UPLC-MS/MS法测定盐酸曲唑酮片剂中遗传毒性杂质双(2-氯乙基)胺盐酸盐和1-(3-氯苯基)-4-(3-氯丙基)哌嗪盐酸盐  

Determination of bis(2-chloroethyl)amine hydrochloride and 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride in trazodone hydrochloride by UPLC-MS/MS

作　　者：万君玥 陈华[2] 尹婕[2] WAN Jun-yue;CHEN Hua;YIN Jie(China Pharmaceutical University,Nanjing 210000,China;NMPA Key Laboratory for Quality Research and Evaluation of Chemical Drugs,National Institutes for Food and Drug Control,Beijing 100050,China)

机构地区：[1]中国药科大学,江苏南京210000 [2]中国食品药品检定研究院,化学药品质量研究与评价重点实验室,北京100050

出　　处：《药学学报》2021年第5期1439-1443,共5页Acta Pharmaceutica Sinica

摘　　要：建立了一种超高效液相色谱-串联质谱法(UPLC-MS/MS)同时测定盐酸曲唑酮原料药及制剂中2种遗传毒性杂质:双(2-氯乙基)胺盐酸盐和1-(3-氯苯基)-4-(3-氯丙基)哌嗪盐酸盐。本文采用Waters ACQUITY UPLC BEH C18色谱柱(100 mm×2.1 mm,1.7μm)进行色谱分离,以5 mmol·L~(-1)碳酸氢铵水溶液(A)-乙腈(B)作为流动相,流速0.2 mL·min~(-1)进行梯度洗脱;采用电喷雾离子化,在正离子模式下多反应监测模式进行检测。结果表明,两种遗传毒性杂质在质量浓度0.1~10 ng·mL~(-1)内线性关系良好,双(2-氯乙基)胺盐酸盐定量限为0.10 ng·mL~(-1),加样回收率结果为101.53%(RSD=4.06%);1-(3-氯苯基)-4-(3-氯丙基)哌嗪盐酸盐定量限为0.01 ng·mL~(-1),加样回收率结果为97.95%(RSD=1.27%)。两种遗传毒性杂质在供试品溶液中室温保存24 h内稳定。6批制剂样品和1批原料药中均未检测出双(2-氯乙基)胺,检测出1-(3-氯苯基)-4-(3-氯丙基)哌嗪的含量均未超出限度值。由于目前国内盐酸曲唑酮质量标准中并未对这两种遗传毒性杂质进行控制,因此本法可为该品种标准的优化提供参考。An UPLC-MS/MS method was established for the quantification of the genotoxic impurities bis(2-chloroethyl)amine hydrochloride and 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride in trazodone hydrochloride.The chromatographic separation of the two genotoxic impurities was performed on Waters ACQUITY UPLC BEH C18 column(100 mm×2.1 mm,1.7μm)at 20℃.A mixture of 5 mmol·L-1 ammonium hydrogen carbonate aqueous solution and acetonitrile at a flow rate of 0.3 mL·min-1 in gradient elution mode was employed as mobile phase.The UPLC-MS/MS was equipped with electrospray ionization in positive ionization mode and adopted multiple reaction monitoring mode.We found that the calibration curves of the two genotoxic impurities were linear in the range of 0.1-10 ng·mL-1.The limit of detection was 0.10 ng·mL-1 for bis(2-chloroethyl)amine hydrochloride and the average recovery was 101.53%(RSD=4.06%).The limit of detection was 0.01 ng·mL-1 for 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride and the average recovery was 97.95%(RSD=1.27%).The sample solution was stable for 24 h.No bis(2-chloroethyl)amine hydrochloride was detected in the samples,and the content of 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride in the samples was within the limit.This research provides a method to improve the quality control standards of trazadone.

关 键 词：超高效液相色谱-串联质谱 盐酸曲唑酮 遗传毒性杂质 双(2-氯乙基)胺 1-(3-氯苯基)-4-(3-氯丙基)哌嗪 

分 类 号：R917[医药卫生—药物分析学]