Comparative Evaluation of Polar-Organic HPLC, Reversed-Phase HPLC, and Supercritical Fluid Chromatography for Enantioseparation and Gram-Scale Purification of Meclizine and Buclizine.

Rapid enantioseparation and scalable purification processes of chiral drug molecules are crucial to drug development and quality control (QC) but still challenging. Supercritical fluid chromatography is one of the emerging approaches for quicker turnaround times and high throughput to solve these issues. In this study, we report an organized comparison of polar organic HPLC (PO-HPLC), conventional reversed-phase HPLC (RP-HPLC), and supercritical fluid chromatography (SFC) to perform the enantioseparation and gram-scale purification of antihistamine drugs Meclizine (I) and Buclizine (II) with a common polysaccharide-based chiral stationary phase (Chiralpak IJ column). Analytical performance was assessed by examining the retention behavior, resolution, peak symmetry, runtime, and solvent consumption. Effective baseline separations were obtained with polar-organic and reversed-phase HPLC, but longer times for analysis and more organic solvent usage were needed. Chiral SFC, on the other hand, provided quick analyses (5-6 min) with higher resolution (Rs > 2.2), improved peak shapes, and significantly lower organic solvent consumption. Preparative separations of all three techniques were demonstrated at the 1 g scale. Chiral SFC provided the highest overall productivity, with >99% enantiomeric excess and >90% recovery in less than 3 h, while greatly reducing post run work up. The analytical chiral SFC method validation was done according to ICH Q2 (R2) requirements, confirming its specificity, linearity, precision, accuracy, robustness, and solution stability. Taken together, the results illustrate chiral SFC as the most efficient and sustainable platform for analytical and preparative enantioseparation of meclizine and buclizine, with complementary roles for polar organic and reversed phase HPLC.