Sun Wenyu, Qiu Huiyun, Lin Susu, Tong Shengqiang
Department of Pharmacy, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, China; College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310032, China.
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310032, China.
J Chromatogr A. 2024 Sep 27;1733:465255. doi: 10.1016/j.chroma.2024.465255. Epub 2024 Aug 10.
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.
合成了五种不同取代度的磺丁基醚-β-环糊精（SBE-β-CD）和羧甲基-β-环糊精（CM-β-CD），并分别选取六种和五种外消旋体来研究取代度对对映体分离因子的影响。利用核磁共振氢谱和质谱对合成的SBE-β-CD和CM-β-CD进行了表征。结果表明，取代度对不同外消旋体对映体分离的影响表现出显著的差异。CM-β-CD取代度的增加导致对映体分离因子增大，而具有特定取代度的SBE-β-CD对某些外消旋体提供了最佳的对映体分离因子。当选择相对较低的取代度（DS = 3.5）时，获得了N-甲基度洛西汀和度洛西汀的最佳对映体分离因子。而在相对较高的取代度（DS = 7.5）下获得了最佳对映体分离因子。选择取代度为3.5的低取代度SBE-β-CD来优化N-甲基度洛西汀的逆流色谱对映体分离，使峰分辨率从0.51显著提高到0.83。利用分子对接构建了三种具有不同取代度和取代分布的SBE-β-CD，对接结果与实验结果吻合良好。
