LC-MS/MS法监控阿齐沙坦原料中带警示结构的叠氮化杂质残留风险  

Residual Risk Evaluation of an Azide Impurity with Alerting Structure in Azilsartan by LC-MS/MS

作　　者：郭招娣 赵甜 许红霞 郭鑫 赵小君 谌宗永 马昂 刘宇晶 王明娟 GUO Zhaodi;ZHAO Tian;XU Hongxia;GUO Xin;ZHAO Xiaojun;SHEN Zongyong;MA Ang;LIU Yujing;WANG Mingjuan(Beijing Sun-novo Pharmaceutical Research Co.,Ltd,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：《药品评价》2023年第7期807-810,共4页Drug Evaluation

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(NMPA-KLIPCD-2020-06);北京市科委、中关村管委会专项课题(Z211100003421042)。

摘　　要：目的建立可监控阿齐沙坦原料中具有警示结构的叠氮化杂质AMBC含量的方法。方法采用AB SCIEX 4000APILC-MS/MS串联质谱系统,ACE Excel 3 C18柱(150 mm×4.6 mm,3μm),柱温40℃,流动相A为0.01 mol/L乙酸铵水溶液-乙腈(90∶10),流动相B为乙腈,梯度洗脱,总流速:0.5 mL/min。串联质谱的参数设置:大气压化学电离-正电离模式(APCI+),多反应监测模式(MRM),用207.3→180.3离子对定量监测化合物AMBC的残留量,探头温度:450℃,电晕针电流:3.0μA,气帘气:35 psi,碰撞气:4 psi,雾化气:45 psi,采集时间:16 min。结果采用拟定方法测得的AMBC检测限和定量限分别为0.062 ng/mL和0.21 ng/mL(相当于0.07,远低于其杂质限37.5);在10.4~312.2ng/mL范围内,AMBC呈良好的线性响应(r=0.9998),方法的加样回收率介于100.2%~104.2%。结论该方法灵敏度高、准确性好、专属性强,在覆盖限度的较宽范围内均呈良好的线性响应,能用于阿齐沙坦原料中具有警示结构的叠氮杂质AMBC的残留风险监控。Objective To establish an original method for determination of an azide impurity AMBC with alerting structure in azilsartan drug substance.Methods The AB SCIEX 4000 APILC-MS/MS system was applied,with the ACE Excel 3 C18 column(150 mm×4.6 mm,3μm)maintaining at 40°C.Mobile phases A and B were 0.01 mol/L ammonium acetate solutionacetonitrile(90∶10)and acetonitrile,respectively,at a total flow rate of 0.5 mL/min in a gradient elution.The conditions of MS/MS detector were as follows:atmosphere pressure chemical ionization mode positive(APCI+),multi-reaction monitoring(MRM)mode,with the 207.3→180.3 ion pair for quantitative monitoring of compound AMBC running for 16 min,probe temperature at 450°C,current of corona needle at 3.0μA,curtain gas,collision gas and nebulizer gas at 35,4,45 psi,respectively.Results The limits of detection and quantitation of AMBC in azilsartan were 0.062 ng/mL and 0.21 ng/mL,respectively,fulfilling the sensitivity requirement for control of trace AMBC.Good linearity(r=0.9998)in the range of 10.4-312.2 ng/mL was observed.The recoveries ranged from 100.2%to 104.2%.Conclusion The original method established was sensitive,accurate,specific and showed linear response in the range covering the proposed limit,demonstrating its suitability for control of traceazide impurity AMBC residue in azilsartan drug substance.

关 键 词：药物污染 阿齐沙坦 基因毒性杂质 警示结构 叠氮化物 串联质谱 痕量检测 残留风险 

分 类 号：R927[医药卫生—药学]