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In situ product recovery (ISPR) by crystallization: basic principles, design, and potential applications in whole-cell biocatalysis

Abstract

The removal of inhibiting or degrading product from a bioreactor as soon as the product is formed is an important issue in industrial bioprocess development. In this review, the potential of crystallization as an in situ product removal (ISPR) technique for the biocatalytic production of crystalline compounds is discussed. The emphasis of this review is on the current status of crystalline product formation by metabolically active cells for application in fine-chemicals production. Examples of relevant biocatalytic conversions are summarized, and some basic process options are discussed. Furthermore, a case study is presented in which two conceptual process designs are compared. In one process, product formation and crystallization are integrated by applying ISPR, whereas a second, nonintegrated process is based on a known conventional process equivalent for the production of 6R-dihydro-oxoisophorone. The comparison indicates that employing ISPR leads to significant advantages over the nonintegrated case in terms of increased productivity and yield with a corresponding decrease in the number of downstream processing steps, as well as in the quantity of waste streams. This leads to an economically more interesting process alternative. Finally, a general outlook on the various research aspects of ISPR by crystallization is given.

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References

  1. Agaisse H, Lereclus D (1995) How does Bacillus thuringiensis produce so much insecticidal crystal protein. J Bacteriol 177:6027–6032

  2. Alba-Perez A (2001) Enhanced microbial production of natural flavours via in situ product adsorption. Ph.D. thesis. Swiss Federal Institute of Technology Zurich (ETHZ), Zurich

  3. Arimatsu Y, Bao J, Furumoto K, Yoshimoto M, Fukunaga K, Nakao K (2004) Continuous production of calcium gluconate crystals in an integrated bioreaction–crystallization process using external loop airlift bubble columns with immobilized glucose oxidase gel beads. J Chem Eng Jpn 37:1035–1040

  4. Astley OM, Chanliaud E, Donald AM, Gidley MJ (2001) Structure of acetobacter cellulose composites in the hydrated state. Int J Biol Macromol 29:193–202

  5. Bao J, Koumatsu K, Furumoto K, Yoshimoto M, Fukunaga K, Nakao K (2001) Optimal operation of an integrated bioreaction-crystallization process for continuous production of calcium gluconate using external loop airlift columns. Chem Eng Sci 56:6165–6170

  6. Blacker AJ, Holt RA (1997) Development of a multi-stage chemical and biological process for an optically active intermediate for an anti-glaucoma drug. In: Collins AN, Sheldrake GN, Crosby J (eds) Chirality in industry II. Wiley, Chichester, pp 245–261

  7. Buque-Taboada EM, Straathof AJJ, Heijnen JJ, van der Wielen LAM (2004) In situ product removal using a crystallization loop in the asymmetric reduction of 4-oxoisophorone by Saccharomyces cerevisiae. Biotechnol Bioeng 86:795–800

  8. Buque-Taboada EM, Straathof AJJ, Heijnen JJ, van der Wielen LAM (2005a) Microbial reduction and in situ product crystallization coupled with biocatalyst cultivation during the synthesis of 6R-dihydro-oxoisophorone. Adv Synth Catal 347:1147–1154

  9. Buque-Taboada EM, Straathof AJJ, Heijnen JJ, van der Wielen LAM (2005b) Substrate inhibition and product degradation during the reduction of 4-oxoisophorone by Saccharomyces cerevisiae. Enzyme Microb Technol 37:625–633

  10. Cardoso JP (1993) A simple model for the optimization of the extraction yield of antibiotics isolated from fermented broths by direct crystallization. Biotechnol Bioeng 42:1068–1076

  11. Chartrain M, Roberge C, Chung J, McNamara J, Zhao DL, Olewinski R, Hunt G, Salmon P, Roush D, Yamazaki S, Wang T, Grabowski E, Buckland B, Greasham R (1999) Asymmetric bioreduction of (2-(4-nitro-phenyl)-N-(2-oxo-2-pyridin-3-yl-ethyl)-acetamide) to its corresponding (R) alcohol [(R)-N-(2-hydroxy-2-pyridin-3-yl-ethyl)-2-(4-nitro-phenyl))-acetamide] by using Candida sorbophila MY 1833. Enzyme Microb Technol 25:489–496

  12. Coulson JM, Richardson JF, Backhurst JR, Harker JH (1998). Coulson & Richardson’s chemical engineering, vol 2, 4th edn. Butterworth Heinemann, Oxford

  13. Crocq V, Masson C, Winter J, Richard C, Lemaitre G, Lenay J, Vivat M, Buendia J, Prat D (1997) Synthesis of trimegestone: the first industrial application of baker’s yeast mediated reduction of a ketone. Org Process Res Dev 1:2–13

  14. Douglas JM (1988) Conceptual design of chemical processes. McGraw-Hill, New York

  15. Dufosse L, Galaup P, Yaron A, Arad SM (2005) Microorganisms and microalgae as sources of pigments for food use: a scientific oddity or an industrial reality? Trends Food Sci Technol 16:389–406

  16. Ehrlich HL (1999) Microbes as geologic agents: their role in mineral formation. Geomicrobiol J 16:135–153

  17. Fernandes P, Prazeres DMF, Cabral JMS (2003) Membrane-assisted extractive bioconversions. Adv Biochem Eng Biotechnol 80:115–148

  18. Freeman A, Woodley JM, Lilly MD (1993) In situ product removal as a tool for bioprocessing [review]. Biotechnol 11:1007–1012

  19. Fukuoka M, Hiraga K, Sekihara T (2001) Microbial production of levodione. European Patent 1074630A2

  20. Furui M, Sakata N, Otsuki O, Tosa T (1988) A bioreactor-crystallizer for l-malic acid production. Biocatalysis 2:69–77

  21. Furui M, Furutani T, Shibatani T, Nakamoto Y, Mori T (1996) A membrane bioreactor combined with crystallizer for production of optically active (2R,3S)-3-(4-methoxyphenyl)-glycidic acid methyl ester. J Ferment Bioeng 81:21–25

  22. Grievink J, Luteijn CP, Swinkels PLJ (2004) Instructions manual for conceptual process design. Delft University of Technology, Delft

  23. Harano Y, Hibi T, Ooshima H (1986) Enzymatic reaction crystallization of aspartame precursor. Proc World Congress III Chemical Engineering, Tokyo. 8g-303, pp 1044–1047

  24. Hurh B, Ohsima M, Yamane T, Nagasawa T (1994) Microbial production of 6-hydroxynicotinic acid, an important building block for the synthesis of modern insecticides. J Ferment Bioeng 77:382–385

  25. Iyer JK, Shi LR, Shankar AH, Sullivan DJ (2003) Zinc protoporphyrin IX binds heme crystals to inhibit the process of crystallization in Plasmodium falciparum. Mol Med 9:175–182

  26. Jauregi P, van der Lans RGJM, van der Wielen LAM, Kwant G, Hoeben M (2000) Method of separating a particle mixture. British Patent Application 0015776.8

  27. Johnson ME, Riesterer BA, Olson NF (1990) Influence of nonstarter bacteria on calcium lactate crystallization on the surface of cheddar cheese. J Dairy Sci 73:1145–1149

  28. Kaščák JS, Kominek J, Roehr M (1996) Lactic acid. In: Roehr M (ed) Biotechnology, vol 6. VCH, Weinheim, pp 294–306

  29. Kuimova TF, Kazakov GA (1976) Spontaneous crystallization of antibiotic in submerged fermentation of Actinomyces hygroscopicus. Microbiologia 45:746–749

  30. Leuenberger HGW (1985) Microbiologically catalyzed reaction steps in the field of vitamin and carotenoid synthesis. In: Tramper J, van der Plas HC, Linko P (eds) Biocatalysts in organic synthesis. Elsevier, Amsterdam, pp 99–118

  31. Leuenberger HGW, Boguth W, Widmer E, Zell R (1976) Synthesis of optically active natural carotenoids and structurally related compounds. I. Synthesis of the chiral key compound (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone. Helv Chim Acta 59:1832–1849

  32. Li SZ, Li XY, Wang DZ (2004) Crystallization of oxytetracycline from fermentation waste liquor: influence of biopolymer impurities. J Colloid Interface Sci 279:100–108

  33. Lide DR (ed) (2004) CRC handbook of chemistry and physics, 85th edn. CRC Press, Boca Raton

  34. Lye GJ, Woodley JM (1999) Application of in situ product removal techniques to biocatalytic processes. Trends Biotechnol 17:395–402

  35. Matsumae H, Akatsuka H, Shibatani T (1999) Diltiazem synthesis. In: Flickinger MC, Drew SJ (eds) Encyclopedia of bioprocess technology. Wiley, New York, pp 823–840

  36. McPherson A (1999) Crystallization of biological macromolecules. CSHL Press, New York

  37. Michielsen MJF, Frielink C, Wijffels RH, Tramper J, Beeftink HH (2000a) Growth of Ca-D-malate crystals in a bioreactor. Biotechnol Bioeng 69:548–558

  38. Michielsen MJF, Frielink C, Wijffels RH, Tramper J, Beeftink HH (2000b) Modeling solid-to-solid biocatalysis: integration of six consecutive steps. Biotechnol Bioeng 69:597–606

  39. Miller TL (1985) Steroid fermentations. In: Moo-Young M (ed) Comprehensive biotechnology, vol 3. Pergamon, Oxford, pp 297–318

  40. Mullin JW (2001) Crystallization, 4th edn. Butterworth Heinemann, Oxford

  41. Nakayama K (1985) Tryptophan. In: Moo-Young M (ed) Comprehensive biotechnology, vol 3. Pergamon, Oxford, pp 621–631

  42. Perry RH, Green DW (1999) Perry’s chemical engineers’ handbook, 7th edn. McGraw-Hill, New York

  43. Plattner H (2002) My favorite cell — Paramecium. Bioessays 24:649–658

  44. Reid RC, Prausnitz JM, Sherwood TK (1977) The properties of gases and liquids, 3rd edn. McGraw-Hill, New York

  45. Schügerl K (2000) Integrated processing of biotechnology products. Biotechnol Adv 18:581–599

  46. Schügerl K, Hubbuch J (2005) Integrated bioprocesses. Curr Opin Microbiol 8:294–300

  47. Sinnott RK (1999) Coulson & Richardson’s chemical engineering, vol. 6, 3rd edn. Butterworth Heinemann, Oxford

  48. Sode K, Kajiwara K, Tamiya E, Karube I (1987) Continuous asymmetric reduction of 4-oxoisophorone by thermophilic bacteria using a hollow fiber reactor. Biocatalysis 1:77–86

  49. Stankiewicz A, Moulijn JA (eds) (2004) Re-engineering the chemical processing plant. Marcel Dekker, New York

  50. Stark D, von Stockar U (2003) In situ product removal (ISPR) in whole cell biotechnology during the last 20 years. Adv Biochem Eng Biotechnol 80:149–175

  51. Straathof AJJ (2003) Auxiliary phase guidelines for microbial biotransformations of toxic substrate into toxic product. Biotechnol Prog 19:57–62

  52. Straathof AJJ, Panke S, Schmid A (2002) The production of fine chemicals by biotransformations. Curr Opin Biotechnol 13:548–556

  53. Takamatsu S, Ryu DDY (1988a) Recirculating bioreactor-separator system for simultaneous biotransformation and recovery of product: immobilized l-aspartate β-decarboxylase reactor system. Biotechnol Bioeng 32:184–191

  54. Takamatsu S, Ryu DDY (1988b) New recirculating bioreactor-separator combination system for continuous bioconversion and separation of products. Enzyme Microb Technol 10:593–600

  55. Tavare NS (1995) Industrial crystallization. Process simulation analysis and design. The Plenum chemical engineering series. Plenum, New York

  56. Tosa T, Furui M, Sakata N, Otsuki O, Chibata I (1988) Design of a bioreactor using immobilized biocatalysts for the slurry reaction: production of l-malic acid. Ann NY Acad Sci 542:440–443

  57. Ueda H, Koda T, Sato M (2003) Method for producing l-glutamic acid. US Patent 0190713A1

  58. van der Wielen LAM, Luyben KCAM (1992) Integrated product formation and recovery in fermentation. Curr Opin Biotechnol 3:130–138

  59. van Loon APGM, Hohmann HP, Bretzel W, Hübelin M, Pfister M (1996) Development of a fermentation process for the manufacture of riboflavin. Chimia 50:410–412

  60. van’t Riet K, Tramper J (1991) Basic bioreactor design. Marcel Dekker, New York

  61. von Stockar U, van der Wielen LAM (2003) Process integration challenges in biotechnology. Yesterday, today and tomorrow. Adv Biochem Eng Biotechnol 80:IX–XV

  62. Zhang J, Collins A, Chen M, Knyazev I, Gentz R (1998) High-density perfusion culture of insect cells with a Biosep ultrasonic filter. Biotechnol Bioeng 59:351–359

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Acknowledgements

This study has partly been funded by the Joint Financing Program for Cooperation in Higher Education–University of San Carlos–Delft University of Technology Project in Chemical Engineering. The following persons are gratefully acknowledged for their important contributions to this work: Sjoerd Blokker, Marcel Dabkowski, Willem Groendijk, Dirk Renckens, Jeroen de Rond, and Prof.dr.ir. Johan Grievink of the Delft University of Technology.

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Correspondence to Adrie J. J. Straathof.

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Buque-Taboada, E.M., Straathof, A.J.J., Heijnen, J.J. et al. In situ product recovery (ISPR) by crystallization: basic principles, design, and potential applications in whole-cell biocatalysis. Appl Microbiol Biotechnol 71, 1–12 (2006). https://doi.org/10.1007/s00253-006-0378-6

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Keywords

  • Fermentation
  • Base Case
  • Waste Stream
  • Volumetric Productivity
  • Battery Limit