Thermodynamic study and separation mechanism of diltiazem optical isomers in packed-column supercritical fluid chromatography

Abstract

Cellulose tris(4-chlorophenylcarbamate) coated on silica was used as a chiral stationary phase for the separation of diltiazem (a Ca-channel blocker) optical isomers in packed-column supercritical fluid chromatography. The effect of temperature on the separation of the cis- and trans-enantiomers was studied in detail. The Van’t Hoff plots for the retention were found to be curves, while those for the selectivity were found to be linear. The chiral separation of cis-enantiomers was improved with a decrease in temperature, whereas that of trans-enantiomers was improved with an increase in temperature. To obtain a better understanding of the difference in the separations of cis- and trans-enantiomers, the temperature dependence of enantioselectivities was studied to determine the thermodynamic parameters ΔΔ H°, ΔΔ S°, and T iso. The thermodynamic parameters revealed that the separation of trans-enantiomers was entropy-controlled in the range of temperature examined, whereas enthalpy-controlled separation was observed for cis-enantiomers. The separations of both cis- and trans-enantiomers, however, were enthalpy-controlled in normal-phase HPLC. The separations of the related compounds, 3-hydroxy isomers, were compared with those of diltiazem isomers. In addition, the differences in separation mechanisms between cis- and trans-enantiomers of diltiazem optical isomers are discussed by means of three-dimensional structures.