A multi-analyte LC-MS/MS method for screening and quantification of nitrosamines in sartans

Abstract

An incident of sartan medicine contamination was notified by Europe in June 2018. The contaminant was identified as a probable carcinogenic nitrosamine and the recalls of sartan medicines were soon made. Since then, more nitrosamine contaminants in sartan medicines were reported. To broaden the applicability and variety in nitrosamine determination, a multi-analyte method is required. In this study, a feasible and sensitive multi-analyte LC-MS/MS method for determination of 12 nitrosamines in sartans was established, where the active pharmaceutical ingredients and final products merchandised in Taiwan were also examined. Chromatographic separation was achieved on an Xselect ® HSS T3 column (15 cm £ 3 mm i.d., 3.5 mm) with gradient elution using mobile phase A consisting of 0.1% formic acid in water and mobile phase B consisting of 0.1% formic acid in acetonitrile/methanol (2:8). Validation of the proposed method was also carried out. The limit of detection and limit of quantification for 12 nitrosamines were 20 ng/g and 50 ng/g, respectively. The intra-day and inter-day recoveries of nitrosamines were among 80e120% with precision of 20% for most nitrosamines within sartans matrices. The method was successfully established and applied to authentic samples which a total of 98 positive samples containing 5 distinct nitrosamines, including N-nitrosodiethylamine, N-nitrosodimethylamine, N-nitroso-N-methyl-4-aminobutyric acid, N-nitrosomorpholine and Nnitrosopiperidine, were detected from 557 authentic samples.

Comparison of EI-GC-MS/MS, APCI-LC-MS/MS, and ESI-LC-MS/MS for the Simultaneous Analysis of Nine Nitrosamines Eluted from Synthetic Resins into Artificial Saliva and Health Risk Assessment

“…The column temperature was set to 40 • C, and formic acid suitable for the positive mode was applied as solvent A of the mobile phase. In the case of solvent B, acetonitrile, which was the most widely used solvent in previous studies, was applied [18][19][20][21][22][23][24]. By comparing the concentration gradient conditions by testing various A:B ratios, the conditions of the standard test method of Korea were applied [6].…”

“…Indeed, previous studies, as well as Korean guidelines, have successfully analyzed nitrosamines in various types of matrices (medicines, nipples, condoms, water, etc.) using LC-MS/MS [18][19][20][21][22][23][24].…”

Development of a Sensitive Headspace Gas Chromatography–Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients

“…Because of possible nitrosamine formation during API manufacturing, it is essential to monitor nitrosamine impurities in sartan APIs before individual batch release. Since July 2018, the US FDA, EMA, and other national regulatory agencies have released various methods for the determination of nitrosamine contaminants in sartan APIs based on gas chromatography coupled to mass spectrometry (GC–MS) or tandem mass spectrometry (GC–MS/MS), high-performance liquid chromatography with ultraviolet detection (HPLC–UV), and liquid chromatography coupled to mass spectrometry (LC–MS) or tandem mass spectrometry (LC–MS/MS). − The French National Agency for Medicines and Health Products Safety developed an HPLC–UV method to determine the NDMA content in valsartan APIs and drug products . The German Official Medicines Control Laboratory published a validated LC–MS/MS method to analyze NDMA levels in valsartan products .…”

Ultra-Sensitive LC-MS/MS Method for the Trace Level Quantification of Six Potential Genotoxic Nitrosamine Impurities in Telmisartan

“…Several publications are available for the determination of Nitrosamines in food and environmental applications using LC-MS/MS and LC-HRMS [18]- [21]. A multi-analyte screening method also published in five different sartans was also published [22]. There was a publication on analytical methods for the determination of NDMA in valsartan and other pharmaceutical products [23].…”