UPLC-MS/MS法测定注射用头孢美唑钠中潜在亚硝胺类物质的含量  

Determination of potential nitrosamines in cefmetazole sodium for injection by UPLC-MS/MS

作　　者：宋芸峰 耿悦 孙春业 王志军[1] 姚卫峰 张锦琳 裘婧 袁耀佐 SONG Yun-feng;GENG Yue;SUN Chun-ye;WANG Zhi-jun;YAO Wei-feng;ZHANG Jin-lin;QIU Jing;YUAN Yao-zuoa(Nanjing Univerity of Traditional Chinese Medicine,Nanjing 210023,China;Jiangsu Institute of Food and Drug Administration,Nanjing 210019,China;NMPA Key Laboratory for Impurity Profile of Chemical Drugs,Nanjing 210019,China;Jiangsu Institutef of Medical Devices,Nanjing 210012,China;Agilent Technologies Inc,Shanghai 2080,China;Chinese Pharmacopoeia Commission,Bejing 100061,China)

机构地区：[1]南京中医药大学,南京210023 [2]江苏省食品药品监督检验研究院,南京210019 [3]国家局化学药物杂质谱研究重点实验室,南京210019 [4]江苏省医疗器械所,南京210012 [5]安捷伦科技有限公司,上海200080 [6]国家药典委员会,北京100061

出　　处：《药物分析杂志》2022年第7期1186-1194,共9页Chinese Journal of Pharmaceutical Analysis

基　　金：2021年国家药品评价性抽验资助(国药监药管[2021]1号)。

摘　　要：目的:建立一种超高效液相色谱-串联质谱联用法,用于测定注射用头孢美唑钠中的13个潜在亚硝胺类基因毒性杂质的含量(NDELA、NMOR、NPYR、NMPhA、NEPhA、NDiBA、NDBzA、NDBA、NDMA、NDEA、NPIP、NDiPA和NDPA)。方法:使用ACQUITY UPLC BEH C_(8)(100 mm×2.1 mm, 1.7μm)色谱柱和Agilent Infinity Lab Poroshell120 Bonus-RP(100 mm×3.0 mm, 2.7μm)色谱柱,流动相为0.1%甲酸(A)-甲醇(B),梯度洗脱,流速0.4 mL·min^(-1),采用APCI离子源,在多反应监测模式(MRM)下,对全国20个生产厂家以及国外原研厂家的样品进行分析。结果:该方法能同时测定13个亚硝胺类基因毒性杂质。其线性范围、灵敏度、精密度、回收率均满足分析要求。在21批注射用头孢美唑钠中,10批检出了NPIP,但均小于定量限。结论:注射用头孢美唑钠中存在亚硝胺类基因毒性杂质的风险可控;所建立的方法高效灵敏,性能优异,专属性强,可为以四氮唑环为结构特征的抗生素中亚硝胺类基因毒性杂质控制方法提供参考,也可用于胶塞中N-亚硝胺类基因毒性杂质迁移量的检测,为监管部门提供技术储备和数据支持。Objective:To establish an ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method for the simultaneous determination of 13 potential nitrosamin^(-1)e genotoxic impurities(NDELA, NMOR, NPYR, NMPhA, NEPhA, NDiBA, NDBzA, NDBA, NDMA, NDEA, NPIP, NDiPA andNDPA) in cefmetazole sodium for injection. Methods: This assay was performed on chromatographic column ACQUITY UPLC BEH C_(8)(100 mm×2.1 mm, 1.7 μm) and chromatographic column Agilent Infinity Lab Poroshell120 Bonus-RP(100 mm×3.0 mm, 2.7 μm) with mobile phase 0.1% formic acid(A)-methanol(B) by gradient elution at a flow rate of 0.4 mL·min^(-1). Multiple reaction monitoring(MRM) was performed on a triple quadripole mass spectrometer with an APCI source to analyze samples from 20 manufacturers in China and a foreign original manufacturer. Results: 13 kinds of nitrosamin^(-1)e genotoxic impurities were detected simultaneously by this method. The linear range, sensitivity, precision, and recovery of 13 compounds met the analysis requirements. Among 21 batches of cefmetazole sodium for injection, NPIP was detected in 10 batches, but all were less than the limit of quantification. Conclusion: The risk of nitrosamin^(-1)es genotoxic impurities in cefmetazole sodium for injection is controllable. The established method is efficient and sensitive, and has excellent performance and strong specificity. It can be used as a method for controlling nitrosamin^(-1)e genotoxic impurities in antibiotics with a tetrazolium ring as the structural feature. It can also be used for the detection of N-nitrosamin^(-1)e genotoxic impurities migration in rubber stoppers, and provide technical reserves and data support for regulatory authorities.

关 键 词：亚硝胺 四氮唑 基因毒性杂质 超高效液相色谱-串联质谱 药用胶塞 迁移 风险评估 

分 类 号：R917[医药卫生—药物分析学]