药学学报, 2018, 53(4): 604-608
引用本文:
金薇, 江文明, 刘茜, 高旋, 张叶, 郭丹, 钱敏, 任美婷, 杨永健. 卡铂注射液未知杂质结构及其与辅料的相关性研究[J]. 药学学报, 2018, 53(4): 604-608.
JIN Wei, JIANG Wen-ming, LIU Qian, GAO Xuan, ZHANG Ye, GUO Dan, QIAN Min, REN Mei-ting, YANG Yong-jian. Study on the structure of an unknown impurity in carboplatin injection and the relationship with the excipient[J]. Acta Pharmaceutica Sinica, 2018, 53(4): 604-608.

卡铂注射液未知杂质结构及其与辅料的相关性研究
金薇, 江文明, 刘茜, 高旋, 张叶, 郭丹, 钱敏, 任美婷, 杨永健
上海市食品药品检验所, 上海 201203
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,5 μm),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,1.7 μm),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MSE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。
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     
Study on the structure of an unknown impurity in carboplatin injection and the relationship with the excipient
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
Abstract:
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.
Key words:    carboplatin injection    impurity containing platin    disodium edentate    1,1-cyclobutanedicarboxylic acid    2D-LC-MS-QTOF   
收稿日期: 2017-11-14
DOI: 10.16438/j.0513-4870.2017-1126
基金项目: 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).
通讯作者: 杨永健,Tel:86-21-50798190,E-mail:yongjianyang@163.com
Email: yongjianyang@163.com
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