UPLC-MS/MS法测定头孢哌酮钠及其制剂中遗传毒性杂质N-亚硝基二甲胺与N-亚硝基二乙胺  

Determination of genotoxic impurities N-nitrosodimethylamine and N-nitrosodiethylaminein in cefoperazone sodium and its preparations by UPLC-MS/MS

作　　者：李茜 杨博涵 李洁 李倚天 王立萍 刘英 Li Qian;Yang Bohan;Li Jie;Li Yitian;Wang Liping;Liu Ying(Henan Provincial Institute for Drug and Medical Device Control HenanVaccineIssuance Center,Henan Chemical Quality Evaluation and Control Engineering Technology Research Center,Zhengzhou 450018)

机构地区：[1]河南省药品医疗器械检验院,河南省化学药品质量评价与控制工程技术研究中心,郑州450018

出　　处：《中国抗生素杂志》2024年第7期809-814,共6页Chinese Journal of Antibiotics

基　　金：河南省重点研发与推广专项(科技攻关)(No.232102320288)。

摘　　要：目的建立UPLC-MS/MS法测定头孢哌酮钠及其制剂中遗传毒性杂质N-亚硝基二甲胺(NDMA)与N-亚硝基二乙胺(NDEA)的含量。方法采用GL Sciences InertsilTM ODS-3(100 mm×3.0 mm,3μm)色谱柱,流动相A为含0.1%甲酸的水溶液,流动相B为含0.1%甲酸的甲醇溶液,梯度洗脱,流速0.3 mL/min,柱温为35℃;检测方式为正离子(ESI+)模式下选择离子监测(SIM)。结果NDMA在0.5416~270.8 ng/mL范围内线性关系良好,检测限(LOD)与定量限(LOQ)分别为0.008与0.01 ppb,加标回收率为99.3%~107.0%;NDEA在0.1463~73.14 ng/mL范围内线性关系良好,检测限(LOD)与定量限(LOQ)分别为0.001与0.002 ppb,加标回收率为90.0%~96.0%。对7批次原料、66批次制剂与影响因素试验下放置的制剂进行测定,结果3批原料与30批制剂中检出NDMA,所有样品均未检出NDEA;影响因素试验下的制剂NDMA与NDEA均未增加。结论该方法准确、专属性强、灵敏度高,可用于头孢哌酮钠及其制剂中遗传毒性杂质NDMA与NDEA的测定,并建议企业对头孢哌酮钠原料生产工艺进行评估并严格控制。Objective This study established an UPLC-MS/MS method for determination of genotoxic imputrity N-nitrosodimethylamine(NDMA)and N-nitrosodiethylamine(NDEA)in cefoperazone sodium and its preparations.Methods The analytes were separated on a GL Sciences InertsilTM ODS-3(100 mm×3.0 mm,3μm)column.0.1%formic acid was used as mobile phase A,methanol containing 0.1%formic acid was used as mobile phase B,and the gradient elution method was used.The flow was set at 0.3 mL/min,with a column temperature of 35℃.The target compound was analyzed in the positive ion SIM mode.Results The linear range of NDMA was in the range of 0.5416~270.8 ng/mL,the limit of detection(LOD)and the limit of quantitation(LOQ)were 0.008 and 0.01 ppb,and the recoveries were 99.3%-107.0%.The linear range of NDEA was in the range of 0.1463~73.14 ng/mL,the limit of detection(LOD)and the limit of quantitation(LOQ)were 0.001 ppb and 0.002 ppb and the recoveries were 90.0%-96.0%.The method was used to determine NDMA an NDEA in 7 batches of raw material,66 batches of preparations,and influencing factors test samples.NDMA was detected in 3 batches of raw material and 30 batches of preparations.No NDEA was detected in all samples.NDMA and NDEA did not increase under the influence factor test.Conclusion This method was accurate,specific,and sensitive.It could be used for analysis of the NDMA and NDEA in cefoperazone sodium and its preparations.Enterprises should pay attention to the quality control of APIs.

关 键 词：头孢哌酮钠 注射用头孢哌酮钠 N-亚硝基二甲胺(NDMA) N-亚硝基二乙胺(NDEA) UPLC-MS/MS 遗传毒性杂质 

分 类 号：R978.1[医药卫生—药品]