Liquid chromatographic enantioseparation of thalidomide and its derivatives on cyclodextrin-bonded stationary phases

S. István, Foroughbakhshfasaei Mohammadhassan, D. Máté, Noszál Béla, Tóth Gergő
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Abstract

Abstract The chiral separation of three racemic immunomodulatory drugs, thalidomide, pomalidomide and lenalidomide was studied, using three cyclodextrin bonded stationary phases (β-, hydroxypropyl-β- and carboxymethyl-β-CD) in reversed-phase and polar organic mode. In polar organic mode, using acetonitrile and methanol, no chiral separation was observed. In reversed-phase mode pomalidomide showed chiral interactions with all selectors, while lenalidomide showed no chiral interactions with any of the cyclodextrins employed. Thalidomide showed chiral interactions with β-and carboxymethyl-β-CD, only. Based on these observations it can be concluded that the oxo group at position two is necessary for chiral recognition, while the aromatic primary amine group enhances it. Orthogonal experimental design was used to investigate the effect of the eluent composition, flow rate, and the column temperature on chiral separation. Concentration of the organic modifier was the most important factor among the investigated three variables showing high impact on the chiral separations. In the case of thalidomide optimized parameters (β-cyclodextrin-based stationary phase, 0.1% acetic acid/acetonitrile 95/5 (v/v), 5 °C column temperature, 0.6 ml/min flow rate) resulted in a resolution of 1.68 ± 0.02 between enantiomers. For pomalidomide, this value was 2.70 ± 0.02, under the circumstances as follows: β-cyclodextrin-based stationary phase, 0.1% acetic acid/acetonitrile 90/10 (v/v), 15 °C column temperature and 0.8 mL/min flow rate. Utilizing the experimental conditions employed on an LC-MS/MS system, concentrations as low as 2 ng/mL could be determined from mouse plasma for both substances. Elution sequences were determined with enantiopure standards and in both cases the R-enantiomers eluted first. The methods developed are suitable for the chiral separation of the abovementioned compounds and are sound starting points for bioanalytical method development.
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沙利度胺及其衍生物环糊精键合固定相的液相色谱对映分离
摘要采用三种环糊精键合固定相(β-、羟丙基-β-和羧甲基-β- cd),以反相极性有机方式研究了沙利度胺、泊马度胺和来那度胺三种外消旋免疫调节药物的手性分离。在极性有机模式下,使用乙腈和甲醇,未观察到手性分离。在反相模式下,来那度胺与所有选择物均表现出手性相互作用,而来那度胺与所有环糊精均无手性相互作用。沙利度胺仅与β和羧甲基β- cd表现出手性相互作用。基于这些观察,可以得出结论,2位的氧基是手性识别所必需的,而芳香伯胺基则增强了手性识别。采用正交实验设计考察了洗脱液组成、流速和柱温对手性分离的影响。有机改性剂的浓度是影响手性分离的最重要因素。在沙利度胺的情况下,优化参数(β-环糊精为基础的固定相,0.1%醋酸/乙腈95/5 (v/v), 5°C柱温,0.6 ml/min流速)对映体之间的分辨率为1.68±0.02。在以β-环糊精为基础的固定相,0.1%醋酸/乙腈90/10 (v/v), 15℃柱温,0.8 mL/min流速的条件下,泊马度胺的该值为2.70±0.02。利用LC-MS/MS系统的实验条件,可以在小鼠血浆中检测到低至2 ng/mL的两种物质。洗脱序列用对映体标准确定,在两种情况下r -对映体首先被洗脱。所开发的方法适用于上述化合物的手性分离,是生物分析方法发展的良好起点。
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