Department of Pharmaceutical and Therapeutic Chemistry, Faculty of Pharmacy, University of Medicine, Pharmacy, Science and Technology "George Emil Palade" of Târgu Mureș, 540142 Târgu Mureș, Romania.
Department of Toxicology and Biopharmacy, Faculty of Pharmacy, University of Medicine, Pharmacy, Science and Technology "George Emil Palade" of Târgu Mureș, 540142 Târgu Mureș, Romania.
Molecules. 2022 Aug 31;27(17):5603. doi: 10.3390/molecules27175603.
Mexiletine (MXL) is a class IB antiarrhythmic agent, acting as a non-selective voltage-gated sodium channel blocker, used in therapy as a racemic mixture ,-MXL hydrochloride. The aim of the current study was the development of a new, fast, and efficient method for the chiral separation of MXL enantiomers using capillary electrophoresis (CE) and cyclodextrins (CDs) as chiral selectors (CSs). After an initial CS screening, using several neutral and charged CDs, at four pH levels, heptakis-2,3,6-tri-O-methyl-β-CD (TM-β-CD), a neutral derivatized CD, was chosen as the optimum CS for the enantioseparation. For method optimization, an initial screening fractional factorial design was applied to identify the most significant parameters, followed by a face-centered central composite design to establish the optimal separation conditions. The best results were obtained by applying the following optimized electrophoretic conditions: 60 mM phosphate buffer, pH 5.0, 50 mM TM-β-CD, temperature 20 °C, applied voltage 30 kV, hydrodynamic injection 50 mbar/s. MXL enantiomers were baseline separated with a resolution of 1.52 during a migration time of under 5 min; -MXL was the first migrating enantiomer. The method's analytical performance was verified in terms of precision, linearity, accuracy, and robustness (applying a Plackett-Burman design). The developed method was applied for the determination of MXL enantiomers in pharmaceuticals. A computer modeling of the MXL-CD complexes was applied to characterize host-guest chiral recognition.
美西律 (MXL) 是一种 I 类抗心律失常药物，作为一种非选择性电压门控钠通道阻滞剂，作为外消旋混合物盐酸美西律用于治疗。本研究的目的是开发一种新的、快速且有效的手性分离 MXL 对映异构体的毛细管电泳 (CE) 和环糊精 (CD) 方法，作为手性选择剂 (CS)。在初步 CS 筛选中，使用几种中性和带电 CD，在四个 pH 值下，七-(2,3,6-三-O-甲基)-β-CD (TM-β-CD)，一种中性衍生 CD，被选为对映体分离的最佳 CS。为了优化方法，首先应用析因设计筛选确定最显著的参数，然后应用中心复合设计建立最佳分离条件。通过应用以下优化电泳条件获得最佳结果：60 mM 磷酸盐缓冲液，pH 值 5.0，50 mM TM-β-CD，温度 20°C，施加电压 30 kV，流体动力学进样 50 mbar/s。在 5 分钟内迁移时间下，对映异构体基线分离，分辨率为 1.52；-MXL 是第一个迁移的对映异构体。该方法的分析性能通过精密度、线性、准确性和稳健性（应用 Plackett-Burman 设计）进行了验证。该方法应用于药物中美西律对映异构体的测定。应用计算机建模研究了 MXL-CD 配合物，以表征主体-客体手性识别。
