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

Abstract

Complementary techniques were applied for the investigation of the chiral recognition and enantiomeric resolution of lenalidomide using various cyclodextrins and polysaccharides as chiral selectors. The high-performance liquid chromatography enantioseparation of the anticancer drug was achieved using polysaccharide-type chiral stationary phases in polar organic mode. Elution order and absolute configuration were elucidated by combined circular dichroism spectroscopy and time-dependent density functional theory calculations after the isolation of pure enantiomers. Chiral selector dependent and mobile-phase dependent reversal of the enantiomer elution order was observed, and the nonracemic nature of the lenalidomide sample was also demonstrated. Eight anionic cyclodextrins were screened for their ability to discriminate between the uncharged enantiomers by using capillary electrophoresis. Only two derivatives presented chiral interactions, these cases being interpreted in terms of apparent stability constants and complex mobilities. The best results were delivered by sulfobutylether-β-cyclodextrin, where quasi-equal stability constants were recorded and the enantiodiscrimination process was mainly driven by different mobilities of the transient diastereomeric complexes. The optimized high-performance liquid chromatography (Chiralcel OJ column, pure ethanol with 0.6 mL/min flow rate, 40°C) and capillary electrophoresis methods (30 mM sulfobutylether-β-cyclodextrin, 30 mM phosphate pH 6.5, 12 kV applied voltage, 10°C) were validated for the determination of 0.1% (R)-lenalidomide as a chiral impurity, which could be important if a racemic switch is achieved.

HPLC semi‐preparative separation of diclazuril enantiomers and racemization in solution

“…Racemization and configuration transformations of pure enantiomers might take place in solution under high temperature, organic solvent, and acidic and basic conditions, probably forming racemic products . Thus, it is very necessary to investigate stability of diclazuril enantiomers in ethanol.…”

Separation of histidine enantiomers by capillary electrochromatography with molecularly imprinted monolithic columns

“…While one enantiomer can produce the desired therapeutic activities, the other enantiomer can not be active or even exhibit undesirable effects [10‐11]. After studies performed by Gassman and co‐workers for the first time to separate enantiomers for electrokinetically, evaluations based on electrophoresis methods including capillary electrochromatography (CEC) technique have been included in the literature [12–15].…”

Thiol‐ene click derived structurally well‐defined per(3,5‐dimethyl)phenylcarbamoylated cationic cyclodextrin separation material for achiral and chiral chromatography

“…Since the shape of truncated hollow cone favor their ability to form stable inclusion with guest molecules [6], cyclodextrins (CDs) are widely used for enantioseparation, especially as CSPs in HPLC [7][8][9][10]. Besides its inclusion features, CDs can be chemically modified to build hydrogen bonding, π-π, steric repulsion interactions, which are all beneficial for chiral recognition process [11].…”