Development, optimization and scale-up of stereo-selective enzymatic Baeyer.Villiger oxidation of pyrmetazole to esomeprazole active ingredient in an industrial-scale slurry reactor

Marko Herga; Ales Gasparic; Marko Bitenc; Andrej Pohar; Blaz Likozar

Journal of Industrial and Engineering Chemistry, Vol.72, 214-221, April, 2019

DOI10.1016/j.jiec.2018.12.020 Export Citation

Development, optimization and scale-up of stereo-selective enzymatic Baeyer.Villiger oxidation of pyrmetazole to esomeprazole active ingredient in an industrial-scale slurry reactor

Marko Herga, Ales Gasparic^†, Marko Bitenc, Andrej Pohar¹, and Blaz Likozar^{1, †}

Krka, d.d., Smarjeska Cesta 6, SI-8501 Novo Mesto, Slovenia, Slovakia (Slovak Republic)
¹Department of Catalysis and Chemical Reaction Engineering, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia, Slovakia (Slovak Republic)

E-mail:,

An industrial-scale stereo-selective enzymatic oxidation process for the conversion of pyrmetazole to esomeprazole was developed and optimized. Slurry-to-slurry stages are highly demanding synthetic operations due to several deteriorating factors: competing equilibria, mass transfer limitations and longterm bio-catalytic activity. Challenging characteristics of this bio-oxidation included foaming, thickening, continuous dynamic changes in viscosity, mass transport, and bio-catalyst inactivation. By screening pH, optimization of reactant loading ratios, and modification of control, crucial production attributes of materials, such as substrate particle size, were controlled and better batch-to-batch stability and scale-up was achieved.

Keywords:Pyrmetazole substrate molecule;Enzymatic oxidation reaction;Esomeprazole active ingredient;Industrial slurry reactor;Computational fluid dynamics;Crystallization downstream process

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Attia JA, Kholi S, Pilon L, Colloids Surf. A: Physicochem. Eng. Asp., 436, 1000 (2013)
Ceccoli RD, Bianchi DA, Rial DV, Front. Microbiol., 5 (2014)
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[1] Zollinger RM, Ellison EH, Ann. Surg., 142, 709 (1955)

[2] Cotton H, Elebring T, Larsson M, Li L, Sorensen H, von Unge S, Tetrahedron Asymmetry, 11, 3819 (2000)

[3] Holt R, Lindberg P, Reeve C, Taylor S, 1995, Patent No. EP0795024B1.

[4] Graham D, Holt R, Lindberg P, Taylor S, 1994, Patent No. WO9617077A1.

[5] Bong YK, Clay MD, Collier SJ, Mijts B, Vogel M, Zhang X, Zhu J, Nazor J, Smith D, Song S, 2009, Patent No. US8895271B2.

[6] Wilson R, Chim. Oggi, 33 (2015)

[7] deSouza ROMA, Miranda LSM, Bornscheue UT, Chem. Eur. J., 23, 12040 (2017)

[8] Bong YK, Song S, Nazor J, Vogel M, Widegren M, Smith D, Collier SJ, et al., J. Org. Chem., 83(14), 7453 (2018)

[9] Urlacher VB, Eiben S, Trends Biotechnol., 24, 324 (2006)

[10] van Beilen JB, Duetz WA, Schmid A, Witholt B, Trends Biotechnol., 21, 170 (2003)

[11] Denaturation of Proteins upon Adsorption to Bubble Surfaces, (2012).

[12] Khabiri M, Minofar B, Brezovsky J, Damborsky J, Ettrich R, J. Mol. Model., 19, 4701 (2013)

[13] Stevenson P, Foam Engineering: Fundamentals and Applications, John Wiley & Sons, 2012.

[14] Attia JA, Kholi S, Pilon L, Colloids Surf. A: Physicochem. Eng. Asp., 436, 1000 (2013)

[15] Ceccoli RD, Bianchi DA, Rial DV, Front. Microbiol., 5 (2014)

[16] Franceschini S, van Beek HL, Pennetta A, Martinoli C, Fraaije MW, Mattevi A, J. Biol. Chem., 287, 22626 (2012)

[17] Agger JW, Meyer AS, Bioresources, 7, 3378 (2012)

[18] Andersen MW, Kari J, Borch K, Westh P, Math. Biosci., 296, 93 (2017)

[19] Bisswanger H, Practical Enzymology, second ed., John Wiley & Sons, 2013.

[20] Talley K, Alexov E, Proteins, 78, 2699 (2010)

[21] Smith BT, Remington Education: Physical Pharmacy, first ed., Remington Education, 2015.

[22] Van Hecke W, Ludwig R, Dewulf J, Auly M, Messiaen T, Haltrich D, Van Langenhove H, Biotechnol. Bioeng., 102(1), 122 (2009)

[23] Bommarius AS, Karau A, Biotechnol. Prog., 21(6), 1663 (2005)

[24] Pedersen AT, Birmingham WR, Rehn G, Charnock SJ, Turner NJ, Woodley JM, Org. Process Res. Dev., 19, 1580 (2015)

[25] Thomas CR, Geer D, Biotechnol. Lett., 33(3), 443 (2011)

[26] Peixoto SMC, Nunhez JR, Duarte CG, Braz. J. Chem. Eng., 17, 4 (2000)

[27] Rajagopalan A, Kroutil W, Mater. Today, 14, 144 (2011)

[28] Wohlgemuth R, Curr. Opin. Microbiol., 13, 283 (2011)