Chiral Separation of Uncharged Pomalidomide Enantiomers Using Carboxymethyl‐β‐Cyclodextrin: A Validated Capillary Electrophoretic Method

Abstract

The racemic mixture of pomalidomide (POM), a second-generation immunomodulatory uncharged drug, was separated into enantiomers by capillary zone electrophoresis for the first time. Seven different chargeable cyclodextrin (CD) derivatives were screened as complexing agents and chiral selectors, investigating the stability of the POM-CD inclusion complexes and their enantiodiscriminating capacities. Based on preliminary experiments, carboxymethyl-β-CD (CM-β-CD) was found to be the most effective chiral selector. Factors influencing enantioseparation were systematically optimized, using an orthogonal experimental design. Optimal parameters (background electrolyte [BGE]: 50 mM Tris-acetate buffer, pH 6.5, containing 15 mM CM-β-CD; capillary temperature: 20°C; voltage applied +15 kV) allowed baseline separation of POM enantiomers with a resolution as high as 4.87. The developed method was validated, in terms of sensitivity (limit of detection and limit of quantification), linearity, accuracy, repeatability, and intermediate precision.

Liquid chromatography with mass spectrometry enantioseparation of pomalidomide on cyclodextrin‐bonded chiral stationary phases and the elucidation of the chiral recognition mechanisms by NMR spectroscopy and molecular modeling

“…Based on the observed retention times on the investigated CSPs (Supporting Information Table S1) the following stability order can be assumed between POM and CDs: ␤-CD > CM-␤-CD> HP-␤-CD>SB-␤-CD. This is in agreement with our previous results regarding the separation of POM enantiomers using charged CDs in CE, where higher complex stabilities were observed, with CM-␤-CD, when compared to SB-␤-CD [12].…”

Chiral separation of lenalidomide by liquid chromatography on polysaccharide‐type stationary phases and by capillary electrophoresis using cyclodextrin selectors

“…To achieve electrophoretic chiral separation of the uncharged LEN enantiomers, various increasing concentrations (0.2–30 mM) of eight negatively charged, multicomponent CD derivatives were applied, differing in cavity size, type, and number of substituents. Preliminary chiral selector screening was performed with 25 mM Tris‐acetate BGE at pH 5, which also yielded excellent results in our previous studies . The summarized results, presented in Table , reveal that only two CDs displayed chiral interactions with the analyte.…”

Chiral selectors in CE: Recent development and applications (mid‐2014 to mid‐2016)

“…This study, along with some other previously reported studies , suggested that this approach is more reproducible and more favorable, considering the inter‐instrumental transfer capability. CM‐β‐CD also proved to be the most effective CS for several analytes, such as pomalidomide , zopiclone and its active metabolites , propranolol , and 4‐hydroxypropranolol .…”