Thermodynamic models to elucidate the enantioseparation of drugs with two stereogenic centers by micellar electrokinetic chromatography

Abstract

An equilibrium model depicting the simultaneous protonation of chiral drugs and partitioning of protonated ions and neutral molecules into chiral micelles in micellar electrokinetic chromatography (MEKC) has been introduced. It was used for the prediction and elucidation of complex changes in migration order patterns with experimental conditions in the enantioseparation of drugs with two stereogenic centers. Palonosetron hydrochloride (PALO), a weakly basic drug with two stereogenic centers, was selected as a model drug. Its four stereoisomers were separated by MEKC using sodium cholate (SC) as chiral selector and surfactant. Based on the equilibrium model, equations were derived for a calculation of the effective mobility and migration time of each stereoisomer at a certain pH. The migration times of four stereoisomers at different pHs were calculated and then the migration order patterns were constructed with derived equations. The results were in accord with the experiment. And the contribution of each mechanism to the separation and its influence on the migration order pattern was analyzed separately by introducing virtual isomers, i.e., hypothetical stereoisomers with only one parameter changed relative to a real PALO stereoisomer. A thermodynamic model for a judgment of the correlation of interactions between two stereogenic centers of stereoisomers and chiral selector was also proposed. According to this model, the interactions of two stereogenic centers of PALO stereoisomers in both neutral molecules and protonated ions with chiral selector are not independent, so the chiral recognition in each pair of enantiomers as well as the recognition for diastereomers is not simply the algebraic sum of the contributions of two stereogenic centers due to their correlation.