Semmelweis University, Department of Pharmaceutical Chemistry, Hőgyes Endre u. 9, Budapest H-1092, Hungary.
J Pharm Biomed Anal. 2012 Mar 25;62:42-7. doi: 10.1016/j.jpba.2011.12.032. Epub 2012 Jan 3.
The enantiomers of dapoxetine, a serotonin transporter inhibitor for the treatment of premature ejaculation have been separated by cyclodextrin modified capillary zone electrophoresis using uncoated fused-silica capillary. Over 20 cyclodextrins were screened as chiral selectors, investigating the stability of the inclusion complexes and enantioseparating properties. According to the preliminary experiments as chiral selector randomly methylated-γ-cyclodextrin was chosen. The basic chemical and instrumental parameters of enantioseparation as concentration of buffer, chiral selector and organic additive, pH, temperature and applied voltage were optimized afterwards using an orthogonal experimental design. Using this methodology not only the optimal parameter values for chiral separation (15 °C, +15 kV, 70 mM acetate, 20 v/v% MeOH, pH*=4.5, 3 mM methylated-γ-CyD) but also the significance order of factors on resolution was determined. Applying these parameters an optimal resolution of 7.01 was achieved. The optimized method was then validated according to the ICH guideline Q2 (R1) with regard to repeatability, linearity range, LOD, LOQ, accuracy and robustness.
达泊西汀对映异构体，一种用于治疗早泄的 5-羟色胺转运体抑制剂，已通过环糊精修饰的毛细管区带电泳，使用未涂覆的熔融硅毛细管进行分离。筛选了 20 多种环糊精作为手性选择剂，考察了包络复合物的稳定性和对映体分离性能。根据初步实验，选择了随机甲基化-γ-环糊精作为手性选择剂。随后使用正交实验设计优化了手性分离的基本化学和仪器参数，如缓冲液浓度、手性选择剂和有机溶剂添加剂浓度、pH 值、温度和外加电压。使用该方法不仅确定了手性分离的最佳参数值（15°C、+15 kV、70 mM 乙酸盐、20 v/v%甲醇、pH*=4.5、3 mM 甲基化-γ-CyD），还确定了各因素对分辨率的显著顺序。应用这些参数，实现了 7.01 的最佳分辨率。然后根据 ICH 指南 Q2（R1），对优化方法进行了重复性、线性范围、检测限、定量限、准确度和稳健性验证。
