Zhang Ling, Hu Yue, Galella Elizabeth, Tomasella Frank P, Fish William P
Chemical and Synthetic Development, Bristol-Myers Squibb Co., New Brunswick, NJ 08903, USA.
Drug Product Science and Technology, Bristol-Myers Squibb Co., New Brunswick, NJ 08903, USA.
J Pharm Anal. 2017 Jun;7(3):156-162. doi: 10.1016/j.jpha.2017.03.003. Epub 2017 Mar 16.
In the pharmaceutical industry, the analysis of atropisomers is of considerable interest from a scientific and regulatory perspective. 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 is achieved on a derivatized β-cyclodextrin bonded stationary phase. Further investigation shows 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 peak 1/2 as a pair of enantiomers and peak 3/4 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 kJ/mol to 2.42 kJ/mol.
在制药行业，从科学和监管的角度来看，对阻转异构体的分析具有相当大的意义。由于连接芳基的单键旋转受阻，目标化合物含有两个手性轴，这导致了四种潜在的构型异构体（阻转异构体）。在衍生化的β-环糊精键合固定相上实现了四种阻转异构体的分离。进一步研究表明，低温条件，包括样品制备（-70°C）、样品储存（-70°C）和色谱分离（6°C），对于防止相互转化至关重要。LC-UV-激光偏振分析确定峰1/2为一对对映体，峰3/4为另一对对映体。保留数据的热力学分析表明，对映体对的分离主要受焓控制，如范特霍夫图的正斜率所示。绝对Δ（ΔH）的差异范围为2.20kJ/mol至2.42kJ/mol。
