Effect of Reaction Parameters on the Lipase-Catalyzed Kinetic Resolution of (RS )-Metoprolol


Mariani Rajin(1*), Asiah binti Zulkifli(2), Sariah Abang(3), S.M Anissuzzaman(4), Azlina Harun Kamaruddin(5)

(1) Chemical Engineering Program, Faculty of Engineering, Universiti Malaysia Sabah, Kota Kinabalu, Sabah
(2) Chemical Engineering Program, Faculty of Engineering, Universiti Malaysia Sabah, Kota Kinabalu, Sabah
(3) Chemical Engineering Program, Faculty of Engineering, Universiti Malaysia Sabah, Kota Kinabalu, Sabah
(4) Chemical Engineering Program, Faculty of Engineering, Universiti Malaysia Sabah, Kota Kinabalu, Sabah
(5) School of Chemical Engineering, Engineering Campus, Universiti Sains Malaysia, Nibong Tebal, Penang
(*) Corresponding Author


Racemic metoprolol is a selective ß1-blocker, which is used in cardiovascular disease treatment. It has been found that (S)-metoprolol has a higher affinity to bind the ß-adrenergic receptor compared to (R)-metoprolol. Moreover, the regulatory authorities’ high market demand and guidelines have increased the preference for single enantiomer drugs. In this work, the lipase-catalyzed kinetic resolution of racemic metoprolol was performed to obtain the desired enantiomer. The type of lipase, acyl donor, and solvent were screened out. This was achieved by Candida antarctica B lipase-catalyzed transesterification of racemic metoprolol in hexane and vinyl acetate as the solvent and an acyl donor, which gave maximum conversion of (S)-metoprolol (XS) of 52%, enantiomeric excess of substrate, (ees) of 92% and product (eeP) of 90% with enantiomeric ratio (E) of 62. This method can be considered as green chemistry, which can be applied to produce other enantiopure beta-blockers.


Beta-blocker; Chiral drug; Metoprolol; Kinetic resolution; Lipase

Full Text:



  1. Agustian, J., and Harun Kamaruddin, A. (2016). "The Reaction Mechanism and Kinetics Data of Racemic Atenolol Kinetic Resolution via Enzymatic Transesterification Process Using Free Pseudomonas fluorescence Lipase," Inter. J. Chem. Kine, 48, 253–265.
  2. Banoth, L., Narayan, T. K., and Banerjee, U. C. (2012). “New chemical and chemo-enzymatic routes for the synthesis of (RS)-and (S)-enciprazine,” Tetra.: Asym., 23(17), 1272-1278.
  3. Banoth, L., Chandarrao, B., Pujala, B., Chakraborti, A. K., and Banerjee, U. C. (2014). “Efficient chemoenzymatic synthesis of (RS)-, (R)-, and (S)-bunitrolol,” Syn., 46(04), 479-488.
  4. Banoth, L., Thakur, N. S., Bhaumik, J., and Banerjee, U. C. (2015). "Biocatalytic Approach for the Synthesis of Enantiopure Acebutolol as a β1-Selective Blocker," Chir., 27, 382–391.
  5. Barbosa, O., Ariza, C., Ortiz, C. and Torres, R., (2010). "Kinetic resolution of (R/S)-propranolol (1-isopropylamino-3-(1-naphtoxy)-2-propanolol) catalyzed by immobilized preparations of Candida antarctica lipase B (CAL-B)," N. bio., 27, 844-850.
  6. Benfield, P., Clissold, S. P., and Brogden, R. N. (1986). "Metoprolol. An update review of its pharmacodynamic and therapeutic efficacy, in hypertension, ischaemic heart disease, and related cardiovascular disorders," Dru., 31, 376–429.
  7. Chen, C. S., Fujimoto, Y., Girdaukas, G., and Sih, C. J. (1982). "Quantitative analyses of biochemical kinetic resolutions of enantiomers," J. Am. Chem. Soc., 104, 7294–7299.
  8. Chrysant, S. G., Chrysant, G. S., and Desai, A. (2005). "Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan," J. Hum. Hype., 19, 173–183.
  9. Dwivedee, B. P., Ghosh, S., Bhaumik, J., Banoth, L., and Chand Banerjee, U. (2015). "Lipase-catalyzed green synthesis of enantiopure atenolol," RSC Adv., 5(21), 15850–15860.
  10. Ettireddy, S., Chandupatla, V., and Veeresham, C. (2017). “Enantioselective Resolution of (R, S)-Carvedilol to (S)-(−)-Carvedilol by Biocatalysts,” Nat. Pro. Biopro., 7, 171-179.
  11. Gumustas, M., Ozkan, S. A., and Chankvetadze, B. (2018). "Analytical and Preparative Scale Separation of Enantiomers of Chiral Drugs by Chromatography and Related Methods," Cur. Med. Chem., 25, 4152–4188.
  12. Guo, Z.W. and Sih, C.J., (1989). "Enantioselective inhibition: strategy for improving the enantioselectivity of biocatalytic systems," J. Am. Chem. Soc., 111, 6836-6841.
  13. Kim, J. H., Huy, B. T., and Lee, Y.-I. (2016). "Facile Synthesis and Enantioseparation of Chiral Drugs Using Zirconia Magnetic Microspheres Coated with Cyclodextrin/Poly(amidoamine) Dendrimers," Bull. Kor. Chem. Soc., 37, 1393–1394.
  14. Kumar, A., Dhar, K., Kanwar, S. S., and Arora, P. K. (2016). "Lipase catalysis in organic solvents: advantages and applications," Bio. Pro. Onl., 18, 2.
  15. Lersbamrungsuk, V., and Srinophakun, T. (2013). “Design and Control of Alkali-Catalyzed Transesterification Reactors,”. ASEAN Journal of Chemical Engineering, 2, 22-26.
  16. Long, W. S., Kamaruddin, A., and Bhatia, S. (2005a). "Chiral resolution of racemic ibuprofen ester in an enzymatic membrane reactor," J. Mem. Sci., 247, 185–200.
  17. Long, W. S., Kamaruddin, A., and Bhatia, S. (2005b). "Enzyme kinetics of kinetic resolution of racemic ibuprofen ester using enzymatic membrane reactor," Chem. Eng. Sci., 60, 4957–4970.
  18. Mane, S. (2016). "Racemic drug resolution: a comprehensive guide," Anal. Meth., 8, 7567–7586.
  19. Nguyen, L. A., He, H., and Pham-Huy, C. (2006). "Chiral drugs: an overview," Int. J. Bio. Sci., 2, 85–100.
  20. Paravidino, M., and Hanefeld, U. (2011). “Enzymatic acylation: assessing the greenness of different acyl donors,” Gre. Chem., 13(10), 2651-2657.
  21. Pchelka, B. K., Loupy, A., Plenkiewicz, J., and Blanco, L. (2000). "Resolution of racemic 1-azido-3-aryloxy-2-propanols by lipase-catalyzed enantioselective acetylation," Tetra. Asym., 11, 2719–2732.
  22. Pchelka, B. K., Loupy, A., Plenkiewicz, J., Petit, A., and Blanco, L. (2001). "Resolution of racemic 3-aryloxy-1-nitrooxypropan-2-ols by lipase-catalyzed enantioselective acetylation," Tetra. Asym., 12, 2109–2119.
  23. Soni, S., Dwivedee, B. P., Sharma, V. K., and Banerjee, U. C. (2017). “Kinetic resolution of (RS)-1-chloro-3-(4-(2-methoxyethyl) phenoxy) propan-2-ol: a metoprolol intermediate and its validation through homology model of Pseudomonas fluorescens lipase,” RSC Adv., 7, 36566-36574.
  24. Swetha, E., Vijitha, C., and Veeresham, C. (2018). “Enantioselective conversion of racemic sotalol to R(-)sotalol by lipase AP6,”. Indian J. Pharm. Sci., 80, 676–685.
  25. WHO Expert Committee on Speci-fications for Pharmaceutical Preparations & World Health Organization & WHO Expert Committee on Specifications for Pharmaceutical Preparations (34th: 1994: Geneva, Switzerland) (1996). WHO Expert Committee on Specifications for Pharmaceutical Preparations: thirty-fourth report. World Health Organization, Geneva.
  26. Wielechowska, M. and Plenkiewicz, J. (2005). “Lipase-catalyzed separation of the enantiomers of 1-substituted-3-arylthio-2-propanols,” Tetra.: Asy. 16, 1199–1205.
  27. Van Rantwijk, F., and Sheldon, R. A. (2004). "Enantioselective acylation of chiral amines catalysed by serine hydrolases," Tetra., 60, 501–519.
  28. Yusof, N. A. B., Mat Hadzir, N., and Ashari, S. E. (2016). "Identification and Optimisation of Lipase-Catalysed Synthesis of Betulinic Acid Amide in a Solvent System," Jour. App. Chem., 2016, 1–5.

DOI: https://doi.org/10.22146/ajche.51857

Article Metrics

Abstract views : 2511 | views : 2202


  • There are currently no refbacks.

ASEAN Journal of Chemical Engineering  (print ISSN 1655-4418; online ISSN 2655-5409) is published by Chemical Engineering Department, Faculty of Engineering, Universitas Gadjah Mada.