Computational contribution to the electrophoretic enantiomer separation mechanism and migration order using modified β‐cyclodextrins

Abstract

Capillary electrophoresis (CE) is an extremely effective technique in many kinds of separations, including separation of enantiomers. Some additional techniques may be necessary to determine the enantiomer migration order (EMO) and also the mechanism involved in chiral recognition. This paper reports the development and optimization of a CE method for enantioseparation of racemic mixture of both R- and S-stereoisomers of tramadol (TRM) with a computational contribution for the EMO determination and the responsible mechanisms for chiral distinction. Parameters such as composition and concentration of background electrolyte (BGE) and type and concentration of cyclodextrins (CD) were evaluated. For calculations, a sequential methodology was used, resorting to semiempirical Parametric Model 3 (PM3) followed by calculations accomplished using density functional theory. The best results were obtained with sulfated-β-CD (s-β-CD) and carboxymethyl-β-cyclodextrin (cm-β-CD) as chiral selector. Calculations show that the inclusion of TRM is not a probable process due to the shape of the TRM molecule and the size CDs cavities. Therefore, the chiral recognition process occurs by the formation of association complexes between modified β-CD and groups of TRM molecules. The structural analysis of the fragments of complexes at a pH of 10 and a thermodynamic analysis of the complexes' formation process allows determining the EMO. Comparing results obtained experimentally and computationally, it seems that the developed method is adequate for separation of TRM enantiomers and the computational methodology is also adequate to get a sense of the system at a molecular level.

Chiral Selectors in Capillary Electrophoresis: Trends during 2017–2018

“…β-CD derivatives, i.e., neutral (hydroxyethyl-, hydroxypropyl- and methyl-) and anionic (carboxymethyl-, and sulphated-) [21,22,23,24,25,26,27,28,29,30,31,32,33] derivatives were the most commonly used CSs reported. Other commercially-available modified CDs or laboratory-prepared modified CDs with known synthesis were reported.…”

“…There were two studies that compared anionic and neutral β-CD derivatives, and both studies concluded that the anionic derivatives provided better selectivity for the analytes tested (cationic higenamine [26] and neutral tramadol [22]). The host-guest interaction with anionic β-CDs are driven by electrostatic interactions, hydrophobic inclusion and hydrogen bonding, which is the case with higenamine.…”

“…Molecular modelling can help the researcher understand the different steps involved in the molecular recognition process, the non-bonding interactions involved between the analyte and the CS and the binding energies for their association. During this review period, ten studies utilised molecular modelling, with the intention of understanding chiral recognition mechanism and elution migration order [22,32,35,44,60,62,72,73,94,95]. Molecular modelling has also been utilised to design new CSs [40].…”

Capillary Electrophoresis Methods for the Determination of Tramadol: A Review

“…It seems that enantiorecognition depends on the formation of association complexes between the anionic β-CD and certain functional groups of tramadol. 31 Tramadol along with other four basic analytes (amlodipine, hydroxyzine, fluoxetine, tolterodine) was used as model compound for the assessment of sulphated maltodextrin potential as chiral selector in CE. Using a 50 mM phosphate BGE at pH 3.0 and 2% (w/v) sulphated maltodextrin as chiral selector baseline enantioseparation December 2019, 25(4), 278-286 | 283 was achieved for all studied analytes.…”

Predefine resolution of enantiomers in partial filling capillary electrophoresis and two discontinuous function plugs coupling in‐capillary

“…CE has proved to be one of the most effective methods for enantiomers' separation due to its high efficiency, robustness, low cost, simplicity, and diversity regarding different modes, such as ACE , MEKC , and NACE . The enantioseparation can be achieved using different types of chiral selectors, such as cyclodextrin and its derivatives , cyclofructans , crown ether , DNA , macrocyclic antibiotics , ionic liquids , chiral metal‐ion complexes , and proteins . However, when using selectors with UV absorbances, such as proteins and DNA, or when the separation is combined with mass spectrometric detection, the bad effects of selectors on detection must be considered.…”