卡铂注射液未知杂质结构及其与辅料的相关性研究  

Study on the structure of an unknown impurity in carboplatin injection and the relationship with the excipient

作　　者：金薇[1] 江文明[1] 刘茜[1] 高旋[1] 张叶[1] 郭丹[1] 钱敏[1] 任美婷[1] 杨永健[1] JIN Wei, JIANG Wen-ming, LIU Qian, GAO Xuan, ZHANG Ye, GUO Dan, QIAN Min, REN Mei-ting, YANG Yong-jian(Shanghai Institute for Food and Drug Control, Shanghai 201203, China)

机构地区：[1]上海市食品药品检验所,上海201203

出　　处：《药学学报》2018年第4期604-608,共5页Acta Pharmaceutica Sinica

基　　金：国家重大新药创制-化药制剂质量评价关键技术研究课题(2015ZX09303001)

摘　　要：采用二维快速液相色谱-串联飞行时间质谱(UPLC-QTOF)对卡铂注射液中的未知杂质结构及其与辅料的相关性开展研究。一维采用苯基-己基硅烷键合硅胶色谱柱(250 mm×4.6 mm,5μm),硫酸四丁基铵缓冲液(pH 7.5)-乙腈为流动相进行梯度洗脱,二维采用快速液相色谱-串联飞行时间质谱(UPLC-QTOF),HSS T3色谱柱(100 mm×2.1 mm,1.7μm),以0.1%甲酸水溶液-乙腈为流动相进行梯度洗脱。在电喷雾离子源(electrospray ionization,ESI+)模式下,采用MS^E采集模式,对待测未知杂质进行定性研究和分子量准确测定,初步确定杂质的结构。通过加速稳定性实验以及ICP-MS/MS、ICP-AES考察杂质与主药和处方中辅料的相关性。结果显示,某企业处方中加入了辅料依地酸二钠,反而与主药卡铂相互作用,生成含铂有关物质,从而导致卡铂降解产生更多的1,1-环丁烷二羧酸。因此,本研究表明依地酸二钠的添加加剧了卡铂注射液有关物质的增加,辅料添加的合理性值得进一步关注。The study was designed to establish a 2D UPLC-QTOF method to extrapolate the structure of an unknown substance in carboplatin injection and its relationship with the excipient. By using phenyl-hexyl column （250 mm×4.6 mm, 5 μm） with mobile phase consisting of tetrabutylammonium sulfate buffer （pH 7.5） and acetonitrile in gradient elution mode, an unknown impurity in carboplatin injection was found and quantitatively determined. Then a 2D UPLC-QTOF, HSS T3 column （100 mm×2.1 mm, 1.7 μm） was employed to confirm the molecular weight and the structure of the unknown impurity （electrospray ionization source, positive ion mode, MSE mode） with mobile phase consisting of 0.1% formic acid and acetonitrile. The relationship among impurities, API and excipient was investigated by accelerated stability test with ICP-MS/MS, ICP-AES. Results showed that disodium edetate in the formulation interacted with carboplatin producing an unknown impurity containing platin, and induced the increase of 1,1-cyclobutanedicarboxylic acid. The research should be done on the rationality of the addition of disodium edetate in such injections containing heavy metals.

关 键 词：卡铂注射液 含铂杂质 依地酸二钠 1 1-环丁烷二羧酸 二维液相色谱-串联飞行时间质谱 

分 类 号：R917[医药卫生—药物分析学]