Modelling the simultaneous chiral separation of a group of drugs by electrokinetic chromatography using mixtures of cyclodextrins

Abstract

Two mixtures of neutral cyclodextrins (CDs) were used in Electrokinetic Chromatography (EKC) to model and optimize the simultaneous enantiomeric separation of a group of seven drugs. Heptakis(2,6-di-O-methyl)-β-CD (DM-β-CD) combined with methyl-γ-CD (M-γ-CD) or with carboxyethyl-γ-CD (CE-γ-CD) was employed in a 25 mM formate buffer at pH 3.0 to have the drugs studied positively charged. Dubsky's model was applied to calculate the enantiomer effective electrophoretic mobilities for each combination of CDs at different averaged molar fractions and total CDs concentrations. The most adequate averaged molar fraction and total CDs concentration in terms of the simultaneous enantiomeric separation of the drug mixture were predicted by the model and results were experimentally corroborated. The model also foresaw interesting effects, derived from the combination of DM-β-CD with M-γ-CD or with CE-γ-CD, on the individual chiral separation of some of the drugs studied. The observed reversal of the migration order for some compounds when changing the total CDs concentration was also predicted and the model showed its potential even at concentrations out of the experimental range of CD concentrations experimentally employed. The use of an averaged molar fraction of 0.8 for DM-β-CD at a total CDs concentration of 40 mM in the DM-β-CD/CE-γ-CD system predicted by the model enabled the simultaneous enantiomeric separation of six of the drugs studied (except verapamil) with resolutions ranging from 0.6 to 4.0.