Mechanistic study on the opposite migration order of the enantiomers of ketamine with α- and β-cyclodextrin in capillary electrophoresis

Abstract

The enantiomer migration order of the chiral anaesthetic drug ketamine [RS‐2‐(2‐chlorophenyl)‐2‐(methylamino)cyclohexanone] was studied by capillary electrophoresis using various cyclodextrins as chiral selectors. The opposite migration order of the enantiomers of ketamine was observed when native α‐ and β‐cyclodextrins were used as chiral selectors in capillary electrophoresis. The possible mechanisms of the opposite enantiomer migration order were investigated by employing electrospray ionization mass spectrometry, 1H‐NMR spectrometry, one dimensional rotating frame nuclear Overhauser and exchange spectroscopy, X‐ray crystallography, and molecular modeling techniques. As this study indicates, capillary electrophoresis can be used as a reliable experimental technique for examination of the correctness of the results of molecular modeling calculations. In addition, based on X‐ray crystallographic analysis it was confirmed that (–)‐ketamine as a free base possesses S configuration.

Enantioselective separation of azole compounds by EKC. Reversal of migration order of enantiomers with CD concentration

“…There are different ways to change the enantiomeric migration order by CE when CDs are used as chiral selectors [4,[10][11][12][13]: (i) modifying the CD cavity size [14]; (ii) changing the nature of CD substituents [15,16]; (iii) varying the location of substituents on the CD rim [17]; (iv) employing charged CDs in the BGE and changing the polarity of the applied voltage [18,19]; (v) modifying the pH of the BGE [18,20]; (vi) changing the EOF, i.e., eliminating or reversing it [19,20]; (vii) using achiral additives (i.e., micelles or ligandexchange compounds as metals) in chiral systems [21,22], and finally, (viii) varying the concentration of the CD in the separation buffer. However, this last phenomenon has scarcely been observed.…”

Pharmaceutical and biomedical applications of chiral capillary electrophoresis and capillary electrochromatography: An update

“…A similar approach was used to explain the opposite migration order of the ketamine enantiomers in the presence of a-CD and b-CD [61]. NMR studies indicated a deeper inclusion of ketamine into the cavity of b-CD compared to a-CD.…”

Enantioseparation of glutethimide and its 5‐OH‐metabolite in capillary electrophoresis and study of selector‐selectand interactions using one‐dimensional rotating frame nuclear Overhauser and exchange spectroscopy

“…The affinity pattern of GT enantiomers towards these two CDs was the same. Interestingly, the affinity pattern of the enantiomers of aminoglutethimide was opposite towards native a-and b-CD [5]. From single-component charged b-CD derivatives, HMdiSu-b-CD containing 14 sulfate groups did not attain the enantioseparation while all other randomly and selectively substituted charged b-CD derivatives afforded enantioseparation.…”

“…In addition, CE enables to study fine nuances of intermolecular interactions in solution, which are hardly accessible by other techniques [4][5][6]. Several important advantages of CE facilitate its application for the latter purpose.…”

“…As it was recently found, (1)-enantiomer of the structural analog of GT, the chiral nonsteroidal aromatase inhibitor aminoglutethimide is preferentially bonded by native b-CD, whereas (2)-enantiomer of the same compound bounds more tightly with both native a-and g-CD. Interesting structural reasons of this phenomenon were derived based on one-dimensional rotating frame nuclear Overhauser and exchange spectroscopy (1-D ROESY) [5].…”