[关键词]
[摘要]
目的 建立超高效液相色谱-串联质谱法(UPLC-MS/MS)测定奥美沙坦酯中7个基因毒性杂质:N-亚硝基二甲胺、N-亚硝基-4-甲基-4-氨基丁酸、N-亚硝基二乙胺、N-亚硝基乙基异丙基胺、N-亚硝基二异丙胺、N-亚硝基二丙胺、N-亚硝基二丁胺。方法 采用Agilent poroshell PFP (100 mm×2.1 mm,2.7 μm)色谱柱;流动相为0.1%甲酸水溶液(A)-甲醇(B)梯度洗脱;体积流量0.4 mL/min,柱温40℃;采用APCI离子源正离子扫描,多反应监测(MRM)模式下,对7个基因毒性杂质同时进行定量检测。结果 各杂质质量浓度在1~100 ng/mL内具有良好线性关系,r>0.995;低、中、高3个浓度的加样回收率(n=3)为83%~117%,RSD值为0.8%~4.1%,平均加样回收率为87%~106%;检测限范围为0.02~0.19 ng/mL,定量限为0.06~0.65 ng/mL。4批奥美沙坦酯样品中均未检出杂质。结论 该方法灵敏度高,专属性强,可用于测定奥美沙坦酯原料药中7个亚硝胺类杂质,为奥美沙坦酯的质量控制提供参考。
[Key word]
[Abstract]
Objective To establish a UPLC-MS/MS analytical method for the determination of seven N-nitrosamines genotoxic impurities(N-nitroso-dimethylamine, N-nitroso-N-methyl-4-aminobutyric acid, N-nitroso-diethylamine, N-nitroso-ethyl-isoprosylamine, N-nitroso-diisopropylamine, N-nitroso-dipropylamine and N-nitroso-dibutylamine) in olmesartan medoxomil. Methods The separation was performed on an Agilent poroshell PFP (100 mm×2.1 mm, 2.7 μm) column with the mobile phase consisting of 0.1% formic acid aqueous solution (mobile phase A) and methanol (mobile phase B) by gradient elution at a flow rate of 0.4 mL/min and the column temperature was 40℃. Multiple reaction monitoring (MRM) was performed on a triple quadripole mass spectrometer equipped with a APCI source in positive mode to quantitative detection of seven genotoxic impurities. Results The calibration curve was linear for seven compounds in the range of 1-100 ng/mL, r>0.995. The recoveries (n=3) of low, middle, high adding concentrations were 83%-117%, RSD were 0.8%-4.1%, average spike recoveries range were 87%-106%. The limit of detection was 0.02-0.19 ng/mL, and the limit of quantification was 0.06-0.65 ng/mL. No impurities were detected in four batches samples. Conclusion The method is sensitive, accurate, which is applicable for quantifications of seven N-Nitrosamines genotoxic impurities in olmesartan medoxomil. The method can provided a reference for the control of nitrosaminies impurities in olmesartan medoxomil.
[中图分类号]
R927.1
[基金项目]
国家重大研发项目(2016YFE0205400)