Head Space GC-MS/MS Method for Quantification of Five Nitrosoamine-Genotoxic Impurities in Metformin HCl

Abstract

Background: N-nitrosamines have recently been discovered in metformin hydrochloride and other generic drugs. To quantify the five N-nitrosamines in metformin hydrochloride, we devised sensitive and reliable multiple reactions monitoring mode-based GCMS/ MS technique, particularly, N-nitrosodiethy amine (NDEA), N-nitroso ethyl isopropylamine (NEIPA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodipropylamine (NDPA), as well as N-nitrosodibutylamine (NDBA). Objective: To develop a sensitive, precise, and accurate MRM mode based GC-MS/MS method for the quantification of five N-nitrosamines in metformin hydrochloride and valídate as per ICH guidelines. Methods: The settings for mass spectrometry and gas chromatography were optimized. With the linearity, sensitivity, specificity, accuracy, and precision of the parameter, the procedure was as per the recommendation of ICH: International Council for Harmonization guidelines. Results: N-nitrosamines in metformin hydrochloride had detection and quantification limits of 0.001 ppm and 0.004 ppm, correspondingly. The obtained results were within the sensitivity limitations issued by the US Food and Drug Administration. The calibration curve's regression coefficients for five N-nitrosamines were over 0.99, demonstrating the process's good linearity. The retrievals of N-nitrosamines in metformin hydrochloride between 97.1 – 127.4 %. The RSD (Relative Standard Deviation) was lower than 10 % for both inter-day and intra-day precision studies. Conclusion: The proposed method exhibited a rapid analysis capability, high accuracy, sensitivity, and precision, making it a trustworthy method for monitoring N-nitrosamines in metformin hydrochloride.