APPLICATION OF LC-MS FOR THE IDENTIFICATION AND QUANTIFICATION OF NITROSAMINE IMPURITIES IN ORAL METFORMIN-BASED PHARMACEUTICAL FORMULATIONS

Abstract

In this paper, we highlighted the chromatographic conditions employed for the analysis of nitrosamine impurities in pharmaceutical products. Although the described approach is applicable to a broad spectrum of pharmaceutical formulations, the present work specifically addresses products containing metformin as the active pharmaceutical ingredient. The LC-MS technique has demonstrated exceptional sensitivity and selectivity, establishing it as a robust analytical tool for the detection and quantification of nitrosamines at trace levels. Metformin, a commonly prescribed therapy for type 2 diabetes, has recently attracted increased attention due to the presence of nitrosamine impurities, particularly N-nitrosodimethylamine (NDMA). The formation of NDMA in metformin hydrochloride drug is due to residual DMF (N,N-dimethylformamide), one of the reactant solvents used in synthesis. These represent the primary impurities, although not the only ones, their presence raises significant concerns regarding drug safety and quality. An LC-MS method was developed for the separation and quantification of nine nitrosamine impurities, with the aim of applying it to the analysis of these compounds in pharmaceutical dosage forms. Analysis was performed using an UHPLC system coupled to a Sciex 4600 QTOF mass spectrometer. The proposed LC-MS conditions are significantly improved compared to the European Pharmacopoeia recommendations for N-Nitrosamines impurities in active substances analysis. In this regard, the developed chromatographic conditions were applied for the analysis of metformin tablets sample, NDMA impurity emerged as the main nitrosamine impurity, but in concentration significantly below the permissible limits.