WO1996018719A1 - Appareil et procedes destines aux biotransformations - Google Patents

Appareil et procedes destines aux biotransformations Download PDF

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Publication number
WO1996018719A1
WO1996018719A1 PCT/GB1995/002958 GB9502958W WO9618719A1 WO 1996018719 A1 WO1996018719 A1 WO 1996018719A1 GB 9502958 W GB9502958 W GB 9502958W WO 9618719 A1 WO9618719 A1 WO 9618719A1
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WIPO (PCT)
Prior art keywords
membrane
precursor
phase
product
liquid
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PCT/GB1995/002958
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English (en)
Inventor
Andrew Livingston
Andrew Timothy Boam
David Campbell Stuckey
David Jonathon Leak
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Imperial College Of Science, Technology & Medicine
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Publication date
Application filed by Imperial College Of Science, Technology & Medicine filed Critical Imperial College Of Science, Technology & Medicine
Priority to AU42672/96A priority Critical patent/AU4267296A/en
Publication of WO1996018719A1 publication Critical patent/WO1996018719A1/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
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/04—Filters; Permeable or porous membranes or plates, e.g. dialysis
    • 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
    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms

Definitions

  • Biotransformations ' is a generic term for production of a useful chemical from a feedstock via biological reaction, such as a catalysis step.
  • Microorganisms are often able to catalyse complex chemical reactions at ambient conditions of temperature and pressure, and produce products of a greater purity than traditional catalytic routes. Considerable potential therefore exists to exploit these systems commercially.
  • An example is the synthesis of enantiomerically pure chiral compounds, where the biological activity resides in a single enantiomer. This is of increasing importance to both the pharmaceutical and agroche ical industries.
  • chiral epoxides which have a demonstrated utility in synthetic organic chemistry, and will readily undergo nucleophilic substitution. Although there are chemical methods for the synthesis of chiral epoxides these require allylic alcohols as starting compounds, and give rise to relatively expensive manufacturing routes. In contrast, as exemplified in patent applications (EPA 0166527, EPA 0256586) , icrobial systems have the ability to synthesise epoxides of high enantio eric purity from a wide range of substrates with a potential for considerable cost savings.
  • a major problem associated with biotransformations at present is the scarcity of suitable large scale biological reactors.
  • the precursors and products of the biotransformations are often organic materials which are sparingly soluble, and even toxic to microorganisms in high concentrations .
  • one phase is aqueous and contains the biological culture (microorganisms) and the other is an organic phase, containing the biotransformation precursor (and eventually product) dissolved in a suitable organic solvent, or even in a pure form (for instance toluene might be the other liquid phase in a reactor used for converting toluene to cis-diol) .
  • the biological culture is grown in the aqueous phase, and then the two phases are mixed.
  • Biotransformation precursor diffuses from the organic phase into the aqueous phase, and - 4 - is acted on by the microorganisms to form the biotransformation product.
  • bioreactor apparatus suitable for use in liquid phase biotransformation of organic precursor to organic product which comprises a generally hollow housing having an inlet which can receive aqueous phase containing biologically active culture, and a length of at least one selectively permeable polymeric tubular membrane extending - 5 - within the interior of said housing whereby the exterior surface of at least part of the length of the membrane(s) can contact said aqueous phase when present in the interior of said housing, membrane inlet means and membrane outlet means provided in the housing which can permit a flow of other liquid phase containing precursor through the interior of the membrane(s) , the housing further having generally liquid-tight sealing means in the proximity of said membrane inlet and outlet means effective to separate said aqueous phase from said other liquid phase in use of the apparatus.
  • the invention provides a method for effecting a liquid phase biotransformation of organic precursor to organic product which comprises separating by selectively permeable polymeric sheet or tubular membrane(s) a supply of aqueous feedstock containing a biocatalyst such as biologically active culture or an enzyme effective to transform said precursor to said product, from a supply of other liquid phase containing said precursor whereby - 6 - permeation of said precursor through said membrane( ⁇ ) into said aqueous phase occurs, followed by biologically effected reaction to form said product which then permeates back through said membrane(s) into said other liquid phase.
  • a biocatalyst such as biologically active culture or an enzyme effective to transform said precursor to said product
  • biocatalyst Whilst the biocatalyst can be a viable and growing cell mass, it does not have to be since an enzymatic biocatalyst could equally be used.
  • the or each membrane is a dense phase medium, more preferably dense phase homegeneous lipophyllic medium in which perforations are generally absent, tubular (for example a coil with a large surface area) and the method can conveniently be carried out using apparatus according to the said one aspect, or in apparatus adapted for batch processing.
  • aqueous feedstock may be a continuous flow or provided in batches which can be replaced or replenished as the biotransformation reaction proceeds.
  • the other liquid phase can be supplied in a continuous flow or in batches for replacement or replenishment.
  • both aqueous feedstock and other liquid are provided in batches, as in batch processing, with the liquids being physically separated by a barrier constituted by the membrane.
  • a coiled, tubular membrane may work well.
  • the membrane may be hollow tubular with an inlet remotely and independently supplied from any inlet of the bioreactor.
  • the membrane is preferably removable from the bioreactor by withdrawing it, without damage, and whilst liquid is still flowing therethrough to permit cleaning of - 7 - debris or excess micro-organism growth on the exterior of that tubing.
  • the membrane material is preferably one which allows permeation of the biotransformation precursor and product at a rate higher than permeation by chloride ion, under the same conditions.
  • the membrane may comprise silicone rubber, pvc, polyethylene, polypropylene and/or polysulphone and similar organic polymeric materials.
  • biological nutrients or enzyme activators can be added to the biological phase.
  • Oxygen (or air) can be added to the biological phase e.g. by bubbling in a supply of such gas at the base of the receptacle serving as the bioreactor (see e.g. Figures 11 and 12) .
  • the organic phase can be supplied, if required, on a continuous basis to the bioreactor apparatus, or to the interior of the hollow tubular membrane, whichever may be used for that phase.
  • the precursor may be an organic liquid in which case it is preferably dissolved in an organic solvent first.
  • biotransformation precursor may work on a variety of organic substrates e.g. alkanes, alkenes, ethers, alcohols, halogenated species to produce a range of chiral products epoxides, alcohols, ketones , diols, halogenated species, amino acids.
  • organic substrates e.g. alkanes, alkenes, ethers, alcohols, halogenated species to produce a range of chiral products epoxides, alcohols, ketones , diols, halogenated species, amino acids.
  • a range of batch and continuous processing options are possible.
  • the system is preferably an organic phase/aqueous phase system with phase separation by the membrane. Chemical reactions i.e. non-biological may occur on one side of the membrane. - 8 -
  • Figure 1 illustrates one kind of apparatus for evaluating suitability of any given polymeric tubular membrane
  • Figure 2 shows graphs demonstrating permeation of precursor and products through selectively permeable polymeric tubing
  • FIG. 3 shows schematically an embodiment of one preferred bioreactor system, in use
  • Figure 4 shows schematically a simple form of bioreactor apparatus according to the first aspect
  • Figure 5 shows a more complex structure of bioreactor apparatus than Figure 4,
  • FIG. 6 is an enlarged cross sectional detail of membrane inlet or outlet means depicted in Figure 5,
  • Figure 7 shows accumulation of product in the organic phase
  • Figure 8 shows fluctuation in the biomass concentration in the biomedium
  • FIG. 9 and 10 illustrate product formation in batch processing
  • Figure 11 shows product formation during continuous processing, - 9 -
  • Figure 11a shows an alternative arrangement using a gas/liquid phase bioreactor and independently removable membrane
  • Figure 12 shows an arrangement similar to Figure 11 but with reversal of the flows of aqueous and organic phases.
  • the basis of this invention is a membrane which is used to separate the biological and organic phases of the process.
  • This membrane is permeable to the biotransformation precursor and product, but relatively impermeable to the aqueous solutions, the salts and biological material it contains.
  • the bioreactor is separated into two zones; a process zone which contains the biotransformation precursor at the membrane inlet and the product at the membrane outlet (the precursor could be dissolved in water, a suitable solvent such as decanol, or even a pure phase, such as toluene) ; and a biological zone, in which the biotrans ormation is performed by a suitable culture under suitable conditions.
  • the principal processes involved in the present embodiment of bioreactor are shown in Figure la.
  • the biocatalyst is maintained at its optimal conditions (pH, temperature, dissolved oxygen, etc.) in the biomedium.
  • the reactant is transported to the membrane through the organic phase, where it diffuses through the membrane to the biomedium/membrane interface due to a favourable partition coefficient.
  • the reactant diffuses in the biomedium and is transported to the biocatalyst where it is enzymatically converted into the desired product.
  • the product molecule is then transported back to the membrane, - 10 - and diffuses through the membrane into the organic phase, again due to a favourable partition coefficient.
  • the organic phase could simply be pure reactant, without any dilution with another organic solvent, if the product is easily extracted from the biomedium into the reactant.
  • silicone rubber tubing such as an alkylsiloxane silicone rubber membrane of which polydi ethylsiloxane is an effective example.
  • the internal diameter and wall thickness may be determined by routine experiment.
  • Polydimethylsiloxane silicone rubber is a good example of a "dense phase' selectively permeable membrane where pores are absent, even when viewed by electron microscope.
  • Figure 1 shows an apparatus used to test the permeability of potentially useful membranes to allyl phenyl ether (APE) (biotrans ormation precursor) , and its corresponding epoxide (biotransformation product) .
  • APE allyl phenyl ether
  • a flask 1 containing aqueous epoxide 2 is linked via teflon tubing 3 and peristaltic pump 4 to another flask 5 containing aqueous APE 6 and stirred by magnetic stirrer 9.
  • flask 5 there is a partially coiled length of dimethylpolysiloxane rubber tubular membrane 7, connected to supply line 3 and return line 8.
  • the two aqueous solutions, - 11 - one containing epoxide and the other containing APE are separated by the use of the silicone rubber membrane.
  • Figure 2 shows the results from this experiment. In less than 300 minutes equilibrium has been reached and the concentrations of both chemicals are approximately equal on both sides of the membrane.
  • a biosystem of the con iguration shown in Figure 3 can be employed to produce a continuous product flow from a biotransformation process.
  • a traditional, primary bioreactor 10 equipped with stirrer 11, gas inlet 12 and gas outlet 13 can be linked through a recycle to bioreactor apparatus 14 according to the first aspect.
  • the aqueous medium 17 containing biological culture (effective to transform at least some precursor into product) flows over the outer surface of the tubular membranes 7 and is recycled via supply line 3, pump 4 and return line 8.
  • the other liquid phase 18, containing the biotrans ormation precursor either dissolved in aqueous solution, an organic solvent, or - 12 - present as a pure phase, can flow into the tubing at inlet 15.
  • the precursor diffuses from the process side into the biological phase, where it is acted on by the culture to produce the desired product.
  • This product then diffuses back across the membranes 7 into the process 19 stream, and is collected via outlet 16 as a stream containing product and possibly unreacted precursor.
  • the outlet process stream contains no contamination from the biological phase, the (often toxic) process stream is kept out of contact with the biological phase, and a high cell density can be maintained in the biological phase, thus greatly enhancing reaction rates.
  • the almost completely enclosed biological side should be relatively more easy to maintain aseptic.
  • Another advantage is the possibility for continuous operation, and thus high productivities, that are made easily possible by a system such as shown in Figure 3.
  • the primary bioreactor 10 can have a carefully controlled pH, temperature, dissolved oxygen and contain the biological culture performing biotransformation.
  • the secondary bioreactor 14, remote from primary bioreactor 10, is in accordance with the first aspect of the invention.
  • membrane inlet means 15 to allow a flow of the process stream (other liquid phase) in, which contains the organic product to be transformed in a solvent or other liquid medium, which is aqueous and/or organic, or even a pure phase.
  • the membrane module 14 which is a shell and tube module containing a plurality of - 13 - silicone rubber tubes, of which the exterior surface only contacts the aqueous phase containing biologically active culture, the flow exits through membrane outlet means 16, also containing the product.
  • FIG. 4 shows a bioreactor apparatus in simple form in accordance with the first aspect.
  • a rigid housing 20 has inlet 21 for aqueous phase containing biological culture and an outlet 22 therefor.
  • a single silicone rubber tube passes within the interior of the housing.
  • the interior of the tubing is reinforced with teflon or other rigid hollow plastic collars 23. Sealing means, such as O-rings 24, abut the membrane inlet means 15 and outlet means 16 which are projecting extensions of the tubular membrane 7 at the exterior surface of the tubing.
  • tubular membrane which may be straight, partly coiled or tightly coiled could extend between internally projecting glass or other inert rigid hollow tubes which are themselves held in place by holed rubber bungs (not shown) .
  • the glass tubes act as membrane inlet and outlet means.
  • the single piece of silicone rubber tubing is shown straight and elongated, a coiled arrangement can be used providing access by the culture to a much greater surface area of the exterior of the tubular membrane.
  • a more sophisticated bioreactor in accordance with the first aspect is shown in Figure 5 and a detail thereof in Figure 6.
  • This enclosed arrangement permits removal of a bundle of tubular membranes for cleaning or replacement.
  • a - 14 - rigid housing 20 has inlet 21 and outlet 22 for aqueous phase containing biological culture.
  • Membrane inlet 15 for receiving a flow 18 of other liquid phase containing precursor and membrane outlet 16 through which processed liquid 19 passes are detachable from the housing 20. They are held in position by spaced flanges 25 (see Figure 6) which also abut and compress O-rings 24 to make a liquid tight separation of the two respective phases.
  • a bundle of tubular membranes 7 is fastened between the portions 23a which are in the nature of purpose cast silicone rubber end pieces cemented to glass tubes.
  • the system shown in Figure 3 has but one bioreactor apparatus 14 according to the first aspect. Several could be utilised, all supplied in parallel from the primary bioreactor 10.
  • Micro-organism Pseudomonas oleovorans TF4-1L was obtained from the American Type Culture Collection (Rockville, Maryland, U.S.A) , and maintained on Nutrient Broth (Oxoid, Basingstoke, Hants) agar plates.
  • Nutrient media 20 g L of monosodiu glutamate monohydrate was used as the sole carbon and energy source (1 , 7-octadiene and 1 , 2-epoxy-7-octene are not metabolised) .
  • the nutrient salts included 1.4 mg L _1 of ZnS0 4 .7H 2 0 and 0.28 mg L -1 of NiCl 2 .6H 2 0.
  • Biomass concentration measurements Samples of the biomedium were diluted by 1 part in 9 with high purity reverse osmosis water, and the absorbance of the mixture measured at 660 mm in a Philips PU8625 UV/Vis spectrophoto eter. The absorbance of biomass was correlated to actual dry cell mass concentrations using Sartorius MA 30 moisture analyser.
  • the bioreactor consisted of a 1.75 L working volume CSTR connected to a membrane module of 0.05 surface area.
  • the biomedium contained the growing Pseudomonas oleovorans culture, and the organic phase of 0.47 L contained approximately 32 g L -1 of 1, 7-octad ⁇ ene in n-hexadecane . Recirculation of the biomedium to the membrane was started 24 hours after the culture was inoculated.
  • n-Hexadecane 99+% was obtained from Sigma Chemicals (Poole, Dorset) , and 1 , 7-octad ⁇ ene (98+%) , 1,2- epoxy-7-octene (97+%) and 1-octanol (99+%) were obtained from Ald ⁇ ch Chemicals (Gillingham, Dorset) .
  • the bioreactor of the type shown in Figure 3 was continuously run for a period of over 100 hours at a dilution rate of 0.1 h .
  • 2-epoxy-7-octene was produced and accumulated in the organic phase at an approximately linear rate of 2.8 mg (L or . phase) -1 h ⁇ .
  • Figure 8 shows that over the course of the example, the biomass concentration increased slowly to an end value of 2.5 g (L biomedium)- as steady state was approached . Over the course of the example the average biomass concentration was approximately 1.5 g dry wt.
  • Figures 9-11 show data for the biotransformation of 1,7- octadiene to 1 , 2-epoxy-7-octene by growing Pseudomonas oleovorans (ATCC 29347) cells.
  • the data shown in Figures 9 and 10 were obtained for batch growth in shake flasks, and the data shown in Figure 11 was obtained during one week of growth in a continuous stirred tank bioreactor connected to a membrane module.
  • a 'shake' flask is obtainable by clamping the tubing at the dotted line in Figure 1 leading into the flask 5.
  • the membrane tube containing the solvent is clamped at both exits. Alkene from the solvent phase diffuses across the membrane and is epoxidated in the biomedium.
  • the epoxide diffuses back across the membrane - 18 - into the solvent phase contained within the tubular membrane.
  • the aqueous biomedium contained living cells of pseudomonas oleovorans.
  • the data shown in Figures 9 and 10 refer to batch growth in shake flasks. in both cases, the data obtained from the membrane systems was compared with data for a two-phase (aqueous/organic) system containing bacteria from the same inoculum. Two types of membrane were compared with the two-phase system, pvc and silicone rubber.
  • the experiment was carried out by pre-swelling the membrane tubing with pure 1 , 7-octad ⁇ ene, clamping the ends of the tube with metal clamps, and completely filling the tube with 1, 7-octad ⁇ ene.
  • the tubing was then suspended in the bacterial suspension and incubated. Samples were taken and analysed regularly.
  • the data in Figures 9 and 10 show the accumulation of 1, 2-epoxy-7-octene in each of the three systems.
  • the difference in concentration levels m the two graphs may be explained by differences in the total volume of organic phase, variations in the incubation conditions, or more likely, variation in the inocula.
  • Figure 11 shows the accumulation of 1, 2-epoxy-7-octene in a silicone rubber membrane module connected to a continuous stirred tank bioreactor.
  • the relatively low concentrations of 1 , 2-epoxy-7-octene that accumulate are due to a large dilution factor in the membrane module.
  • the concentration of 1 , 7-octad ⁇ ene in the membrane module was 20 g/L, and the remainder of the organic solvent phase was n-hexadecane.
  • the data shown in the graph vas obtained over the first week of growth. - 19 -
  • the membrane bioreactor for biotransformations described can be used to provide higher volumetric productivities and easier downstream processing for such biotransformations than current technologies afford.
  • the bioreactor uses a dense phase membrane to separate an aqueous and organic phase and to control the transport of molecules between the phases. Many biotransformations involve poorly water soluble reactants and products. Thus, in the bioreactor the reactant is delivered through the membrane from the organic solvent phase to the aqueous biomedium, where it is transformed, and the product is back- extracted through the membrane into the organic solvent.
  • the dense phase membranes used allow the permeation of small organic molecules, but not ionic species and large bio olecule ⁇ .
  • the organic solvent phase contains only small organic molecules (e.g. solvent, reactant and product) and the product can be purified relatively easily using conventional separation techniques (e.g. distillation) .
  • Figures 11 and 12 shows arrangements of apparatus which differ from the described modular bioreactor apparatus such as shown in Figure 5. They are easier and less costly to construct whilst still permitting good control over the conditions pertaining in the biological phase. Essentially they are 'open' bioreactors in the sense that a gas/liquid interface is present with the gas being either the open atmosphere or another atmosphere i.e. the gas layer immediately above the maintained level of liquid medium in these 'open' bioreactors.
  • FIG 11 shows the aqueous biocatalytic medium in the receptacle with organic phase flowing through the membrane.
  • the supply of phases to both 'sides' of the apparatus can be batchwise or continuous.
  • Figure 12 the flows of liquid phases are reversed.
  • the key components m these drawings have been identified by appropriate brief keywords as present in the drawings.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Health & Medical Sciences (AREA)
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  • Genetics & Genomics (AREA)
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Abstract

La présente invention concerne un procédé permettant d'effectuer une biotransformation en phase liquide d'un précurseur en un produit; ledit procédé comporte une opération de mise en contact d'une phase aqueuse, contenant un biocatalyseur, avec une phase organique, contenant le précurseur, ceci au travers d'une membrane polymère à perméabilité sélective, qui autorise la pénétration du précurseur à travers ladite membrane, et qui autorise une réaction au cours de laquelle le précurseur est au moins partiellement transformé en un produit au sein de ladite phase aqueuse, ledit produit obtenu pouvant retourner, par pénétration au travers de ladite membrane, dans la phase organique. L'invention concerne également l'appareil permettant de mettre en oeuvre ce procédé. Cet appareil peut être 'fermé', modulaire ou 'ouvert' et pourvu d'une interface gaz-liquide dotée d'un récipient destiné à l'une des phases liquides.
PCT/GB1995/002958 1994-12-16 1995-12-18 Appareil et procedes destines aux biotransformations WO1996018719A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU42672/96A AU4267296A (en) 1994-12-16 1995-12-18 Apparatus and method for biotransformations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9425494A GB9425494D0 (en) 1994-12-16 1994-12-16 Apparatus and method for biotransformation
GB9425494.3 1994-12-16

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WO1996018719A1 true WO1996018719A1 (fr) 1996-06-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000275A1 (fr) * 1998-06-29 2000-01-06 Membrane Extraction Technology Ltd. Separation par membrane comprenant un fluide diphasique d'un cote de la membrane

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0120285A2 (fr) * 1983-02-21 1984-10-03 Nippon Oil And Fats Company, Limited Procédé biochimique de réaction entre substrats hydrophobes et hydrophiles et appareil à utiliser dans ce but
WO1987002380A1 (fr) * 1985-10-11 1987-04-23 Sepracor, Inc. Production de boissons a faible teneur en ethanol par extraction par membranes
US5190879A (en) * 1990-05-08 1993-03-02 Bowolfe, Inc. Controlled environment animal isolation systems

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0120285A2 (fr) * 1983-02-21 1984-10-03 Nippon Oil And Fats Company, Limited Procédé biochimique de réaction entre substrats hydrophobes et hydrophiles et appareil à utiliser dans ce but
WO1987002380A1 (fr) * 1985-10-11 1987-04-23 Sepracor, Inc. Production de boissons a faible teneur en ethanol par extraction par membranes
US5190879A (en) * 1990-05-08 1993-03-02 Bowolfe, Inc. Controlled environment animal isolation systems

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000275A1 (fr) * 1998-06-29 2000-01-06 Membrane Extraction Technology Ltd. Separation par membrane comprenant un fluide diphasique d'un cote de la membrane

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GB9425494D0 (en) 1995-02-15

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