Separation of atropisomers by chiral liquid chromatography and thermodynamic analysis of separation mechanism

作     者：Ling Zhang Yue Hu Elizabeth Galella Frank P. Tomasella William P. Fish 

作者机构：Chemical and Synthetic DevelopmentBristol-Myers Squibb Co.New BrunswickNJ 08903USA Drug Product Science and TechnologyBristol-Myers Squibb Co.New BrunswickNJ 08903USA 

出 版 物：《Journal of Pharmaceutical Analysis》 (药物分析学报（英文版）)

年 卷 期：2017年第7卷第3期

页      面：156-162页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 100701[医学-药物化学] 10[医学] 

主　　题：Atropisomer separation Chiral HPLC Thermodynamic parameters β-cyclodextrin stationary phase Chiral separation mechanism 

摘      要：In the pharmaceutical industry, the analysis of atropisomers is of considerable interest from both scientific and regulatory perspectives. The compound of interest contains two stereogenic axes due to the hindered rotation around the single bonds connecting the aryl groups, which results in four potential configurational isomers(atropisomers). The separation of the four atropisomers was achieved on a derivatized β-cyclodextrin bonded stationary phase. Further investigation showed that low temperature conditions, including sample preparation(-70 °C), sample storage(-70 °C), and chromatographic separation(6 °C), were critical to preventing interconversion. LC-UV-laser polarimetric analysis identified peaks 1 and 2 as a pair of enantiomers and peaks3 and 4 as another. Thermodynamic analysis of the retention data indicated that the separation of the pairs of enantiomers is primarily enthalpy controlled as indicated by the positive slope of the van t Huff plot. The difference in absolute Δ(Δ H), ranged from 2.20 k J/mol to 2.42 k J/mol.