GC-MS/MS测定头孢菌素类药物中8种N-亚硝胺类基因毒性杂质  

Determination of 8 N-nitrosamine Impurities in Cephalosporins by GC-MS/MS

作　　者：李俊 张璐 张瑄 丁敏军 Li Jun;Zhang Lu;Zhang Xuan;Ding Minjun(Zhejiang Taizhou Institute for Drug Control,Zhejiang Taizhou 318000,China;Zhejiang Yongning Pharmaceutical Co.,Ltd.)

机构地区：[1]台州市药品检验研究院,浙江台州318000 [2]浙江永宁药业股份有限公司

出　　处：《中国药师》2022年第2期350-354,共5页China Pharmacist

基　　金：浙江省药品监管系统科技计划项目(编号:2020007)。

摘　　要：目的:建立GC-MS/MS法测定头孢孟多酯钠、头孢地嗪钠、盐酸头孢替安中8种N-亚硝胺类杂质(N-亚硝基二甲胺、N-亚硝基二乙胺、N-亚硝基二丙胺、N-亚硝基二丁胺、N-亚硝基甲基乙基胺、N-亚硝基吡咯烷、N-亚硝基哌啶、N-亚硝基吗啉)。方法:采用VF-WAX ms色谱柱(30 m×0.25 mm,膜厚0.25μm),程序升温,进样口温度250℃,流速:1.0 ml·min^(-1);质谱采用EI源,电压为70 eV,离子源温度250℃、四极杆温度150℃,采用MRM模式对8种杂质进行定量测定;以0.1 mol·L^(-1)氢氧化钠溶液溶解样品,以二氯甲烷进行萃取。结果:在上述条件下,8个N-亚硝胺杂质及相邻色谱峰之间分离效果良好,在所测浓度范围内线性关系良好,定量限为0.0021~0.0033μg·g^(-1),检出限为0.0006~0.0011μg·g^(-1);8种N-亚硝胺杂质的低、中、高浓度的平均回收率为85.5%~110.0%,RSD≤4.8%(n=3)。结论:建立的GC-MS/MS测定3种头孢菌素类药物中8种N-亚硝胺杂质的方法,准确度好,灵敏度高,简便可靠,对仪器污染小,可用于头孢孟多酯钠、头孢地嗪钠、盐酸头孢替安中8个N-亚硝胺基因毒性杂质的质量控制。Objective:To establish a GC-MS/MS method to determine eight N-nitrosamine impurities(N-nitrosodimethylamine,N-nitrosodiethylamine,N-nitrosodipropylamine,N-nitrosodibutylamine,N-nitrosomethylethylamine,N-nitrosopyrrolidine,N-nitrosopiperidine,N-nitrosomorpholine)in cefamandole nafate,cefotiam hydrochloride and cefodizime sodium.Methods:The separation was performed on a VF-WAX ms(30 m×0.25 mm,0.25μm)column at programmed temperature.The inlet temperature was 250℃and the flow rate was 1.0 ml·min^(-1).Mass spectrometry was used with an EI source,the voltage was 70 eV,the ion source temperature was 250℃and the quadrupole temperature was 150℃.Multiple reaction monitoring(MRM)was performed for the quantitative determination of 8 impurities.The samples were dissolved in 0.1 mol·L^(-1)sodium hydroxide solution and extracted by dichloromethane.Results:Under the conditions in this study,the separation between eight N-nitrosamine impurities and adjacent chromatographic peaks was effective.The eight impurities all revealed good linearity within the test concentration ranges.The limits of qualification were 0.0021-0.0033μg·g^(-1)and the limits of detection were 0.0006-0.0011μg·g^(-1).The average recoveries were 85.5%-110.0%at low,medium and high spiked concentrations with the RSDs no more than 4.8%(n=3).Conclusion:The established GC-MS/MS method for the determination of eight N-nitrosamine impurities is accurate,highly sensitive,simple and reliable with less pollution to the instrument,and can be used for the quality control of eight N-nitrosamine genotoxic impurities in cefamandole nafate,cefotiam hydrochloride and cefodizime sodium.

关 键 词：三重四极杆气质联用法 N-亚硝胺杂质 头孢类药物 头孢孟多酯钠 盐酸头孢替安 头孢地嗪钠 

分 类 号：R917[医药卫生—药物分析学]