Process for preparing poly (aryl ether sulfone) (PAES) polymers

Abstract

To provide a membrane for purifying a biological fluid.SOLUTION: A membrane comprising at least one poly (aryl ether sulfone) (PAES) polymer comprising repeating units (RPAES) of formula (I) wherein each R1 is independently at each occurrence an alkyl having 1 to 5 carbon atoms and R is an alkyl having 1 to 10 carbon atoms or a cycloalkyl having 5 to 8 carbon atoms, wherein the weight-average molecular weight (M w) of the PAES is in the range of 70,000g / mole to 200,000g / mole as determined by size exclusion chromatography using methylene chloride as the mobile phase.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 944,121, filed December 5, 2019, and European Patent Application Publication No. 20162138.0, filed March 10, 2020, the entire contents of each of which are incorporated herein by reference for all purposes.

[0002] The present invention relates to a membrane for purifying biological fluids, the membrane comprising at least one poly(aryl ether sulfone) (PAES) polymer based on one specific dihydroxy monomer. The present invention also relates to a method for purifying biological fluids, the method comprising at least a filtration step through the membrane, and a polymer solution for preparing such a membrane, the polymer solution comprising the PAES. [Background technology]

[0003] Poly(aryl ether sulfone) (PAES) polymers are utilized in various application areas, such as the medical market, for the manufacture of membranes, etc., due to their excellent mechanical and thermal properties combined with outstanding hydrolytic stability. PAES is a generic term used to describe polymers containing at least one sulfone group (-SO-), at least one ether group (-O-), and at least one arylene group.

[0004] A commercially important group of PAES includes polysulfone polymers identified herein as polysulfone, or PSU for short. PSU polymers contain repeat units derived from the condensation of the dihydroxy monomer bisphenol A (BPA) with a dihalogen monomer, such as 4,4'-dichlorodiphenyl sulfone (DCDPS). Such PSU polymers are commercially available from Solvay Specialty Polymers USA LLC under the trademark UDEL®. The structure of the repeat unit of such a PSU polymer is shown below: [ka]

[0005] PSU polymers have high glass transition temperatures (eg, about 185° C.) and exhibit high strength and toughness.

[0006] Another important group of PAES includes polyethersulfone polymers, or PES for short. PES polymers are derived from the condensation of the dihydroxy monomer bisphenol S (BPS) with a dihalogen monomer, such as 4,4'-dichlorodiphenyl sulfone (DCDPS). Such PES polymers are commercially available from Solvay Specialty Polymers USA LLC under the trademark VERADEL®. The structure of the repeating unit of such PES polymers is shown below: [ka]

[0007] BPA and BPS are industrial chemicals that have been present in many products, such as plastic bottles and food and beverage cans, since the 1960s. PSU and PES polymers based on BPA and BPS, respectively, are also frequently used to prepare membranes used in contact with biological fluids, such as blood. In recent years, concerns about the safety of BPA and BPS have grown. Therefore, polymeric materials based on BPS and monomers different from BPA are needed.

[0008] The membranes described in this invention are based on BPA- and BPS-free PAES polymers. More precisely, the PAES of the present invention is preferably based on tetraalkylated bisphenol F, such as tetramethylbisphenol F (TMBPF), which has low or no endocrine disrupting potential.

[0009] US Patent Application Publication No. 2014 / 0113093 (Solvay) describes PAES polymers derived from certain aromatic diols, which have weak binding affinity to the estrogen receptor, are well suited for the food and pharmaceutical industries, and advantageously pose a low risk to human health. This document does not describe the use of tetraalkylated bisphenol F.

[0010] Sundell et al. (Polymer (2014), 55(22), 5623-5634) describes the synthesis, oxidation and crosslinking of polymers based on tetramethylbisphenol F (TMBPF) for oxygen / nitrogen gas separation.

[0011] Sundell et al. (International Journal of Hydrogen Energy (2012), 37(12), 9873-9881) describes a self-crosslinked alkaline electrolyte membrane based on quaternary ammonium poly(ether sulfone) for high-performance alkaline fuel cells, and in particular describes the synthesis of tetramethylbisphenol F polysulfone from TMBPF and DCDPS in the presence of potassium carbonate, dimethyl sulfoxide, and toluene.

[0012] However, these articles do not describe the use of such polymers for preparing membranes for purifying biological fluids, and in particular, they do not describe a method for purifying biological fluids, which method includes at least a filtration step through such membranes.

[0013] WO 2018 / 079733 (Mitsui) relates to a forward osmosis membrane comprising a semipermeable membrane and a porous substrate disposed on at least one side of the semipermeable membrane. The semipermeable membrane comprises a protonic acid group-containing aromatic polyether resin. The copolymer of Example 8 is obtained by condensing 40 mol% disulfonated DCDPS and 60 mol% DCDPS with TMBPF in a DMSO / toluene solvent blend. However, such a copolymer is unsuitable for membrane preparation due to its low molecular weight.

[0014] WO 17096140 (GE) generally relates to polymer blends used to manufacture hollow fiber membranes. The polymer blends include at least one polymer containing zwitterionic groups. U.S. Patent Application Publication No. 2019 / 106545 (Fresenius) relates to polysulfone-urethane copolymers and discloses methods for incorporating the copolymers into membranes (e.g., spun hollow fiber membranes or flat membranes). U.S. Patent Application Publication No. 2014 / 113093 (Solvay) relates to novel polymers with reduced estrogenic activity. The invention further relates to compositions containing such polymers and articles made from such polymers. None of these three documents describes the polymers according to the present invention. Summary of the Invention

[0015] One aspect of the present disclosure is a membrane for purifying a biological fluid, the membrane comprising: [ka] (In the formula, - each R1 is independently at each occurrence an alkyl having 1 to 5 carbon atoms; and - R is alkyl having 1 to 10 carbon atoms or cycloalkyl having 5 to 8 carbon atoms Repeating units (R PAES The present invention relates to a membrane comprising a poly(aryl ether sulfone) (PAES) polymer containing

[0016] The PAES used to prepare such membranes is preferably in a solvent, at least a compound of formula (III): [ka] wherein each R1 is, independently at each position, alkyl having 1 to 5 carbon atoms, and R is alkyl having 1 to 10 carbon atoms or cycloalkyl having 5 to 8 carbon atoms. at least one aromatic dihydroxy monomer (a) comprising a monomer (a1) of the formula - at least one aromatic dihalogen sulfone monomer (b), comprising at least one dihalogen compound selected from the group consisting of 4,4'-dichlorodiphenyl sulfone (DCPDS) and 4,4'-difluorodiphenyl sulfone (DFDPS), - at least one carbonate component The reaction mixture (R G ) is derived from the condensation of

[0017] Another aspect of the present invention is a method for purifying a biological fluid, the method comprising at least a filtration step through a membrane as described herein. The biological fluid is preferably blood. The method is preferably carried out in an extracorporeal circuit, such as a hemodialyzer.

[0018] A further aspect of the present invention is a polymer solution for preparing a membrane, the polymer solution comprising a PAES disclosed herein.

[0019] A fourth aspect of the present invention is the use of the PAES polymers described herein for preparing membranes for purifying biological fluids, preferably blood. [Brief explanation of the drawings]

[0020] [Figure 1] Photograph of a membrane obtained using a polymer according to the invention (scale 50 μm). [Figure 2] Photograph of a membrane obtained using Udel® P3500, a polymer commercially available from Solvay Specialty Polymers USA, LLC (scale 50 μm). DETAILED DESCRIPTION OF THE INVENTION

[0021] The inventors have found that using certain dihydroxy monomers with low or no endocrine disrupting potential, PAES polymers with the right set of properties (particularly molecular weight) can be successfully prepared, which can then be used to prepare membranes for use in purifying biological fluids. PAES polymers incorporating such monomers therefore exhibit reduced estrogenic activity and therefore pose a low risk to human health.

[0022] In this application: - any description, even if made in relation to a particular embodiment, is applicable to and interchangeable with other embodiments of the present disclosure; - when an element or component is said to be included in and / or selected from a list of enumerated elements or components, it is to be understood that in the relevant embodiments expressly contemplated herein, the element or component may be any one of the individually enumerated elements or components, or may be selected from a group consisting of any two or more of the explicitly enumerated elements or components, and that any element or component enumerated in a list of elements or components may be omitted from such list; - Any recitation herein of numerical ranges by endpoints includes all numbers subsumed within the recited range, as well as the endpoints of the range and equivalents thereof.

[0023] The terms "(co)polymer" or "polymer" are used herein to designate homopolymers containing substantially 100 mol% of the same repeating units and copolymers that contain at least 50 mol%, e.g., at least about 60 mol%, at least about 65 mol%, at least about 70 mol%, at least about 75 mol%, at least about 80 mol%, at least about 85 mol%, at least about 90 mol%, at least about 95 mol%, or at least about 98 mol% of the same repeating units.

[0024] Polymer PAES The poly(aryl ether sulfone) (PAES) polymers described herein have the formula (I): [ka] (In the formula, - each R1 is independently at each occurrence an alkyl having 1 to 5 carbon atoms; and - R is alkyl having 1 to 10 carbon atoms or cycloalkyl having 5 to 8 carbon atoms Repeating units (R PAES ) is included.

[0025] In some embodiments, the PAES polymer has at least 50 mole % repeat units (R PAES ) is included.

[0026] Thus, the PAES polymer of the present invention can be a homopolymer or a copolymer. If a copolymer, it can be a random, alternating, or block copolymer.

[0027] According to one embodiment of the present invention, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, at least 95 mol%, at least 99 mol% or all of the repeat units in the PAES are repeat units of formula (I) (R PAES Preferably, the PAES polymer of the present invention comprises more than 60 mole % of repeat units (R PAES ) is included.

[0028] The PAES polymer of the present invention preferably has the formula (II): [ka] (wherein each R1 is independently at each position an alkyl having 1 to 5 carbon atoms, preferably methyl at each position). Repeating units (R PAES ) is included.

[0029] According to a preferred embodiment of the present invention, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, at least 95 mol%, at least 99 mol% or all of the repeat units in the PAES are repeat units of formula (II) (R PAES )

[0030] In some embodiments of the present invention, the PAES is a (R PAES ) repeating unit and a different repeating unit (R* PAES ) is included.

[0031] The PAES is a compound represented by the formula (I) or (II) (R PAES ) repeating unit and a different repeating unit (R* PAES When the polymer contains a sulfonated repeat unit (R*) resulting from the condensation of disulfonated DCDPS, this additional repeat unit may be, for example, sulfonated. PAES ), the total number of moles of these repeat units is less than 40 mol%, for example, less than 30 mol%, less than 25 mol%, less than 20 mol%, less than 15 mol%, or less than 10 mol%, based on the total number of moles of the PAES polymer.

[0032] In some other embodiments, the PAES is (R PAES ) repeating unit and a different repeating unit (R* PAES ), provided that the molar percentage of sulfonated repeat units is less than 1 mol %, less than 0.5 mol %, or less than 0.1 mol %, based on the total number of moles of PAES polymer.

[0033] In some embodiments, the PAES polymers of the present disclosure comprise repeating units (R PAES) and less than 40 mol%, less than 30 mol%, less than 25 mol%, less than 20 mol%, less than 15 mol%, less than 10 mol%, less than 1 mol%, less than 0.5 mol%, or even less than 0.1 mol% sulfonated repeat units based on the total number of moles of PAES polymer.

[0034] The PAES polymers described in this disclosure are in a solvent, at least a compound of formula (III): [ka] wherein each R1 is, independently at each position, alkyl having 1 to 5 carbon atoms, and R is alkyl having 1 to 10 carbon atoms or cycloalkyl having 5 to 8 carbon atoms. at least one aromatic dihydroxy monomer (a) comprising a monomer (a1) of the formula - at least one aromatic dihalogen sulfone monomer (b), comprising at least one dihalogen compound selected from the group consisting of 4,4'-dichlorodiphenyl sulfone (DCPDS) and 4,4'-difluorodiphenyl sulfone (DFDPS), - at least one carbonate component The reaction mixture (R G ) can be obtained by condensation with

[0035] The monomer (a1) preferably has the formula (IV): [ka] (wherein each R1 is independently at each position an alkyl having 1 to 5 carbon atoms, preferably methyl at each position). Follow.

[0036] In the above formulas (I) to (IV), R1 is preferably methyl at each position.

[0037] According to one embodiment, the PAES described herein is obtained by condensation of aromatic dihydroxy monomers (a) containing at least 50 mol% of monomer (a1) based on the total moles of aromatic dihydroxy monomers. For example, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the aromatic dihydroxy monomers (a) contain monomer (a1). According to a preferred embodiment, the aromatic dihydroxy monomer (a) consists essentially of monomer (a1).

[0038] According to one embodiment, the PAES described herein is obtained from the condensation of aromatic dihalogen sulfone monomer (b) comprising at least 50 mol% of 4,4'-dichlorodiphenyl sulfone (DCPDS), based on the total moles of aromatic dihalogen sulfone monomers. For example, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, at least 95 mol%, or at least 99 mol% of the aromatic dihalogen sulfone monomer (b) comprises DCDPS.

[0039] According to a preferred embodiment, the aromatic dihalogen sulfone monomer (b) consists essentially of DCPDS.

[0040] The molar ratio of monomers (a) to (b) can vary from 0.9 to 0.1. For example, the molar ratio of (a) to (b) can vary from 1.01 to 1.05.

[0041] The solvent used to prepare the PAES described herein can be selected from the group consisting of dimethyl sulfoxide (DMSO), dimethyl sulfone (DMS), diphenyl sulfone (DPS), 1,3-dimethyl-2-imidazolidinone (DMI), diethyl sulfoxide, diethyl sulfone, diisopropyl sulfone, tetrahydrothiophene-1,1-dioxide, tetrahydrothiophene-1-monoxide, N-methylpyrrolidone (NMP), N-butylpyrrolidone (NBP), N-ethyl-2-pyrrolidone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), tetrahydrofuran (THF), toluene, benzene, chlorobenzene, dichlorobenzene, anisole, chloroform, dichloromethane (DCM), sulfolane, and mixtures thereof.

[0042] When the PAES polymer of the present invention contains sulfonated repeating units, for example, repeating units derived from sulfonated DCDPS (provided that the molar proportion of repeating units derived from sulfonated DCDPS is less than 40 mol %), the solvent is preferably selected from the group consisting of dimethyl sulfone (DMS), diphenyl sulfone (DPS), 1,3-dimethyl-2-imidazolidinone (DMI), diethyl sulfoxide, diethyl sulfone, diisopropyl sulfone, tetrahydrothiophene-1,1-dioxide, tetrahydrothiophene-1-monoxide, N-methylpyrrolidone (NMP), N-butylpyrrolidone (NBP), N-ethyl-2-pyrrolidone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), tetrahydrofuran (THF), benzene, chlorobenzene, dichlorobenzene, anisole, chloroform, dichloromethane (DCM), sulfolane, and mixtures thereof, more preferably sulfolane or NMP.

[0043] The condensation process described herein can be carried out in the presence of a carbonate component selected from the group of alkali metal bicarbonates, e.g., sodium bicarbonate (NaHCO) and potassium bicarbonate (KHCO), or the group of alkali metal carbonates, e.g., potassium bicarbonate (KCO) and sodium carbonate (NaCO). Preferably, the process is carried out in the presence of potassium carbonate (KCO), sodium carbonate (NaCO), or a blend of both. According to one embodiment, the process is carried out in the presence of a low-particle-size alkali metal carbonate, e.g., anhydrous KCO having a volume average particle size of less than about 100 μm, e.g., less than 45 μm, less than 30 μm, or less than 20 μm. According to a preferred embodiment, the process is carried out in the presence of a carbonate component comprising 50 wt. % or more of KCO having a volume average particle size of less than about 100 μm, e.g., less than 45 μm, less than 30 μm, or less than 20 μm, based on the total weight of the base components in the reaction mixture. The volume-average particle size of the carbonates used can be determined, for example, using a Malvern Mastersizer 2000 on a suspension of particles in chlorobenzene / sulfolane (60 / 40).

[0044] The molar ratio of the carbonic acid component to the dihydroxy monomer (a) may be 1.0 to 1.2, for example, 1.01 to 1.15 or 1.02 to 1.1. The molar ratio of the carbonic acid component to the dihydroxy monomer (a) is preferably 1.05 or more, for example, 1.06 or 1.08.

[0045] In a condensation reaction, the components of the reaction mixture usually react simultaneously. The reaction is preferably carried out in one step. This means that the deprotonation of monomer (a) and the condensation reaction between monomers (a) and (b) occur in a single reaction step without separation of intermediate products.

[0046] According to one embodiment of the process of the present invention, the condensation is carried out in a mixture of a polar aprotic solvent and a solvent that forms an azeotrope with water. Examples of solvents that form an azeotrope with water include aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and chlorobenzene. Toluene or chlorobenzene is preferred. The azeotrope-forming solvent and the polar aprotic solvent are typically used in a weight ratio of about 1:10 to about 1:1, preferably about 1:5 to about 1:1. Water is continuously removed from the reaction mixture as an azeotrope with the azeotrope-forming solvent, thereby maintaining substantially anhydrous conditions during polymerization. The azeotrope-forming solvent, e.g., chlorobenzene, is typically removed from the reaction mixture by distillation after the water formed in the reaction has been removed, leaving the PAES dissolved in the polar aprotic solvent.

[0047] Preferably, the reaction mixture (R G ) does not include substances that form azeotropes with water.

[0048] In some embodiments, the process is such that the conversion (C) is at least 95%.

[0049] The temperature of the reaction mixture is maintained at about 150°C to about 350°C, preferably about 210°C to about 300°C, for about 1 hour to 15 hours.

[0050] The reaction mixture is polycondensed within this temperature range until the required degree of condensation is reached. The polycondensation time may be from 0.1 to 10 hours, preferably from 0.2 to 4 hours or from 0.5 to 2 hours, depending on the nature of the starting monomers and the reaction conditions selected.

[0051] Inorganic components, such as sodium chloride or potassium chloride or excess base, can be removed by suitable methods such as dissolution and filtration, sieving or extraction before or after isolation of the PAES.

[0052] According to some embodiments, the amount of PAES at the end of the condensation is at least 30% by weight, such as at least 35% by weight, or at least 37% by weight, or at least 40% by weight, based on the total weight of PAES and polar aprotic solvent.

[0053] At the end of the reaction, the PAES polymer is separated from the other components (salt, base, ...) to obtain a PAES solution. For example, filtration can be used to separate the PAES polymer from the other components. The PAES solution can then be used as is in step (b), or alternatively, the PAES can be recovered from the solvent, for example, by coagulation or solvent devolatilization.

[0054] The PAES polymers described herein can be characterized by their weight average molecular weight (Mw). The PAES polymers described herein can be advantageously characterized in that their weight average molecular weight (Mw) ranges from 70,000 g / mol to 200,000 g / mol, e.g., from 75,000 g / mol to 190,000 g / mol, or from 80,000 g / mol to 180,000 g / mol.

[0055] The weight average molecular weight (Mw) of PAES is determined by size exclusion chromatography (SEC) using methylene chloride as the mobile phase.

[0056] film The membranes of the present invention are used to purify biological fluids, preferably blood.

[0057] The membrane preferably contains less than 0.1% by weight of 4,4'-dihydroxydiphenyl sulfone (BPS) and 4,4'-isopropylidenediphenol (BPA).

[0058] The term "membrane" is used herein in its ordinary sense, i.e., a discrete, usually thin, interface that moderates the permeation of chemical species in contact with the membrane. This interface may be molecularly uniform (i.e., completely uniform in structure) (dense membrane) or chemically or physically heterogeneous, for example, containing voids, holes, or pores of finite dimensions (porous membrane).

[0059] According to the present invention, the membranes are typically microporous membranes that can be characterized by their average pore size and porosity (ie, the percentage of the membrane that is porous).

[0060] The membranes of the present invention can have a weight porosity (%) of 20 to 90% and contain pores, at least 90% by volume of which have an average pore size of less than 5 μm. The weight porosity of a membrane is defined as the volume of pores divided by the total volume of the membrane.

[0061] Membranes with a uniform structure throughout their thickness are generally known as symmetric membranes, while membranes with pores not uniformly distributed throughout their thickness are generally known as asymmetric membranes. Asymmetric membranes are characterized by a thin, selective layer (0.1-1 μm thick) and a thick, highly porous layer (100-200 μm thick) that acts as a support and has little effect on the separation properties of the membrane.

[0062] The membrane may be in the form of a flat sheet or in the form of a tubular membrane.

[0063] Based on their dimensions, tubular membranes are classified into tubular membranes with a diameter of more than 3 mm, capillary membranes with a diameter between 0.5 mm and 3 mm, and hollow fibers with a diameter of less than 0.5 mm. Capillary membranes are also called hollow fibers.

[0064] Hollow fibers are particularly advantageous in applications where a compact module with a large surface area is required.

[0065] The membranes of the present invention may be made using any of the conventional known membrane preparation methods, for example, by solution casting or solution spinning.

[0066] Preferably, the membranes according to the invention are prepared by a phase inversion method carried out in the liquid phase, said method comprising: (i) preparing a PAES polymer solution comprising a PAES as described herein and a polar solvent; (ii) processing the solution into a membrane; (iii) contacting the membrane with a non-solvent bath Includes.

[0067] The membrane of the present invention may comprise the PAES described herein in an amount of at least 1 wt. %, for example at least 5 wt. %, at least 10 wt. %, at least 15 wt. %, at least 20 wt. %, at least 25 wt. %, or at least 30 wt. %, based on the total weight of the polymer composition (C).

[0068] The membranes of the present invention may comprise the PAES described herein in an amount greater than 50 wt%, for example greater than 55 wt%, greater than 60 wt%, greater than 65 wt%, greater than 70 wt%, greater than 75 wt%, greater than 80 wt%, greater than 85 wt%, greater than 90 wt%, greater than 95 wt%, or greater than 99 wt%, based on the total weight of the polymer composition (C).

[0069] According to one embodiment, the membrane of the present invention may comprise the PAES described herein in an amount ranging from 1 to 99 wt %, for example, from 3 to 96 wt %, from 6 to 92 wt %, or from 12 to 88 wt %, based on the total weight of the polymer composition (C).

[0070] The membranes of the present invention may further comprise at least one polymer different from the PAES described herein, such as another sulfone polymer, such as polysulfone (PSU), polyethersulfone (PES), or polyphenylene sulfide (PPS), a poly(aryletherketone) (PAEK), such as poly(etheretherketone) (PEEK), poly(etherketoneketone) (PEKK), a copolymer of poly(etherketone) (PEK) or PEEK with poly(diphenyletherketone) (PEEK-PEDEK copolymer), polyetherimide (PEI), and / or polycarbonate (PC). The other polymer component may be polyvinylpyrrolidone and / or polyethylene glycol.

[0071] The membranes of the present invention may further comprise at least one non-polymeric ingredient such as solvents, fillers, lubricants, release agents, antistatic agents, flame retardants, anti-fog agents, matting agents, pigments, dyes, and optical brighteners.

[0072] Method for purifying biological fluids The purification method includes at least a filtration step through a membrane as described herein.

[0073] Preferably, the purification method is a method for purifying a human biological fluid (preferably a blood product, such as whole blood, plasma, fractionated blood components, or mixtures thereof) performed in an extracorporeal circuit. The extracorporeal circuit for performing the method includes at least one filtration device (or filter) comprising at least one membrane as described above.

[0074] As intended herein, methods of blood purification through extracorporeal circuits include hemodialysis by diffusion (FD), hemofiltration (HF), hemodiafiltration (HDF), and hemoconcentration. In HF, blood is filtered by ultrafiltration, while in HDF, blood is filtered by a combination of FD and HF.

[0075] Blood purification processes through extracorporeal circuits are typically performed by hemodialysis machines (i.e., machines designed to perform either FD, HF, or HFD). In such processes, blood is filtered from waste solutes and waste fluids, such as urea, potassium, creatinine, and uric acid, resulting in blood that is free of waste solutes and waste fluids.

[0076] Typically, a hemodialyzer for performing a blood purification method includes a cylindrical bundle of hollow fibers of membranes, said bundle having two ends, each fixed with a so-called potting compound, which is usually a polymeric material that acts as an adhesive to hold the ends of the bundle together. Potting compounds are known in the art and include polyurethanes, among others. By applying a pressure gradient, blood is pumped through the membrane bundle via blood ports, and the filtrate product ("dialysate") is pumped through the space surrounding the filter.

[0077] Polymer solutions for preparing membranes One aspect of the present invention is a polymer solution for preparing a membrane, comprising: a) at least one compound of formula (I): [ka] (In the formula, - each R1 is independently at each occurrence an alkyl having 1 to 5 carbon atoms; and - R is alkyl having 1 to 10 carbon atoms or cycloalkyl having 5 to 8 carbon atoms Repeating units (R PAES a poly(aryl ether sulfone) (PAES) polymer containing b) at least one polar solvent The present invention relates to a polymer solution comprising:

[0078] The total concentration of the polymer (PAES) in the solution is at least 8% by weight, preferably at least 12% by weight, based on the total weight of the solution. Typically, the concentration of the polymer (PAES) in the solution does not exceed 50% by weight, preferably does not exceed 40% by weight, and more preferably does not exceed 30% by weight, based on the total weight of the solution (SP).

[0079] The term "solvent" is used herein in its ordinary sense, i.e., it refers to a substance that can dissolve another substance (solute) to form a mixture that is uniformly dispersed at the molecular level. In the case of polymeric solutes, it generally refers to a solution of the polymer in the solvent when the resulting mixture is clear and no phase separation is observed in the system. Phase separation is understood to be the point at which the solution becomes cloudy or hazy due to the formation of polymer aggregates, often referred to as the "cloud point."

[0080] Exemplary solvents are described in patent application WO 2019 / 048652 (Solvay Specialty Polymers USA).

[0081] The total concentration of solvent in the solution can be at least 20% by weight, preferably at least 30% by weight, based on the total weight of the solution. Typically, the concentration of solvent in the solution does not exceed 70% by weight, preferably does not exceed 65% by weight, and more preferably does not exceed 60% by weight, based on the total weight of the solution.

[0082] The solution may contain additional ingredients such as nucleating agents and excipients.

[0083] The solution may also contain pore-forming agents, particularly polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) having a molecular weight of at least 200.

[0084] If the disclosure of any patent, patent application, or publication incorporated herein by reference contradicts the statement of this application to the extent that it may render a term unclear, the statement shall control.

[0085] Illustrative embodiments will now be described in the following non-limiting examples. [Example]

[0086] The present disclosure will now be described in more detail with reference to the following examples, the purpose of which is illustrative only and is not intended to limit the scope of the present disclosure.

[0087] Starting materials Tetramethylbisphenol F, commercially available from TCI America DCDPS (4,4'-dichlorodiphenyl sulfone), commercially available from Solvay Specialty Polymers USA, LLC K2CO 3、 Commercially available from Aldrich Sulfolane, commercially available from Aldrich DMI (1,3-dimethyl-2-imidazolidinone), commercially available from TCI America Chlorobenzene, commercially available from Aldrich DMSO (dimethyl sulfoxide), commercially available from Fisher Udel® P3500, commercially available from Solvay Specialty Polymers USA, LLC DSDCDPS (disulfonated 4,4'-dichlorodiphenyl sulfone), commercially available from Akron Polymer Systems

[0088] Preparation of polymer Example 1 A 1 L resin flask equipped with an overhead stirrer, nitrogen dip tube, and Dean-Stark trap with a reflux condenser was charged with 115.358 g (0.450 mol) of tetramethylbisphenol F, 129.223 g (0.450 mol) of DCPDS, 65.302 g (0.473 mol) of K2CO3, and 494.11 g of sulfolane. Stirring and nitrogen flow were established, and the reaction mixture was purged with nitrogen for 15 minutes. After that, heating was initiated with an external oil bath to a target internal temperature of 200 °C. Water, a polymerization by-product, was continuously distilled from the reactor and collected in the Dean-Stark trap. After reaching 200 °C, the reaction was held at that temperature until the desired Mw was reached. After the desired molecular weight was reached, the polymerization was stopped by blowing gaseous methyl chloride through the reaction mixture at a rate of 1 g / min over a period of 30-60 minutes. The reaction mixture was diluted with 317.64 g of sulfolane. The diluted polymer solution was filtered under pressure through a 2.7 μm glass fiber filter pad to remove salts. The polymer solution was precipitated into methanol or methanol / acetone (1:1) at a polymer solution to non-solvent ratio of 1:5 to obtain a white solid. The isolated white solid was then washed six times with the same non-solvent, vacuum filtered, and dried in a vacuum oven at 100 °C for 12 hours. The molecular weight was determined by GPC.

[0089] Example 2 The polymerization was carried out as in Example 1, but the polymerization was terminated at a lower Mw.

[0090] Example 3 Polymerization was carried out as in Example 1, except that the amounts added were as follows: Tetramethylbisphenol F-17 9.445 g (0.700 mol) DCDPS-20 1.013 g (0.700 mol) Potassium carbonate - 101.581 (0.735 mol) Sulfolane - 494.107g

[0091] After the target Mw was reached, 768.61 g of sulfolane was added to dilute, followed by filtration, coagulation, washing and drying.

[0092] Example 4 A 1 L resin flask equipped with an overhead stirrer, nitrogen dip tube, and Dean-Stark trap with a reflux condenser was charged with 170.66 g (0.666 mol) of tetramethylbisphenol F, 191.172 g (0.0666 mol) of DCPDS, 96.607 g (0.699 mol) of K2CO3, and 313.28 g of DMI. Stirring and nitrogen flow were established, and the reaction mixture was purged with nitrogen for 15 minutes. After that, heating was initiated with an external oil bath to a target internal temperature of 195 °C. Water, a polymerization by-product, was continuously distilled from the reactor and collected in the Dean-Stark trap. After reaching 195 °C, the reaction was held at that temperature until the desired Mw was reached. After the desired molecular weight was reached, the polymerization was terminated by blowing gaseous methyl chloride through the reaction mixture at a rate of 1 g / min over a period of 30-60 minutes. The reaction mixture was diluted with 714.86 g of DMI. The diluted polymer solution was filtered under pressure through a 2.7 μm glass fiber filter pad to remove salts. The polymer solution was precipitated into methanol or methanol / acetone (1:1) at a polymer solution to nonsolvent ratio of 1:5 to obtain a white solid. The isolated white solid was then washed six times with the same nonsolvent, vacuum filtered, and dried in a vacuum oven at 100 °C for 12 h.

[0093] Example 5 A 1 L resin flask equipped with an overhead stirrer, nitrogen dip tube, and Dean-Stark trap with a reflux condenser was charged with 179.445 g (0.700 mol) of tetramethylbisphenol F, 201.013 g (0.700 mol) of DCPDS, 101.581 g (0.735 mol) of K2CO3, and 329.40 g of NMP. Stirring and nitrogen flow were established, and the reaction mixture was purged with nitrogen for 15 minutes. After that, heating was initiated with an external oil bath to a target internal temperature of 195 °C. Water, a polymerization by-product, was continuously distilled from the reactor and collected in the Dean-Stark trap. After reaching 195 °C, the reaction was held at that temperature until the desired Mw was reached. After the desired molecular weight was reached, the polymerization was stopped by blowing gaseous methyl chloride through the reaction mixture at a rate of 1 g / min over a period of 30-60 minutes. The reaction mixture was diluted with 988.21 g of NMP. The diluted polymer solution was filtered under pressure through a 2.7 μm glass fiber filter pad to remove salts. The polymer solution was precipitated into methanol or methanol / acetone (1:1) at a polymer solution to nonsolvent ratio of 1:5 to obtain a white solid. The isolated white solid was then washed six times with the same nonsolvent, vacuum filtered, and dried in a vacuum oven at 100 °C for 12 h.

[0094] Example 6 A 1 L resin flask equipped with an overhead stirrer, nitrogen dip tube, and a Barrett trap with a reflux condenser was charged with 153.81 g (0.600 mol) of tetramethylbisphenol F, 430.67 g of chlorobenzene, and 73.43 g of DMSO. Stirring and nitrogen flow were established, and the reaction mixture was purged with nitrogen for 15 minutes. After the temperature reached approximately 40 °C, 94.84 g of aqueous caustic solution (approximately 50 wt%), followed by 260.34 g of DMSO, was added to the reactor. The internal temperature was slowly raised to approximately 150 °C while continuously removing water / chlorobenzene. After all water of reaction had been removed, a solution of 172.30 g of DCDPS in 172.30 g of chlorobenzene was slowly added to the reactor. After the addition was complete, the reaction temperature was increased to 165-170 °C and held there until a high molecular weight was achieved. The polymerization was quenched with gaseous methyl chloride for 60 minutes and then diluted with chlorobenzene. The diluted polymer solution was filtered under pressure through a 2.7 μm glass fiber filter pad to remove salts. The polymer solution was precipitated into methanol or methanol / acetone (1:1) at a polymer solution to nonsolvent ratio of 1:5 to obtain a white solid. The isolated white solid was then washed six times with the same nonsolvent, vacuum filtered, and dried in a vacuum oven at 100 °C for 12 hours.

[0095] Example 7 in DMSO / toluene This example illustrates the preparation of a polymer according to Example 8 of WO 2018 / 079733 (Mitsui).

[0096] A 1 L resin flask equipped with an overhead stirrer, nitrogen dip tube, and Dean-Stark trap with a reflux condenser was charged with 57.68 g (0.225 mol) of tetramethylbisphenol F, 38.77 g (0.135 mol) of DCPDS, 44.21 g (0.090 mol) of disulfonated DCDPS, 38.87 g (0.2813 mol) of K2CO3, 535.2 g of DMSO, and 178.40 g of toluene. A nitrogen flow was established, and the reactor contents were heated to 130 °C. Azeotropic dehydration was carried out for 12 hours. Water was removed from the Dean-Stark trap, during which time toluene was returned to the reactor. After 12 hours, the toluene was distilled off, and the temperature of the reaction mixture was allowed to reach 160 °C. The polymerization was carried out at 160 °C for 12 hours. After 12 hours, the reactor was diluted with a total of 570 g of toluene. A small amount of the reaction mixture was filtered and used for GPC measurement.

[0097] Example 8 - 10 mol % Disulfonated DCDPS in NMP A 1 L resin flask equipped with an overhead stirrer, nitrogen dip tube, and Dean-Stark trap with reflux condenser was charged with 128.14 g (0.500 mol) of tetramethylbisphenol F, 129.22 g (0.450 mol) of DCPDS, 24.56 g (0.050 mol) of disulfonated DCDPS, 73.94 g (0.535 mol) of K2CO3, and 300.05 g of NMP. The contents of the reactor were purged with nitrogen for 15 minutes and then heated to 190 °C. After approximately 18 hours, the reaction was quenched with 150 g of NMP and quenched with methyl chloride gas for 30 minutes. This was further diluted with 941 g of NMP. The polymer mixture was filtered and coagulated in 5% aqueous NaCl at a ratio of 1:10 (polymer solution:salt solution). This was washed 4 to 5 times with a 5% aqueous sodium chloride solution, filtered, and dried in a vacuum oven at 120° C. A small amount of the filtered reaction solution was used for GPC measurement.

[0098] Example 9 of 10 mol% disulfonated DCDPS in sulfolane A 1 L resin flask equipped with an overhead stirrer, nitrogen dip tube, and Dean-Stark trap with reflux condenser was charged with 128.14 g (0.500 mol) tetramethylbisphenol F, 129.22 g (0.450 mol) DCPDS, 24.56 g (0.050 mol) disulfonated DCDPS, 73.94 g (0.535 mol) K2CO3, and 368.24 g sulfolane. The reactor contents were purged with nitrogen for 15 minutes and then heated to 225°C. After approximately 8 hours, the reaction was quenched with 150 g sulfolane and quenched with methyl chloride gas for 30 minutes. This was further diluted with 941 g sulfolane and filtered while hot. The mixture was coagulated in 5% aqueous NaCl at a ratio of 1:10 (polymer solution:salt solution). This was washed 4 to 5 times with a 5% aqueous sodium chloride solution, filtered, and dried in a vacuum oven at 120° C. A small amount of the filtered reaction solution was used for GPC measurement.

[0099] Example 10 of 20 mol% disulfonated DCDPS in sulfolane The polymer was obtained according to the same synthesis process as in Example 9, except that the moles of DSDCPDS were 0.100 moles (20 mole%), DCDPS was 0.400 moles, and sulfolane was 383.55 g. The reaction time was about 14 hours.

[0100] Example 11 of 30 mol% disulfonated DCDPS in sulfolane The polymer was obtained according to the same synthesis process as in Example 9, except that the moles of DSDCPDS were 0.150 moles (30 mole%), DCDPS was 0.350 moles, and sulfolane was 398.85 g. The reaction time was about 15 hours.

[0101] Example 12 of 40 mol% disulfonated DCDPS in sulfolane The polymer was obtained according to the same synthesis process as in Example 9, except that the moles of DSDCPDS were 0.200 moles (40 mole%), DCDPS was 0.300 moles, and sulfolane was 414.16 g. The reaction time was 17 hours.

[0102] Polymer characterization Molecular weight determination Size exclusion chromatography (SEC) was performed using methylene chloride as the mobile phase. Two 5 μm mixed-D size exclusion chromatography (SEC) columns with guard columns from Agilent Technologies were used for the separation. A 254 nm UV detector was used to obtain the chromatogram. A flow rate of 1.5 ml / min and an injection volume of 20 μL of a 0.2 w / v% solution in the mobile phase were selected.

[0103] Calibration was performed using 10 narrow calibration standards of polystyrene obtained from Agilent Technologies (peak molecular weight range: 371000–580).

[0104] Calibration curve: 1) Type: Calibration by relative, narrow calibration standards 2) Fit: Cubic regression.

[0105] Integration and Calculations: Data, calibration and molecular weight calculations are obtained using Empower Pro GPC software from Waters. Peak integration start and end points are determined manually from significant differences across the baseline.

[0106] For copolymers prepared using disulfonated DCDPS, two MiniMIX-D SEC columns were used with guard columns from Agilent Technologies. The mobile phase was 0.1 M LiBr in DMAc. A UV detector set at 270 nm was used to obtain chromatograms. A 5 μl injection volume was used at a flow rate of 0.3 mL / min and a concentration of 0.2% w / v.

[0107] Calibration was performed using 10 narrow calibration standards of polystyrene obtained from Agilent Technologies (peak molecular weight range: 364,000–580).

[0108] Calibration curve: 1) Type: Calibration by relative, narrow calibration standards 2) Fit: Cubic regression.

[0109] Integration and Calculations: Data, calibration and molecular weight calculations are acquired using Empower3 GPC software from Waters. Peak integration start and end points are determined manually from significant differences across the baseline.

[0110] solution viscosity A 25 w / w% polymer solution was prepared in HPLC-grade N'N-dimethylacetamide. The viscosity of the polymer solution was measured using a ThermoHaake Viscotester VT550 equipped with a ThermoHaake sensor system with an MV-DIN and stator, and a temperature vessel controlled by a ThermoHaake DC-30 circulating bath. Calibration of the instrument was performed using certified viscosity standards. The viscosity of the solution was measured at 40 °C and 30 s. -1 The measurements were carried out at a shear rate of .

[0111] DSC DSC was used to determine the glass transition temperature (Tg). DSC experiments were performed using a TA Instrument Q100. DSC curves were recorded by heating, cooling, reheating, and then recooling the sample from 25°C to 320°C at heating and cooling rates of 20°C / min. All DSC measurements were taken under a nitrogen purge. Reported Tg and Tm values ​​were determined using the second heating curve unless otherwise specified.

[0112] result The data table below summarizes the Mw, solution viscosity and glass transition temperature obtained.

[0113] [Table 1]

[0114] [Table 2]

[0115] Membrane preparation Two flat membranes were prepared using the following procedure.

[0116] Membrane #1: A 20 wt% NMP solution of the polymer from Example 2 (inventive example) was filtered through a 2.7 μm syringe filter. A membrane was manually cast onto a glass plate with a 6-mil drawbar. The cast membrane was submerged in a water bath maintained at room temperature. The formed membrane was peeled off from the glass plate. The membrane was washed with fresh deionized water by immersing it in another bath for 1 hour. They were then stored in a sample bottle containing clean deionized water.

[0117] Membrane #2: A comparative membrane using Udel® P3500 as the polymer was prepared similarly.

[0118] Before imaging by SEM, the membrane samples were patted dry and then immersed in liquid nitrogen for 1 minute. The samples were then fractured. The fractured samples were placed on aluminum stubs and then sputter-coated with AuPd. Photographs of cross sections of these membranes are shown in Figures 1 and 2.

[0119] The morphology of membranes made from the polymers of the present invention is equivalent in structure to those made using Udel P3500.

[0120] contact angle The contact angles of the films were measured using a KRUESS EASYDROP instrument according to ASTM D5946-09.

[0121] [Table 3]

Claims

1. 1. A membrane for purifying a biological fluid, comprising: 【Chemistry 1】 (In the formula, - Each R １ is independently at each occurrence alkyl having 1 to 5 carbon atoms; and R is alkyl having 1 to 10 carbon atoms or cycloalkyl having 5 to 8 carbon atoms. Repeating units (R ＰＡＥＳ 1. A membrane comprising at least one poly(aryl ether sulfone) (PAES) polymer comprising a hydroxy group selected from the group consisting of hydroxy groups, ...

2. The PAES polymer comprises at least 60 mole % of repeating units of formula (I) (R ＰＡＥＳ 2. The membrane of claim 1 , comprising:

3. 3. The membrane of claim 1 or 2, containing less than 0.1% by weight of 4,4'-dihydroxydiphenyl sulfone (BPS) and 4,4'-isopropylidenediphenol (BPA).

4. 4. The membrane according to any one of claims 1 to 3, in the form of a flat sheet; a tubular membrane, optionally a tubular membrane having a diameter of more than 3 mm; a capillary membrane having a diameter comprised between 0.5 and 3 mm; or a hollow fibre having a diameter of less than 0.5 mm.

5. in a solvent, at least a compound of formula (II): 【Chemistry 2】 (In the formula, R １ is alkyl having 1 to 5 carbon atoms at least one aromatic dihydroxy monomer (a) comprising a monomer (a1) of the formula at least one aromatic dihalogen sulfone monomer (b), comprising at least one dihalogen compound selected from the group consisting of 4,4'-dichlorodiphenyl sulfone (DCPDS) and 4,4'-difluorodiphenyl sulfone (DFDPS); - at least one carbonate component The reaction mixture (R Ｇ 5. The membrane according to claim 1, obtained by condensation with methyl methyl ether.

6. 6. The membrane of claim 5, wherein the aromatic dihydroxy monomer (a) comprises at least 50 mole % of monomer (a1), based on the total moles of aromatic dihydroxy monomer.

7. 7. The membrane of claim 5 or 6, wherein monomer (b) comprises at least 50 mole % of 4,4'-dichlorodiphenyl sulfone (DCPDS) based on the total moles of aromatic dihalogen sulfone monomers.

8. 8. The membrane of any one of claims 5 to 7, wherein the solvent is selected from the group consisting of dimethyl sulfoxide (DMSO), dimethyl sulfone (DMS), diphenyl sulfone (DPS), 1,3-dimethyl-2-imidazolidinone (DMI), diethyl sulfoxide, diethyl sulfone, diisopropyl sulfone, tetrahydrothiophene-1,1-dioxide, tetrahydrothiophene-1-monoxide, N-methylpyrrolidone (NMP), N-butylpyrrolidone (NBP), N-ethyl-2-pyrrolidone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), tetrahydrofuran (THF), chlorobenzene, anisole, chloroform, dichloromethane (DCM), sulfolane, and mixtures thereof.

9. The membrane according to any one of claims 5 to 8, wherein the molar ratio of monomers (a) to (b) is between 1.01 and 1.

05.

10. 10. The membrane of any one of claims 1 to 9, wherein the PAES comprises less than 1 mole % of sulfonated repeat units, based on the total number of moles in the polymer.

11. A method for purifying a biological fluid, comprising at least a filtration step through the membrane according to any one of claims 1 to 10.

12. The method of claim 11 , wherein the biological fluid is blood.

13. 13. The method of claim 11 or 12, which is carried out by an extracorporeal circuit.

14. 14. The method of claim 13, wherein the extracorporeal circuit includes a hemodialyzer and the membrane is in the form of a cylindrical bundle of hollow fibers.

15. A polymer solution for preparing a membrane, comprising: a) at least a compound of formula (I): 【Transformation 3】 (In the formula, R １ is alkyl having 1 to 5 carbon atoms Repeating units (R ＰＡＥＳ and a poly(aryl ether sulfone) (PAES) polymer comprising: b) Polar solvent A polymer solution comprising:

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