Method Validation and Monitoring of N-nitrosodimethylamine in Metformin Hydrochloride Products in China by GC-MS/MS

Background: N-nitrosodimethylamine (NDMA) are a sort of genotoxic impurities (GTIs) having strong carcinogenic effects and obvious hepatotoxicity. To monitor the NDMA content of metformin hydrochloride sustained-release tablets and enteric capsules in China from 2018 to 2022, a GC-MS/MS method was established and validated.Materials and Methods: The chromatographic column was Agilent VF-WAXms capillary column (30 m.25 mm, 0.25 μm). The GC-MS/MS method was equipped with multiple reaction monitoring (MRM) modes. To assess the quantity of NDMA, the molecular ion at mass-tocharge (m/z) of 74-44 was monitored under the 6 V collision energy, and to assess the quality of NDMA monitoring, the molecular ions at m/z 74-42 were determined. A total of 143 batches of metformin hydrochloride-finished products from 35 enterprises were determined by this method.Results: The linear range of the method was 0.25 ~ 50.00 ng/mL, r = 0.9998, S/N > 10, and the limit of detection and quantitation were 0.06 ng/mL and 0.21 ng/mL, respectively. The average recovery was 98.62%, and the RSD was 4.31%. All batches of enteric capsules met the requirements; 38.21% of the 123 batches sustained-release tablets still exceeded the acceptable daily intake.Conclusion: The presented method is sensitive, accurate, precise, and available for both enteric capsules and sustained-release tablets of metformin hydrochloride, which can provide a reference for their quality control. The over-limit phenomenon of NDMA in metformin hydrochloride products poses new challenges and requirements for both the State Drug Administration and enterprises.