Raw material liquid concentration system and concentration device

Abstract

A raw material liquid concentration system for a pharmaceutical manufacturing process uses the following membrane distillation method: a raw material liquid containing a solvent and a solute is brought into contact with cooling water via a membrane for membrane distillation, and the above-mentioned solvent in the above-mentioned raw material liquid is passed through the above-mentioned membrane distillation membrane in a vapor state and moved to the above-mentioned cooling water side. In this raw material liquid concentration system, as the above-mentioned membrane distillation membrane, a porous membrane with a surface water contact angle of 90° or more, an average pore diameter in the range of 0.02μm to 0.5μm, and a porosity of 60% to 90% is used.

Description

Technical Field

[0001] The present invention relates to a raw material liquid concentration system and a concentration device. Specifically, the present invention relates to a raw material liquid concentration system and a concentration device, which separate a part of a solvent from a raw material liquid containing a drug precursor and an intermediate by a membrane distillation method to concentrate the raw material liquid, thereby suppressing the deterioration and reduction of components in the raw material liquid, and can efficiently concentrate the raw material liquid. Background Art

[0002] The raw material liquid to be concentrated contains both water and an organic solvent as solvents, which is common in industry.

[0003] Substances with amino acid sequences, such as peptides and proteins, are widely used as diagnostic / testing reagents and pharmaceuticals. They are very expensive, so it is important to efficiently recover them without denaturation during the manufacturing process.

[0004] As a method for stably and efficiently taking out proteins and purifying, ultrafiltration membranes are generally used. Ultrafiltration membranes are a technique for separating components by screening, and are a separation method that is not accompanied by temperature changes, so the energy load can be reduced. For example, proteins with molecular weights of several thousand to several million can mostly be graded and purified using ultrafiltration membranes. If ultrafiltration membranes are used, components with a size of more than the molecular weight cutoff of the membrane are retained in the stock solution, and water as a solvent passes through the membrane. Therefore, ultrafiltration membranes are effective in the concentration of solutions containing proteins, etc. (e.g., patent document 1).

[0005] In addition, a reverse osmosis (RO) method using a membrane that allows a solvent to pass through at a molecular level is known. The RO method is a method in which a raw material liquid is pressurized to a predetermined pressure higher than the osmotic pressure of the raw material liquid and then supplied to an RO membrane module, and the solvent (typically water) in the raw material liquid is removed by passing through the RO membrane, thereby concentrating the raw material liquid (e.g., Patent Document 2).

[0006] As a different method for concentrating the raw material liquid, a membrane distillation (MD) method is known, which uses the vapor pressure difference of the liquid to separate the solvent in the raw material liquid. As one method of membrane distillation, the following DCMD method (direct contact MD) is well known: the raw material liquid is brought into contact with cooling water having a lower temperature than the raw material liquid through a membrane, and the vapor containing no effective substance in the raw material liquid is moved from the raw material liquid to the cooling water, thereby concentrating the raw material liquid (for example, Patent Document 3).

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: International Publication No. 2013 / 170977

[0010] Patent Document 2: Japanese Patent Application Laid-Open No. 11-75759

[0011] Patent Document 3: International Publication No. 2016 / 006670 Summary of the invention

[0012] Problems to be solved by the invention

[0013] However, the ultrafiltration membrane described in Patent Document 1 requires pressurization of the raw material liquid, so there is a problem that the solute contained in the raw material liquid is fixed on the membrane surface, and the recovery rate is reduced. In addition, in the case of the middle molecule drugs currently under development, the molecular weight is sometimes less than the molecular weight cut-off of the ultrafiltration membrane, and the ultrafiltration membrane is partially passed through, so the recovery rate is reduced.

[0014] In the RO method of Patent Document 2, the raw material solution needs to be pressurized, so there is a problem that the solute contained in the raw material solution is fixed on the surface of the RO membrane, and the recovery rate is reduced. In addition, in the RO method, the osmotic pressure of the solvent of the concentrated raw material solution does not exceed the pressure of the high-pressure pump used for pressurization, so the concentration rate of the raw material solution based on the RO method has a limit depending on the capacity of the pump.

[0015] On the other hand, according to the membrane distillation method of Patent Document 3, if the membrane for membrane distillation is wetted, the raw material liquid flows into the cooling water side, so it cannot be concentrated. In addition, since a porous membrane with a small pore size is selected as the membrane for membrane distillation, there is a problem of small steam permeation. In addition, in order to increase the steam permeation, it is necessary to increase the temperature of the raw material liquid. In this case, the raw material liquid is usually heated to more than 60°C, and there are few reported examples of applying the membrane distillation method to the concentration of raw material liquids containing solutes such as enzymes and peptides that are worried about thermal denaturation.

[0016] An object of the present invention is to provide a system and a device for concentrating a raw material liquid in a pharmaceutical manufacturing process, which can suppress wetting of a membrane for membrane distillation, which is a problem of membrane distillation, and has an industrially achievable processing speed even at room temperature.

[0017] Means for solving problems

[0018] The present invention is made to achieve the above-mentioned objects.

[0019] That is, the inventors have discovered that when a raw material liquid is concentrated by membrane distillation, by using a porous membrane with high water permeability and high hydrophobicity as a membrane for membrane distillation, the wetting of the membrane for membrane distillation by the raw material liquid can be suppressed, and vapor can be efficiently removed at room temperature. As a result, the denaturation of the effective ingredients in the raw material liquid can be prevented, and efficient concentration can be performed, thereby completing the present invention.

[0020] That is, the present invention is as follows.

[0021] [Method 1] A raw material liquid concentration system for a pharmaceutical manufacturing process, which uses the following membrane distillation method: a raw material liquid containing a solvent and a solute is brought into contact with cooling water via a membrane for membrane distillation, and the solvent in the raw material liquid is moved to the cooling water side through the membrane for membrane distillation in a vapor state,

[0022] In the raw liquid concentration system,

[0023] As the membrane distillation membrane, a porous membrane having a surface water contact angle of 90° or more, an average pore size of 0.02 μm to 0.5 μm, and a porosity of 60% to 90% is used.

[0024] <<Mode 2>> The raw material liquid concentration system according to Mode 1, wherein a hydrophobic polymer is attached to at least a portion of the membrane for membrane distillation.

[0025] <<Method 3>> A raw liquid concentration system as described in Method 2, wherein the amount of the hydrophobic polymer attached is distributed in the thickness direction of the membrane for membrane distillation, and the amount of the hydrophobic polymer attached to the surface of at least one side of the membrane for membrane distillation is greater than the amount of the hydrophobic polymer attached to the inside.

[0026] <<Mode 4>> The raw material liquid concentration system as described in Mode 3, wherein the adhesion amount of the above-mentioned hydrophobic polymer gradually decreases from the surface layer of one side of the above-mentioned membrane for membrane distillation to the surface layer of the opposite side.

[0027] [Method 5] A raw material liquid concentration system as described in Method 4, wherein the opposite surface to which the amount of the hydrophobic polymer attached is less is subjected to a hydrophilic treatment, the surface on the side subjected to the hydrophilic treatment is brought into contact with cooling water, and

[0028] The one side of the above-mentioned single surface on which the amount of the hydrophobic polymer attached was large was not subjected to a hydrophilic treatment, and this single surface was brought into contact with the above-mentioned raw material liquid.

[0029] "Method 6" A raw material liquid concentration system as described in any one of Methods 2 to 5, wherein the above-mentioned hydrophobic polymer is a polymer having a fluorine atom-containing group in the side chain, and has at least one side chain selected from (per)fluoroalkyl, (per)fluoropolyether, alkylsilyl, and fluorosilyl.

[0030] "Method 7" A raw liquid concentration system as described in any one of Methods 1 to 6, wherein the material of the membrane for membrane distillation comprises at least one resin selected from the group consisting of polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinylidene fluoride, polytetrafluoroethylene, ethylene-tetrafluoroethylene copolymer and polychlorotrifluoroethylene.

[0031] <<Method 8>> A raw material liquid concentration system as described in any one of Methods 1 to 7, wherein the above-mentioned solvent contains at least one selected from the group consisting of water, acetonitrile, methanol, ethanol and isopropanol.

[0032] "Method 9" A raw material liquid concentration system as described in any one of Methods 1 to 8, wherein the solute is at least one selected from the group consisting of amino acids, peptides, proteins, sugars, vaccines, nucleic acids, antibiotics, antibody-drug conjugates (ADCs) and vitamins.

[0033] <<Method 10>> The raw material liquid concentration system as described in any one of methods 1 to 9, wherein the number average molecular weight of the above-mentioned solute is 100 to 50,000.

[0034] <<Method 11>> A raw material liquid concentration system as described in any one of Methods 1 to 10, wherein the temperature of the above-mentioned raw material liquid is adjusted to a range of not less than 5°C and not more than 50°C.

[0035] [Method 12] A concentrating device having a membrane for membrane distillation, for concentrating a raw material liquid by membrane distillation, wherein:

[0036] As the membrane distillation membrane, a membrane having a water contact angle of 90° or more on the membrane surface, an average pore diameter of 0.02 μm to 0.5 μm, and a porosity of 60% to 90% is used.

[0037] <<Mode 13>> A concentrating device as described in Mode 13, wherein a hydrophobic polymer is attached to at least a portion of the membrane for membrane distillation.

[0038] <<Mode 14>> A concentrating device as described in Mode 13, wherein the amount of the hydrophobic polymer attached is distributed in the thickness direction of the membrane for membrane distillation, and the amount of the hydrophobic polymer attached to the surface of at least one side of the membrane for membrane distillation is greater than the amount of the hydrophobic polymer attached to the inside.

[0039] Effects of the Invention

[0040] The concentration system of the present invention can concentrate a raw material solution containing a solute having an amino acid sequence, for example, without causing wetting and while substantially maintaining the solute composition of the raw material solution, when concentrating the raw material solution by a membrane distillation process at approximately room temperature.

[0041] When the concentration system of the present invention is used for concentrating a raw material solution containing useful components used in pharmaceutical applications in a production process of pharmaceuticals or the like, useful components that are sensitive to heat and pressure can be concentrated at a high recovery rate without denaturation. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1This is a schematic diagram for explaining an example of an embodiment of a membrane module applied to the raw liquid concentration system of the present invention.

[0043] Figure 2 This is a schematic diagram for explaining an example of an embodiment of the raw material liquid concentration system of the present invention.

[0044] Figure 3 This is a schematic diagram for explaining an example of an embodiment related to the membrane and the attachment of a hydrophobic polymer applied to the raw material liquid concentration system of the present invention.

[0045] Figure 4 This is a schematic diagram for explaining an example of an embodiment related to a membrane and hydrophilization applied to the raw material liquid concentration system of the present invention. DETAILED DESCRIPTION

[0046] Hereinafter, preferred embodiments of the present invention will be described in detail as non-limiting examples.

[0047] 《Raw material concentration system》

[0048] The raw material liquid concentration system of the present invention will be described with reference to the drawings.

[0049] Figure 1 An example of a membrane module for membrane distillation which is preferably used when a raw material liquid is concentrated by membrane distillation in the concentration system of the present invention is shown.

[0050] Figure 1 The membrane module (100) for membrane distillation contains a plurality of hollow fiber membranes (20) for membrane distillation in a housing (10), and both ends of the membranes (20) are bonded and fixed by an adhesive resin (30). Here, both ends of the membrane distillation membranes (20) are open and not blocked.

[0051] A first shell side pipe (11) for the inflow of cooling water (CW) and a second shell side pipe (12) for the discharge of cooling water (CW) are provided on the side of the shell (10). The cooling water (CW) can flow to the external space of the membrane (20) for membrane distillation by utilizing these shell side pipes.

[0052] In the axial direction ( Figure 1 The two ends (in the left and right directions) of the membrane have a left opening for the inflow of the raw material liquid (a) and a right opening for the discharge of the raw material liquid (a). These openings can allow the raw material liquid (a) to flow into the hollow part of the membrane (20) for membrane distillation.

[0053] The interior of the membrane module (100) for membrane distillation is divided into a space on the hollow side of the membrane (20) for membrane distillation and a space on the external side of the membrane (20) for membrane distillation. The two spaces are shielded by a fluid except that a predetermined solvent can pass through the outer wall of the membrane (20) for membrane distillation.

[0054] The membrane (20) for membrane distillation is, for example, in the form of a hollow fiber, and its outer wall needs to have the following properties: it has strong hydrophobicity, liquid does not enter the interior although it is porous, and only gas can pass through the outer wall. It is also required to have high vapor permeability at room temperature, so it needs to have a high porosity and an appropriate average pore size.

[0055] In the present invention, as the membrane for membrane distillation, a porous membrane having a water contact angle of 90° or more on the membrane surface, an average pore size of 0.02 μm to 0.5 μm, and a porosity of 60% to 90% is used.

[0056] In order to concentrate the raw material liquid by membrane distillation, the raw material liquid (a) is flowed to one side ( Figure 1 In the hollow fiber membrane distillation membrane, the hollow part side space) is used, and the cooling water (CW) having a lower temperature than the raw material liquid (a) is flowed to the other side ( Figure 1 In the hollow fiber membrane distillation, the outer space side of the hollow fiber membrane). Then, the fine pores in the membrane wall that communicate with the two spaces come into contact with the raw material liquid (a) and the cooling water (CW) through the membrane wall. As a result, the vapor generated from the raw material liquid (a) with high vapor pressure passes through the membrane wall and moves to the cooling water (CW) with low vapor pressure, and is cooled and liquefied, thereby concentrating the raw material liquid (a).

[0057] Figure 2 An example of the concentrating system of the present invention is shown.

[0058] exist Figure 2 In the concentration system Figure 1 The membrane assembly (100) for membrane distillation shown has units (piping systems) for circulating the raw material liquid (a) at both axial ends. The piping system for circulating the raw material liquid (a) is provided with: a raw material liquid storage tank (200); a pump (P) for circulating the raw material liquid (a); a flow meter (FM) for displaying the circulation flow rate; a flow adjustment device (not shown) for adjusting the circulation flow rate; a temperature regulator (TC) for maintaining the temperature of the raw material liquid (a) at a set temperature; and a pressure gauge (PG) for indicating the hydraulic pressure when the raw material liquid (a) is supplied to the membrane assembly (100) for membrane distillation. The raw material liquid storage tank (200) is equipped with a liquid level gauge (LG), and the concentration rate can be estimated by the degree of liquid level reduction.

[0059] On the other hand, the shell side pipe of the membrane module (100) for membrane distillation is equipped with a unit (piping system) for circulating cooling water (CW). The piping system is provided with: a cooling water storage tank (300); a pump (P) for circulating cooling water (CW); a flow meter (FM) for displaying the circulation flow rate; a flow adjustment device (not shown) for adjusting the circulation flow rate; and a temperature regulator (TC) for maintaining the temperature of the cooling water (CW) at a set temperature. Through membrane distillation, the solvent moves from the raw material liquid (a) to the cooling water (CW), and the capacity of the cooling water (CW) increases over time. Therefore, the storage capacity of the cooling water storage tank (300) increases as the membrane distillation continues. At this time, if the cooling water (CW) can be discarded, an overflow port can be provided in the cooling water storage tank (300) to maintain the storage capacity of the cooling water (CW) at a constant volume.

[0060] In a raw material liquid concentration system for the production of pharmaceuticals, etc., in order to handle a raw material liquid (a) containing a substance that can be decomposed by heating, such as a peptide or protein, it is necessary to keep the raw material liquid (a) at a low temperature (e.g., 50° C. or less). In addition, as a solvent (b) for the raw material liquid (a), a liquid with a low surface tension, such as acetonitrile, methanol, ethanol, isopropanol, etc., is used.

[0061] Therefore, the membrane for membrane distillation is required to have strong hydrophobicity so as not to be wetted by liquids with low surface tension, and high vapor permeability in order to efficiently remove the vapor of the solvent (b) from the raw material liquid (a) at room temperature.

[0062] Therefore, the membrane used for membrane distillation in the present invention needs to be highly hydrophobic and have a water contact angle of 90° or more. In addition, it is necessary to ensure high vapor permeability, and it is required to be a porous membrane with an average pore size of 0.02 μm to 0.5 μm and a porosity of 60% to 90%. These conditions are described below.

[0063] 《Essentials of the Raw Material Concentration System》

[0064] The above is an overview of the concentration of the raw material liquid using the raw material liquid concentration system of the present invention. Next, each element constituting the raw material liquid concentration system of the present invention will be described in detail below.

[0065] <Raw material liquid (a)>

[0066] The raw material liquid (a) is a fluid containing a solute and a solvent (b), and is to be concentrated by the system of the present invention. The raw material liquid (a) may be any fluid, and may be an emulsion.

[0067] As the raw material liquid (a) suitable for the present invention, for example, there can be mentioned: solutions or dispersions containing drugs, drug raw materials, drug precursors, drug intermediates, etc. (hereinafter collectively referred to as "drug precursors, etc."); foods; seawater; associated water discharged from gas fields / oil fields, etc.

[0068] In the raw material liquid concentration system of the present invention, a concentrated liquid (c) can be obtained in which the composition of the raw material liquid a is substantially maintained in its original state and the solvent is removed. Therefore, if the raw material liquid concentration system of the present invention is applied to the concentration of a solution or dispersion containing a drug substance or the like as a solute, the concentration can be performed while maintaining the efficacy of the drug.

[0069] [Solute of raw material solution a]

[0070] As a drug precursor, for example, it is preferred that a useful substance selected from the group consisting of amino acids, peptides, proteins, sugars, vaccines, nucleic acids, antibiotics, antibody-drug conjugates (ADCs) and vitamins is used as a solute, and the solute is dissolved or dispersed in an appropriate solvent.

[0071] Amino acids are compounds having an amino acid skeleton consisting of a carboxyl group and an amino group, and a portion connecting them. Amino acids in this specification are a concept including essential amino acids, non-essential amino acids, and unnatural amino acids.

[0072] Examples of essential amino acids include tryptophan, lysine, methionine, phenylalanine, threonine, valine, leucine, isoleucine, etc. Examples of non-essential amino acids include arginine, glycine, alanine, serine, tyrosine, cysteine, asparagine, glutamine, proline, aspartic acid, glutamic acid, etc.

[0073] Unnatural amino acids refer to all artificial compounds that have an amino acid skeleton in the molecule and do not exist naturally. However, as unnatural amino acids used as drug precursors, substances obtained by binding a desired labeled compound to the amino acid skeleton can be cited. As labeled compounds, for example, pigments, fluorescent substances, luminescent substances, enzyme substrates, coenzymes, antigenic substances, protein-binding substances, etc. can be cited.

[0074] Examples of unnatural amino acids that are preferably used as pharmaceutical precursors include labeled amino acids and functionalized amino acids.

[0075] The labeled amino acid is a non-natural amino acid in which a labeling compound is bonded to the amino acid backbone. Specific examples thereof include an amino acid in which a labeling compound is bonded to an amino acid backbone having an aromatic ring in the side chain.

[0076] Examples of functionalized amino acids include photoresponsive amino acids, photoconvertible amino acids, fluorescent probe amino acids, and fluorescently labeled amino acids.

[0077] Peptide refers to a compound obtained by combining amino acid residues of 2 or more residues and less than 70 residues, and can be chain-shaped or cyclic. Examples of peptides include L-alanyl-L-glutamine, β-alanyl-L-histidine cyclosporine, glutathione, and the like.

[0078] Proteins generally refer to compounds in which amino acid residues are linked and have a longer chain than peptides. Proteins in the present specification are preferably those that can be used as protein preparations, for example.

[0079] Examples of protein preparations 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, coagulation factor VIII, somatomedin, glucagon, growth hormone releasing factor, serum albumin, calcitonin, and the like.

[0080] Examples of the sugar include monosaccharides, disaccharides, sugar chains (excluding disaccharides), and sugar chain derivatives.

[0081] Examples of monosaccharides include glucose, fructose, galactose, mannose, ribose, deoxyribose, etc. Examples of disaccharides include maltose, sucrose, lactose, etc.

[0082] Sugar chain in this specification refers to a concept other than disaccharides, and examples thereof include glucose, galactose, mannose, fucose, xylose, glucuronic acid, iduronic acid, etc. Examples of sugar chain derivatives include sugar derivatives such as N-acetylglucosamine, N-acetylgalactosamine, and N-acetylneuraminic acid.

[0083] Examples of vaccines include hepatitis A vaccine, hepatitis B vaccine, and hepatitis C vaccine.

[0084] Examples of nucleic acids include oligonucleotides, RNA, aptamers, decoy nucleic acids, and the like;

[0085] Examples of the antibiotics include streptomycin and vancomycin.

[0086] Vitamins include, for example, group A vitamins, group B vitamins, group C vitamins, and the like, and the concept also includes derivatives and salts thereof. Group B vitamins include, for example, vitamin B6 and vitamin B12.

[0087] The solute contained in the raw material liquid may be a low molecular weight compound having a number average molecular weight of about 100 to 75,000, preferably about 100 to 50,000, more preferably about 100 to 10,000, and particularly preferably 100 to 6,000.

[0088] If the molecular weight of the solute is too small, the solute may pass through the membrane for membrane distillation. If the molecular weight is too large, the solute may adhere to the membrane surface, which is not preferable.

[0089] [Solvent (b) in Raw Material Solution (a)]

[0090] The solvent (b) in the raw material liquid (a) is a liquid, and may be any inorganic solvent or organic solvent as long as it can dissolve or disperse the solute in the raw material liquid (a).

[0091] The solvent is preferably water, acetonitrile, methanol, ethanol or isopropanol, and one or more selected from these can be appropriately selected and used. The solvent may be, for example, a mixture containing two or more selected from water, acetonitrile, methanol and isopropanol.

[0092] 〈Concentrated liquid (c)〉

[0093] The concentrated solution (c) obtained by concentrating the raw material solution (a) is obtained by maintaining the solute in the raw material solution (a) substantially in its original state and preferentially separating the solvent (b). In the raw material solution concentration system of the present invention, the amount of the solvent (b) separated from the raw material solution (a) can be arbitrarily controlled.

[0094] 〈Membrane for membrane distillation〉

[0095] As the membrane for membrane distillation used in the present invention, a porous membrane is preferably used.

[0096] The porous membrane has pores (connecting pores) that connect from one surface of the membrane to the other surface in the thickness direction. The pores can be gaps in the network of the membrane material (e.g., polymer), and can be branched or straight. The pores allow vapor to pass through, but not liquid.

[0097] From the perspective of avoiding wetting of the membrane, the water contact angle of at least one side of the membrane for membrane distillation used in the present invention is 90° or more, preferably greater than 90°, more preferably 110° or more, and even more preferably 120° or more. There is no upper limit to the water contact angle of the membrane in terms of the effect of the present invention, and it can be 150° or less in practice.

[0098] The water contact angle in this specification is a value measured by a droplet method in accordance with JIS R 3257. Specifically, 2 μL of pure water is dropped onto the surface of a measurement object, and the angle formed between the measurement object and the droplet is analyzed from a projected image to obtain a numerical value.

[0099] In the membrane for membrane distillation used in the present invention, it is preferred that substantially the entire surface area on one side thereof shows a water contact angle within the above range.

[0100] In addition, as described later, the shape of the membrane for membrane distillation used in the present invention is a hollow fiber, and it is preferred that the outer surface of the hollow fiber shows a water contact angle within the above range.

[0101] The average pore size of the membrane for membrane distillation is in the range of 0.02 μm to 0.5 μm, preferably in the range of 0.03 μm to 0.3 μm. When the average pore size is 0.02 μm or more, the permeation resistance of the vapor does not become too large, and the concentration rate of the raw liquid a is improved. When the average pore size is 0.5 μm or less, the effect of suppressing membrane wetting is good. The average pore size is a value measured by a semi-dry method according to ASTM: F316-86.

[0102] From the perspective of both vapor permeability and wetting inhibition, the membrane preferably has a narrow pore size distribution. Specifically, the pore size distribution as the ratio of the maximum pore size to the average pore size is preferably in the range of 1.2 to 2.5, more preferably in the range of 1.2 to 2.0. The above maximum pore size is a value measured using a bubble point method.

[0103] From the perspective of achieving both high vapor permeability and long-term durability, the porosity of the membrane for membrane distillation is in the range of 60% to 90%. In order to obtain high vapor permeability, the porosity of the membrane for membrane distillation is 60% to 60%, preferably 70% to 70%. From the perspective of maintaining the strength of the membrane itself and preventing problems such as breakage during long-term use, the porosity of the membrane for membrane distillation is 90% to 90%, preferably 85% to 85%.

[0104] From the perspective of obtaining an efficient concentration rate, the surface opening rate of the membrane for membrane distillation is preferably 15% or more, more preferably 18% or more, and further preferably 20% or more for each surface, and is preferably 60% or less, more preferably 55% or less, and further preferably 50% or less from the perspective of maintaining the strength of the membrane itself well and preventing problems such as breakage during long-term use. The surface opening rate is a value obtained by detecting pores in an image of the membrane surface observed by a scanning electron microscope (SEM) using image analysis software.

[0105] As the material constituting the membrane for membrane distillation, there can be mentioned a material containing at least one resin selected from the group consisting of polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinylidene fluoride, polytetrafluoroethylene, ethylene-tetrafluoroethylene copolymer and polychlorotrifluoroethylene. From the aspect of being able to produce a membrane having excellent hydrophobicity, mechanical durability and thermal durability with high film-forming property, polyvinylidene fluoride, ethylene-tetrafluoroethylene copolymer or polychlorotrifluoroethylene is preferred.

[0106] As one embodiment of the present invention, a hydrophobic polymer may be attached to at least a portion of the membrane for membrane distillation in order to improve hydrophobicity. The hydrophobic polymer forms a hydrophobic coating on at least one surface of the membrane for membrane distillation or inside the membrane, which can impart water repellency to the membrane or improve the water repellency of the membrane.

[0107] The hydrophobic polymer can be applied to the membrane for membrane distillation in a solution state dissolved in a suitable solvent such as water or a fluorine-based solvent, and then the solvent is evaporated to adhere to the surface or the inside of the membrane, or both. The application of the hydrophobic polymer solution can be carried out by a suitable method such as atomization such as spraying, dipping, etc.

[0108] In this specification, "hydrophobic polymer" refers to a polymer with low affinity for water, for example, a polymer having a hydrophobic structure. As the hydrophobic structure, non-polar groups or low-polar groups, non-polar skeletons or low-polar skeletons, etc. can be cited. As the non-polar group or low-polar group, for example, hydrocarbon groups, fluorine-containing groups, etc. can be cited, and as the non-polar skeleton or low-polar skeleton, for example, hydrocarbon main chains, siloxane main chains, etc. can be cited.

[0109] Examples of the hydrophobic polymer include polymers having a siloxane bond and polymers containing fluorine atoms. More specifically, for example, the following polymers can be mentioned:

[0110] (A) Examples of polymers having siloxane bonds include dimethyl silicone gel, methylphenyl silicone gel, reactive modified silicone gel having an organic functional group (amino group, fluoroalkyl group, etc.), silicone polymers that react with a silane coupling agent to form a cross-linked structure, and polymer gels that are cross-linked products thereof.

[0111] (B) The fluorine-containing polymer is a polymer having a fluorine-containing group in a side chain. Here, the fluorine-containing group is a (per)fluoroalkyl group, a (per)fluoropolyether group, an alkylsilyl group, a fluorosilyl group, or the like.

[0112] It is particularly preferred that the hydrophobic polymer is a polymer of a (meth)acrylate monomer and / or a vinyl monomer having a (per)fluoroalkyl group and / or a (per)fluoropolyether group having 1 to 12 carbon atoms.

[0113] The hydrophobic polymer can be attached to the entire pores of the membrane used for membrane distillation. From the perspective of preventing liquid from entering the pores and ensuring the permeability of vapor, it is preferred that the amount of hydrophobic polymer attached is distributed in the thickness direction of the membrane used for membrane distillation, with more polymer attached to the surface layer of the membrane in contact with the liquid and less polymer attached to the inside of the membrane in the thickness direction, thereby maintaining the pore structure.

[0114] From this viewpoint, the amount of the hydrophobic polymer adhered is preferably greater on at least one surface of the membrane distillation membrane than on the inside, and more preferably gradually decreases from the surface of one surface of the membrane distillation membrane toward the surface of the opposite surface.

[0115] The "surface layer of the membrane" mentioned here refers to the part of the membrane in contact with the liquid and its vicinity. Quantitatively speaking, it refers to the range of about 10 μm from the outermost part of the membrane to the inside in the thickness direction of the membrane. On the other hand, the "inside of the membrane" refers to the part of the membrane that is not in contact with the liquid and only the vapor passes through, and refers to the part other than the surface layer of the membrane.

[0116] In the present invention, the ratio of the amount of hydrophobic polymer attached to the surface layer (inner and / or outer surface) of the membrane for membrane distillation to the amount of hydrophobic polymer attached to the inside (central part) is preferably 1.2 times or more, more preferably 2.0 times or more, and particularly preferably 3.0 times or more.

[0117] When comparing the adhesion amount of the hydrophobic polymer on the surface layer and inside of the membrane distillation membrane by analysis using an appropriate surface analysis device described below, the comparison is made using the measured values ​​of the following regions of the membrane distillation membrane.

[0118] Surface layer of membrane distillation membrane: The area from the surface of the membrane distillation membrane to a depth of 10 μm

[0119] Inside the membrane for membrane distillation: The area within ±5% of the membrane thickness, centered at a depth of 1 / 2 of the membrane thickness from the surface of the membrane for membrane distillation

[0120] Figure 3 An example of the distribution of the hydrophobic polymer when the membrane for membrane distillation is in the form of a hollow fiber is shown in FIG. Figure 3 (a) shows the distribution of the hydrophobic polymer in the cross section perpendicular to the length direction of the hollow fiber, Figure 3 (b) shows the distribution of the hydrophobic polymer in the cross section along the length direction of the hollow fiber. Figure 3 In (a) and (b), the darker the grey color, the higher the concentration of the hydrophobic polymer.

[0121] Reference Figure 3(a) and (b), in the case of the hollow fiber membrane for membrane distillation, the hydrophobic polymer is attached more near the inner surface of the hollow fiber membrane, and the amount of the hydrophobic polymer near the outer surface is small. In this case, from the perspective of preventing the wetting of the membrane, it is preferred to pass the raw material liquid (a) through the hollow portion in contact with the inner side surface where the amount of the hydrophobic polymer attached is large.

[0122] The hydrophobic polymer may be distributed more near the outer surface of the hollow fiber and less near the inner surface. In this case, the raw material solution (a) is preferably passed through the outer space of the hollow fiber in contact with the outer surface where the hydrophobic polymer is more attached.

[0123] The amount of the hydrophobic polymer attached to the membrane distillation membrane can be directly determined as mass by extracting the membrane distillation membrane to which the hydrophobic polymer is attached with a good solvent for the hydrophobic polymer and removing the solvent from the obtained extract.

[0124] In addition, a suitable surface analysis device can be used to analyze the membrane distillation film attached with a hydrophobic polymer, and the attachment amount can be obtained by the signal intensity ratio of the constituent material of the membrane distillation film and the hydrophobic polymer. According to the surface analysis device, any part of the membrane distillation film can be analyzed, and thus by comparing the signal intensity ratios of various parts of the membrane, the attachment distribution of the hydrophobic polymer can be known. As the surface analysis equipment at this time, for example, IR (infrared spectroscopy absorption) device, XPS (X-ray photoelectron spectroscopy) device, TOF-SIMS (time-of-flight secondary ion analysis) device, etc. can be exemplified.

[0125] In order to make the hydrophobic polymer adhere to the membrane for membrane distillation, the following method can be used: the hydrophobic polymer is dissolved in an appropriate solvent, the obtained coating solution is applied to the membrane and dried. In order to obtain the desired distribution of the hydrophobic polymer, the coating site, the volatility (boiling point) of the solvent of the coating solution, the concentration of the hydrophobic polymer in the coating solution, the drying conditions after coating and other methods can be used to appropriately adjust the coating conditions. For example, in the case of coating by immersion method, the lower the volatility of the solvent in the coating solution (the higher the boiling point) and the milder the drying conditions after coating, the more the coating solution containing the hydrophobic polymer can be moved toward the membrane surface during the drying process, and therefore, distribution can be generated in the thickness direction of the membrane.

[0126] When the hydrophobic polymer is attached in a distribution that gradually decreases from the surface layer of one surface of the membrane distillation membrane toward the surface layer of the other surface, the surface on which the amount of the hydrophobic polymer attached is smaller may be subjected to a hydrophilic treatment.

[0127] The surface on the side with less amount of hydrophobic polymer attached has low hydrophobicity and high affinity with highly hydrophilic solvents, whereas the surface on the side with more hydrophobic polymer attached has high hydrophobicity and low affinity with highly hydrophilic solvents. By utilizing this, only the surface on the side with less amount of hydrophobic polymer attached can be made hydrophilic by being wetted with highly hydrophilic solvents.

[0128] For example, when a membrane for membrane distillation in which the amount of hydrophobic polymer attached gradually decreases from the surface layer of one side toward the surface layer of the opposite side is immersed in ethanol or the like, Figure 4 As shown, only the portion with a small amount of hydrophobic polymer attached is wetted with ethanol (21). If the membrane distillation membrane in this state is used for concentration by membrane distillation, the distance that the vapor passes through in the membrane thickness direction is substantially shortened, thereby increasing the vapor passing rate per unit time.

[0129] When using such a hydrophilized membrane for membrane distillation, it is preferred that the hydrophilized surface be in contact with cooling water and the raw material liquid (a) be in contact with the opposite surface where a larger amount of the hydrophobic polymer is attached.

[0130] [Shape and size of membrane for membrane distillation]

[0131] The shape of the membrane for membrane distillation can be, for example, a flat membrane, a hollow fiber membrane, a tubular membrane, or any other shape. When a flat membrane is used, the shape of the membrane module can be selected from spiral, pleated, laminated, etc. In order to prevent the raw liquid from mixing with the coolant and to ensure the flow path, the membrane is sealed in a bag shape and a spacer is appropriately inserted.

[0132] From the perspective of achieving both vapor permeability and mechanical strength of the membrane, the thickness of the membrane for membrane distillation of the present invention is preferably 10 μm to 1,000 μm, and more preferably 20 μm to 500 μm. If the membrane thickness is 1,000 μm or less, high vapor permeability can be obtained, while if the membrane thickness is 10 μm or more, the membrane can be used without deformation.

[0133] When the membrane for membrane distillation is a hollow fiber membrane, the outer diameter is 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 3,000 μm.

[0134] 〈Membrane distillation module〉

[0135] In the present invention, when the membrane for membrane distillation is in the form of a hollow fiber, a plurality of hollow fiber membranes for membrane distillation may be bundled into a membrane bundle, and the membrane bundle may be packed into an appropriate module to be used in the form of a membrane module for membrane distillation.

[0136] The shape of the component can be cylindrical, polygonal, or other polyhedral, and there is no limitation on the shape.

[0137] Preferably, the following structure may be adopted: the hollow fiber membrane bundle is housed in a cylindrical or polygonal shell in such a manner that the length direction of the hollow fiber is consistent with the axial direction of the shell, and both ends of the hollow fiber bundle are fixed in the shell by using a suitable adhesive resin. In this case, it is preferred to use an adhesive resin to fix the hollow fiber bundle in a liquid-tight manner so that the inner and outer flow paths of the hollow fiber membrane are not mixed.

[0138] It is desirable that the adhesive resin has high mechanical strength and heat resistance at 100° C. Examples of the adhesive resin include thermosetting epoxy resins and thermosetting urethane resins. From the perspective of heat resistance, epoxy resins are preferred. From the perspective of handling properties, urethane resins are preferred.

[0139] The bonding and fixing method may be based on a known bonding method related to the production of membrane modules for membrane distillation.

[0140] Regarding the composition of the shell, the shell is mainly selected from the aspects of pressure resistance, heat resistance, impact resistance, weather resistance, etc., with various properties not being deteriorated by the solutes and solvents contained in the raw material liquid (a) and the cooling water (CW). For example, resins, metals, etc. can be used. From the above aspects, it is preferably selected from synthetic resins such as polypropylene, polysulfone, polyethersulfone, polyvinylidene fluoride, ABS resin, fiber reinforced plastic, vinyl chloride resin, and metals such as stainless steel, brass, and titanium.

[0141] <Component maintenance of the raw material liquid concentration system of the present invention>

[0142] According to the raw material liquid concentration system of the present invention, a high-concentration concentrate in which the composition of the solute contained in the raw material liquid is substantially maintained can be efficiently obtained.

[0143] Therefore, the raw material liquid concentration system of the present invention is suitable for use in, for example, medical manufacturing processes.

[0144] The analysis of the solute in the obtained concentrate can be appropriately selected according to the types of components contained in the raw material liquid and its concentrate. For example, the analysis can be performed by various known analytical methods such as ICP-MS (inductively coupled plasma mass spectrometry), nuclear magnetic resonance spectroscopy (NMR), gas chromatography mass spectrometry (GC / MS), colorimetry, fluorescence, and high performance liquid chromatography (HPLC).

[0145] <Concentration device of the present invention>

[0146] The concentrating device of the present invention comprises the membrane for membrane distillation of the present invention.

[0147] Therefore, the concentrator of the present invention is provided with a membrane for membrane distillation and is used to concentrate a raw material liquid by membrane distillation, wherein:

[0148] As the membrane distillation membrane, a membrane having a water contact angle of 90° or more on the membrane surface, an average pore size of 0.02 μm to 0.5 μm, and a porosity of 60% to 90% is used.

[0149] The hydrophobic polymer may be attached to at least a portion of the membrane distillation membrane. The amount of the hydrophobic polymer attached may have a distribution in the thickness direction of the membrane distillation membrane, with the amount of the hydrophobic polymer attached to at least one surface of the membrane distillation membrane being greater than that to the inside.

[0150] For other aspects of the concentrating device of the present invention, reference can be made to the description of the concentrating system of the present invention.

[0151] Example

[0152] Hereinafter, examples and the like which specifically illustrate the configuration and effects of the present invention will be further described, but the present invention is not limited to the following examples at all.

[0153] 《Various physical properties of hollow fiber membranes for membrane distillation》

[0154] In the present examples, various physical properties of the hollow fiber membrane distillation membrane were determined by various measuring methods described below.

[0155] [Water contact angle on the outer surface of hollow fiber membrane]

[0156] The water contact angle of the hollow fiber membrane for membrane distillation was measured by the liquid drop method according to JIS R 3257.

[0157] At 23°C and 50% relative humidity, 2 μL of pure water was added to the outer surface of the hollow fiber membrane sample, and the angle between the droplet and the outer surface of the hollow fiber membrane was calculated by image analysis to obtain the contact angle. The measurement was performed 5 times, and the number average was used as the water contact angle.

[0158] [Outer diameter, inner diameter and membrane thickness of hollow fiber membrane]

[0159] The outer diameter and inner diameter of the hollow fiber membrane distillation membrane are obtained by microscopic observation. Specifically, the hollow fiber membrane is thinly cut in a direction perpendicular to the length direction using a razor or the like, and a microscopic image of the cross section is obtained, and the outer diameter and inner diameter of the cross section are measured and obtained. The membrane thickness of the hollow fiber membrane is calculated by the following mathematical formula (1).

[0160] [Number 1]

[0161]

[0162] [Average pore size of hollow fiber membrane]

[0163] The average pore size of the hollow fiber membrane for membrane distillation is measured by the average pore size measurement method described in ASTM: F316-86 (also referred to as a semi-dry method).

[0164] For a hollow fiber membrane having a length of about 10 cm, ethanol was used as a liquid, and the measurement was performed under standard measurement conditions at 25° C. and a pressure increase rate of 0.01 atm / sec.

[0165] The average pore diameter is calculated from the following mathematical formula (2).

[0166] Average pore size [μm] = 2,860 × (s [dyne / cm]) / (p [Pa])… (2)

[0167] {In the above mathematical formula, s is the surface tension of the liquid used, and p is the semi-dry air pressure.}

[0168] Here, the surface tension s of liquid ethanol at 25°C is 21.97 dyne / cm, so 2,860×s=62,834. Mathematical formula (2) is transformed into the following mathematical formula (3), and the value of the semi-dry air pressure p is substituted into the mathematical formula (3) to calculate the average pore size of the hollow fiber membrane.

[0169] Average pore size [μm] = 62,834 / (p[Pa])…(3)

[0170] [Maximum pore size of hollow fiber membrane]

[0171] The maximum pore size of the hollow fiber membrane distillation membrane was measured by the bubble point method using ethanol as an immersion liquid.

[0172] One end of a hollow fiber membrane of 8 cm in length was blocked, and a nitrogen supply line was connected to the other end by means of a pressure gauge. Nitrogen was supplied in this state, and after the inside of the pipeline was replaced with nitrogen, the hollow fiber membrane was immersed in ethanol. At this time, in order to prevent ethanol from flowing back into the pipeline, the hollow fiber membrane was immersed in a state of slight pressurization with nitrogen. While the hollow fiber membrane was immersed in ethanol, the pressure of nitrogen was slowly increased, and the pressure P (kg / cm2) when nitrogen bubbles began to steadily emerge from the hollow fiber membrane was recorded. 2 ). Substitute P into the following mathematical formula (4):

[0173] d=C1γ / P…(4)

[0174] {In mathematical formula (4), d is the maximum pore size of the hollow fiber, C1 is a constant, γ is the surface tension of the impregnation liquid, and P is the pressure}, the maximum pore size d of the hollow fiber membrane is calculated. At this time, the value of C1γ when ethanol is used as the impregnation liquid is 0.632 (kg / cm), and the maximum pore size d (μm) is calculated.

[0175] [Porosity of hollow fiber membrane]

[0176] The porosity of the hollow fiber membrane for distillation is calculated from the mass of the hollow fiber membrane and the density (true density) of the material constituting the hollow fiber membrane.

[0177] That is, the hollow fiber membrane is cut into a certain length, and its mass is measured, and the void ratio of the hollow fiber is calculated from the following mathematical formula (5).

[0178] [Number 2]

[0179]

[0180] {In the above mathematical formula, d is the true density of the raw material polymer of the hollow fiber membrane, and π is the circumference of a circle.}

[0181] [Amount of hydrophobic polymer attached]

[0182] (1) IR and ATR methods

[0183] The amount of hydrophobic polymer attached to the hollow fiber membrane distillation membrane was compared by IR spectroscopy and ATR (total reflection method, internal reflection method) using a ZnSe crystal as a prism.

[0184] The measurement apparatus used was Spectrum One manufactured by PerkinElmer, and the crystal pressing pressure was measured with the pressure contour value set to about 30. Then, the ratio of the peak intensity derived from the hydrophobic polymer to the peak intensity derived from the constituent material of the hollow fiber membrane was obtained from the obtained IR spectrum, thereby calculating the amount of the hydrophobic polymer attached to the membrane surface.

[0185] Hollow fiber membrane samples were cut from the module. The hollow fiber membrane was cut at 1 cm intervals along a cross section perpendicular to the longitudinal direction as the sample for analyzing the outer surface of the hollow fiber membrane, and the hollow fiber membrane was cut along the longitudinal direction as the sample for analyzing the inner surface.

[0186] In the examples, the constituent material of the hollow fiber membrane is polyvinylidene fluoride resin (PVDF), and an acrylate polymer having a perfluoroalkyl group in the side chain is used as the hydrophobic polymer. -1 ν(C=O) and 1,180cm -1The peak intensity ratio of (ν(CF)+ν(CO)) in the vicinity, ν(C=O) / (ν(CF)+ν(CO)), was used as an index of the amount of hydrophobic polymer adhesion.

[0187] The peak intensity ratio is measured at each site of the hollow fiber membrane, and when the minimum value is set to 1.0, sites showing a value of 1.2 times or more can be judged to have a large amount of hydrophobic polymer attached.

[0188] (2)TOF-SIMS analysis

[0189] In addition to the above-mentioned IR and ATR methods, the amount of hydrophobic polymer attached to the hollow fiber membrane for membrane distillation can be compared by observing the cross section of the hollow fiber membrane using TOF-SIMS.

[0190] As the observation sample, a hollow fiber membrane cut into a thin sheet was used.

[0191] The equipment used is nano-TOF manufactured by ULVAC-PHI, and the primary ion is Bi3 ++ , acceleration voltage 30kV, current 0.1nA (in DC form), analysis area 350μm×350μm, integration time 120 minutes, detection ions are negative ions, neutralized by electron gun. For the materials constituting the hollow fiber membrane and the hydrophobic polymer, the m / z with strong characteristic intensity is mapped, and the obtained intensity ratio is compared to obtain the existence rate of the hydrophobic polymer in each part.

[0192] It should be noted that, in the TOF-SIMS under the above conditions, an integration time of 30 minutes is sufficient, but in this example, the analysis was performed with the integration time set to 120 minutes.

[0193] In the examples, the constituent material of the hollow fiber membrane is polyvinylidene fluoride resin (PVDF), and as the hydrophobic polymer, an acrylate polymer having a perfluoroalkyl group in the side chain is used. Therefore, the intensity ratio of PVDF, which has a particularly strong m / z of 67, and the intensity ratio of perfluoroacrylate polymer, which has a particularly strong m / z of 293, is calculated.

[0194] Here, when the intensity ratio is 2.0 times or more, it can be determined that the existence rate of the hydrophobic polymer has a significant difference.

[0195] 《Example 1》

[0196] (1) Fabrication of membrane modules for membrane distillation and determination of physical properties of membranes for membrane distillation

[0197] In Example 1, a hollow fiber porous membrane is used as a membrane distillation membrane (20), and the raw material liquid (a) is concentrated by membrane distillation in a state where no hydrophobic polymer is attached. The membrane distillation membrane (20) is filled with Figure 1 The membrane module (100) for membrane distillation having the structure shown is used.

[0198] As the membrane (20) for membrane distillation, a porous hollow fiber membrane made of PVDF with an inner diameter of 0.7 mm, an outer diameter of 1.3 mm, an average pore size of 0.21 μm, a maximum pore size of 0.29 μm, and a porosity of 72% was used and cut into a membrane with a length of 15 cm.

[0199] The water contact angle of the porous hollow fiber membrane was measured by the above-mentioned method and found to be 92°.

[0200] A plurality of the membrane distillation membranes (20) are bundled into a membrane bundle, and the membrane bundle is housed in a housing (10). A thermosetting epoxy resin is used as an adhesive resin (30), and the membrane bundle of the membrane distillation membrane (20) is bonded and fixed in the housing (10) by centrifugal bonding.

[0201] Through the above operation, two membrane distillation membranes (20) were prepared, each having an effective length (length of the portion not buried in the adhesive resin (30)) of 10 cm and a total membrane area of ​​200 cm on the inner surface. 2 A membrane module (100) for membrane distillation comprising a hollow fiber membrane bundle for membrane distillation.

[0202] One of the obtained membrane modules for membrane distillation was disassembled and subjected to measurement of physical properties of the hollow fiber membrane.

[0203] The measurement results are shown in Table 1.

[0204] The remaining membrane distillation membrane module is used for concentrating the raw material solution (a).

[0205] (2) Implementation of membrane distillation

[0206] Using the membrane distillation membrane module (100) prepared as described above, Figure 2 The membrane distillation apparatus having the structure shown is used to carry out membrane distillation.

[0207] As a simulated solution of the raw material solution (a) containing a drug substance or the like, a solution having the following composition was used.

[0208] Solvent (b): A mixed solvent of water and acetonitrile. The mixing ratio of water to acetonitrile was varied, and the concentration operation was carried out at each ratio.

[0209] Solute: dipeptide 1,000ppm and NaCl 1,000ppm

[0210] Liquid volume: 0.5L

[0211] As a means of confirming whether the membrane for membrane distillation is wet, NaCl was added to the raw material solution a.

[0212] The raw material liquid a is filled into the raw material liquid storage tank (200).

[0213] The raw material liquid a was circulated through the hollow fiber membrane of the membrane module (100) for membrane distillation at a flow rate of 600 ml / min by a pump. At this time, the temperature of the raw material liquid a was adjusted by a temperature regulator (TC) so as to be maintained at 30° C. on the inlet side of the membrane module (100) for membrane distillation.

[0214] On the other hand, a cooling water storage tank (300) is provided for holding about 2 L of cooling water (CW), and a pump is used to flow the cooling water at a flow rate of 600 ml / min to the outside of the hollow fiber membrane of the membrane assembly (100) for membrane distillation. At this time, the temperature of the cooling water (CW) is adjusted by a temperature regulator (TC) in such a way that the temperature is maintained at 10°C. In addition, the conductivity of the cooling water (CW) discharged from the membrane assembly (100) for membrane distillation is measured from time to time. When the conductivity of the cooling water (CW) rises to more than 500 μS / cm, it is considered that this is due to the mixing of NaCl added to the raw material solution (a) into the cooling water (CW). Therefore, in this case, it is determined that the membrane for membrane distillation has been wetted.

[0215] When the volume of the raw material liquid (a) measured by the liquid level gauge (LG) installed in the raw material liquid storage tank (200) reaches 100 ml, it is determined that the concentration ratio has reached 5 times, and the concentration is terminated.

[0216] In Example 1, the raw material solution (a) with a mixing ratio of water to acetonitrile of 95:5 (volume ratio) was concentrated 5 times in 39 hours. In addition, the conductivity of the cooling water (CW) was always 5 μS / cm or less, and the membrane for membrane distillation was not wetted.

[0217] However, when the mixing ratio of water and acetonitrile was 90:10 (volume ratio), the conductivity of cooling water (CW) exceeded 500 μS / cm 8 hours after the start of operation, and the membrane distillation membrane became wet, indicating that membrane wetting occurred.

[0218] 《Example 2》

[0219] (1) Fabrication of membrane modules for membrane distillation and determination of physical properties of membranes for membrane distillation

[0220] In Example 2, a hydrophobic polymer was attached to the hollow fiber porous membrane used in Example 1, and the raw material solution (a) was concentrated by membrane distillation in this state. As the hydrophobic polymer, a fluororesin-based waterproofing agent "DP02H" manufactured by AGC Seimi Chemical Co., Ltd. was used. This "DP02H" is a solution containing an acrylate polymer having a perfluoroalkyl group in the side chain.

[0221] Two membrane modules were produced by the same method as in Example 1. These modules were completely immersed in "DP02H" manufactured by AGC Seimi Chemical Co., Ltd. at one time, and then pulled out. Dry air was then passed through the inside and outside of the hollow fiber membrane at a flow rate of 20 L / min to dry the membrane, thereby attaching the hydrophobic polymer to the hollow fiber membrane, thereby obtaining a membrane module (100) for membrane distillation.

[0222] One of the two obtained membrane modules for membrane distillation (100) was disassembled and subjected to measurement of physical properties of the hollow fiber membrane (IR, ATR method and TOF-SIMS analysis). The various physical properties were measured using the center portion in the longitudinal direction of the hollow fiber membrane.

[0223] The water contact angle of the porous hollow fiber membrane to which the hydrophobic polymer was attached was measured by the above-mentioned method and the result was 120°.

[0224] The measurement results are shown in Table 1.

[0225] The remaining membrane distillation membrane module is used for concentrating the raw material solution (a).

[0226] (2) Implementation of membrane distillation

[0227] A method was prepared in the same manner as in Example 1 except that the membrane module for membrane distillation (100) prepared above was used. Figure 2 Membrane distillation was carried out using a membrane distillation apparatus having the structure shown.

[0228] When the membrane module of Example 2 was used, the raw material liquid (a) with a mixing ratio of water to acetonitrile of 95:5 (volume ratio) could be concentrated to 5 times in 39 hours. In addition, the conductivity of the cooling water (CW) was always below 5 μS / cm, and the membrane for membrane distillation did not wet. In addition, the raw material liquid (a) with a mixing ratio of water to acetonitrile of 90:10 (volume ratio) could also be concentrated to 5 times in 32 hours.

[0229] However, when the mixing ratio of water and acetonitrile was 50:50 (volume ratio), the conductivity of cooling water (CW) exceeded 500 μS / cm 3 hours after the start of operation, and the membrane distillation membrane became wet, indicating that membrane wetting occurred.

[0230] 《Example 3》

[0231] (1) Fabrication of membrane modules for membrane distillation and determination of physical properties of membranes for membrane distillation

[0232] In Example 3, as the membrane distillation membrane (20), a membrane distillation membrane in which a hydrophobic polymer was attached to a hollow fiber-shaped porous membrane was used.

[0233] As the hollow fiber porous membrane, a PVDF porous hollow fiber membrane having an inner diameter of 0.7 mm, an outer diameter of 1.3 mm, an average pore size of 0.05 μm, a maximum pore size of 0.12 μm, and a porosity of 70% was cut into a membrane having a length of 15 cm.

[0234] As the hydrophobic polymer, a fluororesin-based water repellent "DP02H" manufactured by AGC Seimi Chemical Co., Ltd. was used.

[0235] Using the above-mentioned hollow fiber porous membrane, two membrane modules were produced by the same method as in Example 1. Using these modules, the hydrophobic polymer was attached to the hollow fiber membrane by immersing and pulling out in "DP02H" manufactured by AGC Seimi Chemical Co., Ltd. and drying in the same method as in Example 2, thereby obtaining a membrane module (100) for membrane distillation.

[0236] One of the two obtained membrane modules for membrane distillation (100) was disassembled and subjected to measurement of physical properties of the hollow fiber membrane (IR, ATR method and TOF-SIMS analysis). The various physical properties were measured using the center portion in the longitudinal direction of the hollow fiber membrane.

[0237] The water contact angle of the porous hollow fiber membrane to which the hydrophobic polymer was attached was measured by the above-mentioned method and the result was 120°.

[0238] The measurement results are shown in Table 1.

[0239] The remaining membrane distillation membrane module is used for concentrating the raw material solution (a).

[0240] (2) Implementation of membrane distillation

[0241] A method was prepared in the same manner as in Example 1 except that the membrane module for membrane distillation (100) prepared above was used. Figure 2 Membrane distillation was carried out using a membrane distillation apparatus having the structure shown.

[0242] When the membrane assembly of Example 3 was used, in the case of a raw liquid (a) having a mixing ratio of water to acetonitrile of 95:5 (volume ratio), it was possible to concentrate 5 times in 48 hours. In the case of a raw liquid (a) having a mixing ratio of water to acetonitrile of 90:10 (volume ratio), it was also possible to concentrate 5 times in 41 hours. In addition, in the case of a mixing ratio of water to acetonitrile of 50:50 (volume ratio), it was possible to concentrate 5 times in 36 hours. In addition, the conductivity of the cooling water (CW) was always below 5μS / cm during all concentrations, and no wetting of the membrane for membrane distillation occurred.

[0243] 《Example 4》

[0244] (1) Fabrication of membrane modules for membrane distillation and determination of physical properties of membranes for membrane distillation

[0245] In Example 4, as the membrane distillation membrane (20), a membrane distillation membrane in which a hydrophobic polymer was attached to a hollow fiber-shaped porous membrane was used.

[0246] As the hollow fiber porous membrane, a PVDF porous hollow fiber membrane having an inner diameter of 0.7 mm, an outer diameter of 1.3 mm, an average pore size of 0.45 μm, a maximum pore size of 0.80 μm, and a porosity of 71% according to ASTM-F316-86 was cut into a membrane having a length of 15 cm.

[0247] As the hydrophobic polymer, a fluororesin-based water repellent "DP02H" manufactured by AGC Seimi Chemical Co., Ltd. was used.

[0248] Using the above-mentioned hollow fiber porous membrane, two membrane modules were produced by the same method as in Example 1. Using these modules, the hydrophobic polymer was attached to the hollow fiber membrane by immersing and pulling out in "DP02H" manufactured by AGC Seimi Chemical Co., Ltd. and drying in the same method as in Example 2, thereby obtaining a membrane module (100) for membrane distillation.

[0249] One of the two obtained membrane modules for membrane distillation (100) was disassembled and subjected to measurement of physical properties of the hollow fiber membrane (IR, ATR method and TOF-SIMS analysis). The various physical properties were measured using the center portion in the longitudinal direction of the hollow fiber membrane.

[0250] The water contact angle of the porous hollow fiber membrane to which the hydrophobic polymer was attached was measured by the above-mentioned method and the result was 120°.

[0251] The measurement results are shown in Table 1.

[0252] The remaining membrane distillation membrane module is used for concentrating the raw material solution (a).

[0253] (2) Implementation of membrane distillation

[0254] A method was prepared in the same manner as in Example 1 except that the membrane module for membrane distillation (100) prepared above was used. Figure 2 Membrane distillation was carried out using a membrane distillation apparatus having the structure shown.

[0255] When the membrane module of Example 2 was used, the raw material liquid (a) with a mixing ratio of water to acetonitrile of 95:5 (volume ratio) could be concentrated 5 times in 24 hours. Also, the raw material liquid (a) with a mixing ratio of water to acetonitrile of 90:10 (volume ratio) could be concentrated 5 times in 18 hours. In these cases, the conductivity of the cooling water (CW) was often 5 μS / cm or less, and the membrane for membrane distillation did not wet.

[0256] However, when the mixing ratio of water and acetonitrile was 50:50 (volume ratio), the conductivity of the cooling water (CW) exceeded 500 μS / cm 2 hours after the start of operation, and the membrane distillation membrane became wet, indicating that membrane wetting occurred.

[0257] 《Example 5》

[0258] (1) Fabrication of membrane modules for membrane distillation and determination of physical properties of membranes for membrane distillation

[0259] In Example 3, a hydrophobic polymer was attached to the hollow fiber porous membrane used in Example 1 by a method different from that in Example 2, and the raw material liquid (a) was concentrated by membrane distillation in this state. As the hydrophobic polymer, a fluororesin-based water-repellent agent "FS-392B" (polymer concentration 0.15 mass %) manufactured by FluoroTechnology was used, and the concentrate having the polymer concentration increased to 0.5 mass % by removing the low boiling point solvent was subjected to the hydrophobic polymer attachment operation.

[0260] Two membrane modules were prepared by the same method as in Example 1. These membrane modules were completely immersed in the "FS-392B" concentrate manufactured by Fluoro Technology Co., Ltd. at one time, and then dried by passing dry air at a flow rate of 200 ml / min only to the inner side of the hollow fiber membrane. The immersion and drying operation was repeated twice in total, thereby attaching the hydrophobic polymer to the hollow fiber membrane, and obtaining a membrane module (100) for membrane distillation.

[0261] One of the two membrane modules for membrane distillation obtained was disassembled and subjected to measurement of physical properties of the hollow fiber membrane.

[0262] The water contact angle of the porous hollow fiber membrane to which the hydrophobic polymer was attached was measured by the above-mentioned method and the result was 130°.

[0263] The measurement results are shown in Table 1.

[0264] The remaining membrane distillation membrane module is used for concentrating the raw material solution (a).

[0265] (2) Implementation of membrane distillation

[0266] A method was prepared in the same manner as in Example 1 except that the membrane module for membrane distillation (100) prepared above was used. Figure 2 Membrane distillation was carried out using a membrane distillation apparatus having the structure shown.

[0267] When the membrane module of Example 3 was used, the raw liquid (a) with a mixing ratio of water to acetonitrile of 95:5 (volume ratio) could be concentrated 5 times in 41 hours. In addition, the conductivity of the cooling water (CW) was always below 5 μS / cm, and the membrane for membrane distillation was not wetted.

[0268] In the case of a raw material liquid (a) with a mixing ratio of water to acetonitrile of 90:10 (volume ratio), it was also concentrated to 5 times in 33 hours. In the case of a mixing ratio of water to acetonitrile of 50:50 (volume ratio), it was also concentrated to 5 times in 24 hours, and the conductivity of the generated water was always below 5 μS / cm.

[0269] In addition, when the raw material liquid (a) was concentrated using a mixed solvent containing water and isopropyl alcohol in a volume ratio of 50:50 as the solvent (b), it was also possible to concentrate it 5 times in 20 hours, and the conductivity of the cooling water (CW) was always below 5μS / cm.

[0270] Example 6

[0271] The membrane assembly prepared in the same manner as in Example 5 was immersed in ethanol for 5 minutes. Thereafter, the outer side of the hollow fiber membrane in the membrane assembly was washed with running water for 10 minutes. By this operation, the inner side of the hollow fiber membrane was not wetted by ethanol, but only the outer side was wetted, forming a hydrophilic state.

[0272] The membrane module in this state was used to prepare the same method as in Example 1. Figure 2 The membrane distillation apparatus having the structure shown concentrated the raw material liquid (a) using a mixed solvent containing water and isopropyl alcohol at a volume ratio of 50:50.

[0273] As a result, the time required to concentrate the raw material solution (a) 5 times was shortened to 14 hours. In addition, the electrical conductivity of the cooling water (CW) was always 5 μS / cm or less.

[0274] This is considered to be because, by hydrophilizing a portion of the hollow fiber membrane, a portion of the membrane for membrane distillation contains water, the effective thickness of the membrane decreases, and the distance that the solvent (b) that becomes vapor during membrane distillation passes in the membrane thickness direction is shortened.

[0275] Comparative Example 1

[0276] In Comparative Example 1, as the membrane distillation membrane (20), a hollow fiber membrane made of polyacrylonitrile having an inner diameter of 0.7 mm, an outer diameter of 1.2 mm, an average pore size of 0.01 μm, a maximum pore size of 0.03 μm, and a porosity of 68% was cut into a membrane having a length of 15 cm. The water contact angle of the porous hollow fiber membrane was measured by the above-mentioned method and the result was 84°.

[0277] Two membrane modules (100) for membrane distillation were produced in the same manner as in Example 1 except that the above-mentioned porous hollow fiber membrane was used.

[0278] One of the obtained membrane modules for membrane distillation was disassembled and subjected to measurement of physical properties of the hollow fiber membrane. The measurement results are shown in Table 1.

[0279] The remaining membrane distillation membrane module is used for concentrating the raw material solution (a).

[0280] A product was prepared in the same manner as in Example 1 except that the obtained membrane distillation membrane module (100) was used. Figure 2 The membrane distillation apparatus having the structure shown above carried out membrane distillation of the raw material liquid (a) using a mixed solvent containing water and acetonitrile at a volume ratio of 95:5.

[0281] However, even after 50 hours of operation, the concentration did not reach 5 times.

[0282] Comparative Example 2

[0283] As the membrane distillation membrane (20), a PVDF hollow fiber membrane having an inner diameter of 0.7 mm, an outer diameter of 1.3 mm, an average pore size of 0.12 μm, a maximum pore size of 0.60 μm, and a porosity of 69% was used, which was cut into a membrane having a length of 15 cm. The water contact angle of the porous hollow fiber membrane was measured by the above method and the result was 92°.

[0284] Two membrane modules (100) for membrane distillation were produced in the same manner as in Example 1 except that the above-mentioned porous hollow fiber membrane was used.

[0285] One of the obtained membrane modules for membrane distillation was disassembled and subjected to measurement of physical properties of the hollow fiber membrane. The measurement results are shown in Table 1.

[0286] The remaining membrane distillation membrane module is used for concentrating the raw material solution (a).

[0287] The same method as in Example 1 was used except that the membrane module for membrane distillation (100) was used. Figure 2 The membrane distillation apparatus having the structure shown above carried out membrane distillation of the raw material liquid (a) using a mixed solvent containing water and acetonitrile at a volume ratio of 95:5.

[0288] However, when the operation time had elapsed for 13 hours, the electrical conductivity of the cooling water (CW) exceeded 500 μS / cm, causing wetting of the membrane and making it impossible to further concentrate.

[0289]

[0290] [Table 2]

[0291] Table 1 (Continued)

[0292]

[0293] (Table 1 ends)

[0294] The abbreviations in Table 1 have the following meanings.

[0295] 〈Hollow fiber membrane constituent materials〉

[0296] PVDF: Polyvinylidene fluoride

[0297] PAN: Polyacrylonitrile

[0298] 〈Hydrophobic polymer〉

[0299] DP02H: Fluorine resin water repellent "DP02H" manufactured by AGC Seimi Chemical

[0300] FS-392B: Fluoro Technology Co., Ltd., fluororesin-based water repellent "FS-392B"

[0301] <Solvent (b)>

[0302] AcCN: acetonitrile

[0303] IPA: Isopropyl alcohol

[0304] Explanation of symbols

[0305] 10. Housing

[0306] 11 1st casing side pipe

[0307] 12 Second casing side pipe

[0308] 20 Membrane for membrane distillation

[0309] 30 Adhesive resin

[0310] 100 Membrane modules for membrane distillation

[0311] 200 Raw material liquid storage tank

[0312] 300 Cooling water storage tank

[0313] a Raw material liquid

[0314] b. Solvent

[0315] c Concentrate

[0316] CW Cooling Water

[0317] FM Flow Meter

[0318] LG Liquid Level Meter

[0319] P Pump

[0320] PG pressure gauge

[0321] TC Temperature Regulator

Claims

1. A raw material liquid concentration system for a pharmaceutical manufacturing process, which uses the following membrane distillation method: a raw material liquid containing a solvent and a solute is brought into contact with cooling water via a membrane distillation membrane, and the solvent in the raw material liquid is moved to the cooling water side through the membrane distillation membrane in a vapor state, In the raw liquid concentration system, As the membrane distillation membrane, a porous membrane having a surface water contact angle of 90° or more, an average pore diameter of 0.02 μm to 0.5 μm, and a porosity of 60% to 90% is used. A hydrophobic polymer is attached to at least a portion of the membrane distillation membrane. The amount of the hydrophobic polymer attached is distributed in the thickness direction of the membrane distillation membrane. The amount of the hydrophobic polymer attached to at least one surface of the membrane distillation membrane is greater than that attached to the inside.

2. The feedstock liquid concentration system according to claim 1, wherein: The amount of the hydrophobic polymer attached gradually decreases from the surface layer on one side of the membrane for membrane distillation toward the surface layer on the opposite side.

3. The feedstock liquid concentration system according to claim 2, wherein: The opposite side to which the hydrophobic polymer is less attached is subjected to a hydrophilic treatment, and the hydrophilic treated side is brought into contact with cooling water, and The one side of the single surface on which the amount of the hydrophobic polymer attached is large is not subjected to a hydrophilic treatment, and the single surface is brought into contact with the raw material liquid.

4. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The hydrophobic polymer is a polymer having a fluorine atom-containing group in a side chain, and has at least one side chain selected from a fluoroalkyl group, a fluoropolyether group, and a fluorosilyl group.

5. The feedstock liquid concentration system according to claim 4, wherein: The fluoroalkyl group is a perfluoroalkyl group.

6. The feedstock liquid concentration system according to claim 4, wherein: The fluoropolyether group is a perfluoropolyether group.

7. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The material of the membrane for membrane distillation includes at least one resin selected from the group consisting of polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinylidene fluoride, polytetrafluoroethylene, ethylene-tetrafluoroethylene copolymer and polychlorotrifluoroethylene.

8. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The solvent includes at least one selected from the group consisting of water, acetonitrile, methanol, ethanol and isopropanol.

9. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The solute is at least one selected from the group consisting of amino acids, peptides, proteins, sugars, vaccines, nucleic acids, antibiotics, antibody drug conjugates (ADCs) and vitamins.

10. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The number average molecular weight of the solute is 100 to 50,000.

11. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The temperature of the raw material liquid is adjusted to a range of 5° C. to 50° C.

12. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The solvent comprises at least one selected from the group consisting of water, acetonitrile, methanol, ethanol and isopropanol, The solute is at least one selected from the group consisting of amino acids, peptides, proteins, sugars, vaccines, nucleic acids, antibiotics, antibody drug conjugates (ADCs) and vitamins, The number average molecular weight of the solute is 100 to 50,000, The temperature of the raw material liquid is adjusted to a range of 5° C. to 50° C.

13. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The membrane for membrane distillation has a pore size distribution in which the ratio of the maximum pore size to the average pore size is in the range of 1.2 to 2.

5.

14. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The porosity of the membrane for membrane distillation is 70% to 85%.

15. The feedstock liquid concentration system according to claim 7, wherein: The material of the membrane for membrane distillation includes at least one resin selected from the group consisting of polyvinylidene fluoride, ethylene-tetrafluoroethylene copolymer and polychlorotrifluoroethylene.

16. The feedstock liquid concentration system according to claim 15, wherein: The material of the membrane for membrane distillation includes polyvinylidene fluoride.

17. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The membrane for membrane distillation is selected from the group consisting of flat membranes, hollow fiber membranes and tubular membranes.

18. The raw material liquid concentration system according to any one of claims 1 to 3, wherein: The membrane used for membrane distillation is a hollow fiber membrane.

19. A concentrating device comprising a membrane for membrane distillation, for concentrating a raw material liquid by membrane distillation, wherein: As the membrane distillation membrane, a membrane having a water contact angle of 90° or more on the membrane surface, an average pore size of 0.02 μm or more and 0.5 μm or less, and a porosity of 60% to 90% is used. A hydrophobic polymer is attached to at least a portion of the membrane distillation membrane. The amount of the hydrophobic polymer attached is distributed in the thickness direction of the membrane distillation membrane. The amount of the hydrophobic polymer attached to at least one surface of the membrane distillation membrane is greater than that attached to the inside.

20. The concentrating device of claim 19, wherein: The amount of the hydrophobic polymer attached gradually decreases from the surface layer on one side of the membrane for membrane distillation toward the surface layer on the opposite side.

21. The concentrating device of claim 20, wherein: The opposite surface on which the amount of the hydrophobic polymer attached is small is subjected to a hydrophilic treatment, and the one side on which the amount of the hydrophobic polymer attached is large is not subjected to a hydrophilic treatment.

22. The concentrating device according to any one of claims 19 to 21, wherein: The hydrophobic polymer is a polymer having a fluorine atom-containing group in a side chain, and has at least one side chain selected from a fluoroalkyl group, a fluoropolyether group, and a fluorosilyl group.

23. The concentrating device of claim 22, wherein: The fluoroalkyl group is a perfluoroalkyl group.

24. The concentrating device of claim 22, wherein: The fluoropolyether group is a perfluoropolyether group.

25. The concentrating device according to any one of claims 19 to 21, wherein: The material of the membrane for membrane distillation includes at least one resin selected from the group consisting of polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinylidene fluoride, polytetrafluoroethylene, ethylene-tetrafluoroethylene copolymer and polychlorotrifluoroethylene.

26. The concentrating device of claim 25, wherein: The material of the membrane for membrane distillation includes at least one resin selected from the group consisting of polyvinylidene fluoride, ethylene-tetrafluoroethylene copolymer and polychlorotrifluoroethylene.

27. The concentrating device of claim 26, wherein: The material of the membrane for membrane distillation includes polyvinylidene fluoride.

28. The concentrating device according to any one of claims 19 to 21, wherein: The membrane for membrane distillation has a pore size distribution in which the ratio of the maximum pore size to the average pore size is in the range of 1.2 to 2.

5.

29. The concentrating device according to any one of claims 19 to 21, wherein: The porosity of the membrane for membrane distillation is 70% to 85%.

30. The concentrating device according to any one of claims 19 to 21, wherein: The membrane for membrane distillation is at least one selected from the group consisting of a flat membrane, a hollow fiber membrane and a tubular membrane.

31. The concentrating device according to any one of claims 19 to 21, wherein: The membrane used for membrane distillation is a hollow fiber membrane.

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