WO2023151877A1 - Réacteur à membrane catalytique - Google Patents

Réacteur à membrane catalytique Download PDF

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Publication number
WO2023151877A1
WO2023151877A1 PCT/EP2023/050229 EP2023050229W WO2023151877A1 WO 2023151877 A1 WO2023151877 A1 WO 2023151877A1 EP 2023050229 W EP2023050229 W EP 2023050229W WO 2023151877 A1 WO2023151877 A1 WO 2023151877A1
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area
reactor
areas
fluid
flow
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PCT/EP2023/050229
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German (de)
English (en)
Inventor
Matthias Franzreb
Ruijie TAN
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Karlsruher Institut für Technologie
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Publication of WO2023151877A1 publication Critical patent/WO2023151877A1/fr

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    • 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
    • C12M21/00—Bioreactors or fermenters specially adapted for specific uses
    • C12M21/18—Apparatus specially designed for the use of free, immobilized or carrier-bound enzymes
    • 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
    • C12M21/00—Bioreactors or fermenters specially adapted for specific uses
    • C12M21/14—Bioreactors or fermenters specially adapted for specific uses for producing enzymes
    • 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
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/34—Internal compartments or partitions
    • 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
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/02—Membranes; Filters
    • 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
    • C12M29/10—Perfusion

Definitions

  • the present invention relates to reactors with a plurality of flow areas divided from one another by membranes, their use and methods for the catalytic conversion of substrates.
  • EMR enzyme membrane reactor
  • the biocatalyst In the case of an EMR with free, dissolved enzymes, the biocatalyst is retained by an ultrafiltration membrane, while the product is allowed to pass through this membrane.
  • the enzyme When the EMR is operated as dead-end filtration, the enzyme rapidly accumulates above the membrane surface, leading to concentration polarization and potential fouling.
  • the corresponding depletion of the enzyme in the bulk volume of the reactor leads to reduced conversion rates and yields/space-time-yield STY.
  • the cross-flow operation of the EMRs and the recycling of the reaction solution in a loop reduces the concentration polarization, but the concept is only conditionally suitable for the realization of continuous flow enzyme cascades, especially when the substrates involved and products are of comparable size.
  • the object of the present invention was therefore, with regard to the prior art, to provide improved reactors for catalytic reactions, with which the disadvantages of the prior art can be circumvented and particularly good results can be achieved.
  • ambient temperature means a temperature of 20° C. Unless otherwise stated, temperatures are in degrees Celsius (° C.).
  • the subject of the present invention is a reactor comprising, or in variants consisting of, at least three, or in variants also more than three, for example four, five, six, seven or even more, flow areas arranged concentrically around one another or in layers one above the other are each separated from one another by membranes, preferably semipermeable membranes.
  • the reactor has exactly three areas.
  • the regions are arranged in layers one above the other.
  • Semi-permeable membranes are membranes whose pores are only permeable for some of the substances flowing into the areas, i.e. only molecules below a certain molar mass or colloids or particles below a certain size be let through.
  • the electrical charge of the molecules and their hydrophilic or hydrophobic character also play a role in retention by the membranes. In the simplest case, this means that the respective membrane allows the solvent to pass through, but not the dissolved substance.
  • This principle is well known to those skilled in the art. In this respect, the selection of appropriate membranes by the person skilled in the art, optionally as a function of the desired reactions to be carried out in the reactor according to the invention, is clear to the person skilled in the art and requires no further explanation.
  • Suitable membranes include nanofiltration membranes composed of polyamide thin film composites having a molecular weight cut off (MWCO) of, for example, 150, 300 or 700 daltons (Da).
  • MWCO molecular weight cut off
  • Other common nanofiltration membranes consist, for example, of polypiperazinamide or cellulose acetate, also with MWCO values between 150 and 1000 daltons.
  • Suitable ultrafiltration membranes include those made of polyamide thin film composites, polyethersulfones or polyacrylonitrile with MWCO values of 1000 Da, 2000 Da, 3000 Da, 5000 Da up to 50000 Da or more.
  • the membranes used are therefore selected from the group consisting of
  • Nanofiltration membranes consisting of polyamide thin-film composites with a molecular weight cut-off of 150, 300 or 700 daltons, nanofiltration membranes made of polypiperazinamide with MWCO values between 150 and 1000 daltons,
  • the respective membranes can be the same or different. In some embodiments of the present invention it is preferred if the membranes between the first region and the two adjacent regions are the same. In some other embodiments of the present invention, it is preferred if the membranes are different between the first area and the two adjacent areas, in particular when no reversal of the direction of flow through the membrane is provided during operation.
  • the first membrane is used for the controlled supply of an exchange solution to the first (middle) area (flow channel) in which the immobilized catalyst (the immobilized enzyme) is located and in which the catalytic conversion (reaction of the substrate to product) takes place.
  • the second membrane is used for the simultaneous, controlled removal of solvent from the first (middle) area (flow channel). At the same time, the membrane holds back the product. This also applies to an intermittent change of supply from the second to the third area (or vice versa), except that then only the direction of flow is reversed transversely to the direction of flow through the first area and the two membranes exchange their roles.
  • the reactor according to the invention also has at least two fluid supply devices and at least two fluid discharge devices, one fluid supply device and one fluid discharge device being connected to the first area, which in the preferred embodiments has three areas between the other areas, and the other fluid supply devices and fluid discharge devices being connected to the others areas are connected.
  • each of these devices can have control and/or throttle valves. This allows the or discharged amounts of fluid (in addition to regulation via pressure, etc.) even more precisely and, if necessary, simplify the mixing of individual components.
  • each area prefferably has more than one fluid supply device or fluid discharge device.
  • the reactor according to the invention has at least one fluid supply device per area and at least one fluid discharge device per area.
  • the reactor according to the invention is configured such that the direction of flow in a (the) first region located between (the) other two regions is cocurrent with or opposite to the direction of flow in the other two regions.
  • An essential feature of the present invention is, moreover, that immobilized catalyst particles are arranged in the first area of the reactor according to the invention, which is arranged between the two other areas.
  • the fluids fed in and removed are preferably liquids, ie substances or mixtures of substances which are liquid under the respective operating conditions of the reactor, for example an operating temperature between 5° C. and 80° C. and atmospheric pressure.
  • gaseous fluids at atmospheric pressure or higher or lower pressure or higher or lower temperatures.
  • the fluids supplied and specified are particularly preferably aqueous solutions.
  • the reactor according to the invention has at least two supply and discharge devices for fluids.
  • the reactor according to the invention in which the reactor according to the invention has three areas, it is preferred if the reactor according to the invention at least one fluid supply device per region, and at least one fluid discharge device per region. In this way, a particularly good mixing of the substances passing through the membranes can be achieved, particularly in the case of countercurrent flow, ie when the direction of flow in the first area lying between the other areas is opposite to that of the two outer areas.
  • the reactor according to the invention has a fluid supply device and a fluid discharge device for the first region lying between the other regions, and a fluid supply device for the upper region (but no fluid drain) and a lower region fluid drain (but no fluid supply). Accordingly, in still other variants of the present invention, in which the reactor according to the invention has three regions, it is preferred if the reactor according to the invention has a fluid supply device and a fluid discharge device for the first region lying between the other regions, and a fluid supply device for the lower region (but no fluid removal device) and an upper region fluid removal device (but no fluid delivery device).
  • a volume flow of a solution enters the first area due to pressure differences from an adjoining area through a membrane and at the same time from the first area a volume flow exits through another membrane into another adjacent area.
  • a modification of the solution in the first area is possible, independently of the main flow direction, which is defined by the fluid supply device and fluid discharge device of the first area.
  • the direction of flow in the first area is opposite to the direction of flow in the adjacent areas, this is not absolutely necessary within the scope of the present invention and in other (not quite as preferred) variants of the present invention it can it may be preferred if the directions of flow are the same. Because there are cases in which the direction of flow is irrelevant or in which a direct current is more favorable, for example if the flow direction of the membranes is not changed at the same time.
  • the catalyst particles are immobilized means that they cannot move freely in the first area.
  • immobilization There are various possibilities for immobilization, which are known to the person skilled in the art.
  • the catalyst particles do not necessarily have to be arranged on a framework, but can also be fixed on carrier particles and then arranged in the form of a bed or suspension in the first region.
  • the catalysts are immobilized on support materials, preferably selected from the group consisting of fibers, particles, in particular microparticulate particles, lattice structures, or combinations thereof.
  • Microparticulate particles which can also be referred to as microparticles, preferably means that the particles have a size in the micrometer range, in particular in the range from 0.5 ⁇ m to 500 ⁇ m, preferably from 2 ⁇ m to 300 ⁇ m.
  • lattic structures refers to structures that are constructed like a lattice or a sieve.
  • the respective webs of the lattice or sieve are not restricted in their dimensions, except that the resulting lattice or sieve structure is not too large for an arrangement in the first range and that, after the catalyst particles have been immobilized thereon, sufficient free volume for the fluid flow must remain.
  • covalent immobilization on carrier particles by chemical bonding for example (preferred) via l-ethyl-3-(3-dimethylaminopropyl )carbodiimide (EDC) or glutaraldehyde (GA);
  • Immobilization via tagged enzymes and corresponding ligands on the carrier particles for example (preferred) His-tagged enzymes and particles with imminodiacetic acid ligands or enzymes and particles that form a covalent bond via the so-called spytag/spycatcher technology during immobilization;
  • particles such as (preferred) hydrogel particles; particulate enzyme immobilizates that can be synthesized by cross-linking the enzymes, e.g. cross-linked enzyme aggregates (CLEAs).
  • CLSAs cross-linked enzyme aggregates
  • carrier particles known in the art are suitable as carrier particles for the first three variants mentioned; in particular, they can be both porous and non-porous in nature. Their chemical character can be polymer based, mineral based or a combination of these.
  • the carrier particles are selected from the group consisting of carriers made of agarose, dextran, chitosan, gelatin, alginate, Polyethylene glycol, polyvinyl alcohol, polymethyl methacrylate, polystyrene, silica, iron oxides, aluminum oxides, organometallic cage compounds or mixtures thereof.
  • the immobilized catalysts are biocatalysts, in particular enzymes.
  • any enzyme can be used within the scope of the present invention.
  • the enzymes are selected from the group consisting of oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, translocases, and mixtures thereof.
  • the reactors according to the invention are particularly preferably enzyme membrane reactors; however, the present invention is not limited thereto.
  • the first region arranged between the two other regions has retaining devices, preferably frits, for the catalyst particles on its fluid supply devices and fluid discharge devices.
  • these restraining devices can be openable or exchangeable. In this way, for example, catalyst beds can then be easily removed and replaced, for example with new but identical or new but different or also regenerated catalyst beds.
  • the respective fluid supply devices and the respective fluid discharge devices are also configured to be switched and regulated independently of one another. This enables particularly good control over the currents. For example, this can prevent the end of the upper area facing away from the inflow from "running empty” if the inflow is too low, or it can be achieved that a sufficiently high supply pressure in a lower area results in a good flow through to the upper area, or other effects can be achieved.Combined effects can also be achieved.
  • flow-influencing internals such as baffle plates or support grids, in the various areas, each independently of other areas. This can, for example, further improve or regulate the mixing of fluid components.
  • a preferred embodiment of the present invention relates to an enzyme membrane reactor comprising, or consisting of, a) three flow areas arranged in layers one above the other, each of which is separated from one another by semipermeable membranes, b) at least one fluid supply device per area, c) at least one fluid discharge device per area, wherein the reactor is configured in such a way that the flow direction in the first area arranged between the two other areas is opposite to the flow direction in the two other areas, characterized in that in the first area arranged between the two other areas as immobilized catalyst particles on carrier materials, preferably selected from the group consisting of fibers, particles, in particular microparticulate particles, lattice structures or mixtures thereof, immobilized enzymes are arranged.
  • the fluid supply devices and the fluid discharge devices are attached to the respective ends of the regions of the reactor.
  • the reactors according to the invention or their components are produced by means of 3D printing.
  • the reactor housing and/or the support for immobilizing the catalyst particles is produced by means of 3D printing and corresponding semipermeable membranes not produced by 3D printing are inserted into the housing.
  • the reactors according to the invention each have one or more further feed devices for all or individual, preferably all, of the first region adjacent areas. Fluids can then also be supplied via these further supplies. These fluids, each independently, may be the same fluids as those in the other feeds mentioned, or different.
  • these additional feeds are arranged upstream, seen from the discharge of the first region.
  • the reactor is designed in such a way that downstream, seen in the direction of flow of the first region, an area is provided from the additional feeds which is free of immobilized catalyst.
  • appropriate retaining devices for the immobilized catalyst can be provided in the first area.
  • all feeds to the reactors according to the invention are configured in such a way that they can be switched (used) independently of the other feeds and independently of the discharges.
  • At least two reactors according to the invention are connected in series.
  • the reactions carried out can be made even more effective, for example.
  • conventional apparatus such as preferably fluid washing devices, fluid separators, heat exchangers or the like, can be arranged between two reactors according to the invention.
  • the feed devices to the respective reactors can be the same or different and feed the same or different fluids. In this way, it is also possible to carry out staged reactions separately according to stages using a plurality of reactors according to the invention connected in series, which entails a considerable increase in controllability.
  • conventional apparatus such as preferably fluid washing devices, fluid separators, heat exchangers or the like, can be arranged between two reactors according to the invention.
  • the feed devices for the respective reactors can be the same or different and feed in the same or different fluids. In this way, it is also possible to carry out staged reactions separately according to stages using a plurality of reactors according to the invention connected in series, which entails a considerable increase in controllability.
  • reactors according to the invention with reactors which are not according to the invention, even if a number of reactors according to the invention are connected in series and/or in parallel.
  • Another object of the present invention is an automated reactor system comprising at least two reactors according to the invention and at least one control and monitoring device; the automated reactor system of the present invention is thus distinguished by the control and monitoring device(s) from the other reactor systems of the invention where the control (and control) is manual.
  • a special feature of the reactor systems according to the invention and automated reactor systems according to the invention is that buffer changes can take place simultaneously with the reaction along the flow path in the middle (first) area directly in the reactor.
  • a further object of the present invention is a method for the catalytic conversion of a substrate, with a substrate solution being passed as the first fluid into a reactor in and through a first region arranged between two other regions, preferably uniformly and continuously, independently of fluid supplies to the other regions a solution that is based on the same solvent as the substrate solution or is miscible with this solvent is introduced as the second and third fluid alternately into the other areas, with the same or opposite direction of flow to the first fluid.
  • an immobilized catalyst is arranged in the first zone and the first zone is separated from the other zones by membranes, preferably semipermeable membranes, and that the membranes are configured for the substrate, the main product and the catalyst to be impenetrable.
  • auxiliaries and undesired by-products can pass through the membranes.
  • the designation second and third fluid refers to the fact that these fluids are conducted into a second and third area.
  • the second and third fluids can be the same or different.
  • miscible with this solvent means that the solution is at least 1:2 miscible with the solvent in the first region without phase separation or precipitation.
  • the fluid is fed into the first area in countercurrent to the direction of flow in the two adjacent areas.
  • the reaction (of the respective reactants) is carried out in a reactor according to the invention, a reactor system according to the invention or an automated reactor system according to the invention.
  • immobilized enzymes are used as catalyst in the first area arranged between two other areas.
  • the second and third fluids supplied are the same or the same and pure solvent, or contain one or more elements selected from the group consisting of the same or different solvent as the solvent in the first region, excipients, buffers , cocatalysts, cofactors, other reactants, other reactants, and mixtures thereof.
  • a buffered enzymatic reaction takes place in the first area, buffer solution, preferably containing other substances, is subsequently supplied via the inlets of the other areas and any depleted buffer solution is removed through the outlets of the other areas. It is also preferred if all areas are filled with fluid during operation.
  • the fluid is supplied alternately in (the) two areas adjoining the first area (the (both) adjoining areas are thus alternately supplied with fluid and not supplied).
  • the alternating supply can take place by switching the supply with a predetermined time, for example every 30 seconds or every 5 minutes, or be triggered by measured values, for example falling or rising pH value, or also be carried out manually.
  • a solution exchange via the semipermeable membranes is carried out in parallel with an enzymatic reaction taking place in the first region.
  • an auxiliary stream is additionally supplied to all or individual, preferably all, regions adjoining the first region at a further point in each case. This respective additional auxiliary stream can be the same as or different from the other auxiliary streams.
  • This additional supply makes it possible, for example (seen in the direction of flow of the stream in the first region) to achieve further dilution or purification downstream.
  • these additional feed devices can be used, for example, to supply exchange buffer with an auxiliary for the reaction in the middle region (the first region), while exchange buffer or just solvent can be supplied via the feeds arranged at the ends of the reactor according to the invention for product cleaning and formulation in the area of the product flow (the product discharge).
  • a section in which there is no immobilized catalyst, preferably no catalyst, can be provided downstream of the further feeds (seen in the flow direction of the first region) in the middle (first) region of the reactor according to the invention, in particular if this constellation/process control is intended for this purpose to clean the product in this section.
  • a retaining device for the (immobilized) catalyst can be used in the first region, in particular at the level of the additional feed devices.
  • the present invention also relates to uses of the reactors according to the invention, the reactor systems according to the invention, the automated reactor systems according to the invention.
  • the present invention makes it possible to supply further reactants in a targeted manner, which then pass through the semi-permeable membrane into the reaction area or just as well to remove by-products which are transported away from the reaction area through the semi-permeable membranes.
  • diffusion/diffusion is occasionally spoken of in relation to substances and their passage through the semi-permeable membranes, this includes the flow-induced substance flow (convective substance flow), which is otherwise included in the As a rule, the main part of the amount of substances passing through the membranes is caused by auxiliary substances or by-products.
  • Some preferred variants of the present invention relate to the use for the production of fine chemicals, preferably caprolactone by oxidation of cyclohexanone.
  • oligosaccharides in particular the enzymatic production of oligosaccharides, glycans, glycoconjugates, therapeutic glycoproteins or hyaluronic acids.
  • Still other preferred variants of the present invention relate to the use for enzymatic reactions that use H2O2, in particular hydroxylations, epoxidations, halogenations or Baeyer-Villiger oxidations.
  • the present invention makes it possible to connect one or more reactors, in particular enzyme membrane reactors, to one another sequentially and thus to carry out complex, multi-stage enzymatic cascades continuously and thus optimally synthesize new, sophisticated products.
  • the present invention makes it possible to obtain an EMR system which optimally fulfills the partial functions of enzyme immobilization and integrated product purification with continuous flow.
  • the enzyme is immobilized in/on/on in the enzyme membrane reactor (EMR) pumpable, particulate or fibrous carrier materials, and
  • EMR enzyme membrane reactor
  • a further advantage of the present invention is that an additional purification, concentration or rebuffering of the product of enzymatic reactions can take place.
  • a further advantage of the present invention is that the buffer exchange required for optimum operation of a downstream reactor in a reactor cascade can already be achieved in the outflow area of an upstream reactor by means of auxiliary material supplied.
  • One advantage of the present invention is that cofactors (additional starting materials for the reaction, such as oxygen or hydrogen peroxide) that are still required for the reaction are supplied to the (reaction) system via a flushing solution that is supplied to a second or third area and, in addition, components can be discharged from the respective third or second area.
  • Another advantage of the present invention is that three flow areas are used. This makes it possible to feed in the reactants in the first and to convert them to product by means of an immobilized catalyst.
  • Components of a rinsing solution can reach the reaction area from a second area, for example through the membrane, in order to supply auxiliary substances here, for example, or to bring about a change in the reaction medium.
  • Undesirable substances that have passed through the membrane, for example can then be discharged via a third area; for example, one area (the second) can be responsible for the supply of an excipient and another area (the third) for the removal of the used excipient or contaminants. This was not possible with the prior art reactors.
  • the reactor according to the invention which can also be referred to as a reactor module according to the invention or simply as a module according to the invention, comprises two side parts and a central part, all of which have a channel structure through which solutions can flow; the side parts and the middle part are the areas defined above, the middle part being the first area.
  • a membrane is arranged between the side parts and the middle part, ie the module according to the invention has two membranes arranged in parallel, which delimit the middle channel (first area) at the top and bottom.
  • the support materials with the immobilized catalysts, in particular enzymes, are located in this middle channel.
  • the feed solution with the dissolved substrate (educt) enters the region of this middle channel at one end and the product solution, which has been purified if necessary, exits at the other end of the middle channel.
  • the supplied substrate molecules are continuously converted into the desired product by the immobilized catalysts, in particular enzymes.
  • the buffer (buffer solution) of the middle channel is replaced by new buffer (new buffer solution), which is also continuously fed through a membrane delimiting the middle channel, this buffer from the fluid feed to one of the adjacent areas (into one of the side parts) originates.
  • the original buffer to be exchanged in the central channel area is simultaneously discharged via the second limiting membrane (into the third area or the other side part).
  • the gradual exchange of buffers means that auxiliaries can be added continuously which, for example, would be harmful to the catalyst, in particular an enzyme, if they were added directly to the inflowing substrate stream due to the high local concentration (e.g. hydrogen peroxide in the connection with the use of peroxygenases).
  • auxiliaries can be added continuously which, for example, would be harmful to the catalyst, in particular an enzyme, if they were added directly to the inflowing substrate stream due to the high local concentration (e.g. hydrogen peroxide in the connection with the use of peroxygenases).
  • Another important option for gradual buffer exchange in the context of the present invention is the removal of unwanted by-products of the reaction (if they occur), which makes it possible for the target product to enter the reactor according to the invention in a purified form in an optimal manner for storage or a subsequent reaction Exchange buffer exits.
  • the set (continuous) substrate flow in the first area (the middle channel) and the volume flow of the exchange buffer penetrating through the membranes are completely independent of one another and freely selectable;
  • the volume flow exiting through the second membrane can be greater than the volume flow of new buffer entering through the first membrane, which means that, in addition to an exchange of the buffer solution, the product formed is also concentrated in the first area (the middle channel), which is often advantageous can be.
  • the buffer exchange process achieves very good efficiencies, i.e. the amounts of new buffer required for a more than 99% exchange are only in the range of 2 to 5 times the flow rate of the middle channel (of the first area).
  • the countercurrent principle is achieved in that the exchange buffer enters at the end of the reactor according to the invention (module end) at which the solution exits from the central channel (the first region).
  • the end of the middle flow channel is in contact with the inlet of the pure exchange buffer, as a result of which, for example, the last residues of the undesired by-product can be flushed out.
  • membrane module according to the invention membrane module according to the invention
  • its mode of operation ie the method according to the invention
  • an accumulation of particles e.g. from not completely fixed enzyme carriers or aggregations of substances
  • the system can cyclically change the flow direction of the membrane switch without having to interrupt the center channel's pump current.
  • the switching can be done, for example, with the help of multiport valves, whereby the inflow, for example of exchange buffer, can take place either in the upper or in the lower module part (the areas adjoining the first area).
  • the reactor system according to the invention or the automated reactor system according to the invention has devices for independently feeding the substrate stream into the middle flow area (the first area), the product stream exiting from this area and the volume flow of the exchange buffer (which would be fed into at least one adjacent area). to control each other.
  • the direction of flow (for example switched from top to bottom to from bottom to top) can be switched through the two membranes and thus their respective role (see above) during the process or during operation. This prevents the permanent formation of a concentration polarization or fouling layer due to substances accumulated on the membrane surface, such as in particular product and/or enzyme carrier particles.
  • An essential feature of the present invention is that the catalysts, in particular enzymes, are not fixed in or on the membranes (semipermeable membranes) (as in the case of the bi- or trilayer membranes of the prior art).
  • the catalysts in particular enzymes, are not immobilized on or in the membranes, in particular semipermeable membranes.
  • the membranes cannot stop mobile catalyst particles (enzyme particles), especially if they are supported - because such particles can accumulate in front of/at the respective membrane under sustained flow - but that the catalyst particles are not connected to or bonded to the membrane, so that the particles become detached from the respective membrane again if the flow ceases or the direction of flow reverses.
  • the catalyst particles in particular enzymes, are rather immobilized in the first area (ie the central area/channel in the case of three layers arranged one above the other).
  • the reactor according to the invention then preferably has retaining devices at its ends retain the immobilized particles inside the first region.
  • This variant enables the catalyst particles/enzyme carrier to be replaced quickly and easily if the catalysts/enzymes become increasingly inactive over the course of the period of operation. To do this, the module does not have to be dismantled and no membranes have to be replaced.
  • further structures can be arranged in the first region, such as lattice or sieve structures, which additionally immobilize the supported catalyst particles.
  • a substrate stream with e.g. 1 mol/L feed concentration becomes a product stream with a concentration of 2 mol/L with a complete 1:1 conversion to product according to this example, since the solvent volume draining from the middle channel has halved.
  • the reactor module according to the invention can, in variants, consist of three parts, including two side parts through which, for example, a diafiltration buffer or permeate flows, and a central part containing the feed inlet and the retentate outlet.
  • the reactors according to the invention can have different dimensions; the present invention is thus not limited to specific sizes of the reactors.
  • the present invention can be used or applied to all products that are produced biocatalytically.
  • products that require other reactants in addition to the main substrate as well as products that are generated via enzyme cascades with disruptive by-products.
  • the individual parts of the devices/systems according to the invention are functionally connected to one another in a manner known and customary in the art.
  • FIG. 1 shows an illustrative membrane reactor R according to the invention.
  • This figure shows a variant according to the invention in which three fluid channels or regions 2, 2a, 3 are arranged one above the other. Between these are each (semipermeable) membranes 1, 1a.
  • the immobilized catalyst preferably enzyme, is arranged in the middle area 3 . Flow directions for the individual streams are also indicated (which do not have to be in the indicated direction in all variants of the invention).
  • a substrate or substrate mixture stream S is introduced from the left, flows to the right through region 3 and exits the reactor on the right as a discharge of the product P-; here, as with the other streams in the figures, the plus sign means a supply and the minus sign means a drain.
  • auxiliary stream B which can be a buffer solution, for example; this is illustrated by the solid line arrow.
  • Arrows shown with solid lines illustrate here that these are the switched (used) inlets and outlets.
  • the arrows shown with dashed lines mean alternative inlets and outlets. These can be switched (used) in alternation with the others (with the solid lines).
  • the flows supplied in each case can be the same or different. It is therefore possible either to maintain a switching position and thus a direction of flow through the membranes during the entire operation, or to change this position, in particular cyclically, during operation.
  • FIG. 2 shows a reactor R according to FIG. 1, but here the flow path SW of an auxiliary flow B′ is illustrated in a highly schematic manner, as it occurs when the switching position for the feeds is changed cyclically during operation.
  • the excipient B' initially flows to the left into the area 2a. then passes through the membrane la in the middle region 3 and is pushed back there by the opposite flow of the product stream S back to the right.
  • the flow of B' orthogonal to the flow of P is not zero, so that B' reaches the other semipermeable membrane 1 and enters the region 2.
  • the volume passed through the first area (middle channel) (right axis) is compared to the measured UV signal (vertical axis, left ) or the simultaneously measured pH value (vertical axis, right).
  • the flow rates Q for the substrate flow (QF) and the buffer flow (QP) are each indicated with double arrows, which illustrates the range in which the stated flow rate is present.
  • FIG. 4 shows the pH and UV signal curve plotted against the volume passed through in the outflow of the central channel according to example 2 and corresponds in principle; except for the data, the chart of Figure 3 (Example 1).
  • FIG. 5 schematically shows the interconnection of two reactors R according to the invention to form a reactor system RS, in particular for an enzyme cascade.
  • substrate (mixture) S is fed from the left into the middle region with immobilized catalyst 3 of the left reactor Rimks.
  • the discharge of the product from the first (left) reactor is carried out as a new substrate (mixture) in the middle area with immobilized catalyst 3 of the right reactor R right hts (for the sake of clarity in the figure only shown as an arrow, without labeling) and then discharged as the final product P from the right reactor Rrechts to the extreme right.
  • Auxiliaries B′ are fed from the right to the right-hand reactor Rright and auxiliary materials B are fed analogously to the left-hand reactor Ri in ks between the two reactors.
  • waste (products/solution) W is discharged from the left reactor Rimks.
  • Undesired by-products BP flushed out of the right-hand reactor Rright can still be discharged between the reactors.
  • the respective supply devices for the auxiliary materials to the reactor Ri in ks or Rrechts each comprise (multiport) valves V, with which the supply to the upper and/or lower areas 2, 2a can be regulated so that either in the upper area , or the lower area, or in both areas excipients can be added; the discharge devices can also be equipped with such valves (shown in the figure only for the waste W but not for the by-products BP).
  • FIG. 6 shows a further variant of the reactors R according to the invention. The reactor R shown corresponds to the reactor R shown in FIG.
  • the flow path SW which is already shown very schematically, does not change in principle, it can only be “flattened” or “pressed in” a little in the area of the additional feeds, since the flows B" or B'" exert a certain back pressure/side pressure; however, this is not illustrated for the sake of simplicity.
  • These additional feed devices can be used, for example, to feed exchange buffer with an auxiliary B" for the reaction in the central area (the first area), while the feeds for B or B' arranged at the ends of the reactor R can be used, for example, for exchange buffer or just solvent for product purification and formulation in the area of the product outlet (the product discharge).
  • a section can be provided in which there is no immobilized catalyst, preferably no catalyst, particularly when this constellation/procedure is intended to purify the product in this section.
  • B' second excipient (stream) (solvent/diluent/buffer/co-
  • Stream in connection with a substance stream means in each case a discharge of a stream, possibly depleted in (individual) ingredients and possibly enriched with other ingredients/reaction products from another stream
  • the lattices exhibited anisotropic structures in which, in the x-direction (if the reactor is thought of in a Cartesian coordinate system), the fluid flow through about 80 cubic chambers of about 3 x 3 x 2 mm 3 with narrow windows of about lxl mm 2 in the walls between the chambers had to step; and wherein the lattice had short, fully open, square channels in the y-direction with no obstructions to fluid flow.
  • the module was integrated into an FPLC system ( ⁇ kta Purifier UPC 10, GE Healthcare, Uppsala, Sweden) with an additional sampling pump and online detectors for UV/Vis adsorption, conductivity and pH.
  • an (enzyme) membrane reactor module according to the invention was produced for the laboratory scale by means of 3D printing. 1, the module consisted of a central part (the first area) and two side parts (the adjacent areas), each of which had a flow channel with dimensions of 50 ⁇ 20 ⁇ 2 mm 3 . A support structure through which a flow could flow was located within the flow channels. A partially permeable (semipermeable) membrane was located between the central part and the side parts, which separated the flow channels (areas) from one another.
  • the support structure within the channels served not only to direct the flow but also as a mechanical support for the two membranes.
  • the middle channel of the module was filled with 0.2 g of enzyme-loaded microparticles (diameter ca. 30 pm) with an esterase loading of 20 mg enzyme per gram of microparticles (esterase of EC number 3.1.1.1 on PureCube Ni-IDA MagBeads).
  • the module according to the invention described was connected to an FPLC system ( ⁇ KTA purifier UPC 10, GE Healthcare, Uppsala, Sweden). Additionally additional sensors were installed to record the pressure and to measure the accumulated masses of the inflow and outflow streams. This combination enabled detailed and precise control of the operating conditions as well as online monitoring of the most important process parameters.
  • the three piston pumps of the FPLC system guaranteed pressure-independent control of the feed flow of the substrate solution, the discharge flow of the product formed, and the feed flow of the fresh buffer solution to regulate the pH value.
  • the effluent flow of the spent buffer resulted automatically from the incompressibility of the aqueous medium and the mass balance.
  • the sensors of the FPLC system also enabled online monitoring of the pH value and monitoring of the product concentration in the module flow via the UV adsorption of the para-nitrophenol.
  • a solution of 4 mM pNPA in TBS buffer (100 mM, pH 7.8) was pumped continuously through the middle channel (first region) of the enzyme membrane reactor at a flow rate (QF) of 1 ml/min.
  • the product solution was also discharged at a flow rate (QP) of 1 ml/min via the drain (fluid discharge device) of the middle channel.
  • a TBS buffer solution (500 mM, pH 7.8) was conveyed at 0.3 ml/min into the upper side part and used buffer solution was drained from the lower side part at the same volume flow.
  • the direction of flow of the buffer solution in the side parts was countercurrent to the direction of flow of substrate and product in the middle channel (the first region) of the (enzyme membrane) reactor.
  • the flow rate of the substrate feed (Q F ) was reduced to 0.75 ml/min in order to achieve higher substrate conversions and thus higher product concentrations through a slightly longer residence time.
  • reducing the flow rate led to a significant increase in the UV signal.
  • the higher substrate conversions led to a slight drop in pH due to the increased formation of acid.
  • the continuous supply of fresh buffer solution which is possible in the (enzyme membrane) module according to the invention also made possible continuous operation in the optimum pH range of 7.8 under these conditions.
  • the inventive (enzyme membrane) reactor was first operated with the same substrate and buffer solutions at a flow rate of the substrate solution (Q F ) of 1 ml/min and a flow rate of the buffer solution (Q P ) of 0.3 ml/min. Accordingly, the UV and pH curve initially resembles the curve described in Example 1 (a corresponding diagram is reproduced as FIG. 4). At the start of product formation, there was a brief drop in pH, but this was quickly compensated for by the buffer flow fed through the membrane. In the further course, however, the para-nitrophenol formed in addition to octanoic acid was regarded as an undesirable by-product.
  • the buffer solution to substrate feed volume flow ratio was increased to a value of 2 from a throughput volume of 33 ml.
  • the flow rate of the substrate solution (Q F ) was reduced to 0.5 ml/min, while that of the buffer solution (Q P ) was increased to 1 ml/min.
  • the countercurrent principle implemented within the (enzyme) reactor and the simultaneous supply and removal of fresh buffer solution or buffer solution enriched with the contaminants via two separate membranes led to the desired strong depletion of the model contaminants in the effluent, recognizable by the rapid and severe decrease in UV signal.
  • the decrease in the UV signal went far beyond the level that would result from a pure dilution of the para- Nitrophenols would result by adding the buffer solution in the stated ratio.

Abstract

L'invention concerne des réacteurs comprenant au moins trois régions d'écoulement placées concentriquement les unes autour des autres ou en couches superposées, chacune séparée des autres par des membranes, comprenant au moins deux dispositifs d'alimentation en fluide et au moins deux dispositifs de décharge de fluide, le réacteur étant conçu afin que le sens d'écoulement dans une première région située entre deux autres régions soit le même que le sens d'écoulement dans les deux autres régions ou qu'il lui soit opposé, un dispositif d'alimentation en fluide et un dispositif d'évacuation de fluide sont reliés à la première région, et les autres dispositifs d'alimentation en fluide et dispositifs d'évacuation de fluide sont reliés aux autres régions, et des particules de catalyseur immobilisées sont situées dans la première région située entre les deux autres régions. L'invention concerne également des systèmes de réacteurs, des procédés et des utilisations fondés sur ce principe.
PCT/EP2023/050229 2022-02-11 2023-01-06 Réacteur à membrane catalytique WO2023151877A1 (fr)

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Citations (10)

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US4786597A (en) 1981-04-15 1988-11-22 University Patents, Inc. Method and apparatus for conducting catalytic reactions with simultaneous product separation and recovery
US5449848A (en) 1989-06-13 1995-09-12 Agency Of Industrial Science And Technology Dehydrogenation process
US5605835A (en) * 1988-05-23 1997-02-25 Regents Of The University Of Minnesota Bioreactor device with application as a bioartificial liver
WO2004022480A2 (fr) 2002-09-05 2004-03-18 Shell Internationale Research Maatschappij B.V. Dispositif et procede de production d'hydrogene a purete elevee
US6979308B1 (en) * 1999-06-03 2005-12-27 University Of North Carolina At Chapel Hill Bioreactor design and process for engineering tissue from cells
DE112004000139T5 (de) * 2003-01-21 2006-01-12 General Motors Corp. (N.D.Ges.D. Staates Delaware), Detroit Brennstoff verarbeitendes System mit einem Membranseparator
WO2006034100A1 (fr) 2004-09-21 2006-03-30 Worcester Polytechnic Institute Reformeur a la vapeur a membrane
US20150118118A1 (en) 2013-10-30 2015-04-30 Atomic Energy Council- Institute Of Nuclear Energy Research Membrane reaction apparatus for recovering heat of reaction
EP3194067B1 (fr) * 2014-08-20 2018-07-11 Bayer Aktiengesellschaft Procédé de phosgénation de composés contenant des groupes hydroxyle, thiol, amino et/ou formamide
WO2021186148A1 (fr) 2020-03-20 2021-09-23 Dairy Crest Limited Réacteur continu à boucle de filtration à courant transversal

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4786597A (en) 1981-04-15 1988-11-22 University Patents, Inc. Method and apparatus for conducting catalytic reactions with simultaneous product separation and recovery
US5605835A (en) * 1988-05-23 1997-02-25 Regents Of The University Of Minnesota Bioreactor device with application as a bioartificial liver
US5449848A (en) 1989-06-13 1995-09-12 Agency Of Industrial Science And Technology Dehydrogenation process
US6979308B1 (en) * 1999-06-03 2005-12-27 University Of North Carolina At Chapel Hill Bioreactor design and process for engineering tissue from cells
WO2004022480A2 (fr) 2002-09-05 2004-03-18 Shell Internationale Research Maatschappij B.V. Dispositif et procede de production d'hydrogene a purete elevee
DE112004000139T5 (de) * 2003-01-21 2006-01-12 General Motors Corp. (N.D.Ges.D. Staates Delaware), Detroit Brennstoff verarbeitendes System mit einem Membranseparator
US7537738B2 (en) 2003-01-21 2009-05-26 Gm Global Technology Operations, Inc. Fuel processing system having a membrane separator
WO2006034100A1 (fr) 2004-09-21 2006-03-30 Worcester Polytechnic Institute Reformeur a la vapeur a membrane
US20150118118A1 (en) 2013-10-30 2015-04-30 Atomic Energy Council- Institute Of Nuclear Energy Research Membrane reaction apparatus for recovering heat of reaction
EP3194067B1 (fr) * 2014-08-20 2018-07-11 Bayer Aktiengesellschaft Procédé de phosgénation de composés contenant des groupes hydroxyle, thiol, amino et/ou formamide
WO2021186148A1 (fr) 2020-03-20 2021-09-23 Dairy Crest Limited Réacteur continu à boucle de filtration à courant transversal

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