Stereoselective Analysis by Design in the Development of a Cation-Selective Exhaustive Injection and Sweeping Coupled with Cyclodextrin Modified Electrokinetic Chromatography Method for the Determination of Citalopram Enantiomers

Abstract

A highly sensitive, rapid and enantioselective method was developed and fully validated for the enantioseparation and determination of citalopram enantiomers by cation selective exhaustive injection-sweeping-cyclodextrin modified electrokinetic chromatography (CSEI-sweeping-CDEKC). Satisfactory resolution (Rs=8.04) and enrichment factor (EF=2163) was achieved within 15 min employing sulfated-β-cyclodextrin (S-β-CD) as the chiral pseudostationary phases at a concentration of 25 mg mL^-1. Comprehensive validation of this method was rigorously conducted over the concentration range of 12.5-100 ng mL^-1 for R-citalopram and 400-2000 ng mL ^-1 for S-citalopram in solution samples, and 10-1250 ng mL^-1 for both enantiomers in plasma samples. All the validation data demonstrated that the desirable linearity, sensitivity, precision, accuracy, recovery, and stability were attained from the proposed approach. The established method was successfully applied to an enantiomer impurity inspection of escitalopram oxalate, the R-citalopram impurity in all batches was within the limit amount as required. Ulteriorly, the stereoselective pharmacokinetic study of citalopram enantiomers in rat plasma after oral administration of 20 mg kg^-1 racemic citalopram or S-citalopram was also carried out, and no chiral inversion was observed during the experimental procedure.

Keywords: Citalopram enantiomers, CSEI-sweeping-CDEKC, enantioseparation, Enantiomer impurity inspection, Stereoselective pharmacokinetic study