药学学报, 2016, 51(6): 965-971
引用本文:
张才煜, 李婕, 高家敏, 张启明, 施亚琴. UPLC-MS/MS法研究紫杉醇及其注射液的杂质谱[J]. 药学学报, 2016, 51(6): 965-971.
ZHANG Cai-yu, LI Jie, GAO Jia-min, ZHANG Qi-ming, SHI Ya-qin. The impurity profiling of paclitaxel and its injection by UPLC-MS/MS[J]. Acta Pharmaceutica Sinica, 2016, 51(6): 965-971.

UPLC-MS/MS法研究紫杉醇及其注射液的杂质谱
张才煜, 李婕, 高家敏, 张启明, 施亚琴
中国食品药品检定研究院, 北京 100050
摘要:
本文采用超高效液相-三重四级杆质谱联用技术(UPLC-MS/MS)对国内多个生产企业的紫杉醇原料与注射液的有关物质及杂质谱进行了深入研究,对紫杉醇及杂质的质谱裂解规律进行了分析与总结。采用对紫杉醇乙醇溶液进行酸、碱、氧化、光照等强制降解实验对紫杉醇原料与注射液中的降解杂质进行分析,该方法模拟了紫杉醇注射液的处方,但避免了其中辅料聚氧乙基蓖麻油的基质干扰,降解杂质基本涵盖了紫杉醇注射液中所有的杂质。本文共推定了杂质10个,分别为三尖杉宁碱(cephalomannine, 1)、7-表-10-脱乙酰紫杉醇(7-epi-10-deacetylpaclitaxel, 2)、7-表紫杉醇(7-epi-paclitaxel, 3)、巴卡汀(baccatin Ⅲ, 4)、侧链乙酯化合物(ethyl esterside chain, 5)、7-表巴卡汀(7-epi-baccatin Ⅲ, 6)、10-脱乙酰紫杉醇(10-deacetylpaclitaxel, 7)、紫杉醇C3-C11桥联异构体(paclitaxel isomer, C3-C11 bridge, 8)、紫杉醇异构体(paclitaxel isomer, 9)和N-苯甲酰-(2R,3S)-3-苯基异丝氨酸[N-benzoyl-(2R,3S)-3-phenylisoserine, 10],其中1~3为工艺杂质,紫杉醇乙醇溶液酸降解产生的主要杂质为3~7,碱降解产生的主要杂质为2~710,氧化降解产生的主要杂质为7,高温降解产生的主要杂质为3~57,光照产生的主要降解杂质为2~5及本文首次报道的9,原料直接光照产生的主要杂质为8,该研究成果对于国内紫杉醇及其注射液的工艺研究、质量控制与评价有较大的意义。
关键词:    紫杉醇      杂质谱      UPLC-MS/MS      7-表巴卡汀      紫杉醇异构体     
The impurity profiling of paclitaxel and its injection by UPLC-MS/MS
ZHANG Cai-yu, LI Jie, GAO Jia-min, ZHANG Qi-ming, SHI Ya-qin
National Institutes for Food and Drug Control, Beijing 100050, China
Abstract:
An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method was developed to elucidate the impurity profiles of paclitaxel and paclitaxel injections from different Chinese pharmaceutical companies. The fragmentation patterns for paclitaxel and the related impurities were analyzed and summarized. To remove the interference from auxiliary materials, such as hydrogenated castor oil, paclitaxel was dissolved in ethanol for acid, base, peroxide, and light induced forced degradation analysis, which could produce all the impurities exist in the paclitaxel injection. A total of 10 impurities were characterized, such as cephalomannine (1), 7-epi-10-deacetylpaclitaxel (2), 7-epipaclitaxel (3), baccatin Ⅲ (4), ethyl ester side chain (5), 7-epi-baccatin Ⅲ (6), 10-deacetylpaclitaxel (7), paclitaxel isomer (C3-C11 bridge) (8), paclitaxel isomer (9), and N-benzoyl-(2R, 3S)-3-phenylisoserine (10), respectively. Among them, compounds 1-3 could be introduced during manufacture processing. In the forced degradation studies, while acid induced degradation products included 3-7, base induced degradation could produce 2-7 and 10; while 7 is the main compound produced by hydrogen peroxide treatment, 4 compounds (3-5 and 7) were produced by high temperature environment and 5 compounds (2-5 and 9 which is the first reported) from intensity light exposure. Furthermore, 8 was the main impurity came from intensity light exposed paclitaxel powder. The results from this study provide an important reference in processing, optimization, quality control and evaluation of paclitaxel.
Key words:    paclitaxel    impurity profiling    UPLC-MS/MS    7-epi-baccatin Ⅲ    paclitaxel isomer   
收稿日期: 2015-09-28
DOI: 10.16438/j.0513-4870.2015-0750
基金项目: 国家科技支撑计划课题资助项目(2008BAI55B01).
通讯作者: 张启明,Tel:86-10-67095292,E-mail:zqm@nicpbp.org.cn;施亚琴,Tel:86-10-67095760,E-mail:yaqinshi@yahoo.com
Email: zqm@nicpbp.org.cn;yaqinshi@yahoo.com
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