目的 建立超高效液相色譜-串聯(lián)質(zhì)譜法（UPLC-MS/MS）測(cè)定奧美沙坦酯中7個(gè)基因毒性雜質(zhì)：N-亞硝基二甲胺、N-亞硝基-4-甲基-4-氨基丁酸、N-亞硝基二乙胺、N-亞硝基乙基異丙基胺、N-亞硝基二異丙胺、N-亞硝基二丙胺、N-亞硝基二丁胺。方法 采用Agilent poroshell PFP （100 mm×2.1 mm，2.7 μm）色譜柱；流動(dòng)相為0.1%甲酸水溶液（A）-甲醇（B）梯度洗脫；體積流量0.4 mL/min，柱溫40℃；采用APCI離子源正離子掃描，多反應(yīng)監(jiān)測(cè)（MRM）模式下，對(duì)7個(gè)基因毒性雜質(zhì)同時(shí)進(jìn)行定量檢測(cè)。結(jié)果 各雜質(zhì)質(zhì)量濃度在1~100 ng/mL內(nèi)具有良好線性關(guān)系，r>0.995；低、中、高3個(gè)濃度的加樣回收率（n=3）為83%~117%，RSD值為0.8%~4.1%，平均加樣回收率為87%~106%；檢測(cè)限范圍為0.02~0.19 ng/mL，定量限為0.06~0.65 ng/mL。4批奧美沙坦酯樣品中均未檢出雜質(zhì)。結(jié)論 該方法靈敏度高，專屬性強(qiáng)，可用于測(cè)定奧美沙坦酯原料藥中7個(gè)亞硝胺類雜質(zhì)，為奧美沙坦酯的質(zhì)量控制提供參考。

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.

R927.1

國(guó)家重大研發(fā)項(xiàng)目（2016YFE0205400）