抗痴呆症药中加兰他敏对映异构体的毛细管电泳分离及药物质量控制

高等学校化学学报 ›› 2004, Vol. 25 ›› Issue (2): 256.

抗痴呆症药中加兰他敏对映异构体的毛细管电泳分离及药物质量控制

颜流水, 赵基源, 罗国安, 孙命, 王义明, 杨学东

清华大学化学系, 北京 100084

收稿日期:2002-08-14 出版日期:2004-02-24 发布日期:2004-02-24
通讯作者: 罗国安(1946年出生),男,教授,博士生导师,从事毛细管电泳及新药开发研究.E-mail;luoga@chem.tsinghua.edu.cn E-mail:luoga@chem.tsinghua.edu.cn
基金资助:
国家重大基础研究规划项目(批准号;G1999054404)资助

Enantiomeric Separation of Galantamine in Drug for Alzheimer's Disease and Its Quality Control by Capillary Electrophoresis

YAN Liu-Shui, ZHAO Ji-Yuan, LUO Guo-An, SUN Ming, WANG Yi-Ming, YANG Xue-Dong

Department of Chemistry, Tsinghua University, Beijing 100084, China

Received:2002-08-14 Online:2004-02-24 Published:2004-02-24

摘要/Abstract

摘要： 建立了以α-环糊精为手性选择剂的毛细管区带电泳用于分离治疗老年性痴呆病药物加兰他敏手性异构体的方法,测定了加兰他敏对映体与α-环糊精包结物的键合常数和手性识别过程的热力学参数.通过计算机模拟构象分析,探讨了分离机理.研究结果表明,对映异构体最大分离度为3.60,R和S对映异构体与α-环糊精的键合常数分别为K_R-CD=33.98L/mol和K_S-CD=23.90L/mol.将该方法用于加兰他敏原料药分析,分离出10种结构相似的化合物,测得非药效成分R型异构体含量为0.82%,测定的线性范围为0.015～1.0mmol/L,迁移时间和峰面积的精度分别为0.20%和2.6%.该方法可作为该药物质量控制与快速检测的有效手段.

关键词: 加兰他敏, 环糊精, 键合常数, 手性分离, 药物分析

Abstract: A method for capillary electrophoretic enantiomeric separation of a novel drug for Alzheimers disease, Galantamine, has been established with α-cyclodextrin as the chiral additive. General equations and data analysis approach are presented to relate molibilities to equalibrium constants in simple binding equilibria and used to determine bonding constants and thermodynamic parameters for host-guest complexation of galantamine enantiomers with cyclodextrin selector. The effects of cyclodextrin concentration and type, buffer concentration and its pH, and separation voltage were investigated. The mechanism of enantioselectivity is discussed by combining with the computer simulating conformational analysis. The maximal resolution of 3.60 was obtained . The bonding constants of host-guest complex of galantamine enantiomers with α-cyclodextrin, K_R-CD and K_S-CD, is 33.98 L/mol and 23.90 L/mol, respectively. The established method was successfully applied to the detect ion of the non-effective component in the raw material of galantamine. Ten structural analogues were found, and the content of R enantiomer is 0.82%. The concentration linear rang is 0.015—1.0 mmol/L with the analysis precision of 0.20% and 2.6% for the measurement of migration time and peak area, respectively. Thus, the method could be used as a rapid and reliable tool for quantity control of the drug.

Key words: Galantamine, Cyclodextrin, Bonding constant, Chiral separation, Pharmaceutical analysis

中图分类号:

O657.8

TrendMD:

颜流水, 赵基源, 罗国安, 孙命, 王义明, 杨学东. 抗痴呆症药中加兰他敏对映异构体的毛细管电泳分离及药物质量控制. 高等学校化学学报, 2004, 25(2): 256.

YAN Liu-Shui, ZHAO Ji-Yuan, LUO Guo-An, SUN Ming, WANG Yi-Ming, YANG Xue-Dong . Enantiomeric Separation of Galantamine in Drug for Alzheimer's Disease and Its Quality Control by Capillary Electrophoresis. Chem. J. Chinese Universities, 2004, 25(2): 256.

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