Virus removal filter membrane and preparation method therefor

Abstract

Provided in the present application are a virus removal filter membrane and a preparation method therefor, belonging to the technical field of membrane separation. The filter membrane preparation method comprises blending a hydrophilic polymer and a bulk polymer to prepare casting solutions having different viscosities, and on the basis of a double-layer homogeneous compounding method and a phase conversion method, preparing the filter membrane. The filter membrane has an integrated structure, and comprises a dense separation layer distributed along the thickness direction of the filter membrane and a pre-filter support layer having a loose sponge structure. The separation layer is adjacent to the support layer, but there is no obvious interface or stratification. The pore diameters of the separation layer and the support layer has a continuous gradient change along the thickness direction, wherein the pore diameter of the support layer is greater than the pore diameter of the separation layer.

Description

Virus removing membrane and preparation method thereof

[0001] The present application claims priority to the Chinese patent application No. 202510392827X, filed on March 31, 2025, and entitled "A virus removing membrane and preparation method thereof", the entire content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of membrane separation technology, and particularly relates to a virus removing membrane and a preparation method thereof. BACKGROUND

[0003] Membrane filtration is a precise separation technology that uses membrane pores as the filtration medium and utilizes the selective permeability of the membrane pores to separate solvents, inorganic ions, small molecules or proteins from viruses, microparticles and macromolecules under the action of a driving force such as pressure difference. For organic polymer membranes, the main preparation methods include phase inversion, stretching, track etching and sintering, etc. Among them, the phase inversion method is widely used due to its easy operation, simple equipment, good controllability of membrane structure, etc., which greatly promotes the development of membrane technology. According to different principles, the phase inversion method can be divided into non-solvent induced phase separation (NIPS), thermal induced phase separation (TIPS), reverse thermal induced phase separation (RTIPS) and solvent evaporation induced phase separation (VIPS), etc.

[0004] NIPS method is the most commonly used method for preparing polymer membranes by phase inversion. First, a uniform polymer solution or casting solution is prepared by mixing and dissolving the polymer, solvent and additives, etc. Then, the polymer solution is coated or cast into a thin film on a support (such as a glass plate, non-woven fabric, etc.), and immediately immersed in a non-solvent coagulation bath to induce phase separation and solidify into a membrane. CN116943451B discloses a method for preparing a polyether sulfone (PES) virus removing membrane by NIPS method. However, the phase inversion process of NIPS method is difficult to accurately control the membrane formation process due to its instantaneous nature, and the prepared membrane has a wide pore size distribution and the mechanical strength needs to be improved.

[0005] TIPS method is based on temperature change to induce phase inversion. TIPS method is to mix the polymer and diluent (usually solvent or small molecule additive) at high temperature to form a uniform solution. When the temperature decreases, the compatibility between the polymer and the diluent changes, leading to phase separation and membrane formation. WO2018 / 088232 discloses a method for preparing a polyvinylidene fluoride (PVDF) hollow fiber virus removing membrane by TIPS method. TIPS method can prepare membranes with high strength and good pore structure, but it is only suitable for some polymer materials with high thermal stability requirements, and it is difficult to control small pores (~20nm).

[0006] RTIPS method is also based on temperature change to induce phase inversion. But it requires to select a low critical solution temperature (LAST) casting solution system, that is, for some polymer-solvent systems, at lower temperatures, the polymer and solvent are mutually soluble to form a stable homogeneous system. When the temperature rises to a certain value, the solubility of the polymer in the solvent decreases sharply, and phase separation occurs to form a film. US10118133B2 discloses a method for preparing a PES virus removal filter membrane by RTIPS method using a casting solution system with LAST. The membrane prepared by RTIPS method will form a more dense or special pore structure film due to the rapid solidification of the polymer during temperature rise. But the special casting solution system suitable for RTIPS method is less, and the membrane pore size is usually larger (~100 nm).

[0007] Currently, the membrane materials used as virus removal membranes include regenerated cellulose (CA), polysulfone (PSF), polyether sulfone (PES) and polyvinylidene fluoride (PVDF) and the like. Among them, PES has good thermal stability, excellent chemical stability, high strength, good mechanical properties and good biocompatibility, and is the preferred virus removal membrane material. However, the pure polymer membrane material is affected by the molecular structure and membrane preparation parameters, and has the problems of poor permeation performance, poor protein adsorption resistance and short service life. For example, US10118133B2 discloses a stacked multi-layer composite PES ultrafiltration membrane with at least one ultrafiltration layer, which is prepared by co-casting method. The membrane has good virus retention effect, high flux and can effectively meet the actual demand. However, in the stacked multi-layer composite method, if there is a mutual repulsion between molecules between the two layers of casting solution, the composite process will inevitably produce two or more phase interfaces, increasing the filtration resistance. At the same time, the US patent selects PES with strong hydrophobicity as the polymer, which has poor hydrophilicity and will cause serious protein adsorption, low membrane flux and low protein recovery rate. In order to improve the permeation and separation performance and anti-pollution or anti-protein adsorption performance of the virus removal filter membrane, the filter membrane needs to be properly hydrophilic modified.

[0008] Common hydrophilic modification methods of ultrafiltration membranes include bulk modification, surface modification, and blending modification. Among them, bulk modification is to introduce hydrophilic monomers into the bulk polymer or copolymer or graft to prepare hydrophilic polymers during polymerization, so that the prepared filtration membrane has hydrophilicity. For example, CN118594294A discloses a kind of porous membrane of polysulfone block copolymer for high-efficiency separation of virus and antibody. The porous membrane of polysulfone block copolymer is formed by chemical bond between hydrophilic block A and polysulfone high polymer block B, and the hydrophilic block A is one or more of polyethylene glycol, polyethylene glycol monomethyl ether and other high molecular materials, and the polysulfone high polymer block B is one or more of polysulfone, polyethersulfone and other polysulfone materials. The porous membrane of polysulfone block copolymer has a retention rate of more than 4 logs for fine viruses of more than 15 nm, and a recovery rate of more than 98% for antibodies, and has excellent separation performance for virus and antibody. However, the synthesis process of bulk modification is complex, the cost is high, the mechanical strength of the formed membrane is usually low, and there are risks of polymer stability, etc.

[0009] Surface modification can be further divided into surface coating modification and surface crosslinking modification. Surface coating modification is to coat hydrophilic materials on the surface of high molecular membrane, and form a hydrophilic layer through hydrogen bond, van der Waals force and other actions, so as to improve the hydrophilicity of the membrane surface. For example, US4413074A discloses a hydrophobic polymer (PES) membrane substrate, the surface of which is coated with hydroxyalkyl cellulose and treated with water vapor to form a hydrophilic surface, which can have a large pure water flux (~1500L / m 2 ). However, it is difficult for hydroxyalkyl cellulose to penetrate into the small pores of the ultrafiltration membrane, and the hydrophilic effect or protein adsorption resistance is slightly insufficient; and the effect of surface coating modification will gradually fall off with the extension of storage time, resulting in the decrease of hydrophilicity, and the stability needs to be improved.

[0010] In addition, surface crosslinking modification directly introduces hydrophilic groups into the membrane surface by chemical treatment to improve the hydrophilicity of the membrane. For example, CN114653222B discloses a virus removal filtration membrane with low protein adsorption and a preparation method thereof. The filtration membrane is a PES filter membrane or a PVDF filter membrane, which includes a pre-filtration zone and a separation zone for virus retention, and a hydrophilic crosslinking layer. The hydrophilic crosslinking layer is formed by crosslinking of hydrophilic monomers and crosslinking agents under ultraviolet irradiation, and covers the surface of the fiber entity part of the separation zone, so that the protein adsorption of the filtration membrane is greatly reduced. The flux changes slowly during use, the load is large, and the protein yield is high. However, the process technology of surface crosslinking modification is more complex, and the types of surface modification are less, and the actual effect and stability still need to be improved.

[0011] Blending modification is to add inorganic, organic or amphiphilic modified particles to the polymer system, and the high polymer bulk polymer is fused by efficient blending to improve the hydrophilicity of the filter membrane. Among them, direct blending of hydrophilic membrane materials is a more preferred method. In recent years, hydrophilic polymer materials such as sulfonated polyether sulfone (SPES) and hydroxyl-terminated polyether sulfone (PES-OH) have been widely used to prepare large-pore microfiltration membranes with excellent performance. The reason is that the hydrophilic polymer has the same or similar structure as the bulk polymer repeat unit, and has good compatibility, and can easily form a homogeneous polymer solution under certain blending ratio conditions. For example, CN117563441A discloses a low protein adsorption PES sterilization membrane and its preparation method. The method realizes the hydrophilization of PES microfiltration membrane by adding sulfonated polyether sulfone (SPES) in the casting solution system, and the average pore size of the sterilization membrane is 0.15-0.4 μm. At the same time, the microfiltration membrane obtained has a significantly reduced protein adsorption rate, high retention efficiency and relatively high flux. Direct use of membrane materials with hydrophilic groups is simple and easy to operate, and can achieve permanent hydrophilic modification, but the strength of the polymer membrane is relatively low, and it is difficult to prepare small pore membranes (~20 nm). In addition, CN117504628A introduces a mesoporous layer or an intermediate layer, which will inevitably increase the filtration resistance and the difficulty of forming processing.

[0012] In addition, at present, due to the high protein concentration (20-23 g / L) of the feed liquid in the virus membrane filtration process, the operation pressure is relatively high (50 psi or 0.3-0.4 MPa), and the mechanical properties and hydrophilicity of the filter membrane are required to be higher. The excellent breaking strength and breaking elongation (toughness) of the filter membrane can maintain good integrity and stability during the processing and use of the membrane filter. However, the toughness of the currently commercialized filter membrane is relatively low, for example, CN114653222B discloses a low protein adsorption virus removal filter membrane and its preparation method. The breaking elongation of the virus removal filter membrane prepared by the method is <10%, which has a risk of rupture during actual use.

[0013] CN114345151 B discloses a polymer ultrafiltration membrane with high toughness and high anti-pollution performance and a preparation method thereof. Any one of polyvinylidene fluoride, polyvinyl chloride and polyacrylonitrile is dissolved in an appropriate amount of organic solvent to form a homogeneous solution together with polystyrene-maleic anhydride, polyethylene glycol is used as an additive and modifier, the structure of the polymer / polystyrene-maleic anhydride blended ultrafiltration membrane is controlled by a reaction controlled phase inversion method, and the grafting rate of the reaction is controlled. The reaction system at this moment is directly used as a casting solution to prepare a polymer / polystyrene-maleic anhydride grafted polyethylene glycol ultrafiltration membrane by an immersion precipitation phase inversion method. The ultrafiltration membrane prepared based on this method has significantly improved toughness and anti-pollution performance due to the intermolecular and intramolecular forces between the bulk polymer and the hydrophilic polymer, while ensuring high flux and high rejection. However, the average pore size of the ultrafiltration membrane prepared by this method is too small (6-8 nm), and the protein rejection is too large, which cannot be used in the field of virus removal filtration.

[0014] In general, the current problems of nanoscale virus removal filtration membranes are insufficient hydrophilicity, which leads to high protein adsorption and low protein flux, insufficient toughness of the filtration membrane, and large filtration resistance, which poses a risk of stability during the processing and actual use of the membrane filter. The existence of these problems also limits the development of virus removal filtration membranes to some extent. SUMMARY

[0015] In order to overcome some problems in the prior art, the first aspect of the present application provides a preparation method of a virus removal filtration membrane, which uses a hydrophilic polymer and a bulk polymer to blend and prepare a casting solution, and is prepared based on a double-layer homogeneous composite method and a phase inversion method. The obtained integrated filtration membrane includes a separation layer with a dense skin layer and a pre-filtration support layer with a complete sponge structure, the separation layer and the support layer form a sandglass-shaped structure with a continuous gradient change in effective pore size, and there is no obvious interface or delamination phenomenon.

[0016] More specifically, in the preparation method of the virus removal filtration membrane, a hydrophilic polymer and a bulk polymer are blended to prepare casting solutions with different viscosities, and the filtration membrane is prepared based on a double-layer homogeneous composite method and a phase inversion method. The filtration membrane is an integrated structure, including a dense separation layer and a loose sponge structure pre-filtration support layer distributed along the thickness direction of the filtration membrane; the separation layer and the support layer are adjacent, but there is no obvious interface or delamination phenomenon; the pore size of the separation layer and the support layer continuously changes along the thickness direction; and the pore size of the support layer is larger than that of the separation layer.

[0017] The density and porosity are relative, and conventionally, the larger the pore, the more porous, and the smaller the pore, the more dense. The pore size of the support layer is larger than that of the separation layer, and in use, the support layer is the liquid inlet end, which is usually located on the upper surface; the separation layer is the liquid outlet end, which is usually located on the lower surface. The liquid to be filtered first passes through the large-pore support layer for pre-filtration, and then enters the small-pore separation layer for further filtration. In addition, in the art, the pore structure of the filter membrane generally has a sponge pore structure, a large pore structure, a finger-like pore structure, a honeycomb pore structure, etc. The pore structure of the support layer in the present application is approximately a sponge pore structure.

[0018] Optionally, the filter membrane is prepared based on a double-layer homogeneous composite method and a phase inversion method, specifically comprising:

[0019] The bulk polymer, the hydrophilic polymer, the solvent and the additive are blended to prepare two casting solutions A and B with the same or similar composition and different viscosity ranges;

[0020] The obtained casting solutions A and B are combined on the carrier by co-casting, and the casting solution A is overlaid on the casting solution B to obtain a nascent membrane;

[0021] The carrier and the nascent membrane are immersed in a coagulation bath for phase inversion, and then immersed in hot water at 40-60°C for sufficient water washing, and then dried at 75-85°C to obtain a virus removal filter membrane.

[0022] The double-layer homogeneous composite method in the present application refers to a method of combining the casting solutions A and B with the same or similar composition and different viscosity ranges by co-casting; the same composition means that the same composition is used, but the mass percentage of the composition is different, and the viscosity of the casting solution can be adjusted by adjusting the mass percentage; the similar composition means that the composition is different (different chemical formula), but the properties of the composition are similar, for example, both belong to hydrophilic polymers, and the mass percentage can be the same or different, so that the viscosity of the casting solutions A and B is different.

[0023] In addition, the obtained nascent membrane is combined on the carrier, and relatively, the casting solution B (approximately corresponding to the support layer, the liquid inlet end) in the nascent membrane is close to the carrier, and the casting solution A (approximately corresponding to the separation layer, the liquid outlet end) is away from the carrier; the casting solution A is overlaid on the casting solution B.

[0024] Optionally, the addition amount of each component in the casting solution A is, by mass percentage: bulk polymer: 18%-24%, hydrophilic polymer: 2%-5%, solvent: 40%-50%, and additive: 28%-35%; and the addition amount of each component in the casting solution B is: bulk polymer: 14%-16%, hydrophilic polymer: 2%-6%, solvent: 24%-30%, and additive: 52%-58%.

[0025] Optionally, the viscosity of casting solution A is in the range of 20000 mPa-s to 25000 mPa-s and the viscosity of casting solution B is in the range of 10000 mPa-s to 15000 mPa-s at 25 °C.

[0026] Optionally, the bulk polymer is selected from at least one of the following group: polyether sulfone (PES), polysulfone (PSF), polyvinylidene fluoride (PVDF), polyvinyl chloride (PVC); the hydrophilic polymer is selected from at least one of the following group: sulfonated polysulfone (SPSF), hydroxyl-terminated polyether sulfone (PES-OH), sulfonated polyether sulfone (SPES) and polyether sulfone-polyethylene glycol block copolymer (PES-b-PEG).

[0027] It can be understood that, when PES-OH (or PES-b-PEG) is used alone as the hydrophilic modification material, higher mass ratio of PES-OH (PES-b-PEG) is added in the system or pure PES-OH (PES-b-PEG) is used to prepare the casting solution (PES-OH:PES blending mass ratio > 50:50 wt. / wt.), which can introduce more hydrophilic groups, but the molecular weight of PES-OH is relatively low, the viscosity of the casting solution is low, the film forming effect is not good, and the strength of the membrane is very low; when less mass ratio of PES-OH (or PES-b-PEG) is added in the system for blending hydrophilic modification (PES-OH:PES blending ratio < 10:90 wt. / wt.), the number of hydrophilic groups grafted in PES-OH or PES-b-PEG is less, and the hydrophilic modification effect is not good. Therefore, the preferred addition amount of PES-OH or PES-b-PEG (in the hydrophilic polymer and the bulk polymer) includes but is not limited to 10-30 wt.%.

[0028] When SPES (sulfonation degree: 10-20%) is used alone as the hydrophilic modification material, it is theoretically calculated that SPES (sulfonation degree: 10-20%) and PES are partially compatible systems, and the introduction of sulfonic acid groups will reduce the strength of the filtration membrane, so adding too much SPES will cause the strength of the filtration membrane to deteriorate. Therefore, the preferred addition amount of SPES (in the hydrophilic polymer and the bulk polymer) includes but is not limited to 0-30 wt.%.

[0029] Optionally, the solvent is selected from at least one of the following group: N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), gamma-valerolactone (GVL); the additive is selected from at least one of the following group: triethylene glycol (TEG), diethylene glycol (DEG), isopropyl alcohol (IPA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG).

[0030] In combination with the foregoing, the components of casting solution A and casting solution B are the same, for example, casting solution A and casting solution B both select PSF as the bulk polymer, SPSF as the hydrophilic polymer, DEG as the additive, and NMP as the solvent; but the mass percentages of the four components in casting solution A and casting solution B are different. The components of casting solution A and casting solution B are similar, for example, casting solution A selects PES as the bulk polymer, SPES as the hydrophilic polymer, DEG as the additive, and NMP as the solvent; casting solution B selects PES as the bulk polymer, PES-OH as the hydrophilic polymer, DEG as the additive, and NMP as the solvent; although SPES and PES-OH are different, the components are similar, and both are hydrophilic polymers.

[0031] Optionally, the composition of the coagulation bath is selected from at least one of the following group: water, ethanol, DMF, NMP, and DMAc; the temperature of the coagulation bath is 30-60°C, for example, it can be 40°C, 45°C, 50°C, 55°C, and the like.

[0032] Optionally, the carrier is selected from at least one of the following group: polyethylene (PE), polypropylene (PP), polyester (PET), and polycarbonate (PC).

[0033] Optionally, the phase inversion method is selected from at least one of the following methods: NIPS, TIPS, and RTIPS.

[0034] Optionally, the co-casting method is selected from one of the following processes: a double-layer synchronous blade coating process, a double-layer slot spraying process, and a blade-spraying process. When the blade-spraying process is used, the support layer corresponding to the casting solution B selects the blade coating process, and the separation layer corresponding to the casting solution A selects the spraying process. In each process, the casting solution B is close to the carrier, and the casting solution A is formed above the casting solution B, away from the carrier.

[0035] It can be understood that common co-casting methods for preparing double-layer or multi-layer composite membranes include, but are not limited to, layer-by-layer coating, a double-layer synchronous blade coating process, a double-layer slot spraying process, and a blade-spraying process, etc.; the double-layer synchronous blade coating process has a higher requirement for equipment precision, and is prone to produce obvious interfaces and even delamination, and has poor uniformity (the uniformity of the two layers cannot be guaranteed); the double-layer slot spraying process has a higher manufacturing cost, and spraying is more suitable for systems with a relatively thin coating thickness; the uniformity of the double-layer slot spraying process is higher than that of the blade-spraying process; the support layer selects the blade coating process, and then a dense separation layer is sprayed, the two layers do not affect each other, which guarantees the uniformity and saves costs.

[0036] The two prepared casting solutions are synchronously and uniformly cast on a flat and smooth moving carrier by a synchronous composite coating device (for example, a composite coating machine) at a certain speed, and then immersed in a coagulation bath. At this time, solvent-nonsolvent double diffusion occurs between the nascent film formed by the casting solution and the coagulation bath, and the solvent in the nascent film diffuses into the coagulation bath, while the nonsolvent in the coagulation bath diffuses into the nascent film. After a period of time, the double diffusion reaches equilibrium, the nascent film becomes a thermodynamically unstable state, and thus delamination occurs, and finally an asymmetric structure film, i.e., a filtration membrane, is formed. The carrier mainly serves as a support and does not substantially participate in the phase inversion process; after preparation, the filtration membrane and the carrier are separated.

[0037] Optionally, the running speed of the coating device is 3-15 m / min. It can also be understood that adjusting the running speed of the device will affect the exchange rate of the solvent and the nonsolvent in the coagulation bath. Increasing the running speed accelerates the mass transfer process between the coagulation bath and the nascent film, which is beneficial to the phase inversion of the filtration membrane into a film and the regulation of the pore structure, and increasing the running speed has a stretching effect on the membrane, so that a filtration membrane with more uniform pore size distribution can be obtained.

[0038] The second aspect of the present application provides a high-toughness and high-flux virus removal filtration membrane obtained by the preparation method according to any one of the above-mentioned solutions. The obtained integrated filtration membrane includes a separation layer having a dense skin layer and a pre-filtration support layer having a complete sponge structure, which simultaneously provides high mechanical strength and toughness; the separation layer and the support layer form an hourglass-shaped structure with a continuous gradient change in effective pore size, and there is no obvious interface or delamination phenomenon.

[0039] More specifically, the second aspect of the present application provides a virus removal filtration membrane, which is an integrated structure including a dense separation layer distributed along the thickness direction and a loose sponge structure pre-filtration support layer; the separation layer and the support layer are adjacent but have no obvious interface or delamination phenomenon; the pore sizes of the separation layer and the support layer continuously and gradiently change along the thickness direction; and the pore size of the support layer is larger than that of the separation layer.

[0040] Optionally, the obtained filtration membrane has a pure water permeability of 600-900 L m -2 h -1 bar -1 , a protein recovery rate of >99%, a virus retention rate LRV of not less than 6, and a thickness of 120-170 μm.

[0041] Optionally, the filtration membrane has a breaking strength of 6.0-9.0 MPa and an elongation at break of 30-50%.

[0042] Optionally, the PMI average pore size of the filter membrane is 16-22 nm; the SEM (Scanning Electron Microscope) particle size range of the lower surface corresponding to the separation layer is 16-37 nm, and the open porosity of the lower surface is 15-35%; the SEM particle size range of the upper surface corresponding to the support layer is 0.32-1.48 μm, and the open porosity of the upper surface is 25-45%; the ratio of the pore sizes of the upper and lower surfaces is 6:1-90:1, and a more suitable ratio is 19:1-31:1.

[0043] Compared with the prior art, the application has the advantages and positive effects that:

[0044] The preparation method of the virus-removing filter membrane provided by at least one embodiment of the application improves the toughness and compression resistance of the filter membrane by blending the bulk polymer with the hydrophilic polymer containing sulfonic acid or hydroxyl group, etc. through the intermolecular and intramolecular forces (such as hydrogen bond) between the bulk polymer and the hydrophilic polymer.

[0045] The preparation method of the virus-removing filter membrane provided by at least one embodiment of the application uses the homogeneous compounding method to prepare an integrated filter membrane by using the co-casting method (such as one of the double-layer slit spraying process and the doctor-blade-spraying process) of the casting solutions of two polymers with the same type, composition and property (different solid contents), that is, the homogeneous compounding. The integrated filter membrane includes a separation layer with a dense skin layer and a pre-filtering support layer with a complete sponge structure, which simultaneously provides high mechanical strength and toughness, and the separation layer and the support layer form a sandglass-shaped structure with a continuous gradient change in effective pore size and without obvious interface or delamination phenomenon. The fusion between the multiple layers is closer, which is beneficial to reducing the filtration resistance and improving the protein permeation rate. While maintaining a higher virus retention rate and a lower protein adsorption amount, the flux and the maximum processing volume are improved, and the processing time is shortened.

[0046] The virus-removing filter membrane provided by at least one embodiment of the application has the following advantages in the preparation mechanism of the filter membrane. The integrated filter membrane is prepared by the phase inversion of two casting solutions with different viscosities. Under the same process conditions, the high-viscosity casting solution A phase inversion obtains a dense separation layer with a smaller PMI average pore size (16-22 nm) for the purpose of virus retention, and the low-viscosity casting solution B phase inversion obtains a pre-filtering support layer with a larger average pore size (0.32-1.48 μm) and a lower filtration resistance, while having a higher mechanical strength.

[0047] The virus-removing filter membrane provided by at least one embodiment of the application has the following advantages in the hydrophilicity and protein adsorption. The introduction of the hydrophilic groups in the filter membrane can effectively improve the hydrophilicity of the filter membrane. The improvement of the hydrophilicity can improve the permeation flux while reducing the protein adsorption, and accordingly the protein yield is also improved.

[0048] The virus removal filtration membrane provided by at least one embodiment of the present application has size effect and electrostatic repulsion effect in virus interception mechanism. The hydrophilic polymer with electric charge or negative electric charge (such as sulfonic acid polyether sulfone) introduced in the casting solution of the filtration membrane can increase the electric charge of the filtration membrane. Common protein antibodies are negatively charged substances, and the sulfonic acid group and the protein antibodies produce electrostatic repulsion. This means that the size effect and the synergistic effect of electrostatic repulsion of the filtration membrane can further improve the virus interception rate, reduce the protein adsorption amount, and improve the flux and the maximum feed liquid treatment volume, and shorten the treatment time.

[0049] The virus removal filtration membrane and the preparation method thereof provided by at least one embodiment of the present application use the hydrophilic polymer and the bulk polymer to blend to prepare casting solutions with different viscosities, and are prepared based on the double-layer homogeneous composite method and the phase inversion method. The intermolecular and intramolecular forces between the bulk polymer and the hydrophilic polymer can significantly improve the compatibility of the casting solution and the mechanical properties of the composite membrane, and finally obtain a high-toughness virus removal filtration membrane with high virus interception rate, large protein load, and high feed liquid filtration flux. BRIEF DESCRIPTION OF DRAWINGS

[0050] FIG. 1 is a schematic diagram of the cross-sectional SEM of the filtration membrane obtained in Example 1, with a magnification of 400x;

[0051] FIG. 2 is a schematic diagram of the upper surface SEM of the filtration membrane obtained in Example 1, with a magnification of 5,000x;

[0052] FIG. 3 is a schematic diagram of the lower surface SEM of the filtration membrane obtained in Example 1, with a magnification of 50kx;

[0053] FIG. 4 is a comparison diagram of the mechanical properties of the filtration membranes obtained in Examples 1-4;

[0054] FIG. 5 is a comparison diagram of the mechanical properties of the filtration membranes obtained in Comparative Examples 1-3. DETAILED DESCRIPTION

[0055] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0056] The filtration membrane in the present application can also be called a ultrafiltration membrane or a composite membrane due to its performance and structure.

[0057] The performance and physical parameter test methods of the examples and comparative examples are as follows:

[0058] 1. Pure water permeability: The virus-removing composite membrane prepared in the present application is sandwiched in a membrane cell with an effective area of 7.065 cm 2 , and is pre-pressed for 30 min under an operating pressure of 1.5 bar to stabilize the pure water permeability, and then the pressure is adjusted to 1 bar for testing. The pure water permeability can be obtained by the following formula:

[0059] wherein PWP is the pure water permeability (LMH bar -1 , i.e. L m -2 h -1 bar -1 ), V is the volume of filtrate (L), A is the effective area of the membrane (m 2 ), and t is the testing time (h).

[0060] 2. Mechanical property: The virus-removing composite membrane prepared in the present application is made into a sample with a size of 5 x 50 mm, and a precision tensile tester is used to test the breaking strength and breaking elongation of the membrane at a tensile speed of 5 mm / min.

[0061] 3. Average pore size test: A gas-liquid interface pore size analyzer of Porometer 1000L model is used to test the PMI (Pore Mercury Intrusion) pore size and pore size distribution of the virus-removing composite membrane prepared in the present application.

[0062] 4. Virus retention challenge: A polyclonal antibody IgG (Immunoglobulin G) is used as an antibody solution, and then a certain amount of MS2 bacteriophage (Emes virus) is added to the prepared antibody solution, and the antibody solution containing viruses is obtained by sufficient stirring. A dead-end filtration device is used for virus retention challenge test. The virus removal rate can be calculated by the following formula:

[0063] wherein LRV represents the logarithmic removal rate of viruses, C1 is the infectious titer of the virus-containing antibody stock solution, and C2 represents the infectious titer in the filtrate.

[0064] 5. Protein recovery rate: An IgG solution with a concentration of 10 g / L is prepared, and particles and protein aggregates are removed by pre-filtration. Then, the same dead-end filtration device is used for testing. The concentration of the protein is tested by a UV spectrophotometer (SHIMADZU, UV-2600) for the absorbance at 280 nm, and the recovery rate can be obtained by the following formula:

[0065] wherein R is the recovery rate of the protein, C p is the concentration of IgG in the filtrate, and C0 is the concentration of IgG in the stock solution.

[0066] 6. Thickness test: 10 points were randomly sampled on the composite film using a thickness gauge and the average value was calculated.

[0067] Example 1

[0068] The filtration membrane of Example 1 was prepared by co-casting of blade-spraying. First, the hydrophilic polymers (SPES and PES-OH) were blended with the bulk polymer (PES) in a certain ratio to prepare two uniform polymer solutions with different concentrations, and then cast on the carrier for support using the co-casting equipment to prepare the filtration membrane by phase inversion method. The advantage of Example 1 is that the introduction of hydrophilic polymers can improve the hydrophilicity of the filtration membrane and improve the strength of the filtration membrane. The following is a more specific description of Example 1:

[0069] PES (average molecular weight 50000 Da) as the bulk polymer, SPES and PES-OH as the hydrophilic polymer, NMP as the solvent, and DEG as the additive to prepare two casting solutions a and b;

[0070] Preparation of casting solution A: PES, SPES (sulfonation degree: 20%), additive DEG, solvent NMP, etc. were prepared according to the mass ratio of 18:4:28:50 to prepare casting solution A, and stirred at 70°C to make the polymer completely dissolved into a transparent clear viscous solution. The final viscosity of casting solution A was measured to be 23800 mPa·s (25°C).

[0071] Preparation of casting solution B: PES, PES-OH (terminal hydroxyl content ≥ 50%), additive DEG, solvent NMP, etc. were prepared according to the mass ratio of 15:3:58:24 to prepare casting solution B, and stirred at room temperature to make the polymer completely dissolved into a transparent clear viscous solution. The final viscosity of casting solution B was measured to be 12400 mPa·s (25°C).

[0072] The obtained casting solutions A and B were co-cast on the PET carrier by blade-spraying, and the casting solution A was overlaid on the casting solution B to obtain the nascent membrane. Then the carrier and the nascent membrane were immersed in a coagulation bath at 50°C for phase inversion, and then immersed in hot water at 50°C for sufficient water washing to remove the residual solvent in the filtration membrane, and then dried at 85°C to obtain the virus removal filtration membrane. The SEM diagrams of the cross-section, upper surface and lower surface of the obtained high-toughness and high-flux virus removal filtration membrane are shown in Figures 1-3, respectively.

[0073] The average pore size of the filtration membrane was measured to be 21.3 nm, the pure water permeability was 900 L m -2 h -1 bar -1 , the breaking strength was 8.3 MPa, and the elongation at break was 48% (see Table 1 and Figure 4).

[0074] Example 2

[0075] Example 2 is basically the same as Example 1, except that the raw material for film preparation is bulk polymer (PSF) and hydrophilic polymer (SPSF), and the following is a more specific description of Example 2:

[0076] Preparation of casting solution A: PSF, SPSF (sulfonation degree: 20%), additive DEG, solvent NMP, etc. are prepared according to the mass ratio of 18:4:28:50 to prepare casting solution A, and the polymers are completely dissolved into a transparent clear viscous solution by stirring at 70°C. The final viscosity of casting solution A is 24500 mPa·s (25°C).

[0077] Preparation of casting solution B: PSF, SPSF (sulfonation degree: 20%), additive DEG, solvent NMP, etc. are prepared according to the mass ratio of 15:3:58:24 to prepare casting solution B, and the polymers are completely dissolved into a transparent clear viscous solution by stirring at room temperature. The final viscosity of casting solution B is 11000 mPa·s (25°C).

[0078] The subsequent processing procedure of Example 2 is referred to Example 1. The average pore size of the filtration membrane is 20.5 nm, the pure water permeability is 780 L m -2 h -1 bar -1 , the breaking strength is 7.9 MPa, and the elongation at break is 35%, as shown in Table 1 and Figure 4, where the left side of two adjacent column charts represents the breaking strength and the right side represents the elongation at break.

[0079] Example 3

[0080] Example 3 is basically the same as Example 1, except that the raw material for film preparation is bulk polymer (PES), hydrophilic polymer (SPES, PES-b-PEG), and the additive is polyethylene glycol (PEG-400), and the following is a more specific description of Example 3:

[0081] Preparation of casting solution A: PES, SPES, additive PEG-400, solvent NMP, etc. are prepared according to the mass ratio of 18:5:35:42 to prepare casting solution A, and the polymers are completely dissolved into a transparent clear viscous solution by stirring at 70°C. The final viscosity of casting solution A is 21200 mPa·s (25°C).

[0082] Preparation of casting solution B: PES, PES-b-PEG, additive PEG-400, solvent NMP, etc. are prepared according to the mass ratio of 16:2:58:24 to prepare casting solution B, and the polymers are completely dissolved into a transparent clear viscous solution by stirring at room temperature. The final viscosity of casting solution B is 11800 mPa·s (25°C).

[0083] The subsequent processing procedure of Example 3 refers to Example 1. The average pore size of the filtration membrane is measured to be 22 nm, and the pure water permeability is 840 L / m2·bar. -2 h -1 bar -1 The breaking strength is 7.8 MPa, and the breaking elongation is 42% (see Table 1 and FIG. 4).

[0084] Example 4

[0085] Example 4 is basically the same as Example 3, except that the raw material for film preparation is a hydrophilic polymer (PES-b-PEG) and a bulk polymer (PES). The following is a more specific description of Example 4:

[0086] Preparation of casting solution A: PES, PES-b-PEG, additive PEG-400, solvent NMP, etc. are prepared according to the mass ratio of 18:5:35:42 to prepare casting solution A, and the polymer is completely dissolved into a transparent clear viscous solution by stirring at 70°C. The viscosity of the casting solution A is finally measured to be 23300 mPa·s (25°C).

[0087] Preparation of casting solution B: PES, PES-b-PEG, additive PEG-400, solvent NMP, etc. are prepared according to the mass ratio of 16:2:58:24 to prepare casting solution B, and the polymer is completely dissolved into a transparent clear viscous solution by stirring at room temperature. The viscosity of the casting solution B is finally measured to be 12000 mPa·s (25°C).

[0088] The subsequent processing procedure of Example 4 refers to Example 1. The average pore size of the filtration membrane is measured to be 21.5 nm, and the pure water permeability is 720 L / m2·bar. -2 h -1 bar -1 The breaking strength is 7.2 MPa, and the breaking elongation is 36% (see Table 1 and FIG. 4).

[0089] Comparative Example 1

[0090] The key point of Comparative Example 1 is that the filtration membrane is prepared by scraping-coating and spraying-coating. The difference is that the polymer PES (average molecular weight 65000 Da) is used as the bulk polymer, TEG is used as the additive, NMP is used as the solvent, and two casting solutions a and b are prepared:

[0091] Preparation of casting solution a: PES, additive TEG, solvent NMP, etc. are prepared according to the mass ratio of 24:36:40 to prepare casting solution a, and the polymer is completely dissolved into a transparent clear viscous solution by stirring at 70°C. The viscosity of the casting solution a is finally measured to be 22600 mPa·s (25°C).

[0092] Preparation of casting solution b: PES, additive TEG, solvent NMP, etc. were prepared into casting solution b according to the mass ratio of 20:56:24, and the polymer was completely dissolved into a transparent clear viscous solution at room temperature. The viscosity of the casting solution b was finally measured to be 10800 mPa-s (25°C).

[0093] The subsequent processing procedure of Comparative Example 1 was referred to Example 1. The average pore size of the filtration membrane was measured to be 20.3 nm, and the pure water permeability was 330 L / m2·bar. -2 h -1 bar -1 The breaking strength was 5.3 MPa, and the breaking elongation was 20%. See Table 1 and FIG. 5, in which the left side of two adjacent column charts represents the breaking strength, and the right side represents the breaking elongation.

[0094] Comparative Example 2

[0095] The key point of Comparative Example 2 was that the filtration membrane was prepared by scraping-spraying co-casting. The difference was that PES-OH (terminal hydroxyl group ≥ 50%) was used as the bulk polymer, PEG was used as the additive, NMP was used as the solvent, and two casting solutions a and b were prepared:

[0096] Preparation of casting solution a: PES-OH, additive polyethylene glycol (PEG-200), solvent NMP, etc. were prepared into casting solution a according to the mass ratio of 24:36:40, and the polymer was completely dissolved into a transparent clear viscous solution at 70°C. The viscosity of the casting solution a was finally measured to be 19600 mPa-s (25°C).

[0097] Preparation of casting solution b: PES-OH, additive polyethylene glycol (PEG-200), solvent NMP, etc. were prepared into casting solution b according to the mass ratio of 20:56:24, and the polymer was completely dissolved into a transparent clear viscous solution at room temperature. The viscosity of the casting solution b was finally measured to be 8900 mPa-s (25°C).

[0098] The subsequent processing procedure of Comparative Example 2 was referred to Example 1. The average pore size of the filtration membrane was measured to be 22 nm, and the pure water permeability was 450 L / m2·bar. -2 h -1 bar -1 The breaking strength was 4.9 MPa, and the breaking elongation was 18%. See Table 1 and FIG. 5.

[0099] Comparative Example 3

[0100] The key point of Comparative Example 3 was that the filtration membrane was prepared by single-layer coating. The bulk polymer was PES and the hydrophilic polymer SPES, and the additive was polyethylene glycol (PEG-200). The following is a more specific description of Comparative Example 3:

[0101] A casting solution was prepared with PES (average molecular weight 65000 Da) as the matrix polymer, SPES (sulfonation degree: 20%) as the hydrophilic polymer, PEG-200 as the additive, NMP as the solvent, etc. according to the mass ratio of 24:36:40 (wherein: matrix polymer 20%, hydrophilic polymer 4%), and the polymer was completely dissolved into a transparent clear viscous solution by stirring at 70°C. The viscosity of the casting solution was finally measured to be 21600 mPa·s (25°C).

[0102] The obtained casting solution was sprayed on a PET carrier through a slit device to obtain a nascent membrane; the carrier and the nascent membrane were immersed in a coagulation bath at 50°C for phase inversion, and then immersed in hot water at 60°C for sufficient water washing to remove the residual solvent in the membrane, followed by drying at 80°C to obtain a virus removal filtration membrane.

[0103] The average pore size of the filtration membrane was measured to be 18.5 nm, the pure water permeability was 220 L m -2 h -1 bar -1 , the breaking strength was 5.2 MPa, and the elongation at break was 21% (see Table 1 and FIG. 5).

[0104] Comparative Example 4

[0105] Patent CN116943451 B describes a virus removal composite membrane and a preparation method thereof, and the membrane performance and physical parameters are shown in Table 1.

[0106] Comparative Example 5

[0107] Patent CN101690870B describes a filtration membrane and a preparation method and application thereof, and the membrane performance and physical parameters are shown in Table 1.

[0108] Comparative Example 6

[0109] Patent CN114653222B describes a technical solution for the field of membrane material technology. The membrane performance and physical parameters are shown in Table 1.

[0110] The membrane performance and physical parameters of Examples 1-4 and Comparative Examples 1-6 are shown in Table 1.

[0111] Table 1 Membrane performance and physical parameters of Examples 1-4 and Comparative Examples 1-6

[0112] From the data in Table 1, it can be seen that the filtration membranes prepared in Examples 1-4, which added hydrophilic polymers to the casting solution system and used co-casting method, all exhibited excellent separation performance. Among them, the filtration membranes prepared in Examples 2 and 4, which added only one kind of hydrophilic polymer to the system, had lower water permeability than that of Example 1. In addition, due to the reduction of hydrophilic groups in the system, the breaking strength of the filtration membranes also decreased slightly, but their performance was still much better than that of the comparative examples.

[0113] From the comparison between Comparative Example 1 and Example 1, it can be found that the addition of hydrophilic polymer greatly improved the water permeability, mechanical properties and hydrophilicity (protein recovery rate) of the filtration membrane; from the comparison between Comparative Example 2 and Example 1, it can be found that the filtration membrane prepared by simply using hydrophilic polymer as raw material had lower virus retention rate; from the comparison between Comparative Example 3 and Example 1, it can be found that the filtration membrane prepared by co-casting had significantly lower transmembrane resistance, and could have both high retention rate and high permeability.

[0114] From the comparison between Comparative Example 4 and Example 1, it can be found that the filtration membrane prepared in Comparative Example 4 had high protein recovery rate, but its water permeability and virus retention rate were much lower than those of Example 1; from the comparison between Comparative Example 5 and Example 1, it can be found that the filtration membrane prepared in Comparative Example 5 also had much lower water permeability and virus retention rate than Example 1; from the comparison between Comparative Example 6 and Example 1, it can be found that the filtration membrane prepared in Comparative Example 6 had high breaking strength, but its water permeability and breaking elongation were much lower than those of Example 1.

[0115] The embodiments described above are merely preferred embodiments of the present application, and do not limit the scope of the present application. Without departing from the design spirit of the present application, various modifications and improvements to the technical solutions of the present application made by those of ordinary skill in the art shall fall within the protection scope of the present application as defined by the claims.

Claims

1. A method for preparing a virus-removing filtration membrane, wherein, The hydrophilic polymer and the bulk polymer are blended to prepare casting solutions with different viscosities, and the filter membrane is prepared based on a double-layer homogeneous composite method and a phase inversion method; the filter membrane has an integrated structure, including a dense separation layer and a loose sponge structure pre-filter support layer distributed along the thickness direction of the filter membrane; the separation layer and the support layer are adjacent, but have no obvious interface or delamination phenomenon; the pore sizes of the separation layer and the support layer continuously and gradiently change along the thickness direction, wherein the pore size of the support layer is larger than that of the separation layer.

2. The production method according to claim 1, wherein The filter membrane is prepared based on a double-layer homogeneous composite method and a phase inversion method, and specifically includes the following steps: The bulk polymer, the hydrophilic polymer, a solvent and an additive are blended to prepare two casting solutions A and B with the same or similar composition and different viscosity ranges; The obtained casting solutions A and B are combined on a carrier by a co-casting method, and the casting solution A is overlaid on the casting solution B to obtain a nascent membrane; The carrier and the nascent membrane are immersed in a coagulation bath for phase inversion, and then dried to obtain a virus removal filter membrane.

3. The production method according to claim 2, wherein, In terms of mass percentage, the bulk polymer accounts for 18-24%, the hydrophilic polymer accounts for 2-5%, the solvent accounts for 40-50%, and the additive accounts for 28-35% in the casting solution A; the bulk polymer accounts for 14-16%, the hydrophilic polymer accounts for 2-6%, the solvent accounts for 24-30%, and the additive accounts for 52-58% in the casting solution B.

4. The production method according to claim 2 or 3, wherein The viscosity of the casting solution A is 20,000-25,000 mPa·s at 25°C, and the viscosity of the casting solution B is 10,000-15,000 mPa·s at 25°C.

5. The production method according to claim 2 or 3, wherein The bulk polymer is at least one selected from the group consisting of polyether sulfone, polysulfone, polyvinylidene fluoride and polyvinyl chloride; and the hydrophilic polymer is at least one selected from the group consisting of sulfonated polysulfone, hydroxyl-terminated polyether sulfone, sulfonated polyether sulfone and polyether sulfone-polyethylene glycol block copolymer.

6. The production method according to claim 2 or 3, wherein The solvent is at least one selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran and γ-valerolactone; and the additive is at least one selected from the group consisting of triethylene glycol, diethylene glycol, isopropyl alcohol, polyvinylpyrrolidone and polyethylene glycol.

7. The production method according to claim 2 or 3, wherein The composition of the coagulation bath is at least one selected from the group consisting of water, ethanol, DMF, DMAc and NMP; and the temperature of the coagulation bath is 30-60°C. The phase inversion method is at least one selected from the group consisting of NIPS, TIPS and RTIPS. The co-casting method is one selected from the group consisting of a double-layer synchronous blade coating process, a double-layer slot spraying process and a blade coating-spraying process.

8. The virus removal filtration membrane obtained by the production method according to any one of claims 1 to 7, wherein, The filter membrane has an integrated structure, including a dense separation layer and a loose sponge structure pre-filter support layer distributed along the thickness direction of the filter membrane; the separation layer and the support layer are adjacent, but have no obvious interface or delamination phenomenon; the pore sizes of the separation layer and the support layer continuously and gradiently change along the thickness direction, wherein the pore size of the support layer is larger than that of the separation layer.

9. The virus removing filtration membrane according to claim 8, wherein, The pure water permeability of the filter membrane is 600-900 L m -2 h -1 bar -1 , the protein recovery is >99%, the virus interception rate LRV is not less than 6, and the thickness of the filter membrane is 120-170 μm.

10. The virus removing filtration membrane according to claim 8, wherein, The filter membrane has a breaking strength of 6.0-9.0 MPa and an elongation at break of 30-50%.

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