基于UHPLC-Q-Orbitrap HRMS的甲磺酸阿帕替尼有关物质结构鉴定  

Structural identification of related substances of apatinib mesylate based on UHPLC-Q-Orbitrap HRMS

作　　者：贾雪冬 李卓伦 杨彦涛 左莉华[1,2] 贾清泉 孙志[1,2] 杜书章 JIA Xue-dong;LI Zhuo-lun;YANG Yan-tao;ZUO Li-hua;JIA Qing-quan;SUN Zhi;DU Shu-zhang(Department of Pharmacy,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Henan Key Laboratory of Precision Clinical Pharmacy,Zhengzhou 450052,China)

机构地区：[1]郑州大学第一附属医院药学部,郑州450052 [2]河南省精准临床药学重点实验室,郑州450052

出　　处：《药物分析杂志》2020年第10期1848-1862,共15页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:对甲磺酸阿帕替尼有关物质进行结构鉴定。方法:采用ACQUITY UHPLC? HSS C18色谱柱(50 mm×2.1 mm,1.7μm),以0.1%甲酸水-乙腈为流动相梯度洗脱,对阿帕替尼有关物质进行分离;采用电喷雾正离子化的四极杆/静电场轨道阱高分辨质谱(Q-Orbitrap HRMS)测定离子的准确质量,然后结合碎片裂解规律和化学结构,推测阿帕替尼原料药及其强制破坏溶液中有关物质的结构。结果:共发现了21种有关物质,鉴定了其可能的化学结构,并根据其来源主要分为6类:合成中间体(有关物质10、11)、合成副产物(有关物质8、15)、酰胺键水解后相关破坏产物(有关物质1、2、3)、氰基水解破坏产物(有关物质12)、氧化加O的破坏产物(有关物质4、5、7、9、13、17、18、19、20)、氧化脱2H破坏产物(有关物质14、16、21)。结论:UHPLC-Q-Orbitrap HRMS技术能有效地鉴定阿帕替尼中的有关物质,对其生产工艺优化和质量控制具有重要意义。Objective:To identify the structure of related substances of apatinib mesylate.Methods:A ACQUITY UHPLC? HSS C18 column(50 mm×2.1 mm,1.7 μm) was used for the separation of the related substances of apatinib,with a mixture of 0.1% formic acid water and acetonitrile as mobile phase gradient elution;the structures of the related substances were speculated by electrospray positive ionization Q-Orbitrap HRMS accurate ion mass determination and elucidation,and then combined the fragmentation law and chemical structure to further determine the structure of related substances.Results:Twenty-one related substances were identified and divided into six categories according to the source:synthetic intermediates(related substances 10 and 11),synthetic by-products(related substances 8 and 15),related destruction products after amide bond hydrolysis(related substances 1,2 and 3),cyano hydrolysis destruction products(related substance 12),the destruction products of oxidation plus O(related substances 4,5,7,9,13,17,18,19 and 20),the destruction products of oxidation deprivation 2 H(related substances 14,16 and 21).Conclusion:UHPLC-Q-Orbitrap HRMS technology can effectively identify related substances in apatinib,which is of great significance for its production process optimization and quality control.

关 键 词：超高效液相色谱-四极杆/静电场轨道阱高分辨质谱 甲磺酸阿帕替尼 酪氨酸激酶抑制剂 抗肿瘤活性 靶向药物 有关物质 结构鉴定 

分 类 号：R917[医药卫生—药物分析学]