WO1988004317A1 - Method for carrying out biotechnological processes by means of a multiphase system in a loop reactor - Google Patents

Method for carrying out biotechnological processes by means of a multiphase system in a loop reactor Download PDF

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Publication number
WO1988004317A1
WO1988004317A1 PCT/NL1987/000035 NL8700035W WO8804317A1 WO 1988004317 A1 WO1988004317 A1 WO 1988004317A1 NL 8700035 W NL8700035 W NL 8700035W WO 8804317 A1 WO8804317 A1 WO 8804317A1
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Prior art keywords
water
loop reactor
organic solvent
immiscible
density
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PCT/NL1987/000035
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French (fr)
Inventor
Johannes Tramper
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Rijkslandbouwuniversiteit Wageningen
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Publication of WO1988004317A1 publication Critical patent/WO1988004317A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J10/00—Chemical processes in general for reacting liquid with gaseous media other than in the presence of solid particles, or apparatus specially adapted therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/18—Stationary reactors having moving elements inside
    • B01J19/1812—Tubular reactors
    • B01J19/1837—Loop-type reactors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/18—Stationary reactors having moving elements inside
    • B01J19/1868—Stationary reactors having moving elements inside resulting in a loop-type movement
    • B01J19/1875—Stationary reactors having moving elements inside resulting in a loop-type movement internally, i.e. the mixture circulating inside the vessel such that the upwards stream is separated physically from the downwards stream(s)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/06—Nozzles; Sprayers; Spargers; Diffusers
    • C12M29/08—Air lift
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/18—External loop; Means for reintroduction of fermented biomass or liquid percolate
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes

Definitions

  • the invention relates to carrying out biotechnological processes by means of a multiphase system in a loop reactor, which system comprises an aqueous phase.
  • Loop reactors are described in detail in "Biotechnology” by H.J. Rehm and G. Reed, vol. 2, “Fundamentals of Biochemical Engineering", VCH, Weinheim (1985), chapter 21 entitled “Biochemical Loop Reactors", pages 465-517. More particularly, in a loop reactor, at least one defined circulatory flow of a liquid medium present therein takes place and loop reactors have in principle either an "internal circulation” (see Figure 1a) or an “external circulation” (see Figure 1b).
  • an organic solvent which is immiscible with water is understood to mean a solvent which is not miscible with water or soluble in water in all proportions so that a liquid multiphase system can be created.
  • the method according to the invention differs in principle from the method described in the abovement ioned Swiss Patent 478,282.
  • the reason is that, according to said Swiss patent, two liquids which are immiscible with each other are subjected to a mixing action by means of a stirring device, i.e. the stirring device provides the driving force for the mixing action, whereas, in the method according to the invention, the difference in density between the liquid components used functions as driving force.
  • reaction systems according to the invention are very readily. usable in biocatalysis, use being made of organic media.
  • organic media By replacing a portion of the aqueous phase by an organic solvent which is immiscible with water, it is possible, in addition to eliminating completely or partially the abovementioned disadvantages, also to obtain a number of additional advantages, namely: a displacement of reaction equilibria as a consequence of modified distribution of substrates and reaction products between the phases present, a lowering of the substrate/reaction product inhibition, an improved product and biocatalyst working up and a stabilization of the biocatalyst.
  • an organic solvent which is immiscible with water and which has a lower density than water use is made of an organic solvent which is immiscible with water and which has a lower density than water.
  • the possibility is, however, also available of using an organic solvent which is immiscible with water and which has a higher density than water.
  • organic solvents which can be used in the method according to the invention are listed in the table below.
  • Figure 2a illustrates an internal loop reactor which contains water (1) as the continuous phase and an organic solvent (2) having a density lower than water as the disperse phase.
  • Figure 2b illustrates an external loop reactor which contains water (1) as the continuous phase and an organic solvent (2) having a density lower than water as the disperse phase.
  • Figure 2c illustrates an internal loop reactor which contains water (3) as the disperse phase and an organic solvent (4) having a density higher than water as the continuous phase.
  • Figure 2d illustrates an external loop reactor which contains water (3) as the disperse phase and an organic solvent (4) having a density higher than water as the continuous phase.
  • Figure 3a illustrates an internal loop reactor which contains water (5) as the continuous phase and an organic solvent (6) having a density higher than water as the disperse phase.
  • Figure 3b illustrates an external loop reactor which contains water (5) as the continuous phase and an organic solvent (6) having a density higher than water as the disperse phase.
  • Figure 3c illustrates an internal loop reactor which contains water (7) as the disperse phase and an organic solvent (8) having a density lower than water as the continuous phase.
  • Figure 3d illustrates an external loop reactor which contains water (7) as the disperse phase and an organic solvent (8) having a density lower than water as the continuous phase.
  • Figure 4 shows a special embodiment of the method according to the invention in which use is made of two organic solvents which are immiscible with water, one (9) having a higher density and the other (10) a lower density than the water (11) present.
  • the use of this three-phase system in a loop reactor with an "internal" circulation is in principle also possible.
  • the loop reactor used for carrying out the method according to the invention may, if desired, be provided with solid particles such as immobilized catalyst particles and the like which are dispersed in the continuous phase or may be provided in another manner (see the abovementioned book entitled "Biotechnology” by H.J. Rehm and G. Reed, vol. 2, chapter 21 entitled
  • Biochemical loop reactors In the event that the disperse phase has a higher density than the continuous phase, air can be introduced into the riser pipe in order to intensify the upwards movement of the liquid medium in said riser pipe.
  • provision of the reaction system in the loop reactor with oxygen can be implemented with this embodiment of the method according to the invention.
  • Loop reactors in which the method according to the invention is carried out may therefore be used as continuous extractors, fermenters and biological reactors using (bio)catalysts.
  • Petroleum ether 40/60 having a density of 0.65 g/cm 3 was pumped in at the bottom of the riser pipe by means of the porous filter fitted in the bottom of the loop reactor and having a diameter of 25 mm (pore size ⁇ P4).
  • the circulation in the loop reactor was made visible with alginate spherules suspended in the aqueous phase and having a diameter of 2 mm.
  • the circulation time of said alginate spherules was approximately 3 seconds.
  • An "internal" loop reactor according to Figure 3c having the dimensions mentioned in Example I was filled with petroleum ether 40/60. Water (9 g/dm 3 NaCl) was pumped into the internal pipe by means of the porous filter fitted in the top of the loop reactor and having a diameter of 25 mm (pore size ⁇ P4). The circulation in the loop reactor was made visible with alginate spherules having a diameter of 2 mm.
  • Example III An "external" loop reactor according to Figure

Abstract

A method for carrying out biotechnological processes by means of multiphase system in a loop reactor, which system comprises an aqueous phase (11) and at least one organic solvent (9, 10) which is immiscible with water and which has a different density from water; one of the liquid components is used as the continuous phase and the other as the disperse phase.

Description

Method for carrying out biotechnoIogicaI processes by means of a multiphase system in a loop reactor.
The invention relates to carrying out biotechnological processes by means of a multiphase system in a loop reactor, which system comprises an aqueous phase. Loop reactors are described in detail in "Biotechnology" by H.J. Rehm and G. Reed, vol. 2, "Fundamentals of Biochemical Engineering", VCH, Weinheim (1985), chapter 21 entitled "Biochemical Loop Reactors", pages 465-517. More particularly, in a loop reactor, at least one defined circulatory flow of a liquid medium present therein takes place and loop reactors have in principle either an "internal circulation" (see Figure 1a) or an "external circulation" (see Figure 1b). As the driving force for the circulatory flow, in such loop reactors use is made of a gaseous medium and, in particular, usually air which is introduced into the riser pipe of the reactor (see Figure 1a and 1b). Owing to the introduction of the gaseous medium, the liquid medium passes through the riser pipe until it reaches the top section of the reactor and then travels through the dowπcomer pipe (see Figure 1a and 1b) after which it again finishes up in the riser pipe via the bottom section under the influence of the driving force generated by the gaseous medium. In a loop reactor permanently fitted elements may be present which are usually situated in the riser pipe. Examples of such elements are sieve plates for redispersing coalesced gas bubbles or packings which serve as carrier material for immobilized cells or enzymes. A more detailed explanation of the process conditions in the loop reactor which is at present of considerable importance and which is driven with air and also termed an "air lift loop reactor", is given for example in PT process technique 40, no. 10, (1985), pages 60-63. With respect to stirred reactors used traditionally in biotechnology such as are described, for example, in the Swiss Patent 478,282, air lift loop reactors have a number of important advantages such as a relatively simple construction and a low susceptibility. to malfunction, a good and regulable phase separation in the top section of the loop reactor, a large specific surface with low energy input, a heat exchange which is relatively easy to control, a unique combination of a controlled flow and good mixing properties and also a good accessibility for measuring and regulating equipment, certainly if the air lift loop reactor is constructed with an external loop (see Figure 1b). Although the presence of water in biotechnological processes is essential, the use thereof as a reaction medium, however, involves various disadvantages. The following may be mentioned as examples of such disadvantages: the difficulty of achieving high concentrations of substrates in the reaction medium which are sparingly soluble in water, the unfavourable position of reaction equilibria, water being one of the reaction products, and also the occurrence of hydrolysis of substrates or reaction products. It has been found that the abovement ioned disadvantages can be completely or partially eliminated if, to carry out biotechnological processes in a loop reactor, use is made of at least one organic solvent which is immiscible with water and which has a different density from water instead of a gaseous medium so that one of the liquid components acts as the continuous phase and the other as the disperse phase. In this connection, an organic solvent which is immiscible with water is understood to mean a solvent which is not miscible with water or soluble in water in all proportions so that a liquid multiphase system can be created.
The method according to the invention differs in principle from the method described in the abovement ioned Swiss Patent 478,282. The reason is that, according to said Swiss patent, two liquids which are immiscible with each other are subjected to a mixing action by means of a stirring device, i.e. the stirring device provides the driving force for the mixing action, whereas, in the method according to the invention, the difference in density between the liquid components used functions as driving force.
The reaction systems according to the invention are very readily. usable in biocatalysis, use being made of organic media. By replacing a portion of the aqueous phase by an organic solvent which is immiscible with water, it is possible, in addition to eliminating completely or partially the abovementioned disadvantages, also to obtain a number of additional advantages, namely: a displacement of reaction equilibria as a consequence of modified distribution of substrates and reaction products between the phases present, a lowering of the substrate/reaction product inhibition, an improved product and biocatalyst working up and a stabilization of the biocatalyst.
Advantageously, use is made of an organic solvent which is immiscible with water and which has a lower density than water. At the same time, the possibility is, however, also available of using an organic solvent which is immiscible with water and which has a higher density than water.
Examples of organic solvents which can be used in the method according to the invention are listed in the table below.
Figure imgf000006_0001
In view of the abovementioned use of an organic solvent which is immiscible with water and which has either a Lower or a higher density than water, eight embodiments of the method according to the invention can be distinguished on the basis of loop reactors with an internal or external loop. These are illustrated in Figures 2a-d and Figures 3a-d.
Figure 2a illustrates an internal loop reactor which contains water (1) as the continuous phase and an organic solvent (2) having a density lower than water as the disperse phase.
Figure 2b illustrates an external loop reactor which contains water (1) as the continuous phase and an organic solvent (2) having a density lower than water as the disperse phase.
Figure 2c illustrates an internal loop reactor which contains water (3) as the disperse phase and an organic solvent (4) having a density higher than water as the continuous phase. . Figure 2d illustrates an external loop reactor which contains water (3) as the disperse phase and an organic solvent (4) having a density higher than water as the continuous phase.
Figure 3a illustrates an internal loop reactor which contains water (5) as the continuous phase and an organic solvent (6) having a density higher than water as the disperse phase.
Figure 3b illustrates an external loop reactor which contains water (5) as the continuous phase and an organic solvent (6) having a density higher than water as the disperse phase.
Figure 3c illustrates an internal loop reactor which contains water (7) as the disperse phase and an organic solvent (8) having a density lower than water as the continuous phase.
Figure 3d illustrates an external loop reactor which contains water (7) as the disperse phase and an organic solvent (8) having a density lower than water as the continuous phase. For completeness. Figure 4 shows a special embodiment of the method according to the invention in which use is made of two organic solvents which are immiscible with water, one (9) having a higher density and the other (10) a lower density than the water (11) present. The use of this three-phase system in a loop reactor with an "internal" circulation is in principle also possible.
The loop reactor used for carrying out the method according to the invention may, if desired, be provided with solid particles such as immobilized catalyst particles and the like which are dispersed in the continuous phase or may be provided in another manner (see the abovementioned book entitled "Biotechnology" by H.J. Rehm and G. Reed, vol. 2, chapter 21 entitled
"Biochemical loop reactors"). In the event that the disperse phase has a higher density than the continuous phase, air can be introduced into the riser pipe in order to intensify the upwards movement of the liquid medium in said riser pipe. In addition, provision of the reaction system in the loop reactor with oxygen can be implemented with this embodiment of the method according to the invention.
Loop reactors in which the method according to the invention is carried out may therefore be used as continuous extractors, fermenters and biological reactors using (bio)catalysts.
The invention is illustrated in more detail by reference to the examples below which should not be interpreted as restrictive. Example I
An "internal" loop reactor according to Figure 2a with a capacity of 1.7 dm3, of which the internal pipe had a diameter of 39 mm and the external pipe a diameter of 60 mm, was filled with water (9 g/dm3 NaCl) .
Petroleum ether 40/60 having a density of 0.65 g/cm3 was pumped in at the bottom of the riser pipe by means of the porous filter fitted in the bottom of the loop reactor and having a diameter of 25 mm (pore size < P4). The circulation in the loop reactor was made visible with alginate spherules suspended in the aqueous phase and having a diameter of 2 mm. The circulation time of said alginate spherules was approximately 3 seconds. Example II
An "internal" loop reactor according to Figure 3c having the dimensions mentioned in Example I was filled with petroleum ether 40/60. Water (9 g/dm3 NaCl) was pumped into the internal pipe by means of the porous filter fitted in the top of the loop reactor and having a diameter of 25 mm (pore size < P4). The circulation in the loop reactor was made visible with alginate spherules having a diameter of 2 mm. Example III An "external" loop reactor according to Figure
2b with a capacity of 1.5 dm3, of which the riser pipe had a diameter of 65 mm and the downcomer pipe a diameter of 30 mm, was filled with water (9 g/dm3 NaCl). Petroleum ether 40/60 was pumped into the riser pipe by means of a glass filter fitted in the bottom of the loop reactor and having a diameter of 25 mm. The circulation in the loop reactor was made visible with alginate spherules suspended in the aqueous phase and having a diameter of 2 mm. The circulation time of said alginate spherules was approximately 3 seconds.

Claims

C LA I M S
1. Method for carrying out biotechnological processes by means of a multiphase system in a loop reactor, which system comprises an aqueous phase, characterized in that use is made at the same time of at least one organic solvent which is immiscible with water and which has a different density from water and one of the liquid components is used as the continuous phase and the other as the disperse phase.
2. Method according to Claim 1, characterized in that use is made of an organic solvent which is immiscible with water and which has a lower density than water.
3. Method according to Claim 1 or 2, characterized in that use is made of n-hexane or n-hexadecane as the organic solvent which is immiscible with water.
4. Method according to Claim 1, characterized in that use is made of an organic solvent which is immiscible with water and which has a higher density than water.
5. Method according to Claim 1 or 4, characterized in that use is made of FC-40 or FC-70 as the organic solvent which is immiscible with water.
6. Method according to Claim 1, characterized in that air is introduced into the riser pipe of the loop reactor if the disperse phase has a higher density than the continuous phase.
7. Method according to Claim 1, characterized in that use is made of water and two organic solvents which are immiscible with water in spaces in the loop reactor which are at least partially separated from each other, one solvent having a lower density and the other a higher density than water.
PCT/NL1987/000035 1986-12-05 1987-12-04 Method for carrying out biotechnological processes by means of a multiphase system in a loop reactor WO1988004317A1 (en)

Applications Claiming Priority (2)

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NL8603105A NL8603105A (en) 1986-12-05 1986-12-05 METHOD FOR PERFORMING BIOTECHNOLOGICAL PROCESSES USING A MULTI-PHASE SYSTEM IN A LOOP REACTOR
NL8603105 1986-12-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2328943B (en) * 1997-09-05 2002-05-22 Advanced Phytonics Ltd Improvements in or relating to the preparation of a compound
WO2008051301A2 (en) 2006-07-10 2008-05-02 Exxonmobil Chemical Patents Inc. Internal loop reactor and oxo process using same
CN107460231A (en) * 2017-08-21 2017-12-12 湖北省农业科学院植保土肥研究所 A kind of wheat powdery mildew spray inoculation method

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2053770A (en) * 1933-08-15 1936-09-08 Dreyfus Henry Removal from a fermenting medium of organic compounds produced by the fermentation
FR1529536A (en) * 1965-12-07 1968-06-21 Inst Francais Du Petrole Improved process for making intimate mixtures of several immiscible liquid phases
WO1982001563A1 (en) * 1980-10-23 1982-05-13 Bo Mattiasson Biological and chemical conversion processes in liquid phase-system

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2053770A (en) * 1933-08-15 1936-09-08 Dreyfus Henry Removal from a fermenting medium of organic compounds produced by the fermentation
FR1529536A (en) * 1965-12-07 1968-06-21 Inst Francais Du Petrole Improved process for making intimate mixtures of several immiscible liquid phases
WO1982001563A1 (en) * 1980-10-23 1982-05-13 Bo Mattiasson Biological and chemical conversion processes in liquid phase-system

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2328943B (en) * 1997-09-05 2002-05-22 Advanced Phytonics Ltd Improvements in or relating to the preparation of a compound
WO2008051301A2 (en) 2006-07-10 2008-05-02 Exxonmobil Chemical Patents Inc. Internal loop reactor and oxo process using same
US7666366B2 (en) 2006-07-10 2010-02-23 Exxonmobil Chemical Patents Inc. Internal loop reactor and Oxo process using same
US7875254B2 (en) 2006-07-10 2011-01-25 Exxonmobil Chemical Patents Inc. Internal loop reactor and Oxo process using same
CN107460231A (en) * 2017-08-21 2017-12-12 湖北省农业科学院植保土肥研究所 A kind of wheat powdery mildew spray inoculation method

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Publication number Publication date
EP0292549A1 (en) 1988-11-30
NL8603105A (en) 1988-07-01

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