无催化剂衍生GC-MS法测定利伐沙班基因毒杂质5-氯-2-酰氯噻吩  

Determination of genotoxic 5-chlorothiophene-2-carbonyl chloride in rivaroxaban by GC-MS with catalyst-free derivatization

作　　者：陈轶嘉 石玲玲 陈阳 王建伟[2] CHEN Yi-jia;SHI Ling-ling;CHEN Yang;WANG Jian-wei(Hangzhou Huadong Medicine Group Pharmaceutical Research Institute Co.,Ltd,Hangzhou 310011,China;Zhejiang University of Technology,Hangzhou 310014,China)

机构地区：[1]杭州华东医药集团新药研究院有限公司,杭州310011 [2]浙江工业大学,杭州310014

出　　处：《药物分析杂志》2021年第4期714-719,共6页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:建立无催化剂作用下衍生化GC-MS法测定利伐沙班原料药中基因毒杂质5-氯-2-酰氯噻吩。方法:采用气相色谱-质谱联用法,色谱柱为Agilent HP-INNOWAX毛细管柱(30 m×0.32 mm×0.25μm),柱温为程序升温(起始温度110℃,保持2 min,10℃·min-1升温至230℃,保持6 min),进样口温度230℃,分流比5∶1,氦气流速1.5 mL·min^(-1),直接进样体积1μL;离子源为EI,电子能量70 eV,离子源温度230℃,四极杆温度150℃,扫描方式及碎片离子分别为SIM及m/z 145、m/z 176。结果:基因毒杂质5-氯-2-酰氯噻吩质量浓度在8.21~101.47 ng·mL^(-1)范围内与峰面积积分值呈良好的线性关系,相关系数r=0.9981,平均加样回收率(n=9)为99.2%,精密度试验RSD(n=6)为2.5%,且衍生化产物在常温下8 h内稳定。6批样品的基因毒杂质5-氯-2-酰氯噻吩含量结果分别为6.48、6.94、1.83、46.70、49.93、46.35 ng·mL^(-1)。结论:本方法专属性强,准确度、精密度高,耐受性、灵敏度好,可用于利伐沙班原料药中基因毒杂质5-氯-2-酰氯噻吩的检测和质量控制。Objective:To establish a method for the determination of genotoxic impurity(5-chlorothiophene-2-carbonyl chloride)in rivaroxaban by GC-MS with catalyst-free derivatization.Methods:GC-MS method was adopted.The determination was performed on capillary column of Agilent HP-INNOWAX(30 m×0.32 mm,0.25μm);the column temperature was programmed to start at 110℃,maintained for 2 min,and then rose to 230℃at a rate of 10℃·min^(-1),maintained for 6 min;the inlet temperature was 230℃,helium(1.5 mL·min^(-1))was used as the carrying gas;the split ratio was 5∶1;the injection volume was 1μL.The detector was MS;the ion source was EI;the electron energy was 70 eV;the temperature of the ion source was 230℃;the temperature of the fourth pole was 150℃;scanning mode and fragment ions were SIM,m/z 145,m/z 176,respectively.Results:The genotoxic impurity(5-chlorothiophene-2-carbonyl chloride)showed good linear relationships within the ranges of 8.21-101.47 ng·mL^(-1)(r=0.9981).The average recovery was 99.2%(n=9).RSD(n=6)of precision test was 2.5%and the derivative product was stable within 8 hours at room temperature.The contents of 5-chloro-2-acylthiphene in six samples were 6.48,6.94,1.83,46.70,49.93,46.35 ng·mL^(-1),respectively.Conclusion:This method has high specificity,accuracy,precision and tolerance sensitivity,which can be used for the test and quality control of the genotoxic impurity(5-chlorothiophene-2-carbonyl chloride)of rivaroxaban.

关 键 词：利伐沙班 XA因子抑制剂 基因毒杂质 5-氯-2-酰氯噻吩 气相色谱-质谱联用法 

分 类 号：R917[医药卫生—药物分析学]