HPLC-QDa检测器法控制米拉贝隆中具有警示结构的苯胺类杂质含量研究  

Determination of Anilines with Alerting Structures in mirabegron drug substance by HPLC-QDa

作　　者：许红霞 秦永香 吴淑霞 刘智 孙跃军 郭鑫 袁伟锋 孟旻 谌宗永 刘宇晶 王明娟 XU Hong-xia;QIN Yong-xiang;WU Shu-xia;LIU Zhi;SUN Yue-jun;GUO Xin;YUAN Wei-feng;MENG Min;SHEN Zong-yong;LIU Yu-jing;WANG Ming-juan(Bejing Sun-Novo Pharmaceutical Research Co.,Lid.,Beijing 102200,China)

机构地区：[1]北京阳光诺和药物研究股份有限公司,北京102200

出　　处：《中国药学杂志》2023年第5期447-452,共6页Chinese Pharmaceutical Journal

基　　金：国家药品监督管理局化学药品杂质谱研究重点实验室开放课题资助(NMPA-KLIPCD-2020-06);北京市科委、中关村管委会专项课题资助(Z211100003421042)。

摘　　要：目的建立可监控米拉贝隆原料中3种具有警示结构的苯胺类杂质(MLB-IM-K、MLB-IM-L、MLB-3-IM01)含量的方法。方法采用高效液相色谱法(HPLC)-QDa色谱系统,XBridge Shield RP18柱(4.6 mm×150 mm,3.5μm),流动相为乙腈-0.01 moL·L^(-1)乙酸铵溶液(用乙酸调节pH值至6.5)(30∶70);流速:0.8 mL·min^(-1),柱温:35℃,进样体积:10μL。QDa检测器的参数设置:电喷雾离子化-正电离模式(ESI+),多反应监测模式(MRM),探头温度:600℃,采集速率:每秒10点,气流量:20 L·min^(-1);采集时间:12 min。结果3种目标苯胺类杂质在0.02~0.2μg·mL^(-1)内(相当于主成分的0.0007%~0.007%水平;3种目标杂质的总量限度为0.01%),线性关系均良好(r≥0.9980),回收率介于95.6%~110.8%,检测限和定量限分别低于0.003、0.01μg·mL^(-1)(相当于0.0003%),能较好的满足目标杂质的检测灵敏度要求。结论该方法灵敏度高、准确性好、在拟定限度范围内呈线性响应,可用于米拉贝隆原料中潜在苯胺类具有警示结构杂质的残留量监控。OBJECTIVE E To establish an original method for determination of three anilines with alerting structure(MLB-IM-K,MLB-IM-L and MLB-3-IMO1)in mirabegron drug substance.METHODS The Waters Acquity HPLC-QDa system was applied,with the XBridge Shield RP18 column(4.6 mm×150 mm,3.5μm)maintained at 35℃.Mobile phase consist of acetonitrile/0.01 moL·L^(-l)ammonium acetate solution(pH 6.5,adjusted by acetic acid)(30:70)at a flow rate of O.8 mL·min^(-1).The injection volumes were 10μL.The conditions of QDa detector were as follows:electrospray ionization mode positive(ESI^(*)),multi-reaction monitoring(MRM)mode,probe temperature at 600℃,flow rate of nitrogen at 20 L·min^(-1),with the acquisition rate of 10 points·s^(-1)for 12 min.RESULTS Three anilines all showed good linearity(r≥0.9980)in the range of 0.02-0.2μgmL^(-1)(equivalent to 0.0007%-0.007%of mirabegron,meanwhile the total limit for the three anilines was 0.01%).Their recoveries were between 95.6%-110.8%(ideal range:80%-120%),and their limits of detection and quantitation were all below 0.003μg·mL^(-1)and 0.01μg·mL^(-1)(0.0003%),respectively,fulflling the sen-sitivity requirements for trace control of the target impurities.CONCLUSION The original method established is sensitive,accurate and shows linear response in the range covering the proposed limit,demonstrating its suitability for trace control of ani-lines in mirabegron drug substances.

关 键 词：高效液相色谱法 QDa检测器 米拉贝隆 苯胺 杂质 

分 类 号：R917[医药卫生—药物分析学]