Chiral Separation of Propranolol Hydrochloride Through an SMB Process Integrated with Crystallization

Xin Wang; Yue Liu; Hong Wei Yu; Chi Bun Ching

Journal of Industrial and Engineering Chemistry, Vol.12, No.6, 868-876, November, 2006

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Chiral Separation of Propranolol Hydrochloride Through an SMB Process Integrated with Crystallization

Xin Wang^†, Yue Liu, Hong Wei Yu, and Chi Bun Ching

Division of Chemical and Biomolecular Engineering, School of Chemical and Biomedical Engineering, NanyangTechnological University, Singapore

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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.

Keywords:separation;propranolol hydrochloride;simulated moving bed (SMB) chromatography;crystallization;chiral drugs

[References]

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[1] Nation R, Clin. Pharmacokinet., 27, 249 (1994)

[2] Aboul-Enein HY, Wainer IW, The Impact of Stereochemistry on Drug Development and Use, John Wiley and Sons, New York (1997)

[3] Rekoske JE, AIChE J., 47(1), 2 (2001)

[4] Francotte E, Richert PM, Mazzotti M, Morbidelli M, J. Chromatogr. A, 796, 239 (1998)

[5] Pais LS, Loureiro JM, Rodrigues AE, Chem. Eng. Sci., 52(2), 245 (1997)

[6] Pedeferri M, Zenoni G, Mazzotti M, Morbidelli M, Chem. Eng. Sci., 54(17), 3735 (1999)

[7] Schulte M, Strube J, J. Chromatogr. A, 906, 399 (2001)

[8] Mazzotti M, Storti G, Morbidelli M, J. Chromatogr. A, 769, 3 (1997)

[9] Storti G, Mazzotti M, Morbidelli M, Carra S, AIChE J., 39, 471 (1993)

[10] Ruthven DM, Ching CB, Chem. Eng. Sci., 44, 1011 (1989)

[11] Charton F, Nicoud RM, J. Chromatogr. A, 702, 97 (1995)

[12] Lim BG, Ching CB, Tan RB, Ng SC, Chem. Eng. Sci., 50(14), 2289 (1995)

[13] Lorenz H, Sheehan P, Seidel-Morgenstern A, J. Chromatogr. A, 908, 201 (2001)

[14] Amanullah M, Abel S, Mazzotti M, Adsorption, 11, 893 (2005)

[15] Strohlein G, Schulte M, Strube J, Sep. Sci. Technol., 38(14), 3353 (2003)

[16] Ruthven DM, Principle of Adsorption and Adsorption Processes, John Wiley and Sons, New York (1984)

[17] Wang X, Ching CB, Ind. Eng. Chem. Res., 42(24), 6171 (2003)

[18] Jen SC, Pinto NG, J. Chromatogr. A, 662, 396 (1994)

[19] Helfferich FG, J. Chromatogr. A, 768, 169 (1997)

[20] Mazzotti M, Storti G, Morbidelli M, AIChE J., 40(11), 1825 (1994)

[21] Mazzotti M, Storti G, Morbidelli M, AIChE J., 42(10), 2784 (1996)

[22] Storti G, Masi M, Carra S, Chem. Eng. Sci., 44, 1329 (1989)

[23] Storti G, Baciocchi R, Mazzotti M, Morbidelli M, Ind. Eng. Chem. Res., 34(1), 288 (1995)

[24] Ching CB, Lim BG, J. Chromatogr. A, 634, 215 (1993)

[25] Wang X, Wang XJ, Ching CB, Chirality, 14, 318 (2002)