Abstract
A GC–MS/MS method with EI ionization was developed and validated to detect and quantify N-nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of metformin tablets from 13 different manufactures. Good linearity for each compound was demonstrated over the calibration range of 0.5–9.5 ng/mL. The assay for all substances was accurate and precise. NDMA was not detected in the acquired active pharmaceutical ingredient (API); however, NDMA was detected in 64 (85.3%) and 22 (91.7%) of the finished product and prolonged finished product samples, respectively. European Medicines Agency recommends the maximum allowed limit of 0.032 ppm in the metformin products. Hence, 28 finished products and 7 pronged dosage products were found to exceed the acceptable limit of daily intake of NDMA contamination. The implications of our findings for the testing of pharmaceutical products are discussed.
Highlights
N-nitrosamines (NAs) are the products of reactions between a nitrosating agent and a secondary or tertiary amine; NAs are formed preferentially at elevated temperature
Due to possible contamination of water with NDMA, the World Health Organization (WHO) and U.S Environmental Protection Agency (EPA) have set the drinking water guideline limits to 100 ng/L and 0.4 ng/L in tap water, respectively [8,9]
Additional studies revealed that the peak can be N,N-dimethylformamide (DMF), which can be used in the synthesis of metformin
Summary
N-nitrosamines (NAs) are the products of reactions between a nitrosating agent and a secondary or tertiary amine; NAs are formed preferentially at elevated temperature. NAs are mainly detected in food and drinks after processing [1]. N-nitrosodimethylamine (NDMA) is the most simple and volatile NA that can form during the degradation of dimethylhydrazine (a component of rocket fuel) by chloramination of amine-based precursors or as a byproduct of anion exchange purification of water [2]. Due to possible contamination of water with NDMA, the World Health Organization (WHO) and U.S Environmental Protection Agency (EPA) have set the drinking water guideline limits to 100 ng/L and 0.4 ng/L in tap water, respectively [8,9]. There are currently no maximum regulatory limits for the level of N-nitroso-compounds in food in the European Union [11]
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