Enantioseparation of beta-blocker drugs for pharmaceutical applications

Abstract

Beta-Blocker drugs of propranolol and nadolol, which has one and multi chiral centre respectively, were chosen as the target substances in the chiral separation studies. Combination of different techniques such as thermodynamic calculations, structural studies as well as ternary solubility diagram was proposed and demonstrated to be a powerful and reliable method to identify the nature of racemic species (e.g., propranolol), which is important for the correct choice of resolution methods. Complete resolution of three components of nadolol was achieved in heptakis (6-azido-6-deoxy-2, 3-di-O-phenylcarbamolyted) beta-CD bonded CSP by HPLC. Various factors that affect the enantioseparation were examined systemically. The equilibrium and kinetics constants were evaluated by moment analysis on the basis of solid film linear driving force model. The h-root method without dummy species was proposed and applied to determine the competitive Langmuir isotherm for stereoisomers of nadolol. The difference and equivalence of two approaches for countercurrent chromatographic separation process has been established. Continuous chromatographic separation of enantiomer (RSR)-nadolol from its racemate in both five-zone and four-zone SMB has been studied.