Chiral separation of propranolol hydrochloride through an SMB process integrated with ciystallization

Resolution of propranolol hydrochloride was studied in self-packed columns of perphenyl carbamoylated beta-cyclodextrin (beta-CD). Both the bed voidage and linear equilibrium constants were evaluated by moment analysis of a series of linear elution chromatograms. A modified h-root method was used to determine the competitive Langmuir isotherm of propranolol hydrochloride in the nonlinear region. Continuous separation of the target enantiomer from its racemic mixture was studied using Simulated Moving Bed (SMB) chromatography in both the linear and nonlinear region. Desired (S)-propranolol hydrochloride was produced in the raffinate product in high purity. The solubility of propranolol hydrochloride was determined experimentally in methanol at different temperatures. The crystallization of propranolol hydrochloride from solutions of different initial composition in a mixed solvent of methanol and acetone was also investigated with different product purity and yield. The SMB productivity was further increased at the sacrifice of decreasing the product purity. The obtained solution was further purified by crystallization. Compared with direct crystallization, which is suitable only for the racemic conglomerate, the integrated process is especially suitable for the majority of chiral drugs, which belong to racemic compounds as long as suitable and economic chiral stationary phases (CSPs) are available in the SMB separation.