Separation of atropisomers by chiral liquid chromatography and thermodynamic analysis of separation mechanism / 药物分析学报

ABSTRACT

In the pharmaceutical industry, the analysis of atropisomers is of considerable interest from both scientific and regulatory perspectives. The compound of interest contains two stereogenicaxes due to the hindered rotation around the single bonds connecting the aryl groups, which results in fourpotential configurational isomers (atropisomers). The separation of the four atropisomers was achieved on aderivatized β-cyclodextrin bonded stationary phase. Further investigation showed that low temperatureconditions, 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 2as a pair of enantiomers and peaks 3 and 4 as another. Thermodynamic analysis of the retention data indicatedthat the separation of the pairs of enantiomers is primarily enthalpy controlled as indicated by the positiveslope of the van't Huff plot. The difference in absolute Δ (Δ H), ranged from 2.20 kJ/mol to 2.42 kJ/mol.