Method for trace determination of N-nitrosamines impurities in metronidazole benzoate using high-performance liquid chromatography coupled with atmospheric-pressure chemical ionization tandem mass spectrometry |
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Authors: | Mingxing Yin Yinuo Hu Huajun Fan Qiulan Wang Mengdie Wang Wenqing Wang Chunyang Shi |
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Institution: | 1. Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China;2. Hubei Hongyuan Pharmaceutical Technology Ltd., Huanggang, P. R. China
These authors contributed equally to this work.;3. ICAS Testing Technology Service (Shanghai) Ltd., Shanghai, P. R. China |
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Abstract: | Genotoxic impurity control has been a great concern in the pharmaceutical industry since the recall of the large round of sartans worldwide in 2018. In these sartans, N-nitrosamines were the main contaminants in active pharmaceutical ingredients and formulations. Numerous analytical methods have been developed to detect N-nitrosamines in food, drugs, and environmental samples. In this study, a sensitive method is developed for the trace determination of N-nitrosamine impurities in metronidazole benzoate pharmaceuticals using high-performance liquid chromatography/atmospheric-pressure chemical ionization tandem mass spectrometry in the multiple reaction monitoring mode. The method was validated regarding system suitability, selectivity, linearity, accuracy, precision, sensitivity, solution stability, and robustness. The method showed good linearity with R2 ≥ 0.999 and FMandel < Ftab(95%) ranging from 0.33 to 8.00 ng/ml. The low limits of detection of N-nitrosamines were in the range of 0.22–0.80 ng/ml (0.0014–0.0050 ppm). The low limits of quantification were in the range of 0.33–1.20 ng/ml (0.0021–0.0075 ppm), which were lower than the acceptable limits in metronidazole benzoate pharmaceuticals and indicated the high sensitivity of the method. The recoveries of N-nitrosamines ranged from 84% to 97%. Thus, this method exhibits good selectivity, sensitivity, and accuracy. Moreover, it is a simple, convenient, and scientific strategy for detecting N-nitrosamine impurities in pharmaceuticals to support the development of the pharmaceutical industry. |
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Keywords: | genotoxic impurities high-performance liquid chromatography metronidazole benzoate multiple reaction monitoring mode N-nitrosamines |
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