Impact of the degree of substitution on the enantioseparation of anionic β-cyclodextrin in liquid‒liquid extraction and countercurrent chromatography: Insights from molecular docking simulations.

Five types of sulfobutylether-β-cyclodextrin (SBE-β-CD) and carboxymethyl-β-cyclodextrin (CM-β-CD) with different degrees of substitution were synthesized, and six and five racemates were respectively chosen to study the influence of the degree of substitution on the enantioseparation factor. The synthesized SBE-β-CD and CM-β-CD were characterized using H NMR spectroscopy and mass spectrometry. The results indicated that the influence of the degree of substitution on enantioseparation for distinct racemates exhibited significant variability. Increasing the degree of substitution of CM-β-CD led to an increasing enantioseparation factor, while SBE-β-CD with a specific degree of substitution provided the optimum enantioseparation factor for some racemates. The optimum enantioseparation factors of N-methyl duloxetine and duloxetine were obtained when a relatively low degree of substitution (DS = 3.5) was selected. And the optimum enantioseparation factor was obtained with a relatively high degree of substitution (DS = 7.5). SBE-β-CD with a low substitution degree of 3.5 was chosen to optimize the countercurrent chromatographic enantioseparation of N-methyl-duloxetine, which resulted in a significant improvement in peak resolution from 0.51 to 0.83. Molecular docking was used to construct three SBE-β-CDs with different degrees and distributions of substitution, and a good agreement was found between the docking results and the experimental results.