were detected in any of the three drug substances under investigation. Alkyl sulfonates are often described as hypothetical or potential impurities, which should not remove the obligation to set out an evidence-based rationale as to why they might be formed.…”

Commentary on “time-dependent selected reaction monitoring-based GC-MS/MS method for estimation of genotoxic impurities in a new antibacterial agent: alalevonadifloxin mesylate”

“…We believe that such information is necessary to support or refute the hypotheses employed to justify the development of the GC-MS/MS assay. There is one recent exception to this normal pattern (Jin et al 2019); these researchers actually applied their assay method for 15 sulfonate esters to commercial samples of three drug products: phentolamine mesylate, amlodipine besylate, and tosufloxacin tosylate. None of esters was detected in any of the drug products under investigation.…”