Detection of trace genotoxic impurities in rivaroxaban by HPLC-MS/MS
Objective:To establish an HPLC-MS/MS method for the determination of the genotoxic impurities(S)-5-chloro-N-(3-chloro-2-hydroxypropyl)thiophene-2-amide and 4-(3-oxy-4-morpho-line)nitrobenzene in rivaroxaban.The factors affecting impurities separation and the response of mass spectrome-try were systematically investigated.Methods:A ZORBAX SB-C18 column(150 mm ×2.1 mm,3.5 µm)was used with 10 mmol·L-1 ammonium formate solution-methanol as mobile phase at flow rate of 0.4 mL·min-1.And MRM detection by electrospray positive ionization was used.Results:(S)-5-chloro-N-(3-chloro-2-hydroxypropyl)thiophene-2-amide and 4-(3-oxy-4-morpholine)nitrobenzene had good linear rela-tionships in the range of 0.008-3.4 ng·mL-1 and 0.2-3.4 ng·mL-1,respectively.The average recoveries(n=9)were 97.9％and 98.9％,RSD were 0.94％and 0.68％respectively.The limits of quantita-tion were 0.008 ng·mL-1 and 0.2 ng·mL-1 respectively.The results of genotoxic impurity residue determina-tion in 15 batches of rivaroxaban samples were far below the limit value.Conclusion:The method is sensitive and specific,and can effectively detect trace genotoxic impurities in rivaroxaban.
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维普
