Chiral Separation of Four Stereoisomers of Ketoconazole Drugs Using Capillary Electrophoresis

Abstract

This work aimed to develop a chiral separation method of ketoconazole enantiomers using electrokinetic chromatography. The separation was achieved using heptakis (2, 3, 6-tri-O-methyl)-β-cyclodextrin (TMβCD), a commonly used chiral selector (CS), as it is relatively inexpensive and has a low UV absorbance in addition to an anionic surfactant, sodium dodecyl sulfate (SDS). The influence of TMβCD concentration, phosphate buffer concentration, SDS concentration, buffer pH, and applied voltage were investigated. The optimum conditions for chiral separation of ketoconazole was achieved using 10 mM phosphate buffer at pH 2.5 containing 20 mM TMβCD, 5 mM SDS, and 1.0% (v/v) methanol with an applied voltage of 25 kV at 25 °C with a 5-s injection time (hydrodynamic injection). The four ketoconazole stereoisomers were successfully resolved for the first time within 17 min (total analysis time was 28 min including capillary conditioning). The migration time precision of this method was examined to give repeatability and reproducibility with RSDs ≤5.80% (n =3) and RSDs ≤8.88% (n =9), respectively.

Theoretical and Molecular Docking Study of Ketoconazole on Heptakis(2,3,6‐tri‐O‐methyl)‐β‐cyclodextrin as Chiral Selector

“…These results correlated with our previous experimental studies (Fig. ) using capillary electrophoresis, since the more favorable energy state should have a greater migration time. From the results of binding energy, the sequence of migration time for the ketoconazole stereoisomers is as follows: P1: 2S4R; P2: 2R4S; P3: 2R4R; P4: 2S4S.…”

Investigation of maltodextrin‐based synergistic system with amino acid chiral ionic liquid as additive for enantioseparation in capillary electrophoresis

“…Only one literature study reported that four ketoconazole stereoisomers were successfully enantioseparated by using heptakis (2, 3, 6‐tri‐O‐methyl)‐β‐cyclodextrin (TM‐β‐CD) in addition to sodium dodecyl sulfate (SDS). The reason is presumably attributed the fact that the other two enantiomers have no UV signal because of the lower percentage in the racemic mixture of the compound resulting from steric hindrance in the structure . Additionally, an appropriate separation condition is also a key factor, including the addition of SDS and lower buffer pH …”

“…42 Additionally, an appropriate separation condition is also a key factor, including the addition of SDS and lower buffer pH. 43 Several experimental parameters, such as the concentration of AACILs and maltodextrin, buffer pH, applied voltage, and capillary temperature, were optimized in the established synergistic system.…”

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

“…Ibrahim et al. investigated the chiral separation of four stereoisomers of ketoconazole drugs by using trimethyl‐β‐CD (TM‐β‐CD) as the CS in CE. They examined the effect of CD concentration, SDS concentration, buffer concentration, pH, and applied voltage value on enantioseparation.…”