Composite semipermeable membrane and method for concentrating raw material liquid

Abstract

Provided is a composite semipermeable membrane having a porous support film and a separation function layer containing a polyamide, wherein the separation function layer has an average pore size of 0.55-0.90 nm, has a pore size distribution with a geometric standard deviation of 1.00-1.30, and has a surface zeta potential of -20.0 mV to 20.0 mV at pH 2.0.

Description

Composite semipermeable membrane and method for concentrating raw material liquid

[0001] The present invention relates to a composite semipermeable membrane for concentrating a raw material liquid containing valuable substances and a method for concentrating the raw material liquid using the same.

[0002] Concentration of raw material solutions containing valuable substances is widely carried out industrially. Examples of valuable substances include peptides, DNA, RNA, enzymes, and derivative compounds thereof, as well as raw materials for these (hereinafter referred to as "peptides, etc."). In addition to peptides, etc. and water, raw material solutions in purification processes may contain various organic solvents, acids such as organic acids, salts, etc. In such raw material solutions, the solvent composition and the concentrations of organic acids, salts, etc. are adjusted to predetermined ranges, allowing the valuable substances to be stably present in the raw material solution. Therefore, if the solvent composition changes or the concentrations of organic acids, salts, etc. fluctuate during the concentration process of the raw material solution, the peptides, etc. may precipitate, aggregate, denature, etc., resulting in a poor yield of the peptides, etc. In this regard, because peptides, etc. are very expensive, a high yield is required for the concentration process of raw material solutions containing these substances.

[0003] From the above viewpoints, there is a demand for a method for concentrating a raw material solution that provides a high yield of valuable products such as peptides.

[0004] International Publication No. 2013 / 047398

[0005] In the process of concentrating a raw material solution containing peptides and acids, if the concentration of the acid increases, the properties of the membrane used for concentration change, resulting in a problem of a decrease in the rejection rate of peptides, etc.

[0006] For example, Patent Document 1 discloses a composite semipermeable membrane that has high acid resistance by adjusting the zeta potential of the separating functional layer of the composite semipermeable membrane, but does not disclose the concentration of peptides or the like.

[0007] Furthermore, in order to improve the yield of valuable substances such as peptides, it is important that the composite semipermeable membrane has both high water permeability and high rejection.

[0008] An object of the present invention is to provide a composite semipermeable membrane that, when concentrating a raw material solution containing valuable substances such as peptides, has both high water permeability and high rejection and is capable of concentrating the valuable substances with a high yield, and a raw material solution concentration method using this membrane.

[0009] That is, one example of an embodiment of the present invention is as follows. <Aspect 1> A composite semipermeable membrane having a porous support membrane and a separation functional layer containing polyamide, wherein the separation functional layer has an average pore size of 0.55 nm or more and 0.90 nm or less, a geometric standard deviation of the pore size distribution of 1.00 or more and 1.30 or less, and the separation functional layer has a surface zeta potential of -20.0 mV or more and 20.0 mV or less at pH 2.0. <Aspect 2> The composite semipermeable membrane according to Aspect 1, wherein the geometric standard deviation of the pore size distribution is 1.00 or more and 1.22 or less, and the separation functional layer has a surface zeta potential of -20.0 mV or more and 15 mV or less at pH 2.0. Aspect 3: The composite semipermeable membrane according to Aspect 1 or 2, wherein the separation functional layer has an average pore size of 0.55 nm or more and 0.90 nm or less, a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less, and a surface zeta potential of the separation functional layer at pH 2.0 of -20.0 mV or more and 10 mV or less. Aspect 4: The composite semipermeable membrane according to Aspect 1 or 2, wherein the separation functional layer has an average pore size of 0.55 nm or more and 0.80 nm or less, a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less, and a surface zeta potential of the separation functional layer at pH 2.0 of -20.0 mV or more and 10 mV or less. Aspect 5: The composite semipermeable membrane according to Aspect 1 or 2, wherein the separation functional layer has an average pore size of 0.60 nm or more and 0.75 nm or less, a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less, and a surface zeta potential of the separation functional layer at pH 2.0 of -20.0 mV or more and 10 mV or less. Aspect 6: The composite semipermeable membrane according to any one of Aspects 1 to 5, wherein the composite semipermeable membrane is in the form of a hollow fiber membrane. Aspect 7: The composite semipermeable membrane according to any one of Aspects 1 to 6, wherein the separation functional layer comprises a polymer of a polyfunctional acid halide and a polyfunctional amine containing 50 mass% or more of an aliphatic polyfunctional amine. Aspect 8: A method for concentrating a raw material liquid, comprising a step of concentrating a raw material liquid containing an electrolyte, one or more valuable substances, and a solvent, using the composite semipermeable membrane according to any one of Aspects 1 to 7. Aspect 9: The method for concentrating a raw material solution according to Aspect 8, wherein the concentration is carried out by one or more methods selected from the group consisting of a reverse osmosis membrane method, a forward osmosis membrane method, a nanofiltration membrane method, a dialysis method, and a salt exchange method.Aspect 10: The method for concentrating a raw material liquid according to Aspect 8 or 9, wherein the valuable substance is one or more compounds selected from the group consisting of nucleic acids, proteins, peptides, amino acids, antibiotics, small molecule drugs, and vitamins. Aspect 11: The method for concentrating a raw material liquid according to any one of Aspects 8 to 10, wherein the composite semipermeable membrane is in the form of a hollow fiber membrane. Aspect 12: The method for concentrating a raw material liquid according to any one of Aspects 8 to 11, wherein the electrolyte is an organic compound having a molecular weight of 50 to 200. Aspect 13: The method for concentrating a raw material liquid according to any one of Aspects 8 to 12, wherein the pKa of the electrolyte is -2 to 4. Aspect 14: The method for concentrating a raw material liquid according to any one of Aspects 8 to 13, wherein the molecular weight of the valuable substance is 300 to 3,000. Aspect 15: The method for concentrating a raw material liquid according to any one of Aspects 8 to 14, wherein the raw material liquid contains one or more organic solvents.

[0010] According to the composite semipermeable membrane of the present invention, when a raw material solution containing valuable substances such as peptides is concentrated, precipitation, aggregation, and denaturation of the valuable substances are suppressed, and the valuable substances can be concentrated in a high yield. Furthermore, by using the composite semipermeable membrane of the present invention, the raw material solution concentration method having the above-mentioned advantages can be efficiently carried out.

[0011] Fig. 1 is a conceptual diagram for explaining the mechanism of action of a forward osmosis membrane method, which is an example of the method for concentrating a raw material liquid of the present invention. Fig. 2 is a schematic cross-sectional view for explaining an example of the structure of a forward osmosis membrane module used for concentrating a raw material liquid of the present invention. Fig. 3 is a conceptual diagram for explaining the mechanism of action of a dialysis method, which is an example of the method for concentrating a raw material liquid of the present invention. Fig. 4 is a schematic cross-sectional view for explaining an example of the structure of a dialysis membrane module used for concentrating a raw material liquid of the present invention.

[0012] <Composite Semipermeable Membrane> The composite semipermeable membrane of the present embodiment has a porous support membrane and a separation function layer. In one aspect, the composite semipermeable membrane of the present embodiment has a separation function layer with an average pore size of 0.55 nm or more and 0.90 nm or less. In one aspect, the composite semipermeable membrane of the present embodiment has a separation function layer with a geometric standard deviation of 1.00 or more and 1.30 or less. In one aspect, the composite semipermeable membrane of the present embodiment has a separation function layer with an average pore size of 0.55 nm or more and 0.90 nm or less, and a pore size distribution with a geometric standard deviation of 1.00 or more and 1.30 or less. In one aspect, the composite semipermeable membrane of the present embodiment has a separation function layer with a surface zeta potential of -20.0 mV or more and 20.0 mV or less at pH 2.0. In one aspect, the composite semipermeable membrane of the present embodiment is in the form of a hollow fiber membrane.

[0013] <Porous Support Membrane> The porous support membrane is intended to provide strength to the separation functional layer having separation performance, and does not itself have substantial separation performance for ions, etc. The porous support membrane is composed of a substrate and a porous support layer.

[0014] The size and distribution of the pores in the porous support membrane are not particularly limited, but for example, a support membrane having uniform, fine pores, or pores that gradually become larger from the surface on which the separation functional layer is formed to the other surface, and in which the size of the pores on the surface on which the separation functional layer is formed is 0.1 nm or more and 100 nm or less, is preferred.

[0015] The porous support membrane can be obtained, for example, by casting a high molecular weight polymer onto a substrate to form a porous support layer on the substrate. The material used for the porous support membrane and its shape are not particularly limited.

[0016] Examples of the substrate include fabrics made of at least one material selected from polyester and aromatic polyamide, with polyester being particularly preferred due to its high mechanical and thermal stability.

[0017] As the fabric used for the substrate, long-fiber nonwoven fabrics and short-fiber nonwoven fabrics are preferably used. Excellent film-forming properties are required to prevent excessive penetration and strike-through when a polymer solution is cast onto the substrate, peeling between the substrate and the porous support layer, and defects such as non-uniformity of the membrane and pinholes due to fuzzing of the substrate. Therefore, long-fiber nonwoven fabrics are more preferably used. Examples of long-fiber nonwoven fabrics include long-fiber nonwoven fabrics composed of thermoplastic continuous filaments. By using a long-fiber nonwoven fabric as the substrate, it is possible to suppress non-uniformity during polymer solution casting and membrane defects caused by fuzzing, which occur when using a short-fiber nonwoven fabric. Furthermore, since tension is applied to the substrate in the membrane-forming direction during the continuous membrane-forming process of a composite semipermeable membrane, it is preferable to use a long-fiber nonwoven fabric, which has excellent dimensional stability, as the substrate. In particular, it is preferable to have the fibers on the side of the substrate opposite the porous support layer oriented longitudinally relative to the membrane-forming direction, as this maintains the strength of the substrate and prevents membrane breakage and the like. Here, the term "longitudinal orientation" refers to the orientation of the fibers being parallel to the film-forming direction, whereas the term "transverse orientation" refers to the orientation of the fibers being perpendicular to the film-forming direction.

[0018] The degree of fiber orientation of the fibers arranged on the opposite side of the substrate from the porous support layer is preferably in the range of 0° to 25°. Here, the degree of fiber orientation is an index showing the direction of the fibers of the nonwoven fabric substrate constituting the porous support membrane, and refers to the average angle of the fibers constituting the nonwoven fabric substrate when the film-forming direction during continuous film production is set to 0° and the direction perpendicular to the film-forming direction, i.e., the width direction of the nonwoven fabric substrate, is set to 90°. Therefore, the closer the fiber orientation degree is to 0°, the more longitudinally oriented it is, and the closer it is to 90°, the more transversely oriented it is.

[0019] The manufacturing process of a composite semipermeable membrane or an element includes a heating step, and heating can cause the porous support membrane or composite semipermeable membrane to shrink. In particular, in continuous membrane production, no tension is applied in the width direction, so the membrane is prone to shrinkage in the width direction. Since shrinkage of the porous support membrane or composite semipermeable membrane can cause problems with dimensional stability, a substrate with a small thermal dimensional change rate is desirable.

[0020] In the nonwoven fabric substrate, it is preferable that the difference in orientation between the fibers arranged on the side opposite the porous support layer and the fibers arranged on the porous support layer side is 10° to 90°, since this can suppress changes in the width direction due to heat.

[0021] The air permeability of the substrate is 2.0 cc / cm ２ / sec or more is preferable. When the air permeability is in this range, the water permeability of the composite semipermeable membrane is high. This is thought to be because, in the process of forming the porous support membrane, when a high molecular weight polymer is cast on a substrate and immersed in a coagulation bath, the non-solvent replacement rate from the substrate side increases, changing the internal structure of the porous support layer and affecting the amount of monomer retained and the diffusion rate in the subsequent process of forming the separation function layer.

[0022] The air permeability can be measured using a Frazier tester in accordance with JIS L1096 (2010). For example, a sample of 200 mm x 200 mm is cut out from the substrate. This sample is attached to the Frazier tester, and the intake fan and air holes are adjusted so that the inclined barometer indicates a pressure of 125 Pa. The amount of air passing through the substrate, i.e., the air permeability, can be calculated from the pressure indicated by the vertical barometer at this time and the type of air hole used. A Frazier tester such as the KES-F8-AP1 manufactured by Kato Tech Co., Ltd. can be used.

[0023] The thickness of the substrate is preferably in the range of 10 μm to 200 μm, more preferably in the range of 30 μm to 120 μm.

[0024] The type of resin to be cast onto the substrate can be selected from commonly used materials. However, materials that dissolve or swell in the organic solvent contained in the raw material solution and therefore cannot maintain the pore shape of the membrane cannot be used. Specific examples of materials for the porous support layer include polysulfone, polyethersulfone, polyvinylidene fluoride, polyacrylonitrile, polyethylene, polypropylene, cellulose-based polymers, polyketones, polyamides, polyimides, polyetheretherketones, polybenzimidazoles, and crosslinked products thereof. It is preferable that at least one selected from these be used as the main component. From the viewpoint of solvent resistance, it is preferable that the material for the porous support membrane constituting the hollow fiber forward osmosis membrane be at least one selected from polysulfone, polyethersulfone, polyketones, polyamides, polyimides, and crosslinked products thereof be used as the main component.

[0025] In order to obtain sufficient mechanical strength and packing density, the thickness of the porous support membrane is preferably in the range of 50 μm to 300 μm, more preferably in the range of 100 μm to 250 μm.

[0026] The morphology of the porous support layer can be observed using a scanning electron microscope, a transmission electron microscope, or an atomic force microscope. For example, when observing using a scanning electron microscope, the porous support layer is peeled off from the substrate and then cut by freeze fracturing to obtain a sample for cross-sectional observation. This sample is thinly coated with platinum, platinum-palladium, or ruthenium tetrachloride, preferably ruthenium tetrachloride, and observed using a high-resolution field emission scanning electron microscope (UHR-FE-SEM) at an accelerating voltage of 3 to 15 kV. A Hitachi S-900 electron microscope or the like can be used as the high-resolution field emission scanning electron microscope.

[0027] The porous support membrane of this embodiment can be selected from various commercially available materials such as "Millipore Filter VSWP" (trade name) manufactured by Millipore Corporation and "Ultrafilter UK10" (trade name) manufactured by Toyo Roshi Kaisha, Ltd., or can be produced according to the method described in "Office of Saline Water Research and Development Progress Report" No. 359 (1968).

[0028] The thickness of the porous support layer is preferably in the range of 20 μm to 40 μm. A thickness of 20 μm or more of the porous support layer provides good pressure resistance and a uniform porous support membrane without defects, so that a composite semipermeable membrane including such a porous support layer can exhibit good performance. If the thickness of the porous support layer exceeds 40 μm, the amount of unreacted substances remaining during production increases, which tends to reduce water permeability and chemical resistance.

[0029] The thickness of the substrate and the thickness of the composite semipermeable membrane can be measured using a digital thickness gauge. Furthermore, since the thickness of the separation functional layer is very thin compared to the porous support membrane, the thickness of the composite semipermeable membrane can be considered to be the thickness of the porous support membrane. Therefore, the thickness of the composite semipermeable membrane can be measured using a digital thickness gauge, and the thickness of the porous support layer can be simply calculated by subtracting the thickness of the substrate from the thickness of the composite semipermeable membrane. As a digital thickness gauge, PEACOCK from Ozaki Seisakusho Co., Ltd. can be used. When using a digital thickness gauge, the thickness is measured at 20 locations and the average value is calculated.

[0030] When it is difficult to measure the thickness of the substrate or the thickness of the composite semipermeable membrane using a digital thickness gauge, it may be measured using a scanning electron microscope. The thickness can be determined by measuring the thickness from electron microscope photographs of cross-sections observed at any five points on one sample and calculating the average value.

[0031] <Separation Functional Layer> The separation functional layer of this embodiment is a layer that performs the function of separating solutes in the composite semipermeable membrane of this embodiment. The composition, thickness, and other configurations of the separation functional layer are set according to the intended use of the composite semipermeable membrane. The separation functional layer of this embodiment contains polyamide. A separation functional layer containing polyamide can be formed on a porous support membrane by interfacial polymerization of a polyfunctional acid halide or the like with a polyfunctional amine. Specifically, the separation functional layer of this embodiment contains a polymer (in one aspect, polyamide) obtained by interfacial polymerization of a polyfunctional acid halide with a polyfunctional amine.

[0032] Examples of polyfunctional amines include aromatic polyfunctional amines and aliphatic polyfunctional amines. From the viewpoint of forming a composite semipermeable membrane with an excellent yield of valuables (especially peptides), it is preferable that the polyfunctional amine contains 50% by mass or more of an aliphatic polyfunctional amine relative to 100% by mass of the polyfunctional amine. In one embodiment, the separation functional layer contains a polymer of a polyfunctional acid halide and a polyfunctional amine containing 50% by mass or more of an aliphatic polyfunctional amine. In one embodiment, the aliphatic polyfunctional amine may be contained in 100% by mass of the polyfunctional amine.

[0033] In the present disclosure, the term "aromatic polyfunctional amine" refers to an aromatic amine having two or more amino groups in one molecule, and is not particularly limited to, but examples thereof include metaphenylenediamine, paraphenylenediamine, 1,3,5-triaminobenzene, etc. Furthermore, examples of N-alkylated products thereof include N,N-dimethylmetaphenylenediamine, N,N-diethylmetaphenylenediamine, N,N-dimethylparaphenylenediamine, and N,N-diethylparaphenylenediamine, etc.

[0034] In the present disclosure, the term "aliphatic polyfunctional amine" refers to an aliphatic amine having two or more amino groups in one molecule, preferably piperazine-based amines, piperidine-based amines, and derivatives thereof. Examples include piperazine, 2,5-dimethylpiperazine, 2-methylpiperazine, 2,6-dimethylpiperazine, 2,3,5-trimethylpiperazine, 2,5-diethylpiperazine, 2,3,5-triethylpiperazine, 2-n-propylpiperazine, 2,5-di-n-butylpiperazine, ethylenediamine, 4,4-bipyridine, and 1,3-di-4-piperidylpropane. In view of the stability of performance development, piperazine or 2,5-dimethylpiperazine is particularly preferred.

[0035] These polyfunctional amines may be used alone or in combination of two or more.

[0036] The polyfunctional acid halide is an acid halide having two or more halocarbonyl groups per molecule, and is not particularly limited as long as it reacts with the above-mentioned amine to give a polyamide. Examples of polyfunctional acid halides include halide compounds of fatty acids such as oxalic acid, malonic acid, maleic acid, fumaric acid, glutaric acid, 1,3,5-cyclohexanetricarboxylic acid, 1,3-cyclohexanedicarboxylic acid, and 1,4-cyclohexanedicarboxylic acid; and halides of aromatic acids such as phthalic acid, isophthalic acid, 1,3,5-benzenetricarboxylic acid, 1,2,4-benzenetricarboxylic acid, 1,3-benzenedicarboxylic acid, and 1,4-benzenedicarboxylic acid. The above-mentioned polyfunctional acid halides may be used alone or in a mixture of two or more. Among polyfunctional acid halides, polyfunctional acid chlorides are preferred, and in particular, trimesoyl chloride alone, or a mixture of trimesoyl chloride and isophthaloyl chloride, or a mixture of trimesoyl chloride and terephthaloyl chloride is preferably used from the viewpoints of economy, availability, ease of handling, ease of reactivity, etc. The interfacial polymerization of a polyfunctional acid halide and a polyfunctional amine can be carried out according to a conventional method.

[0037] The resulting separation functional layer may be obtained through a heat treatment, if desired. This heat treatment may be performed using hot water or high-temperature, high-pressure steam in a pressure cooker such as an autoclave. By subjecting the separation functional layer to a heat treatment, it is expected that back-diffusion of the draw solution will be reduced, although the reason for this is unclear.

[0038] As a result of extensive research, the present inventors have found that there is a close relationship between the surface zeta potential of the separation functional layer and the salt rejection performance of the composite semipermeable membrane. The separation functional layer has amino groups and carboxyl groups, and the value of the zeta potential changes depending on the degree of dissociation of these functional groups. A small absolute value of the zeta potential is preferable to prevent unintended adsorption of the substance to be separated due to electrostatic interaction. The surface zeta potential of the separation functional layer at pH 2.0 is preferably -20.0 mV or more and 20.0 mV or less, more preferably -20.0 mV or more and 15 mV or less, and even more preferably -20.0 mV or more and 10 mV or less.

[0039] The surface zeta potential of the separation functional layer can be measured using an electrophoretic light scattering photometer. For example, the measurement is performed by placing the surface of the separation functional layer of the composite semipermeable membrane in a flat sample cell so that it is in contact with the monitor particle solution. The monitor particles are polystyrene latex coated with hydroxypropyl cellulose, and are dispersed in a 10 mM NaCl solution to form a monitor particle solution. By adjusting the pH of the monitor particle solution, the zeta potential at a predetermined pH can be measured. Examples of electrophoretic light scattering photometers that can be used include Malvern Zetasizer Nano ZS (electrophoretic zeta potential measurement device) and a flat plate zeta potential measurement cell (ZEN1020).

[0040] Methods for controlling the surface zeta potential of the separation functional layer include a method for controlling the amount of functional groups in the separation functional layer when forming the separation functional layer so as to be small, a method for converting the functional groups in the separation functional layer, a method for coating the surface of the separation functional layer with a polymer, etc. A combination of these methods may also be used.

[0041] One method for converting the functional groups of the separation functional layer is to contact the separation functional layer with a reagent that reacts with amino or carboxyl groups. For example, the separation functional layer can be contacted with nitric acid and its salts, nitrosyl compounds, or the like to convert the primary amino groups into diazonium salts or their derivatives. The surface zeta potential of the separation functional layer can be controlled by varying the concentration of the reacting reagent and the reaction temperature and time. Furthermore, when converting functional groups, the amount of functional groups before the reaction also affects the surface zeta potential of the separation functional layer obtained after functional group conversion. Therefore, the surface zeta potential of the separation functional layer can also be controlled by reducing the thickness of the porous support layer to reduce the amount of unreacted substances remaining during the formation of the separation functional layer, or by removing compounds having functional groups by washing with hot water after the formation of the separation functional layer.

[0042] Methods for controlling the amount of functional groups contained in the separation functional layer when forming the separation functional layer include a method of applying an organic solvent solution containing a polyfunctional acid halide and then heating it, and a method of adding an acid trapping agent to an aqueous polyfunctional amine solution or an organic solvent solution containing a polyfunctional acid halide.

[0043] In the present disclosure, it is assumed that the pore size distribution of the separation functional layer and the porous support layer follows a log-normal probability distribution. In this case, the distribution of the pore size χ is expressed by the following formula: It is given as a probability density function f(lnχ) according to 0.5 is the median diameter, and σ g is the geometric standard deviation of the pore size distribution.

[0044] The average pore size of the separation functional layer and the geometric standard deviation of the pore size distribution of the separation functional layer are each calculated using the permeability evaluation results (neutral molecule rejection rate) when an aqueous solution containing neutral molecules with known Stokes radii is filtered through a composite semipermeable membrane (separation functional layer and porous support layer). Examples of neutral molecules include hydrophilic compounds, such as compounds having one or more hydroxyl groups, and may be alcohols, sugars, or sugar alcohols. Examples of such compounds include isopropanol, glycerin, erythritol, salicin, glucose, sucrose, polyethylene glycol, and raffinose pentahydrate. In one embodiment, isopropanol, glycerin, erythritol, glucose, salicin, raffinose pentahydrate, and sucrose are used as neutral molecules. In another embodiment, isopropanol, glycerin, D(-)-glucose, salicin, D(+)-raffinose pentahydrate, and sucrose are used as neutral molecules. The Stokes radius of each neutral molecule can be calculated based on the diffusion coefficient of each molecule, the solvent viscosity, the Boltzmann constant, and the absolute temperature. Literature values ​​may be used for the diffusion coefficient values. Examples of Stokes radii of neutral molecules in water at 25°C are as follows: Isopropanol: 0.21 nm Glycerin: 0.26 nm Erythritol: 0.31 nm Glucose: 0.36 nm Salicin: 0.45 nm Sucrose: 0.46 nm Raffinose pentahydrate: 0.58 nm

[0045] The neutral molecule rejection rate is determined by preparing an aqueous solution containing neutral molecules with a known Stokes radius at a concentration of 300 ppm, and then calculating the neutral molecule concentrations in the permeate after filtration and the aqueous solution before filtration. Based on the relationship between the Stokes radius of neutral molecules and the rejection rate, the percentage of each neutral molecule passing through the composite semipermeable membrane is expressed as a pore size frequency distribution. Assuming that the frequency distribution follows a log-normal distribution, the pore size at a probability of 50% is taken as the average pore size. The square root of the pore size at a probability of 84.13% divided by the average pore size is taken as the geometric standard deviation of the pore size distribution. The rejection rates of the separation functional layer and porous support layer correspond to the number proportion (pore size proportion) of pores in the separation functional layer and porous support layer that have a pore size less than 2 times the Stokes radius. The average pore size value for the composite semipermeable membrane (separation functional layer and porous support layer) obtained above is treated as the average pore size value for the separation functional layer of the present disclosure. Similarly, the value of the geometric standard deviation of the pore size distribution for the composite semipermeable membrane (separation functional layer and porous support layer) obtained above is treated as the value of the geometric standard deviation of the pore size distribution of the separation functional layer of the present disclosure.

[0046] From the viewpoint of preventing defects, the geometric standard deviation of the pore size distribution of the porous support layer of this embodiment is preferably 1.00 or more and 1.30 or less, and more preferably 1.00 or more and 1.22 or less.

[0047] In order to facilitate the formation of the separation functional layer, the porous support layer of this embodiment preferably has an average pore size of 0.55 nm or more and 0.90 nm or less, more preferably 0.55 nm or more and 0.80 nm or less, and even more preferably 0.60 nm or more and 0.75 nm or less.

[0048] The geometric standard deviation of the pore size distribution of the separation functional layer of this embodiment is preferably 1.00 or more and 1.30 or less, and more preferably 1.00 or more and 1.22 or less.

[0049] The separation functional layer of this embodiment has an average pore size of 0.55 nm or more and 0.90 nm or less, and a geometric standard deviation of the pore size distribution of 1.00 or more and 1.30 or less. In one aspect, the separation functional layer of this embodiment has an average pore size of 0.55 nm or more and 0.90 nm or less, and a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less. In one aspect, the separation functional layer of this embodiment has an average pore size of 0.55 nm or more and 0.80 nm or less, and a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less. In one aspect, the separation functional layer of this embodiment has an average pore size of 0.60 nm or more and 0.75 nm or less, and a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less.

[0050] By adjusting the average pore size and pore size distribution of the separation functional layer and the surface zeta potential at pH 2.0 within predetermined ranges, the carboxylic acid residues on the surface of the composite semipermeable membrane interact with valuable substances (particularly peptides). This prevents the interaction between the valuable substances and acid (in one embodiment, trifluoroacetic acid (TFA)), thereby suppressing hydrophilization of the valuable substances and improving the salt rejection performance of the composite semipermeable membrane of this embodiment.

[0051] <<Method for concentrating raw material liquid>> The method for concentrating a raw material liquid of the present embodiment (hereinafter referred to as the concentration method of the present embodiment) includes a step of concentrating a raw material liquid containing an electrolyte, one or more valuable substances, and a solvent, using the composite semipermeable membrane of the present embodiment.

[0052] To ensure the solubility and chemical stability of valuable materials, raw material solutions containing valuable materials often use a mixture of multiple solvents or contain secondary components such as salts and buffer salts. Conventional methods for concentrating such raw material solutions containing valuable materials include dialysis, salt exchange, distillation, reduced-pressure distillation, membrane distillation, pervaporation, vapor permeation, reverse osmosis, nanofiltration, and forward osmosis. However, regardless of the method used, differences in the chemical and physical properties of the multiple components contained in the raw material solution can result in preferential removal of certain components from the raw material solution, resulting in changes in the solvent composition or the concentration of the secondary components. If this occurs, there is a risk of the valuable materials precipitating, agglomerating, or denaturing during the concentration of the raw material solution.

[0053] The method for concentrating a raw material liquid of this embodiment uses the composite semipermeable membrane of this embodiment, thereby making it possible to concentrate the raw material liquid while minimizing the risk of precipitation, aggregation, and denaturation of valuable substances. In the method for concentrating a raw material liquid of this embodiment, concentration is preferably carried out by one or more methods selected from the group consisting of a reverse osmosis membrane method, a forward osmosis membrane method, a nanofiltration membrane method, a dialysis method, and a salt exchange method, but concentration may also be carried out by further combining methods other than these.

[0054] <Feedstock Liquid> The feedstock liquid targeted by the concentration method of this embodiment is a solution or dispersion containing one or more valuable materials, an electrolyte, and a solvent. This feedstock liquid may further contain a secondary component other than the valuable material, the electrolyte, and the solvent, or may contain a mixed solvent containing multiple first and second solvents as the solvent. The feedstock liquid in the present disclosure may contain a valuable material, a first solvent, a second solvent, and a secondary component. Examples of feedstock liquids applicable to the concentration method of this embodiment include food; pharmaceuticals; seawater; and produced water discharged from gas fields, oil fields, etc. However, considering the advantage of this embodiment that concentration can be performed without heating, the concentration method of this embodiment is effective when applied to feedstock liquids containing substances that are likely to decompose when heated, particularly pharmaceutical raw materials, functional chemical species, etc., as valuable materials.

[0055] The temperature of the raw material liquid to be subjected to the method for concentrating the raw material liquid of this embodiment is preferably adjusted to a range of 1°C or higher and 50°C or lower.

[0056] <Valuables> In the present disclosure, valuables refer to pharmaceutical raw materials, functional chemical species, etc. Examples of pharmaceutical raw materials include one or more compounds selected from the group consisting of amino acids, peptides, proteins, sugars, vaccines, nucleic acids, antibiotics, antibody-drug conjugates (ADCs), yeast, small molecule drugs, and vitamins.

[0057] An amino acid is a compound having a single amino acid backbone consisting of a carboxyl group, an amino group, and a moiety connecting them. In the present disclosure, the term "amino acid" encompasses essential amino acids, non-essential amino acids, and unnatural amino acids. Examples of essential amino acids include tryptophan, lysine, methionine, phenylalanine, threonine, valine, leucine, and isoleucine. Examples of non-essential amino acids include arginine, glycine, alanine, serine, tyrosine, cysteine, asparagine, glutamine, proline, aspartic acid, and glutamic acid. Unnatural amino acids are artificial compounds that do not occur in nature and have a single amino acid backbone within the molecule. Examples of unnatural amino acids used as pharmaceutical raw materials in the present disclosure include labeled amino acids and functionalized amino acids. Labeled amino acids are compounds in which a desired labeling compound is bound to the amino acid backbone. Examples of labeling compounds include dyes, fluorescent substances, luminescent substances, enzyme substrates, coenzymes, antigenic substances, and protein-binding substances. Examples of functionalized amino acids include photoresponsive amino acids, photoswitch amino acids, fluorescent probe amino acids, and fluorescently labeled amino acids.

[0058] A peptide refers to a compound in which 2 or more but less than 70 amino acid residues are bonded, and may be linear or cyclic. Examples of peptides in the present disclosure include L-alanyl-L-glutamine, β-alanyl-L-histidine cyclosporine, collagen peptide, glutathione disulfide, and neotame. A protein generally refers to a compound in which amino acid residues are bonded that has a longer chain than a peptide. Examples of proteins in the present disclosure include interferon α, interferon β, interleukins 1 to 12, growth hormone, erythropoietin, insulin, granulocyte-colony stimulating factor (G-CSF), tissue plasminogen activator (TPA), natriuretic peptide, blood coagulation factor VIII, somatomedin, glucagon, growth hormone-releasing factor, serum albumin, calcitonin, and lipase G Amano 50.

[0059] Examples of sugars include monosaccharides, disaccharides, sugar chains (excluding disaccharides), and sugar chain derivatives. Examples of monosaccharides include glucose, fructose, galactose, mannose, ribose, and deoxyribose. Examples of disaccharides include maltose, sucrose, and lactose. The sugar chain in this disclosure is a concept excluding disaccharides, and includes, for example, cellulose, glycosaminoglycan, starch, saccharin, dextran, dextrin, inulin, curdlan, fucoidan, fructan, pullulan, pectin, polydextrose, maltodextrin, lignin, xylan, mannan, glucomannan, glucuronoxylan, and xylose. Examples of sugar chain derivatives include sugar derivatives such as N-acetylglucosamine, N-acetylgalactosamine, and N-acetylneuraminic acid.

[0060] Examples of vaccines include hepatitis A vaccine, hepatitis B vaccine, and hepatitis C vaccine; examples of nucleic acids include oligonucleotides, RNA, aptamers, and decoys; examples of antibiotics include streptomycin and vancomycin; examples of antibody-drug conjugates (ADCs) include brentuximab vedotin (Adcetris), trastuzumab emtansine (Kadcyla), and gemtuzumab ozogamicin (Mylotarg); examples of yeast include Saccharomyces cerevisiae, Pichia stipitis, Candida shehatae, Pachysolen tannophilus, and mutant strains thereof. Examples of small molecule drugs include aspirin. Examples of vitamins include vitamin A, vitamin B, vitamin C, etc., including derivatives and salts thereof. Vitamin B includes, for example, vitamin B6 and vitamin B12.

[0061] The term "functional chemical species" refers to various chemical species used as functional chemical products, as well as their modified products, precursors, raw materials, etc. Examples of functional chemical species include metal nanoparticles, semiconductor nanoparticles, metal colloids, nanodiamonds, porous nanoclays, metal organic frameworks (MOFs), carbon nanotubes, fullerenes, graphene, graphene oxide, carbon nanohorns, cellulose nanofibers, etc., as well as their modified products, precursors, raw materials, etc.

[0062] The molecular weight of the valuable material contained in the raw material liquid subjected to the raw material liquid concentrating method of this embodiment is preferably in the range of 300 to 3000 in terms of polyethylene oxide number average molecular weight measured by gel permeation chromatography. The molecular weight of the valuable material can be determined by calculation from the chemical formula of the valuable material.

[0063] <Solvent> In the present disclosure, a solvent is a compound capable of dissolving or dispersing valuable substances and electrolytes, and, if a minor component is present, a compound capable of dissolving or dispersing the minor component. The solvent in the present disclosure typically includes water and / or one or more organic solvents. The organic solvent is an organic compound having one or more carbon atoms, and in one embodiment, is a compound that exists in a liquid state at a temperature of 0°C or higher and lower than 50°C under normal pressure. However, carboxylic acids are excluded from the solvents in the present disclosure. Examples of organic solvents include alcohols, esters, ethers, aprotic polar compounds, aromatic compounds, aliphatic compounds, chlorinated hydrocarbon ketones, and aldehydes.

[0064] Specific examples of organic solvents include: alcohols such as methanol, ethanol, 1-propyl alcohol, isopropanol, normal butanol, sec-butanol, t-butanol, and hexafluoroisopropyl alcohol; esters such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, t-butyl methyl ether, anisole, and 1,2-dimethoxyethane; aprotic polar compounds such as acetonitrile, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, nitromethane, and sulfolane; aromatic compounds such as benzene, toluene, xylene, cumene, and pyridine; and aliphatic compounds such as heptane, hexane, cyclohexane, methylcyclohexane, and tetralin. Examples of chlorinated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2-dichloroethene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, and chlorobenzene; examples of ketones include acetone, methyl butyl ketone, methyl ethyl ketone, and methyl isobutyl ketone; and examples of aldehydes include formaldehyde, acetaldehyde, propionaldehyde, butanal, acrolein, benzaldehyde, furfural, and vanillin.

[0065] When the solvent of the raw material liquid contains only one type of solvent, that one type of solvent is the first solvent. When the solvent of the raw material liquid contains multiple solvents, one of these may be the first solvent, and one or more solvents other than the first solvent may be the second solvent. In the present disclosure, the first solvent and the second solvent are not fixed concepts, but are variable depending on the type of valuable material contained in the raw material liquid. In other words, solvent A, which is the first solvent in a raw material liquid containing a certain valuable material A, may be the second solvent in a raw material liquid containing another valuable material B. However, the following are non-limiting typical examples of raw material liquids to which the raw material liquid concentration method of this embodiment can be applied. A case where the first solvent is water and the second solvent is one or more selected from acetonitrile, methanol, ethanol, and isopropanol; a case where the first solvent is one or more selected from methanol, ethanol, isopropanol, and acetonitrile, and the second solvent is water; a case where the first solvent is one or more selected from methanol, ethanol, and tetrahydrofuran, and the second solvent is hexane; a case where the first solvent is water and the second solvent is one or more selected from dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, and dimethyl sulfoxide; etc.

[0066] The amount of the first solvent in the raw material liquid may be set arbitrarily before and after concentration, depending on the solubility and chemical stability of the valuable substance, convenience of the reaction planned after concentration, etc. When the solvent of the raw material liquid contains the first solvent and the second solvent, the content ratio of the first solvent and the second solvent may be set arbitrarily before and after concentration, depending on the solubility and chemical stability of the valuable substance, convenience of the reaction planned after concentration, etc.

[0067] <Electrolyte> In the present disclosure, the electrolyte refers to an organic compound contained in the raw material solution. In one embodiment, the electrolyte is an organic compound having a molecular weight of 50 or more and 200 or less. The molecular weight of the electrolyte can be determined by calculation from the chemical formula of the electrolyte. In one embodiment, the acid dissociation constant (pKa) of the electrolyte is -2 or more and 4 or less. The acid dissociation constant (pKa) of the electrolyte can be determined by the method described in the Examples.

[0068] The electrolyte in the present disclosure may include organic acids, such as formic acid, acetic acid, propionic acid, citric acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid (TFA), oxalic acid, gluconic acid, lactic acid, glycolic acid, and glyceric acid.

[0069] Among raw material liquids containing a valuable substance, a first solvent, a second solvent, and an electrolyte, examples that are preferably applied to the raw material liquid concentrating method of this embodiment include those in which the first solvent is water, the second solvent is one or more selected from acetonitrile, methanol, ethanol, and isopropanol, and the electrolyte is one or more selected from citric acid, acetic acid, and trifluoroacetic acid. In particular, examples include those in which the first solvent is water, the second solvent is acetonitrile, and the electrolyte is citric acid or trifluoroacetic acid.

[0070] <Minor Component> In the present disclosure, the minor component refers to a component optionally contained in the raw material solution, and refers to a component other than the valuable substance and the solvent among the components contained in the raw material solution. When the solvent of the raw material solution includes a first solvent and a second solvent, the minor component refers to a component other than the valuable substance, the first solvent, and the second solvent among the components contained in the raw material solution. Examples of the minor component include a polymer (excluding the valuable substance), a salt, and a buffer salt.

[0071] The polymers serving as the minor component exclude those that qualify as valuable materials. Examples of polymers serving as the minor component in this embodiment include polyethylene oxide, polypropylene oxide, and copolymers of ethylene oxide and propylene oxide. Examples of salts or buffer salts serving as the minor component in this embodiment include sodium chloride, magnesium chloride, calcium chloride, sodium bicarbonate, potassium bicarbonate, sodium sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, magnesium sulfate, potassium sulfate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, organic acid salts such as sodium acetate, magnesium acetate, sodium citrate, and magnesium citrate, ammonium chloride, ammonium sulfate, ammonium carbonate, and ammonia. In many cases, the raw material liquid contains multiple minor components. When the raw material liquid contains a minor component, the amount of the minor component in the raw material liquid may be arbitrarily determined depending on the solubility and chemical stability of the valuable material, the convenience of the reaction planned after concentration, and the like.

[0072] <Yield of valuables> In the present disclosure, the yield of valuables refers to the value, expressed as a percentage, obtained by dividing the total amount of valuables obtained by the feedstock liquid concentration method by the total amount of valuables input into the feedstock liquid concentration process. However, if valuables precipitate or aggregate during the feedstock liquid concentration method, they are not considered to be the same valuables even if their chemical structure remains unchanged. Naturally, if the chemical structure of a valuables changes during the feedstock liquid concentration method, they are not considered to be the same valuables. According to the feedstock liquid concentration method of the present disclosure, the yield of valuables can be 70% or more, 80% or more, 90% or more, 95% or more, or even 99% or more.

[0073] <Concentration ratio> In the present disclosure, the concentration ratio refers to the value obtained by dividing the mass of the raw material liquid before concentration by the mass of the raw material liquid after concentration. According to the raw material liquid concentration method of this embodiment, the raw material liquid can be concentrated at a high concentration ratio without impairing the stability of the valuable materials. According to the raw material liquid concentration method of this embodiment, the volume of the raw material liquid can be reduced by a concentration ratio of 3 times or more, 4 times or more, or 5 times or more without impairing the stability of the valuable materials. The upper limit of the concentration ratio is generally about 50 times, although it depends on the concentration and solubility of the valuable materials contained in the raw material liquid.

[0074] As described above, the method for concentrating a raw material liquid of this embodiment is a method for concentrating a raw material liquid containing one or more valuable substances, an electrolyte, and a solvent, using the composite semipermeable membrane of this embodiment, and the concentration is carried out by one or more methods selected from the group consisting of a reverse osmosis membrane method, a forward osmosis membrane method, a nanofiltration membrane method, a dialysis method, and a salt exchange method. Preferred embodiments of the present invention will now be described in detail and specifically as non-limiting examples.

[0075] <Step of concentrating raw material liquid> The method for concentrating a raw material liquid of this embodiment includes a step of concentrating the raw material liquid using the composite semipermeable membrane of this embodiment. Examples of such methods include evaporation, thin film distillation, evaporation, membrane distillation, pervaporation, vapor permeation, reverse osmosis, nanofiltration, forward osmosis, dialysis, and salt exchange. The evaporation method is a method in which a gas is circulated through a container containing the raw material liquid to vaporize the first solvent in the raw material liquid and remove it from the container. In the method for concentrating a raw material liquid of this embodiment, it is preferable to carry out the concentration by one or more methods selected from the group consisting of reverse osmosis, forward osmosis, nanofiltration, dialysis, and salt exchange. Among these methods, dialysis, salt exchange, reverse osmosis, nanofiltration, and forward osmosis can remove the solvent from the raw material liquid without heating, and therefore are effective because they cause less denaturation of valuable materials due to heat.

[0076] (Forward Osmosis Membrane Method) Hereinafter, the forward osmosis membrane method will be described as an example of the method for concentrating a raw material liquid according to this embodiment. FIG. 1 is a schematic diagram showing the mechanism of solvent transfer using a forward osmosis membrane. In FIG. 1, the raw material liquid (a) flows on one side of the forward osmosis membrane (520), and the draw solution (d), which has a higher osmotic pressure than the raw material liquid (a), flows on the other side, and the two liquids are in contact with each other via the forward osmosis membrane (520). Then, driven by the osmotic pressure difference between the raw material liquid (a) and the draw solution (d), mainly the first solvent (b) in the raw material liquid (a) passes through the forward osmosis membrane (520) and moves into the draw solution (d).

[0077] The forward osmosis membrane (520) in Fig. 1 has a substrate layer (521) and an active layer (522) formed on one side of the substrate layer (521). The active layer (522) has a very dense structure that allows small molecules to pass through but does not allow valuable substances to pass through, and is formed on the surface of the substrate layer (521) that comes into contact with the raw material liquid (a). The forward osmosis membrane (520), substrate layer (521), and active layer (522) are similar to the composite semipermeable membrane, porous support membrane, and separation functional layer of this embodiment, and the descriptions thereof can be used.

[0078] A porous membrane is generally used as the material for the substrate layer (521). The draw solution (d) permeates the portion of the forward osmosis membrane (520) that is the substrate layer (521) composed of a porous membrane, and the feed solution (a) and the draw solution (d) are in contact with each other via the active layer (522). In this case, the solvent in the feed solution (a) moves toward the draw solution (d) that has a higher osmotic pressure, thereby performing concentration. The forward osmosis membrane may have any structure, such as a hollow fiber membrane, a tubular membrane, or a flat membrane. A hollow fiber forward osmosis membrane is preferred because it can form a flow path through which the feed solution and the draw solution pass without using a spacer or the like, and can perform uniform concentration.

[0079] When a hollow fiber forward osmosis membrane is used, the outer diameter of the hollow fiber membrane is, for example, 300 μm to 5,000 μm, preferably 350 μm to 4,000 μm, and the inner diameter of the hollow fiber membrane is, for example, 200 μm to 4,000 μm, preferably 250 μm to 1,500 μm. If the inner diameter of the hollow fiber membrane is less than 200 μm, high back pressure may be generated when a liquid flows through the space inside the hollow fiber. If the inner diameter of the hollow fiber membrane exceeds 4,000 μm, when multiple forward osmosis membranes are used in a module, the membrane area per module may become excessively small, preventing effective concentration.

[0080] The draw solution used in the forward osmosis membrane method can be a solution containing, as a solute, an organic solvent, an electrolyte, a buffer salt, or the like. The organic solvent may be any of the organic solvents listed above for the solvent contained in the feedstock solution. Specifically, at least one selected from methanol, ethanol, isopropanol, and t-butanol is preferred. Examples of the electrolyte include formic acid, acetic acid, propionic acid, citric acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, oxalic acid, gluconic acid, lactic acid, glycolic acid, and glyceric acid. Examples of the buffer salt include metal salts of the electrolytes, as well as inorganic salts such as sodium chloride, magnesium chloride, calcium chloride, sodium sulfate, sodium bicarbonate, potassium bicarbonate, sodium hydrogen sulfate, potassium hydrogen sulfate, magnesium sulfate, potassium sulfate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide; and organic acid salts such as sodium acetate, magnesium acetate, sodium citrate, and magnesium citrate.

[0081] The concentration of the solute in the draw solution may be appropriately set depending on the composition of the feed solution, the type of solute in the draw solution, etc., so as to ensure the transfer of the solvent from the feed solution to the draw solution and to generate an osmotic pressure difference that can generate a driving force within a range that does not cause a sudden change in the composition of the feed solution near the forward osmosis membrane.

[0082] In the forward osmosis membrane method, the driving force for the movement of the solvent (b) from the feed solution (a) to the draw solution (d) is the osmotic pressure difference between the feed solution (a) and the draw solution (d). Therefore, it is necessary to refresh the liquid between the active layer (522) of the forward osmosis membrane (520) and the interface between the feed solution (a) or the draw solution. Therefore, it is necessary to flow the feed solution (a) and the draw solution (d) at an appropriate flow rate on both sides of the forward osmosis membrane (520). In FIG. 1, the feed solution (a) and the draw solution (d) are flowed in parallel, but the flows of the two liquids may be countercurrent.

[0083] FIG. 2 is a schematic diagram showing the configuration of an example of a forward osmosis membrane module that is preferably used as a unit for carrying out the feedstock liquid concentration method of this embodiment. In the forward osmosis membrane module (500) of FIG. 2, a plurality of hollow fiber forward osmosis membranes (520) are housed in a housing (510). Both ends of the forward osmosis membranes (520) are adhesively fixed to the housing (510) with an adhesive resin (530). Two housing side tubes are provided on the side of the housing (510). One of these housing side tubes is a draw solution inlet (511), and the other is a draw solution outlet (512). The interior of the housing (510) is divided into two spaces by the outer wall of the forward osmosis membrane (520) and the adhesive resin (530): a space through which the feedstock liquid (a) flows and a space through which the draw solution (d) flows. The two spaces are fluidically isolated except for the solvent being able to pass between them via the inner wall of the forward osmosis membrane (520).

[0084] When a feedstock liquid (a) is introduced into one end of the forward osmosis membrane module (500), the feedstock liquid (a) flows inside the hollow fiber forward osmosis membrane (520) and flows out from the other end as a concentrated feedstock liquid (c). Similarly, when a draw solution (d) is introduced through the draw solution inlet (511) in the side pipe of the housing (510), the draw solution (d) flows through the outer space of the hollow fiber forward osmosis membrane (520) and flows out from the draw solution outlet (512). This allows the feedstock liquid (a) and the draw solution (d) to come into contact with each other via the forward osmosis membrane (520). At this time, substances other than valuable materials move from the feedstock liquid (a) to the draw solution (d) due to the difference in osmotic pressure between the two liquids. In the forward osmosis membrane method, concentration is performed by this mechanism.

[0085] When the forward osmosis membrane (520) has a substrate layer and an active layer formed on one side of the substrate layer, as described above, the active layer is formed on the surface of the substrate layer that contacts the feedstock liquid. Therefore, in the forward osmosis membrane module (500) of FIG. 2, in which the feedstock liquid (a) flows inside the hollow fiber membrane-like forward osmosis membrane, it is preferable that the active layer be formed on the inner surface of the hollow fiber membrane-like substrate layer. When the flow rate of the feedstock liquid (a) and / or the flow rate of the draw solution (d) are high, the influence of the osmotic pressure difference on both sides of the forward osmosis membrane (520), particularly the active layer, becomes greater, resulting in a higher solvent permeation rate per membrane area of ​​the forward osmosis membrane. In the forward osmosis membrane module (500) of FIG. 2, the feedstock liquid (a) and the draw solution (d) flow in parallel, but the flows of the two liquids may be countercurrent.

[0086] The material of the housing (510) in the forward osmosis membrane module (500) of FIG. 2 is selected from the viewpoints of chemical resistance, pressure resistance, heat resistance, impact resistance, weather resistance, etc., so that various performances are not deteriorated by components contained in the feed solution (a) and the draw solution (d). Examples of materials that can be used for the housing (510) include resins and metals. From the above viewpoints, the material of the housing (510) is preferably selected from resins such as polypropylene, polysulfone, polyethersulfone, polyvinylidene fluoride, polytetrafluoroethylene, perfluoroalkoxyalkane, ABS resin, fiber-reinforced plastic, and vinyl chloride resin; and metals such as stainless steel, brass, and titanium. The adhesive resin (530) in the forward osmosis membrane module (500) of FIG. 2 is preferably one that has good mechanical strength and heat resistance at 100°C. Examples of resins that can be used as the adhesive resin (530) include thermosetting epoxy resins, thermosetting urethane resins, ceramic-type adhesives, and sealing materials obtained by melting polyethylene or low-melting-point metals. Epoxy resins are preferred from the viewpoint of heat resistance, and urethane resins are preferred from the viewpoint of handling. The forward osmosis membrane (520) can be adhesively fixed to the housing (510) according to known adhesive methods related to the production of hollow fiber membrane modules.

[0087] (Nanofiltration Membrane Method) A nanofiltration membrane method will be described as another example of the method for concentrating a raw material liquid according to this embodiment. In the nanofiltration membrane method, the raw material liquid is supplied to one side of a nanofiltration membrane, and the raw material liquid supply side is pressurized. Then, mainly the solvent in the raw material liquid passes through the nanofiltration membrane and is removed, concentrating the raw material liquid. If minor components are present, they remain in the raw material liquid. The nanofiltration membrane may have any structure, such as a hollow fiber membrane, a tubular membrane, or a flat membrane. A hollow fiber nanofiltration membrane is preferred because it can form a flow path through which the raw material liquid and the permeate (solvent) pass without using a spacer or the like, and can perform uniform concentration.

[0088] The nanofiltration membrane method is preferably carried out using a nanofiltration membrane module in which a plurality of hollow fiber nanofiltration membranes are housed in a suitable housing.

[0089] For the housing of the nanofiltration membrane module and other module configurations, the above description of the forward osmosis membrane module can be applied by replacing "forward osmosis membrane" with "nanofiltration membrane."

[0090] (Reverse Osmosis Membrane Method) As another example of the method for concentrating a raw material liquid according to this embodiment, a reverse osmosis membrane method will be described. In the reverse osmosis membrane method, the raw material liquid is concentrated by applying a pressure equal to or greater than the osmotic pressure of the raw material liquid (a) and the draw solution (d). The reverse osmosis membrane may have any structure, such as a hollow fiber membrane, a tubular membrane, or a flat membrane. A hollow fiber reverse osmosis membrane is preferred because it can form a flow path through which the raw material liquid and the permeate (solvent) pass without using a spacer or the like, and can perform uniform concentration.

[0091] The reverse osmosis membrane method is preferably carried out using a reverse osmosis membrane module in which a plurality of hollow fiber reverse osmosis membranes are housed in a suitable housing.

[0092] For the housing of the reverse osmosis membrane module and other module configurations, the above description of the forward osmosis membrane module can be applied by replacing "forward osmosis membrane" with "reverse osmosis membrane."

[0093] (Salt Exchange Method) A salt exchange method will be described as another example of the method for concentrating a raw material liquid according to this embodiment. In the salt exchange method, the raw material liquid is concentrated by removing the solvent by penetration. The salt exchange membrane may have any structure, such as a hollow fiber membrane, a tubular membrane, or a flat membrane. A hollow fiber salt exchange membrane is preferred because it can form a flow path through which the raw material liquid and the permeate pass without using a spacer or the like, and can perform uniform concentration.

[0094] The salt exchange method is preferably carried out using a salt exchange membrane module in which a plurality of hollow fiber salt exchange membranes are housed in a suitable housing.

[0095] For the housing of the salt exchange membrane module and other module configurations, the above description of the forward osmosis membrane module can be applied with the "forward osmosis membrane" replaced with "salt exchange membrane."

[0096] (Dialysis method) The use of dialysis is effective in that valuables can be effectively prevented from permeating through the dialysis membrane and being lost. Hereinafter, as an example of the method for concentrating a raw material solution according to this embodiment, a dialysis method using the composite semipermeable membrane of this embodiment as the dialysis membrane will be described.

[0097] Figure 3 is a schematic diagram showing the mechanism of action of dialysis using a dialysis membrane. In Figure 3, a raw material solution (a) flows on one side of a dialysis membrane (120), and a dialysate (e) flows on the other side, with the two solutions in contact via the dialysis membrane (120). At this time, if there is a difference in the concentration of the solvent or subcomponent (g) in the raw material solution (a) and the concentration of the solvent or subcomponent (g) in the dialysate (e), the solvent or subcomponent (g) will move from the concentrated solution to the diluted solution. This movement occurs using the difference in the concentration of the solvent or subcomponent (g) between the two solutions as a driving force, so movement in either direction is possible.

[0098] The dialysis membrane (120) in Figure 3 has a base layer (121) and an active layer (122) formed on one side of the base layer (121). The active layer (122) has a very dense structure that allows small molecules to pass through but not valuable substances to pass through, and is formed on the surface of the base layer (121) that comes into contact with the raw material liquid (a). The dialysis membrane (120), base layer (121), and active layer (122) are the same as the composite semipermeable membrane, porous support membrane, and separation functional layer of this embodiment.

[0099] A porous membrane is generally used as the material for the base layer (121). The dialysate (e) is permeated into the portion of the dialysis membrane (120) that is the base layer (121) made of a porous membrane, and the raw material solution (a) and the dialysate (e) are in contact with each other via the active layer (122).

[0100] The dialysis membrane may be in the form of a hollow fiber membrane, a tubular membrane, or a flat membrane, for example. Hollow fiber dialysis membranes are suitable because they can form flow paths for the raw material solution and the dialysate without using spacers or the like and can maintain uniform flow.

[0101] When a hollow fiber dialysis membrane is used, the outer diameter of the hollow fiber membrane is, for example, 300 μm to 5,000 μm, preferably 350 μm to 4,000 μm. The inner diameter of the hollow fiber membrane is, for example, 200 μm to 4,000 μm, preferably 250 μm to 1,500 μm. Although the reason is unclear, if the inner diameter of the hollow fiber membrane is less than 200 μm, precipitation, aggregation, or denaturation of valuable substances may occur. If the inner diameter of the hollow fiber membrane exceeds 4,000 μm, when multiple dialysis membranes are used in a modular configuration, the membrane area per module may become excessively small, and the concentration of the solvent or minor component may not be sufficiently transferred.

[0102] The composition of the dialysis solution used in dialysis is preferably one that allows valuable substances to exist stably. The appropriate composition of the dialysis solution should be appropriately determined depending on the chemical and physical properties of the valuable substances contained in the raw material solution. One option is to use a dialysis solution with the same composition as the raw material solution from which the valuable substances have been removed. From the viewpoint of avoiding adverse effects on piping, analytical instruments, etc., the pH of the dialysis solution is preferably from 1 to 14, and more preferably from 2 to 13.

[0103] In dialysis, the driving force for the movement of solvents or minor components between the raw solution and the dialysate is the concentration difference between the raw solution and the dialysate. Therefore, for effective component movement, fluid renewal is required between the active layer of the dialysis membrane and the interface between the raw solution or the dialysate. Therefore, the raw solution and the dialysate must be flowed at appropriate flow rates on both sides of the dialysis membrane (120). In FIG. 3 , the raw solution (a) and the dialysate (e) are flowed in parallel, but the two solutions may also flow countercurrently. Depending on the composition of the raw solution, the osmotic pressure difference between the raw solution and the dialysate may cause the first solvent in the dialysate to permeate the dialysis membrane and migrate into the raw solution, resulting in an increase in the volume of the raw solution. In this case, the increase in volume of the raw solution can be suppressed by pressurizing the raw solution in contact with the dialysis membrane. The pressurization pressure of the raw solution is preferably 0.05 MPaG or higher, more preferably 0.1 MPaG or higher, and even more preferably 0.2 MPaG or higher.

[0104] FIG. 4 is a schematic diagram showing the configuration of an example of a dialysis membrane module in the method for concentrating a raw material liquid according to this embodiment. In the dialysis membrane module (100) of FIG. 4 , a plurality of hollow fiber dialysis membranes (120) are housed in a housing (110). Both ends of the dialysis membrane (120) are adhesively fixed to the housing (110) with an adhesive resin (130). Two housing side tubes are provided on the side of the housing (110). One of these housing side tubes is a dialysate inlet (111), and the other is a dialysate outlet (112). The interior of the housing (110) is divided into two spaces by the outer wall of the dialysis membrane (120) and the adhesive resin (130): a space through which the raw material liquid (a) flows and a space through which the dialysate (e) flows. The two spaces are fluidically isolated from each other except that the solvent or minor components can pass between them via the inner wall of the dialysis membrane (120).

[0105] When a raw liquid (a) is introduced into one end of the dialysis membrane module (100), the raw liquid (a) flows inside the hollow fiber dialysis membrane (120) and exits the other end as a raw liquid (f) with an adjusted component concentration. Similarly, when a dialysate (e) is introduced through the dialysate inlet (111) of the side pipe of the housing (110), the dialysate (e) flows through the outer space of the hollow fiber dialysis membrane (120) and exits through the dialysate outlet (112). This allows the raw liquid (a) and the dialysate (e) to come into contact with each other via the dialysis membrane (120). Depending on the component concentrations contained in the raw liquid (a) and the dialysate (e), a solvent or a minor component (g) moves from the raw liquid (a) to the dialysate (e) or from the dialysate (d) to the raw liquid (a). In dialysis, the concentration of the solvent or minor component is adjusted by such a mechanism. When the flow rate of the raw material solution (a) and / or the dialysate (e) is high, the effect of the concentration difference on both sides of the dialysis membrane (120), particularly the active layer, becomes greater, and the amount of solvent or minor component transferred per membrane area of ​​the dialysis membrane increases. In the dialysis membrane module (100) of Figure 4, the raw material solution (a) and the dialysate (e) flow in parallel, but the flows of the two solutions may also be countercurrent.

[0106] The above description of the forward osmosis membrane module (500) of Figure 2 can be applied directly to the materials of the housing (110) and adhesive resin (130) in the dialysis membrane module (100) of Figure 4, and the method of adhesively fixing the dialysis membrane (120) to the housing (110).

[0107] The concentration of at least one of the components in the raw material liquid can be determined using the results of measurements such as specific gravity measurement, pH measurement, conductivity measurement, liquid level measurement, optical rotation measurement, refractive index measurement, near-infrared spectroscopy, and weight measurement of the raw material liquid. Then, when the raw material liquid has been concentrated to a desired concentration rate, the concentration of the raw material liquid is terminated. The concentration rate can be determined by an appropriate method such as weight measurement of the raw material liquid or liquid level measurement.

[0108] The component analysis of the final concentrated dialysate (e) may be appropriately selected depending on the types of components contained in the concentrated starting solution, and various known analytical methods can be used, such as inductively coupled plasma mass spectrometry (ICP-MS), nuclear magnetic resonance spectroscopy (NMR), gas chromatography / mass spectrometry (GC / MS), colorimetry, fluorometry, and high performance liquid chromatography (HPLC).

[0109] The performance of the composite semipermeable membrane of this embodiment includes water permeability and rejection, which can be evaluated by the water permeation rate and rejection rate, respectively. These membrane performances are basically evaluated at room temperature (25°C). Here, the water permeation rate (Flux) refers to the amount of solution (unit: kg m) that permeates the membrane per membrane area during pressure filtration. -2 ・hr -1 ・bar -1 ) and is the amount of solution (unit: kg m) that permeates the membrane per membrane area for various solutions pressurized in the range of 0.1 to 5 bar. -2 ・hr -1 ・bar -1 ) The rejection rate is a value (unit: %) calculated by the following formula in pressure filtration of a raw liquid containing a solute: 100 × (1 - solute concentration (wt %) in the permeate that has permeated the membrane / solute concentration (wt %) in the raw liquid). The water permeability indicated by the water permeation rate and the rejection rate indicated by the rejection rate are usually in a trade-off relationship, and it is difficult to achieve both performance levels at the same time. However, the composite semipermeable membrane of the present embodiment can achieve a good balance between water permeability and rejection rate, and is therefore excellent in processes such as the separation, purification, and concentration of valuable materials in the raw liquid. The water permeability rate (flux) and rejection rate are measured by the methods described in the Examples.

[0110] The configuration and effects of the present invention will be further described below with reference to examples, but the present invention is not limited to the following examples.

[0111] <Dialysis membrane module> A hollow fiber ultrafiltration membrane made of polyethersulfone with an inner diameter of 0.7 mm and an outer diameter of 1.0 mm was used as the substrate layer. 130 of these hollow fiber ultrafiltration membranes were packed into a cylindrical plastic housing with a diameter of 2 cm and a length of 10 cm, and both ends were fixed with an adhesive, resulting in an effective membrane inner surface area of ​​approximately 0.02 m.２ The insides of the hollow fiber dialysis membranes obtained in the examples described below were washed with pure water to produce a dialysis membrane module containing 130 hollow fiber dialysis membranes, each having a separation function layer made of polyamide on the inner surface of a porous support membrane layer made of a hollow fiber ultrafiltration membrane made of polyethersulfone.

[0112] <Nanofiltration Membrane Module> A module prepared in the same manner as the above-mentioned "dialysis membrane module" was used as a "nanofiltration membrane module."

[0113] <Yield of valuable substances and electrolyte rejection> A raw material solution containing electrolytes at a concentration of 300 ppm of valuable substances and at the concentrations shown in Table 2 was prepared, and filtration and concentration were carried out under the following filtration conditions (Examples 11 to 20, Comparative Examples 4 to 6, and Reference Examples 1 to 6 described below). Filtration conditions: cross-flow filtration, pressure 200 kPa, flow rate 120 ml / min, and temperature 25°C. The concentrations of valuable substances and electrolytes in the permeated liquid and the concentrations of valuable substances and electrolytes in the raw material solution were applied to the following formulas (1) and (2), to calculate the yield of valuable substances and the rejection of electrolytes after concentration of the raw material solution using the composite semipermeable membrane of the Examples, etc. Yield of valuable substances (%)=weight of valuable substances in permeate that permeated the membrane / weight of valuable substances in the feed solution×100...Equation (1) Electrolyte rejection rate (%)=100×(1-electrolyte concentration in permeate that permeated the membrane (wt%) / electrolyte concentration in feed solution (wt%))...Equation (2) The concentration of valuable substances in the permeate was measured using a total organic carbon meter (TOC) (product name: TOC-LCSH, manufactured by Shimadzu Corporation). The concentration of electrolytes in the permeate was measured using ion chromatography (product name: Nexera series, manufactured by Shimadzu Corporation).

[0114] The yield of valuable materials was evaluated according to the following criteria: "A": 98% or more (passable) "B": less than 98% (unacceptable) If the evaluation is A, the composite semipermeable membrane of the present embodiment can be suitably used.

[0115] The evaluation of the electrolyte rejection rate was carried out according to the following criteria: "A": 5% or less, "Excellent" "B": More than 5% and less than 30%, "Good" "C": More than 30% and less than 50%, "Poor" "D": More than 50%, "Unacceptable" If the evaluation is A or B, the composite semipermeable membrane of the present embodiment can be suitably used.

[0116] <Mean Pore Size and Geometric Standard Deviation of Pore Size Distribution of Separation Functional Layer> The mean pore size and geometric standard deviation of the pore size distribution of the separation functional layer were each calculated using the permeability evaluation results (neutral molecule rejection) of an aqueous solution in which neutral molecules with known Stokes radii were dissolved. The rejection of neutral molecules with known Stokes radii was determined by the following method. Specifically, an aqueous solution containing a concentration of 300 ppm of each of a plurality of neutral molecules (isopropanol, glycerin, erythritol, glucose, salicin, and sucrose) was prepared, and the neutral molecule rejection was calculated from the concentration of neutral molecules in the permeate after filtering the prepared aqueous solution under the following filtration conditions and the concentration of neutral molecules in the aqueous solution before filtration. Filtration conditions: cross-flow filtration, pressure 200 kPa, flow rate 120 ml / min, temperature 25°C. The concentration of neutral molecules in the permeate was measured using a total organic carbon (TOC) meter (product name: TOC-LCSH, manufactured by Shimadzu Corporation).

[0117] The Stokes radii of each neutral molecule were calculated based on the literature values ​​of the diffusion coefficient of each molecule and used as follows: Isopropanol: 0.21 nm Glycerin: 0.26 nm Erythritol: 0.31 nm Glucose: 0.36 nm Salicin: 0.45 nm Sucrose: 0.46 nm Raffinose pentahydrate: 0.58 nm

[0118] The frequency distribution of neutral molecules was calculated from the Stokes diameter, which is twice the Stokes radius of the neutral molecule, and the rejection rate, to determine the percentage of each neutral molecule passing through the composite semipermeable membrane. The frequency distribution was evaluated using class values. For example, the frequency, which is the difference between the rejection rates of isopropanol and glycerin, was assigned a class value, which is the average value of isopropanol and glycerin. The frequency distribution and standard deviation of neutral molecules were calculated using the following method. The average value was the Stokes diameter-weighted average, which is the product of the Stokes diameter and the frequency. The standard deviation was calculated using the difference between the class value and the Stokes diameter-weighted average as the deviation. The inverse function of the cumulative distribution function of a log-normal distribution type for the average value and the standard deviation with a probability of 50% associated with the log-normal distribution was calculated, and the natural logarithm was then calculated to determine the pore size value with a probability of 50%. Similarly, the pore size value with a probability of 84.13% was calculated. The pore size at a probability of 50% was taken as the mean pore size, and the square root of the ratio (pore size at a probability of 84.13%) / (pore size at a probability of 50%) was taken as the geometric standard deviation of the pore size distribution.

[0119] The following table shows the rejection rate and alcohol content when each neutral molecule is allowed to pass through the composite semipermeable membrane of Example 1. Neutral molecule: isopropanol Class value: 0.21 Rejection rate: 7.1% Alcohol content: 7.1% Neutral molecule: glycerin Class value: 0.47 Rejection rate: 8.8% Alcohol content: 1.7% Neutral molecule: D(-)glucose Class value: 0.62 Rejection rate: 99.7% Alcohol content: 90.8% Neutral molecule: salicin Class value: 0.81 Rejection rate: 100% Alcohol content: 0.3% Neutral molecule: sucrose Class value: 0.91 Rejection rate: 100% Alcohol content: 0.0% Neutral molecule: D(+)-raffinose pentahydrate Class value: 1.04 Rejection rate: 100% Alcohol content: 0.0%

[0120] In Example 1, the mean value of the frequency distribution was 0.69, the standard deviation was 0.15, and when it was assumed that the pore sizes followed a log-normal distribution, the pore sizes at a probability of 50% were 0.69 nm and the pore sizes at a probability of 84.13% were 0.84 nm. From the above, the mean pore size of the separation functional layer in Example 1 was 0.69 nm, and the geometric standard deviation of the pore size distribution of the separation functional layer in Example 1 was 1.10.

[0121] <Surface zeta potential of separation functional layer at pH 2.0> The hollow fiber membranes prepared in the examples and comparative examples were attached to a sample holder of a flat-plate zeta potential measurement cell to prepare measurement samples. Monitor particles (manufactured by Otsuka Electronics Co., Ltd.) were diluted approximately 200 times with water to prepare a tracer suspension, and the pH was adjusted using aqueous solutions of hydrochloric acid and sodium hydroxide. Measurements were performed twice by immersing a flat-plate zeta potential measurement cell (ZEN1020) (manufactured by Malvern Instruments, Zetasizer Nano ZS) of an electrophoretic zeta potential measurement device equipped with a sample holder in the tracer suspension, and the average value was calculated to determine the surface zeta potential of the separation functional layer. The refractive index, dielectric constant, and viscosity of the solvent were set to the values ​​for water.

[0122] <Measurement of Molecular Weight> The molecular weight of the valuable material was calculated from the chemical formula of the valuable material. The molecular weight of the electrolyte was calculated from the chemical formula of the electrolyte.

[0123] <Measurement of pKa of Electrolyte> The pKa of the electrolyte was measured by neutralization titration, in which titration was performed with sodium hydroxide or the like using methyl orange or the like as an indicator.

[0124] <Water Permeability> The water permeability (Flux) of the composite hollow fiber membrane module in the present disclosure was calculated by the following formula (1): Flux = L / (M × H × bar) (1) where Flux is the water permeability (kg / (m ２ × hr × bar), L is the amount of water permeated (kg), M is the internal surface area of ​​the membrane (m ２ ), H is time (hr), and bar is back pressure. The evaluation of water permeability (concentration rate) was carried out according to the following criteria: "A": 5 kg / (m ２ ×hr×bar) or more “Excellent” “B”: 3kg / (m ２ × hr × bar) or more and less than 5 kg "Good" "C": 1 kg / (m ２ × hr × bar) or more and less than 3 kg "Fail" If the evaluation is A or B, it can be suitably used as a composite semipermeable membrane.

[0125] Concentration conditions for Examples 11 to 20, Comparative Examples 4 to 6, and Reference Examples 1 to 6 Dialysis (without pressure) - The raw material liquid was circulated on the primary side of the dialysis membrane module, and water was circulated on the secondary side of the dialysis membrane module.

[0126] Dialysis (with pressure) - The raw material solution was circulated through the primary side of the dialysis membrane module and water was circulated through the secondary side of the dialysis membrane module at a back pressure of 200 kPa.

[0127] NF membrane: The raw material liquid was circulated through the primary side of the nanofiltration membrane module at a back pressure of 200 kPa.

[0128] NF membrane salt exchange: The raw material liquid was circulated through the primary side of the nanofiltration membrane module at a back pressure of 200 kPa, and 10-fold concentration was carried out. After 10-fold concentration was completed, additional raw material liquid was added and 10-fold concentration was carried out again.

[0129] [Example 1 (Composite Semipermeable Membrane A)] The composite semipermeable membrane housed in the hollow fiber dialysis membrane module in Example 1 was a dialysis membrane that used a hollow fiber membrane made of polysulfone (PSf) as a hollow fiber porous support membrane and had a polyamide separation functional layer on the inner surface of the hollow fiber membrane. The hollow fiber dialysis membrane module in Example 1 was produced as follows.

[0130] <Production of Hollow Fiber-Shaped Porous Support Membrane> A homogeneous polymer solution (spinning dope) consisting of 19% by mass of polysulfone (Udel-P3500, manufactured by Solvay Specialty Polymers), 61% by mass of N-methyl-2-pyrrolidone (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and 20% by mass of tetraethylene glycol (manufactured by Tokyo Chemical Industry Co., Ltd.) was prepared as a spinning dope. The spinning dope was filled into a wet hollow fiber spinning machine equipped with a double spinneret. The spinning dope was discharged from the outer spinneret of the double spinneret, and the internal coagulation liquid (water) was discharged from the inner spinneret. The spinning dope was then introduced into a coagulation bath filled with water as the external coagulation liquid, and coagulation was carried out to obtain a hollow fiber-shaped porous support membrane. The resulting hollow fiber-shaped porous support membrane had an outer diameter of 1.00 mm, an inner diameter of 0.60 mm, and a membrane thickness of 0.20 mm.

[0131] <Production of Support Membrane Module> 130 pieces of the hollow fiber porous support membrane cut to a length of 120 mm were placed in a cylindrical housing made of synthetic resin with a diameter of 20 mm, and both ends were fixed with an adhesive so as not to block the hollow portion of the hollow fiber, thereby producing a module with an effective length of 80 mm and an effective inner membrane surface area of ​​0.02 m. ２ A supported membrane module was manufactured. The internal space of this supported membrane module was divided into two by a membrane wall of a hollow fiber, and the two spaces were fluidically isolated except for the fact that liquid could pass through the membrane wall. The housing had a liquid inlet and outlet (liquid inlet and liquid outlet) that communicated with the space inside the hollow fiber, and a liquid inlet and outlet (liquid inlet and liquid outlet) that communicated with the space outside the hollow fiber.

[0132] <Production of Hollow Fiber Dialysis Membrane Module (Formation of Separation Functional Layer)> An aqueous solution containing 0.5% by mass of piperazine and 0.3% by mass of sodium lauryl sulfate (first solution) was passed through the space inside the hollow fibers of the support membrane module obtained above at a flow rate of 120 mL / min for 20 minutes. After completion of the liquid passage, the support membrane module was held so that the axial direction of the support membrane module was approximately vertical, and the first solution was drained by gravity through the liquid inlet / outlet at the bottom of the module. Next, with the inner surface of the hollow fibers wetted with the first solution, the space outside the hollow fibers of the support membrane module was reduced in pressure to 50 kPaA and maintained at this reduced pressure for 1 minute. Air was then circulated through the space inside the hollow fibers for 1 minute to remove excess first solution.

[0133] Subsequently, an n-hexane solution (second solution) containing 0.20% by mass of trimesoyl chloride (TMC) was passed through the space inside the hollow fibers of the support membrane module at a flow rate of 40 mL / min for 2 minutes to carry out interfacial polymerization and form a polyamide layer on the inner surface of the hollow fibers. Next, nitrogen was passed through the space inside the hollow fibers for 1 minute to remove excess second solution, and then water at 70°C was passed through the space inside the hollow fibers for 20 minutes to wash the inner surface of the hollow fiber membrane.

[0134] Example 2 (Composite Semipermeable Membrane B) Example 2 was produced in the same manner as Example 1, except that an ethanol treatment was performed by immersing the hollow fiber membrane in 100% by mass ethanol in an amount 100 times the membrane volume (volume of the membrane thickness excluding the hollow portion) at a temperature of 25°C for 24 hours.

[0135] Example 3 (Composite Semipermeable Membrane C) Example 3 was produced in the same manner as Example 1, except that autoclave treatment was carried out at 121°C for 2 hours.

[0136] [Example 4 (Composite Semipermeable Membrane D)] Example 4 was prepared in the same manner as Example 1, except that the 0.20% by mass of trimesoyl chloride in the second solution was changed to a mixture of 0.1% by mass of trimesoyl chloride and 0.1% by mass of isophthaloyl chloride.

[0137] Example 5 (Composite Semipermeable Membrane E) Example 5 was prepared in the same manner as in Example 1, except that the 0.5% by mass of piperazine in the first solution was changed to a mixture of 0.25% by mass of piperazine and 0.25% by mass of 1,3-di-4-piperidylpropane.

[0138] Example 9 (Composite Semipermeable Membrane I) Example 9 was prepared in the same manner as Example 1, except that the 0.5% by mass of piperazine in the first solution was changed to 0.5% by mass of 2,5-dimethylpiperazine, and the 0.20% by mass of trimesoyl chloride in the second solution was changed to a mixture of 0.1% by mass of trimesoyl chloride and 0.1% by mass of isophthaloyl chloride.

[0139] [Examples 6 to 8 and 10 (composite semipermeable membranes F to H and J) and Comparative Examples 1 and 3 (composite semipermeable membranes a and c)] Examples 6 to 8 and 10 and Comparative Examples 1 and 3 were produced in the same manner as Example 1, except that the amine monomer and acid chloride monomer and the treatments shown in Table 1 were changed. Note that the "ethanol treatment" and "autoclave treatment" in Examples 7 and 8 were the same as those performed in Examples 2 and 3.

[0140] Comparative Example 2 (Composite Semipermeable Membrane b) Comparative Example 2 was prepared in the same manner as in Example 1, except that the 0.5% by mass of piperazine in the first solution was changed to a mixture of 0.25% by mass of 1,3,5-triaminobenzene and 0.25% by mass of m-phenylenediamine.

[0141] Table 1 shows the physical properties measured for Examples 1 to 10 and Comparative Examples 1 to 3, such as the average pore size.

[0142]

[0143] Example 11 Using the composite semipermeable membrane A prepared in Example 1, a raw material solution containing glutathione disulfide as a valuable substance, water as a solvent, and acetic acid as an electrolyte was concentrated using an NF membrane.

[0144] Example 12 Using the composite semipermeable membrane B prepared in Example 2, a raw material solution containing neotame as a valuable substance, water as a solvent, and trifluoroacetic acid as an electrolyte was concentrated using an NF membrane.

[0145] [Example 13] Using the composite semipermeable membrane C prepared in Example 3, concentration by dialysis (under pressure) was carried out with a raw material solution containing neotame as a valuable substance, a mixed solvent containing water:acetonitrile in a ratio of 70:30 as a solvent, and trifluoroacetic acid as an electrolyte.

[0146] [Example 14] Using the composite semipermeable membrane D produced in Example 4, a raw material solution containing glutathione disulfide as a valuable substance, water as a solvent, and trifluoroacetic acid as an electrolyte was concentrated by dialysis (under pressure).

[0147] Example 15 Using the composite semipermeable membrane E produced in Example 5, concentration by dialysis (under pressure) was carried out using a raw material solution containing neotame as a valuable substance, water as a solvent, and acetic acid as an electrolyte.

[0148] Example 16 Using the composite semipermeable membrane F produced in Example 6, a raw material solution containing neotame as a valuable substance, water as a solvent, and trifluoroacetic acid as an electrolyte was concentrated by dialysis (without pressure).

[0149] [Example 17] Using the composite semipermeable membrane G prepared in Example 7, a raw material solution containing neotame as a valuable substance, a mixed solvent containing water and acetonitrile in a ratio of 70:30 as a solvent, and trifluoroacetic acid as an electrolyte was subjected to concentration by NF membrane salt exchange.

[0150] [Example 18] Using the composite semipermeable membrane H prepared in Example 8, concentration was carried out by dialysis (under pressure) using a raw material solution containing glutathione disulfide as a valuable substance, a mixed solvent containing water:acetonitrile in a ratio of 70:30 as a solvent, and citric acid as an electrolyte.

[0151] Example 19 Using the composite semipermeable membrane I prepared in Example 9, a raw material solution containing glutathione disulfide as a valuable substance, water as a solvent, and acetic acid as an electrolyte was concentrated by dialysis (under pressure).

[0152] Example 20 Using the composite semipermeable membrane J prepared in Example 10, a raw material solution containing neotame as a valuable substance, water as a solvent, and trifluoroacetic acid as an electrolyte was concentrated by dialysis (without pressure).

[0153] Comparative Example 4 Using the composite semipermeable membrane a prepared in Comparative Example 1, concentration by dialysis (under pressure) was carried out using a raw material solution containing neotame as a valuable substance, water as a solvent, and acetic acid as an electrolyte.

[0154] Comparative Example 5 Using the composite semipermeable membrane b prepared in Comparative Example 2, a raw material solution containing neotame as a valuable substance, water as a solvent, and trifluoroacetic acid as an electrolyte was concentrated by dialysis (under pressure).

[0155] Comparative Example 6 Using the composite semipermeable membrane c prepared in Comparative Example 3, a raw material solution containing neotame as a valuable substance, water as a solvent, and trifluoroacetic acid as an electrolyte was concentrated by dialysis (without pressurization).

[0156] Reference Example 1 Using Inopor 750 (manufactured by Inopor Corporation) as a composite semipermeable membrane, a raw material solution containing collagen peptide as a valuable substance, water as a solvent, and trifluoroacetic acid as an electrolyte was concentrated using an NF membrane.

[0157] Reference Example 2 Using Inopor 750 (manufactured by Inopor Corporation) as a composite semipermeable membrane, a raw material solution containing collagen peptide as a valuable substance, a mixed solvent containing water:acetonitrile in a ratio of 70:30 as a solvent, and trifluoroacetic acid as an electrolyte was concentrated using an NF membrane.

[0158] Reference Example 3 Using Inopor 750 (manufactured by Inopor Corporation) as a composite semipermeable membrane, concentration was carried out by dialysis (under pressure) using a raw material solution containing collagen peptide as a valuable substance, a mixed solvent containing water:acetonitrile in a ratio of 98:2 as a solvent, and trifluoroacetic acid as an electrolyte.

[0159] Reference Example 4 Using Inopor 750 (manufactured by Inopor Corporation) as a composite semipermeable membrane, concentration by NF membrane salt exchange was carried out on a raw material solution containing collagen peptide as a valuable substance, a mixed solvent containing water:acetonitrile in a ratio of 98:2 as a solvent, and trifluoroacetic acid as an electrolyte.

[0160] Reference Example 5 Using Inopor 750 (manufactured by Inopor Corporation) as a composite semipermeable membrane, concentration was carried out by dialysis (without pressure) with a raw material solution containing collagen peptide as a valuable substance, a mixed solvent containing water:acetonitrile in a ratio of 98:2 as a solvent, and trifluoroacetic acid as an electrolyte.

[0161] Reference Example 6 Using Inopor 750 (manufactured by Inopor Corporation) as a composite semipermeable membrane, a raw material solution containing collagen peptide as a valuable substance, water as a solvent, and trifluoroacetic acid as an electrolyte was concentrated using an NF membrane.

[0162] For Examples 11 to 20, Comparative Examples 4 to 6, and Reference Examples 1 to 6, the raw material solutions were concentrated, and the yield of valuable substances, the electrolyte rejection rate, and the water permeability were measured. The results are shown in Table 2. The concentrations of valuable substances in each raw material solution are as shown in Table 2.

[0163]

[0164] Looking at the results in Table 2, Comparative Examples 4 to 6, which do not satisfy the requirements of the present disclosure, are unable to improve all of the yield of valuable materials, the rejection of electrolytes, and the water permeation rate. On the other hand, Examples 11 to 20, which satisfy the requirements of the present disclosure, were excellent in all of the performances of the yield of valuable materials, the rejection of electrolytes, and the water permeation rate.

[0165] 1, 2, 3, 4 Raw material solution concentration system 100 Dialysis membrane module 110 Housing 111 Dialysis solution inlet 112 Dialysis solution outlet 120 Dialysis membrane 121 Base layer 122 Active layer 130, 530 Adhesive resin 200 Raw material solution tank 300 Dialysis solution tank 400 Trap 500 Forward osmosis membrane module 510 Housing 511 Draw solution inlet 512 Draw solution outlet 520 Forward osmosis membrane 521 Base layer 522 Active layer 600 Draw solution tank 700 Nanofiltration membrane module 800 Permeate tank 900 Evaporation unit a Raw material solution b Solvent c Concentrated raw material solution d Draw solution e Dialysis solution f Raw material solution with adjusted component concentration g Solvent or auxiliary component

Claims

1. A composite semipermeable membrane having a porous support membrane and a separation functional layer containing polyamide, wherein the separation functional layer has an average pore size of 0.55 nm or more and 0.90 nm or less, and a geometric standard deviation of the pore size distribution of 1.00 or more and 1.30 or less, and the surface zeta potential of the separation functional layer at pH 2.0 is -20.0 mV or more and 20.0 mV or less.

2. The composite semipermeable membrane according to claim 1, wherein the geometric standard deviation of the pore size distribution is 1.00 or more and 1.22 or less, and the surface zeta potential of the separating functional layer at pH 2.0 is -20.0 mV or more and 15 mV or less.

3. The composite semipermeable membrane according to claim 1, wherein the separation functional layer has an average pore size of 0.55 nm or more and 0.90 nm or less, a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less, and a surface zeta potential of the separation functional layer at pH 2.0 of -20.0 mV or more and 10 mV or less.

4. The composite semipermeable membrane according to claim 1, wherein the separation functional layer has an average pore size of 0.55 nm or more and 0.80 nm or less, a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less, and a surface zeta potential of the separation functional layer at pH 2.0 of -20.0 mV or more and 10 mV or less.

5. The composite semipermeable membrane according to claim 1, wherein the separation functional layer has an average pore size of 0.60 nm or more and 0.75 nm or less, a geometric standard deviation of the pore size distribution of 1.00 or more and 1.22 or less, and a surface zeta potential of the separation functional layer at pH 2.0 of -20.0 mV or more and 10 mV or less.

6. The composite semipermeable membrane according to claim 1, wherein the composite semipermeable membrane is in the form of a hollow fiber membrane.

7. The composite semipermeable membrane according to claim 1, wherein the separating functional layer contains a polymer of a polyfunctional acid halide and a polyfunctional amine containing 50% by mass or more of an aliphatic polyfunctional amine.

8. A method for concentrating a raw material liquid, comprising the step of concentrating a raw material liquid containing an electrolyte, one or more valuable substances, and a solvent, using the composite semipermeable membrane according to any one of claims 1 to 7.

9. The method for concentrating a raw material liquid according to claim 8, wherein the concentration is carried out by one or more methods selected from the group consisting of a reverse osmosis membrane method, a forward osmosis membrane method, a nanofiltration membrane method, a dialysis method, and a salt exchange method.

10. The method for concentrating a raw material liquid according to claim 8, wherein the valuable substance is one or more compounds selected from the group consisting of nucleic acids, proteins, peptides, amino acids, antibiotics, low-molecular-weight drugs, and vitamins.

11. The method for concentrating a raw material liquid according to claim 8, wherein the composite semipermeable membrane is in the form of a hollow fiber membrane.

12. The method for concentrating a raw material liquid according to claim 8, wherein the electrolyte is an organic compound having a molecular weight of 50 or more and 200 or less.

13. The method for concentrating a raw material liquid according to claim 8, wherein the pKa of the electrolyte is -2 or more and 4 or less.

14. The method for concentrating a raw material liquid according to claim 8, wherein the molecular weight of the valuable substance is 300 or more and 3,000 or less.

15. The method for concentrating a raw material liquid according to claim 8, wherein the raw material liquid contains one or more organic solvents.

Images