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WO2024007767A1 - Membrane filtrante cellulosique asymétrique utilisée pour l'élimination de virus et son procédé de préparation - Google Patents

Membrane filtrante cellulosique asymétrique utilisée pour l'élimination de virus et son procédé de préparation Download PDF

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Publication number
WO2024007767A1
WO2024007767A1 PCT/CN2023/096735 CN2023096735W WO2024007767A1 WO 2024007767 A1 WO2024007767 A1 WO 2024007767A1 CN 2023096735 W CN2023096735 W CN 2023096735W WO 2024007767 A1 WO2024007767 A1 WO 2024007767A1
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Prior art keywords
filter membrane
membrane
average pore
layer
dirt
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Chinese (zh)
Inventor
贾建东
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Hangzhou Cobetter Filtration Equipment Co Ltd
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Hangzhou Cobetter Filtration Equipment Co Ltd
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Priority to JP2025500194A priority Critical patent/JP2025522635A/ja
Publication of WO2024007767A1 publication Critical patent/WO2024007767A1/fr
Anticipated expiration legal-status Critical
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/08—Polysaccharides
    • B01D71/12—Cellulose derivatives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
    • B01D67/0011—Casting solutions therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
    • B01D67/0016—Coagulation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2325/00—Details relating to properties of membranes
    • B01D2325/02—Details relating to pores or porosity of the membranes
    • B01D2325/022—Asymmetric membranes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2325/00—Details relating to properties of membranes
    • B01D2325/48—Antimicrobial properties
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/10—Process efficiency

Definitions

  • the present invention relates to the technical field of membrane materials, and more specifically to an asymmetric cellulose filter membrane for virus removal and a preparation method thereof.
  • Membrane technology is a new technology for contemporary high-efficiency separation. Compared with traditional distillation, rectification and other technologies, it has the advantages of high separation efficiency, low energy consumption, and small footprint.
  • the core of membrane separation technology is the separation membrane.
  • polymer filter membranes are a type of separation membrane made from organic polymers as raw materials and according to a certain process; according to different types of polymers, polymer filter membranes can be subdivided into cellulose polymer filters.
  • biopharmaceuticals especially antibodies such as immunoglobulins
  • Biomacromolecules such as antibodies are mainly produced by organisms such as animal cells. Therefore, in order to be used as pharmaceuticals, fluids containing biomacromolecules such as antibodies need to be separated and purified, especially to remove various parvoviruses in the fluid (currently The smallest particle size of murine parvovirus is about 20nm) to ensure the safety of the corresponding biological drugs; currently, the most common way to remove viruses from fluids is through membrane separation. This is because membrane separation technology has high separation efficiency, low energy consumption, and can be used in Conducted at room temperature, it can effectively intercept various viruses without inactivating proteins, and can effectively recover various biological macromolecules.
  • Chinese patent CN1759924B (applied by EMD Millipore) discloses a multi-layer composite ultrafiltration membrane (Figure 13 and Figure 14); the composite ultrafiltration membrane includes at least one layer with a first surface and an equivalent second surface.
  • a first porous membrane layer having an equivalent first side and a second side, and at least one second porous membrane layer having an equivalent first side and a second side, the connection between the first layer and the second layer being superimposed and having a connection from the first side to the second porous membrane layer.
  • the filter membrane is a composite membrane, when transitioning from one layer to On the way to another layer, the pore size will suddenly change (decrease), which can easily lead to a large range of particle sizes remaining at the interface of the layer generated by co-casting. This particle loading at the layer boundary reduces the filter life.
  • the film-forming material used to prepare the composite membrane is mainly polyethersulfone, and the sulfone group of polyethersulfone is surrounded by benzene rings on both sides. , making its hydrophilicity poor, the final film formation will have a certain adsorption effect on proteins, and the protein yield is average, reducing economic benefits.
  • US20200238221A1 (applied by Sartorius) also discloses a porous single-layer polymer membrane. At least one major surface of the polymer membrane has a surface porosity of at least 40%, and the total pores of the polymer membrane The rate is 0.8 times to 1.4 times the surface porosity of at least 40%; and the polymer membrane has an asymmetry factor of 1.5 to 10; the polymer membrane is a single-layer filter membrane with good flux and long It has a long service life and is mainly used to filter viruses, proteins or macromolecules; however, the average pore size of this polymer membrane is large, and it can only intercept large particles with a particle size of several hundred nanometers, but cannot intercept small viruses with a particle size of about 20nm. .
  • Chinese patent CN201580007740.0 (applied by Asahi Kasei Co., Ltd.) also discloses a virus-removing membrane, which contains cellulose and is used to remove viruses from a protein-containing solution.
  • the virus-removing membrane has: Supply The surface of the first side of the solution containing the protein, and the surface of the second side through which the permeate that passes through the virus-removing membrane is discharged, the average pore diameter of the membrane is 13nm-21nm; the membrane is made of cellulose material , has strong hydrophilicity, so it can effectively intercept viruses while also having a low protein adsorption rate.
  • the membrane is a single-layer membrane, and does not have the shortcomings of sudden changes in pore size and easy separation between membrane layers; however, This filter membrane also has certain shortcomings; first of all, the virus removal membrane is prepared by the cuprammonium method, that is, film-forming substances are added to the cuprammonium solution for various treatments. This preparation method not only pollutes the environment, but is also extremely dangerous.
  • the thickness of the virus membrane’s contamination-holding layer (generally considered to be the area with an average pore diameter greater than 40nm in the membrane cross-section is called the contamination-holding layer) is very small, which will cause the virus membrane to The dirt holding capacity is small; large particle impurities can easily block the internal flow channel of the membrane, thereby shortening the service life of the virus membrane;
  • the virus removal membrane produced is a hollow fiber membrane, which has low pressure resistance and is easy to Damage, which makes the preparation process of the virus-removing membrane module and its filter relatively complex; in addition, due to the low pressure strength of the virus-removing membrane, the pressure difference between the front and back of the membrane is small, resulting in a low filtration speed. , the economic benefit per unit time is too low.
  • the purpose of the present invention is to provide an asymmetric cellulose filter membrane for virus removal and a preparation method thereof.
  • the cellulose filter membrane is formed in one piece and does not need to be compounded.
  • the preparation process is relatively simple. Green and environmentally friendly; at the same time, the prepared cellulose filter membrane has a strong interception effect on viruses and can obtain a high protein yield, meeting the needs of practical applications;
  • An asymmetric cellulose filter membrane for virus removal including a main body with a non-directional tortuous passage in the main body, one side surface of the main body being a first outer surface, and the other side surface of the main body being a third outer surface.
  • the main body includes a pollution-holding layer and a retention layer for retaining viruses.
  • One side of the pollution-holding layer is a first outer surface, and one side of the retention layer is a second outer surface; the other side of the pollution-holding layer is a first outer surface.
  • One side and the other side of the interception layer transition with continuous fibers;
  • the average pore diameter of the dirt-holding layer is greater than the average pore diameter of the interception layer; and the average pore diameter change gradient of the dirt-holding layer is greater than the average pore diameter change gradient of the interception layer.
  • the filter membrane of the present invention is made of cellulose materials. Compared with other organic polymer film-forming materials such as PES (polyethersulfone), the filter membrane made of cellulose materials has strong hydrophilicity and is biophilic. It has good compatibility and non-toxicity, and has low adsorption capacity for various proteins (cellulose filter membranes are generally considered to be the least likely membrane material to adsorb proteins among organic filter membranes); therefore, it is particularly suitable for use as a virus removal membrane;
  • PES polyethersulfone
  • the pore sizes on the two outer surfaces of the filter membrane are different, and there is a certain gap; the pore size on one of the outer surfaces
  • the outer surface of the filter membrane with a smaller pore size is called the second outer surface in the present invention, that is, the second outer surface is the small pore surface of the filter membrane.
  • the average pore diameter of the second outer surface is 15-40nm; preferably, the average pore diameter of the second outer surface is 18-32nm; the second outer surface (small hole surface) exists, and the inner surface of the main body
  • the non-directional tortuous pathways refer to randomly oriented groove structures and/or discretely distributed hole structures, and the non-directional tortuous pathways are interconnected, thereby improving the filtration accuracy of the filter membrane. , ensuring that the filter membrane also has a high interception effect on parvovirus;
  • the other outer surface of the filter membrane with larger pore diameter is called the first outer surface in the present invention, that is, the first outer surface is the large pore surface of the filter membrane (also the liquid inlet surface), and the average of the first outer surface
  • the pore diameter is at least 4 times the average pore diameter of the first outer surface; the existence of the first outer surface (large pore surface) is conducive to increasing the membrane flux, speeding up the overall filtration speed of the membrane, and shortening the time for the fluid to pass through the filter membrane. , time cost is lower;
  • the average pore size between the first outer surface and the second outer surface is different, and there is a certain gap, indicating that the cellulose filter membrane is an asymmetric membrane, which can ensure that the overall membrane has Fast filtration speed, large dirt holding capacity, and long service life; it can also ensure strong capture ability for parvovirus (especially parvovirus with a particle size of about 20nm), meeting the needs of practical applications;
  • the average pore size of the main body changes to a certain extent from the area close to the first outer surface to the area close to the second outer surface. That is, the average pore size of the membrane main body gradually increases with the thickness. There is no sudden change (but in a certain small area, the pore size may not change basically), and there is no sudden change, which proves that the filter membrane is formed in one piece and has not undergone "composite" and other processes;
  • the entire filter membrane body of the present invention is mainly divided into two areas in the thickness direction.
  • One area is the dirt-holding layer including the first outer surface, and the pore diameter of the internal pores is relatively large (the average pore size of the dirt-holding layer is larger than that of the interception layer). average pore size), mainly used to intercept large particle impurities in the fluid.
  • the dirt-holding layer has a large dirt-holding capacity and a fast flow rate, which plays a pre-filtering role in the fluid. At the same time, it plays a protective role in the retention layer to ensure
  • the membrane as a whole has high mechanical strength; the other area is the interception layer containing the second outer surface.
  • the internal pores have a relatively small pore diameter and are mainly used to intercept small particle impurities, such as small viruses in the fluid, for separation. function, ensuring that the filter membrane has a high capturing ability for various viruses; therefore, the filter membrane is particularly suitable for use as a virus removal membrane.
  • the first outer surface large pore surface
  • the second outer surface is the liquid outlet surface;
  • the average pore diameter change gradient in the present invention refers to the change value of the average pore diameter under unit thickness; the larger the value, the faster the hole diameter changes with the thickness; the smaller the value, the smaller the hole diameter changes with the film thickness;
  • the average pore diameter change gradient is calculated by the difference between the maximum pore diameter and the minimum pore diameter in a certain area (unit: nm) / the thickness between the two locations (the thickness between the maximum pore diameter and the minimum pore diameter in the area).
  • the thickness between the two positions refers to the minimum thickness between the maximum aperture and the minimum aperture; in the present invention, the dirt holding The average pore diameter change gradient of the layer is greater than the average pore diameter change gradient of the interception layer (that is, the pore size of the dirt-holding layer changes faster with the thickness, and the pore size of the interception layer changes slower with the thickness), which illustrates that from the first outer surface to the second outer surface In the main direction of the membrane on the surface, the pore diameter basically decelerates as the thickness changes; while the average pore diameter of the retention layer is smaller, and the average pore diameter change gradient is smaller, that is, in the retention layer, the hole diameter changes very little with the film thickness.
  • the pore diameters in the interception layer will be small, which is very conducive to efficiently intercepting various small particle impurities, such as parvovirus in proteins (about 20nm), and the purification efficiency is very high high;
  • the cellulose filter membrane of the present invention is formed in one piece, and the average pore size of the membrane body changes gradually and slowly with the thickness without sudden changes.
  • the other side of the dirt-holding layer (the side of the dirt-holding layer facing away from the first outer surface) and the other side of the trapping layer (the side of the trapping layer facing away from the second outer surface) transition with continuous fibers.
  • Continuous means that basically all the fibers are integrally connected to each other, such as being formed in one piece, without the need to use additional adhesives, etc. to connect them to each other. Unless they are torn apart by external force, the network-like fibers cannot be connected to each other unless they are torn apart by external force.
  • the continuous network fibers are also interconnected with the first outer surface and the second porous surface; in the present invention, the material of the cellulose filter membrane is uniform everywhere, that is, the entire The membranes are all made of cellulose materials, and there is no change in material;
  • an asymmetric membrane should be understood as a membrane in which the dirt-holding layer and the interception layer are composed of the same material, and the two layers are combined into an integral structure and are formed directly during the membrane preparation process;
  • the two layers are combined into an integral structure and are formed directly during the membrane preparation process;
  • the layer coating is added to a porous, often microporous, support layer or membrane. The materials constituting the support layer and the retention layer in the composite membrane are often different;
  • the average pore size on the membrane surface can be measured by using a scanning electron microscope to characterize the membrane structure, and then using computer software (such as Matlab, NIS-Elements, etc.) or manually to measure and perform corresponding calculations; during the membrane preparation process
  • computer software such as Matlab, NIS-Elements, etc.
  • its various characteristics such as pore size distribution are Roughly uniform and basically consistent; therefore, the average pore size of the partial area on the corresponding plane can be used to reflect the overall average pore size on the plane.
  • the average pore size change gradient of the pollution-holding layer is at least 3 nm/ ⁇ m greater than the average pore size change gradient of the retention layer;
  • the second outer surface has a plurality of round hole-shaped second holes, and the hole area ratio of the second holes on the second outer surface is 2%-15%.
  • the gradient of the average pore size of the dirt-holding layer is consistent with The difference between the average pore size gradient of the retention layer cannot be too small. If the difference between the two is too small, either the average pore size of the entire membrane is too large, and the retention efficiency for various small viruses (particle size is about 20nm) is too high. Low; or the average pore diameter of the entire membrane is too small, causing the overall flux of the membrane to be too low, the time cost is too large, and the economic benefit per unit time is too low.
  • the average pore diameter change gradient of the dirt-holding layer in the present invention is at least higher than the average of the retention layer.
  • the pore size change gradient is larger than 3nm/ ⁇ m, with a suitable difference; further ensuring that the pores in the interception layer have smaller pore diameters, which is conducive to efficient interception of various small viruses), and at the same time further improving the overall flux of the membrane;
  • the second holes on the second outer surface have a round hole-like structure. Some of the second holes are circular, and some of the second holes are circular.
  • the second hole is oval; and the hole area ratio of the second hole on the second outer surface (ratio of the sum of the second hole areas and the membrane area) is 2%-15%, and the hole area ratio is low, that is, the second outer surface
  • the surface is relatively dense; the second holes with a certain pore size, combined with the second outer surface with corresponding hole area ratio, further ensure that the filter membrane has high interception efficiency for various small viruses (particle size is about 20nm).
  • the test method for the hole area ratio can be to use a scanning electron microscope to characterize the morphology of the membrane structure, and then use computer software (such as Matlab, NIS-Elements, etc.) or manual measurement, and perform corresponding calculations; select a certain area, For example, 1 ⁇ m 2 (1 ⁇ m times 1 ⁇ m) or 25 ⁇ m 2 (5 ⁇ m times 5 ⁇ m). The specific area size depends on the actual situation. Then use the corresponding computer software or manually measure the hole area of all holes in the area, and then calculate it.
  • computer software such as Matlab, NIS-Elements, etc.
  • the average diameter of the first fiber in subsequent characteristics is also It can be obtained by a similar method (ie, the average value of the diameters of several first fibers on a certain area).
  • the first outer surface includes a plurality of strip-shaped continuous first fibers, and circular hole-shaped first holes are formed around adjacent continuous first fibers;
  • the average diameter of a fiber is 100-250nm; the average pore diameter of the first hole is 200-600nm; the hole area ratio of the first hole on the first outer surface is 5-25%.
  • first fibers on the first outer surface of the membrane.
  • the first fibers are in a long strip structure.
  • the first hole is surrounded by the first fiber; the average diameter of the first fiber is 100-250nm.
  • Such a thickness of the first fiber ensures the stability of the first hole, which facilitates a certain pre-filtration of the fluid and retains a certain amount of fluid. Impurity particles of various sizes; at the same time, the mechanical strength of the membrane is ensured, meeting the needs of practical applications, and suitable for various processing;
  • first holes with a certain pore size on the first outer surface of the membrane. It is well known that factors such as the size, number and shape of the membrane holes will affect the filtration accuracy (retention efficiency), membrane flow rate and other properties of the membrane.
  • the first holes on the first outer surface are round hole-shaped structures, some of the first holes are circular, and some of the first holes are oval; the average aperture of the first holes is 200 -600nm (preferably 250-550nm); and the hole area ratio of the first hole on the first outer surface is 5-25% (the ratio of the sum of the first hole areas to the membrane area), through the third hole with a certain pore size), through the third hole with a certain pore size
  • a hole, together with the first outer surface corresponding to the hole area ratio, ensures that the filter membrane has a large flow rate, facilitates fluid to quickly pass through the porous membrane, shortens the filtration time, and also has a large tensile strength. meet the needs of practical applications.
  • the average pore size gradient of the cellulose filter membrane is 2-7nm/1 ⁇ m;
  • the ratio of the average pore diameter of the first outer surface to the average pore diameter of the second outer surface is 6-30;
  • the hole area ratio on the first outer surface is at least 3% greater than the hole area ratio on the second outer surface.
  • the filter membrane of the present invention is formed in one piece, and the pore size of the filter membrane gradually changes with the overall thickness of the membrane (in a certain area, the pore size may basically not change with the membrane thickness), and there will be no sudden changes; therefore, through the average pore size
  • the size of the changing gradient reflects how quickly the membrane pore size changes with thickness. The larger the value, the faster the pore size changes. The smaller the value, the smaller the pore size change.
  • the average pore size change gradient of the filter membrane in the present invention is 2-7nm.
  • the dirt-holding layer can play a certain supporting role for the interception layer, and the overall membrane has good mechanical strength.
  • the membrane as a whole has such a pore size gradient, which can It ensures that the membrane can efficiently intercept viruses, has a larger flux, and has a larger dirt-holding capacity.
  • the pore size of the filter membrane gradually changes with the overall thickness of the membrane (in a certain area,
  • the pore size may basically not change with the membrane thickness) and will not undergo sudden changes; in addition to the average pore size change gradient, it can basically reflect the change of the membrane pore size with the thickness; the ratio of the average pore sizes of the two outer surfaces can further better reflect the membrane pore size Changes with thickness; the ratio of the average pore diameters of the two outer surfaces can be called the asymmetry factor.
  • the ratio of the average pore size of the first outer surface to the average pore size of the second outer surface is 6-30.
  • the average of the two The ratio of pore diameters is 10-25, indicating that the two outer surfaces of the filter membrane of the present invention are asymmetrical and have appropriate asymmetry; such asymmetry not only ensures that the filter membrane has a larger flux, but also has a relatively high asymmetry. Long service life; and ensures that the filter membrane has high virus retention efficiency, meeting actual needs;
  • the hole area ratio on the first outer surface is at least greater than that on the second outer surface.
  • the hole area ratio of the second outer surface is greater than 3%, that is, the hole area ratio of the first outer surface (large hole surface) is larger, and the hole area ratio of the second outer surface (small hole surface) is smaller.
  • the fluid can quickly pass through the first outer surface (large pore surface), which plays a pre-filtering role in the fluid and ensures that the overall membrane has a good flux; while the second outer surface (small pore surface) is dense and can filter various Parvoviruses (especially murine parvoviruses with a particle size of about 20nm) are efficiently trapped, and parvoviruses are not prone to leakage, meeting the needs of practical applications.
  • first outer surface large pore surface
  • Parvoviruses especially murine parvoviruses with a particle size of about 20nm
  • the PMI average pore size of the cellulose filter membrane is 15-40 nm
  • the thickness of the cellulose filter membrane is 70-120 ⁇ m
  • the porosity is 25-55%.
  • the average pore size of the filter membrane was tested with a PMI pore size tester, and the PMI average pore size of the filter membrane of the present invention was obtained to be 15-40nm (as the preferred value is 18-30nm).
  • the tortuous path of the main structure and a certain thickness of the membrane it is ensured that This filter membrane has a strong interception effect on nanoscale parvovirus (even murine parvovirus with a particle size of 20nm), can meet the needs of practical applications, and is suitable for use as a virus membrane;
  • the thickness of the film can be calculated and measured by using a scanning electron microscope to characterize the morphology of the film structure, and then using computer software (such as Matlab, NIS-Elements, etc.) or manual measurement. Of course, those skilled in the art can also use other measurements.
  • the above parameters can be obtained by means (such as freeze drying first and then measuring with measuring tools).
  • the above measurement means are for reference only; when the thickness of the membrane is too small, the mechanical strength of the membrane will be low; at the same time, because the filtration time is too short, it cannot Carry out effective filtration; when the thickness of the membrane is too large, the filtration time will be too long and the time cost will be too high; the thickness of the cellulose filter membrane of the present invention is 70-120 ⁇ m, ensuring that the cellulose filter membrane not only has a relatively high It has high mechanical strength and can perform effective filtration with high filtration efficiency, short filtration time and low time cost;
  • the filter membrane of the present invention is made of cellulose materials.
  • the porosity of the filter membrane is 25-55%.
  • Such porosity and the membrane material work together to make the membrane not only have good stretch It has high strength, fast filtration speed, large flow rate, high dirt holding capacity, can intercept more impurity particles, long service life and low economic cost.
  • the average pore diameter of the pollution-holding layer is 80-300nm, and the porosity is 35-70%; the thickness of the pollution-holding layer accounts for 70-90% of the film thickness;
  • the average pore size gradient of the pollution-holding layer is 3-9 nm/ ⁇ m.
  • the area with a pore diameter greater than 40 nm is the pollution-holding layer, and the area with the pore diameter less than or equal to 40 nm is the retention layer; compared with the retention layer, the pores of the pollution-holding layer have larger pore diameters and higher porosity.
  • the average pore diameter of the pollution-holding layer is 80-300nm (preferably 120-250nm), and the porosity is 35-70% (preferably 40-65%); ensuring that the filter membrane has a higher
  • the flow rate can also play a sufficient role in intercepting large particle impurities (large particle size viruses and other impurities) without affecting the subsequent interception of small viruses;
  • the thickness of the dirt-holding layer accounts for 70%-90% of the overall thickness of the membrane, which illustrates Most of the membrane area is a dirt-holding layer, and under the combined effect of large pore size and high porosity, it ensures that the overall membrane has a high flux, fast filtration speed, low time cost, and high sodium content. Contamination volume, long service life and slow flux decay.
  • the average pore diameter change gradient of the dirt-holding layer is too large, that is, the membrane pore size changes too quickly with the thickness, which can easily lead to the overall mechanical strength of the membrane being too low, and the dirt-holding layer cannot provide support for the interception layer, which cannot meet the needs of practical applications; and
  • the average pore size gradient of the dirt-holding layer is too small, that is, when the membrane pore size changes too slowly with the thickness, it will either cause the filter membrane to have a low interception efficiency for various small viruses (the average pore size of the entire membrane is too large), or it will cause the filter membrane to
  • the overall flux is too small, the filtration time is too long, and the time cost is too large (the average pore size of the entire membrane is too small); in the present invention, the average pore size change gradient of the dirt-holding layer is 3-9nm/ ⁇ m, which has a suitable average pore size change.
  • the pore size changes with thickness more reasonably.
  • the dirt-holding layer has a larger dirt-holding capacity and the membrane has a longer service life; at the same time, it ensures that the overall membrane
  • the flux is higher, the flux decay is slower, and the unit economic benefit is high; in addition, it can ensure that the pore diameter in the retention layer is smaller, which does not affect the efficient retention of viruses by the entire filter membrane.
  • the average pore size, porosity, thickness and other parameters of the pollution-holding layer in the present invention can be measured by first tearing the filter membrane apart and dividing it into a pollution-holding layer and a retention layer, and then testing the corresponding parameters of the pollution-holding layer; or by using a scanning electron microscope. After morphological characterization of the membrane cross-sectional structure, computer software (such as Matlab, NIS-Elements, etc.) or manual measurement can be used to calculate and measure; of course, those skilled in the art can also obtain the above parameters through other measurement methods, and the above measurement methods are only for reference;
  • the average pore size of the area on the side of the dirt-holding layer close to the first outer surface is larger than the average pore size of the area on the side of the dirt-holding layer close to the second outer surface;
  • the average pore diameter change gradient of the area on the side of the dirt-holding layer close to the first outer surface is greater than the average pore size change gradient of the area on the side of the dirt-holding layer close to the second outer surface.
  • the size of the membrane pores in the dirt-holding layer of the present invention decelerates with the film thickness (in the direction from the first outer surface to the second outer surface), that is, on the side of the dirt-holding layer close to the first outer surface
  • the pore diameter is relatively large, and the pore diameter changes rapidly with thickness (the average pore diameter change gradient value is large); while in the area on the side of the dirt-holding layer close to the second outer surface, the pore diameter is relatively large.
  • the pore diameter is small and changes slowly with thickness (the average pore diameter change gradient is small), ensuring that the transition from the dirt-holding layer to the interception layer is very natural without any sudden changes, thereby ensuring that the overall membrane has high mechanical strength.
  • a filter membrane in which the pore size of the dirt-holding layer changes deceleratingly with the thickness will have a larger dirt-holding capacity and a higher flux. It has a good pre-filtration effect on fluids.
  • the dirt-holding layer further includes a cortex area, one side of the cortex area includes a first outer surface; the thickness of the cortex area is 1-15 ⁇ m, and the porosity of the cortex area is 10-55%, and the average pore diameter of the area on the side of the cortex area close to the first outer surface is smaller than the average pore size of the area on the side of the cortex area close to the interception layer.
  • the diameter of the membrane holes increases with the The thickness is reduced (whether it is an equal gradient reduction or a deceleration gradient reduction).
  • the holes existing on the first outer surface are the holes with the largest pore diameter in the overall structure of the membrane; but there is also a part of the dirt-holding layer of the filter membrane.
  • the pore size of the membrane will first increase and then decrease with the thickness, and the largest pore size will appear in the overall structure of the membrane.
  • the area is the area close to the first outer surface, rather than at the first outer surface; in such a main structure of the filter membrane, the present invention refers to the area where the pore diameter in the dirt-holding layer increases with the thickness as the cortex area; when the filter membrane When the dirt-holding layer of the membrane includes a cortex area, the side of the cortex area away from the interception layer is the first outer surface; the existence of the cortex area is conducive to improving the tensile strength of the membrane, while further providing support and protection for the interception layer.
  • the thickness of the cortex area is 1-15 ⁇ m (preferably 3-10 ⁇ m), and the porosity is 10-55%; the cortex area
  • the zone has appropriate thickness and porosity, which can not only improve the support strength of the membrane, but will not affect the overall filtration speed and dirt holding capacity of the membrane.
  • the average pore diameter of the interception layer is 20-40nm, and the porosity is 10-45%; the thickness of the interception layer is 5-25 ⁇ m; the average pore diameter variation gradient of the interception layer is 0- 3nm/1 ⁇ m.
  • the retention layer is the area in the main structure of the filter membrane that traps parvovirus; the pore size and thickness of the retention layer will have a greater impact on the virus retention efficiency; in the present invention, the average pore size of the retention layer is 20-40nm.
  • the pores inside the retention layer have smaller pore sizes, which ensures that the filter membrane has a high retention efficiency for impurities with small particle sizes (especially parvoviruses with a particle size of 20nm), meeting the needs of practical applications, and is especially suitable for virus removal.
  • Field In the existing technology, the thickness of the cutoff layer of some filter membranes will be very small (basically about 1-3um), especially some filter membranes with average hydrophilic properties (such as polyethersulfone filter membranes).
  • the cellulose filter membrane is very hydrophilic and basically does not adsorb proteins; in the present invention, the small pore area with a larger thickness (the thickness of the retention layer is 5-25 ⁇ m) ensures low protein content. While adsorbing, it can also achieve high interception efficiency, and there is no risk of virus leakage; at the same time, the thickness of the interception layer will not be too large, and has basically no impact on the overall flux of the membrane; at the same time, the porosity of the interception layer is 10-45 %, indicating that the interception layer can sufficiently retain parvovirus, and the membrane has a higher loading capacity, which further improves the service life of the membrane;
  • the average pore diameter change gradient of the retention layer is 0-3 nm/1 ⁇ m, and the average pore diameter change gradient is small. This shows that within the retention layer, the pore diameter changes very little or even does not change with the thickness; this, combined with the smaller average pore diameter of the retention layer, can further improve the efficient retention of viruses by the filter membrane, even if Murine parvovirus with a particle size of 20nm can also be efficiently intercepted, with no risk of leakage and a long service life.
  • the average pore size, porosity, thickness and other parameters of the interception layer in the present invention can be obtained by first tearing the filter membrane, dividing it into a interception layer and a dirt-holding layer, and then testing the interception layer for corresponding parameters; or by using a scanning electron microscope to measure the membrane cross-section. After the structure is morphologically characterized, computer software (such as Matlab, NIS-Elements, etc.) or manual measurement can be used to calculate and measure; in addition, the thickness of the interception layer can also be tested by using 20nm colloidal gold as impurity particles to filter out the morphology. The length of the 20nm colloidal gold interception area in the film is the thickness of the interception layer.
  • computer software such as Matlab, NIS-Elements, etc.
  • the length of the 20nm colloidal gold interception area in the film is the thickness of the interception layer.
  • Chinese patent CN105980037B - Virus Removal Membrane please refer to Chinese patent CN105980037
  • the average pore diameter in the retention layer is basically unchanged with the thickness; or the average pore diameter in the retention layer changes with the thickness.
  • the thickness continuously decreases; or the average pore size in the retention layer first decreases and then increases with the thickness.
  • the main structure of the membrane will be affected, and filter membranes with different structures can be produced.
  • the main structure of the filter membrane was observed, and it was found that the pores in the retention layer of some filter membranes were average.
  • the pore size basically does not change with the thickness (that is, the average pore size gradient is 0);
  • the average pore diameter of the retention layer In the retention layer of another part of the filter membrane, the average pore diameter continuously decreases with the thickness. At this time, in the retention layer, the position with the smallest pore diameter is on the second outer surface.
  • Such a retention layer structure helps to ensure retention. Efficiency; in some filter membranes, the average pore diameter of the retention layer first becomes smaller and then becomes larger with thickness.
  • Such a retention layer structure is conducive to improving the overall flux of the membrane while ensuring the retention efficiency; different
  • the structure of the retention layer, together with the thickness of the retention layer and the average pore size of the retention layer ensures that the filter membrane has a high retention rate for parvovirus and that the overall filter membrane has high flux and mechanical strength.
  • the ratio of the average pore diameter of the pollution-holding layer to the average pore diameter of the retention layer is 2.5-9.5:1; the thickness of the pollution-holding layer is at least 35 ⁇ m greater than the thickness of the retention layer.
  • the main structure of the filter membrane in the present invention is mainly divided into two areas.
  • the area with relatively large pore diameter is the pollution-holding layer, and the area with relatively small pore diameter is the retention layer.
  • the ratio to the average pore size of the retention layer is 2.5-9.5:1 (preferably 4-9:1).
  • the cellulose filter membrane of the present invention is an asymmetric membrane, and the pore size will change with the thickness.
  • the pore size of the membrane of the present invention does not change too quickly with the thickness, and there are no excessively large holes; at the same time, it has a reasonable membrane pore structure, and the membrane pore size changes reasonably with the thickness, thereby further ensuring that the filter membrane It can efficiently intercept viruses and ensure that the filter membrane has a fast flux and a large dirt-holding capacity.
  • the separation layer is very thin (the thickness is relatively small), and the difference between the thickness of the dirt-holding layer and the thickness of the interception layer is large, so that the filter membrane can have a greater flux; in the present invention, the thickness of the dirt-holding layer is at least 35 ⁇ m greater than the thickness of the interception layer.
  • Such a membrane main structure further illustrates that most areas of the filter membrane are dirt-holding layers and the separation layer is very thin, which further ensures
  • the overall filter membrane has a large flux and a fast filtration speed; at the same time, the filter membrane also has a large dirt holding capacity, a long practical life, and a slow flux decay.
  • the dirt-holding layer includes pre-filter fibers forming a porous structure, and the pre-filter fibers are strip-shaped structures; the retention layer includes separation fibers forming a porous structure, and the separation fibers are strip-shaped.
  • the side of the prefilter fiber close to the interception layer is continuous with the side of the separation fiber close to the dirt holding layer; the average diameter of the prefilter fiber is 40-100nm; the average diameter of the separation fiber is 20-90nm.
  • the pre-filtration fiber strip structure in the dirt-holding layer, and the separation fiber in the retention layer It is also a strip-shaped structure; this further reflects that the filter membrane is formed in one piece and there is no composite; the dirt-holding layer and interception layer formed by the pre-filter fiber and separation fiber of the strip-shaped structure have appropriate porosity and hole distribution, making the overall membrane have Higher flow rate and high virus retention efficiency; the average diameter of the pre-filter fiber is 40-100nm, and the average diameter of the separation fiber is 20-90nm.
  • Such thick and thin pre-filter fiber and separation fiber can make the dirt-holding layer and retention layer
  • the internal holes have strong stability and are not easy to collapse or shrink, thus ensuring the stability of the fluid flow rate; ultimately ensuring that the overall membrane has high mechanical strength and filtration stability, and can filter efficiently for a long time; therefore, this filter membrane is particularly suitable for applications In the field of virus removal;
  • the thickness of the fiber cross section can be considered as the diameter of the fiber.
  • the average diameter of the second fiber in the present invention can be determined by using a scanning electron microscope to characterize the cross-sectional structure of the filter membrane, and then using computer software (such as Matlab, NIS -Elements, etc.) or calculate the average value after manual measurement; of course, it is understood that those skilled in the art can also obtain the above parameters through other measurement methods.
  • the membrane-forming material of the cellulose filter membrane is a cellulose polymer with an acetyl mass percentage of 0-40%.
  • the membrane-forming material of the cellulose filter membrane is at least one of nitrocellulose, cellulose acetate and regenerated cellulose.
  • the film-forming material is a cellulose polymer with an acetyl mass percentage of 0-40% (that is, in the cellulose polymer, the acetyl mass fraction is 0-40%).
  • the fiber The cellulose polymer is at least one of nitrocellulose, cellulose acetate (including cellulose diacetate and cellulose triacetate) and regenerated cellulose (it can be one cellulose material or multiple celluloses) substances); these cellulose polymers are easily soluble in corresponding organic solvents and have good film-forming and fiber-forming properties; the film-forming films are highly hydrophilic and are not easy to absorb effective substances in the fluid (mainly is protein), has high economic benefits and long service life; and cellulose polymers are widely available, easy to obtain, and low in cost.
  • the first water contact angle of the cellulose filter membrane is 25°-70°; the tensile strength of the cellulose filter membrane is 6-15MPa, and the elongation at break is 5- 40%; the flux of the cellulose filter membrane is greater than 300L*h -1 *m -2 @30psi; the LRV of the cellulose filter membrane for viral impurities is not less than 4; the cellulose filter membrane The protein yield is not less than 98%;
  • the initial flux of the filter membrane is 300-1000L*h -1 *m -2 @30psi, and the end point is when the membrane flux decays by 75%.
  • the loading capacity of the membrane is not less than 300L/m 2 .
  • Contact angle test the test found that the first water contact angle of the first outer surface and the second outer surface of the present invention is 25°-70°, that is, the first water contact angle of the cellulose filter membrane is 25°-70° ( The smaller the contact angle, the more hydrophilic), which means that the cellulose filter membrane is very hydrophilic as a whole and has low adsorption to various proteins, so it can have high protein yield and further ensure economic benefits;
  • tensile strength refers to the ability of a film to withstand parallel stretching; when tested under certain conditions, the film sample is subjected to a tensile load until it is destroyed. According to the maximum tensile load corresponding to the failure of the film sample and the size (length) of the film sample changes, etc., the tensile strength and elongation at break of the film can be calculated; the tensile strength and elongation at break can be measured by a universal tensile testing machine.
  • the testing method of tensile strength is well known in the art.
  • the tensile strength test procedure is explained in detail in ASTM D790 or ISO178; the tensile strength of the filter membrane of the present invention is 6-15MPa; the elongation at break is 5-40%, indicating that the filter membrane of the present invention has a larger
  • the tensile strength and elongation at break have good mechanical properties and high industrial practical value, which can fully meet the market demand.
  • Permeation flux also called permeation rate, or flux for short, refers to the amount of material permeable through a unit membrane area per unit time under a certain working pressure during the separation process; the size of the flux reflects the speed of the filtration speed; The larger the amount, the faster the filtration speed of the membrane; the flux of the filter membrane in the present invention is greater than 300L*h -1 *m -2 @30psi, and the larger the flux, the faster the filtration speed of the filter membrane is, ensuring While retaining efficiency, the fluid can quickly pass through the filter membrane, with lower time cost and higher economic benefits.
  • the viruses captured by the present invention are mainly targeted at various viruses with a particle size of 20 nm and above (for example, murine parvovirus, whose particle size is about 20 nm).
  • a retention test it was found that the filter membrane of the present invention is effective against various viruses.
  • the LRV of the filter membrane is not less than 4, indicating that the filter membrane has a very large retention rate for viruses and plays a sufficient role in retaining viral impurities to meet the needs of practical applications; in addition, the protein yield of the filter membrane is not less than 98% , indicating that the effective substance protein in the fluid is not easily adsorbed on the membrane.
  • the membrane pores will not be blocked, ensuring that the filter membrane still has a high service life, and on the other hand, the content of the effective substance protein in the fluid will be guaranteed to change. Very small, there is basically no loss of protein, and economic benefits are guaranteed; for testing methods of viral impurities, please refer to the patents - CN105980037B - virus removal membrane, CN101816898B - ultrafiltration membrane and its preparation method, CN1759924B - ultrafiltration membrane and its preparation method, etc. .
  • IVIG is an injectable immunoglobulin, which is a protein model of antibodies; in the present invention, IVIG acetate buffer with a concentration of 0.4g/L is used as the test solution (except for IVIG, the test solution does not contain other proteins, let alone Corresponding viral impurities), under the pressure of 30 psi, when the filter membrane flux is reduced to 25% of the initial flux (flux attenuation 75%), the volume of the test liquid flowing through at this time is not less than 300L/m 2 , That is, the filter membrane loading capacity is not less than 300L/m 2 , which further illustrates that the filter membrane of the present invention has low non-specific adsorption and has a long service life;
  • the flux of the cellulose filter membrane is 45-150L*h -1 *m -2 @30psi; the LRV of the cellulose filter membrane for viral impurities is not less than 5.
  • cellulose filter membranes prepared by the present invention we found that some filter membranes have relatively small membrane pores. This membrane structure enables the filter membrane to fully capture parvovirus, especially those with a particle size of about 20 nm.
  • the LVR value of parvovirus can reach more than 5, which ensures that various viruses in the fluid are not prone to leakage; however, due to the relatively small membrane pore size of these filter membranes, the flux will decrease to a certain extent.
  • the present invention also provides a method for preparing an asymmetric cellulose filter membrane for virus removal, which includes the following steps:
  • the casting liquid includes the following parts by weight: 10-30 parts of film-forming polymer; 15-40 parts of first organic solvent; 30-75 parts of pore agent; the film-forming polymer is a cellulose polymer; the first organic solvent is acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid , at least one of butyric acid and valeric acid;
  • the pore-forming agent refers to a non-solvent substance with a surface tension lower than 35 dyne/cm, and this substance is miscible with the coagulation bath;
  • the temperature of the casting liquid is 15-40°C;
  • the pore-forming agent is formamide, ethanol, 1-propanol, isopropanol, n-butanol, 1-pentanol, 2- At least one of pentanol and diethylamine.
  • the liquid film before the liquid film is immersed in the coagulation bath for phase separation and solidification, the liquid film is first immersed in a pre-phase separation liquid for pre-phase separation, and the pre-phase separation time is 2-10 s; wherein the pre-phase separation liquid includes a second Organic solvent and non-solvent, the content of the non-solvent is 0-30%; the second organic solvent and the first organic solvent are mutually soluble; the second organic solvent is acetone, dioxane, dimethylacetamide , N-methylpyrrolidone, at least one of acetic acid, propionic acid, butyric acid and valeric acid; the non-solvent is water or ethanol.
  • the pre-phase separation liquid includes a second Organic solvent and non-solvent, the content of the non-solvent is 0-30%; the second organic solvent and the first organic solvent are mutually soluble; the second organic solvent is acetone, dioxane, dimethylacetamide , N-methylpyrrolidone, at least
  • the film is placed in a sodium hydroxide solution for hydrolysis.
  • the hydrolysis temperature is 20-40°C and the hydrolysis time is 15-45 minutes; it is washed after hydrolysis to form a solid film.
  • a film-casting liquid is first prepared.
  • the film-forming liquid includes a film-forming polymer, a first organic solvent and a pore-forming agent; wherein the film-forming polymer is an acetyl group with a mass percentage of 0- 40% cellulose polymer (that is, in the cellulose polymer, the mass fraction of acetyl groups is 0-40%).
  • the cellulose polymer is nitrocellulose, cellulose acetate (including Cellulose diacetate and cellulose triacetate) and at least one of regenerated cellulose; these cellulose polymers are easily soluble in corresponding organic solvents and have good film-forming and fiber-forming properties; the film-forming properties obtained are very Strong hydrophilicity makes it difficult to adsorb effective substances (mainly proteins) in the fluid; and the presence of the first organic solvent is used to fully dissolve the corresponding cellulose polymer.
  • the first organic solvent is The coagulation bath dissolves, thereby causing the cellulose polymer to precipitate, forming a filter membrane with a certain pore size; in addition, a pore-forming agent is added to the film casting liquid.
  • the pore-forming agent added is generally polyvinylpyrrolidone. (Surface energy is about 60-65dyne/cm) and other substances with high specific surface tension. These substances are relatively easy to enrich and easy to form pores; during phase separation solidification, these pore-forming agents are relatively easy to enrich on the air side of the liquid film.
  • the liquid film is immersed in the coagulation bath (such as water, ethanol), the liquid film close to the air side first contacts the coagulation bath, then the liquid film close to the air side will quickly separate phases, and the pore-forming agent will precipitate from the liquid film. As a result, a dense surface layer with small pores is formed on the air side (the side away from the carrier).
  • the pores inside the dense surface layer are also very small, because the thickness is too small, the interception efficiency of the film will be too low and the dirt holding capacity will be too low. It is low, has almost no loading capacity (extremely short service life), and cannot form a virus-removing membrane that can be used in practical applications; and non-solvents with low surface tension, because these substances are not easy to enrich, have relatively poor pore-forming effects, so they are generally not used Used as a pore-forming agent; in an accidental experiment, a low surface tension non-solvent substance (a non-solvent substance with a surface tension lower than 35 dyne/cm, and the substance is miscible with the coagulation bath) was mistakenly used.
  • Formamide, ethanol, 1 -At least one of propanol, isopropanol, n-butanol, 1-pentanol, 2-pentanol and diethylamine) is used as a pore-forming agent, but unexpectedly, this low surface tension is very
  • solvent substances can quickly dissolve with the coagulation bath.
  • the coagulation bath can quickly enter the side of the liquid film close to the carrier, thus causing the area of the liquid film close to the carrier side to quickly separate and form corresponding small pores.
  • the coagulation bath temperature is 15-45°C, the duration is 20-60s, the coagulation bath is water or ethanol
  • the membrane liquid system is only suitable for cellulose film formation and is not suitable for polyethersulfone. The inventor speculates that this has a certain relationship with the structure and shape of the film-forming material itself. Cellulosic materials are more hydrophilic, so they are suitable for this system and can form an ideal membrane structure;
  • the casting liquid of the present invention can be manually cast (for example, poured by hand, cast or spread on the casting surface) or automatically cast (for example, poured or otherwise cast while moving) bed); a variety of equipment known in the art can be used for casting.
  • Casting equipment includes, for example, mechanical coaters including coaters, doctor blades, or spray/pressurization systems. It is known in the art that a variety of casting speeds are suitable, for example, the casting speed is about 2-6 feet per minute (fpm), etc. The specific casting speed depends on the situation;
  • the liquid film before the liquid film is immersed in the coagulation bath for phase separation and solidification, the liquid film is first immersed in a pre-phase separation liquid for pre-phase separation, and the pre-phase separation time is 2-10 s; wherein the pre-phase separation liquid includes a second Organic solvent and non-solvent, the content of the non-solvent is 0-30%; the second organic solvent and the first organic solvent are mutually soluble; the second organic solvent is acetone, dioxane, dimethylacetamide , N-methylpyrrolidone, at least one of acetic acid, propionic acid, butyric acid and valeric acid; the non-solvent is water or ethanol.
  • the pre-phase separation liquid includes a second Organic solvent and non-solvent, the content of the non-solvent is 0-30%; the second organic solvent and the first organic solvent are mutually soluble; the second organic solvent is acetone, dioxane, dimethylacetamide , N-methylpyrrolidone, at least
  • the liquid film is phase-separated and solidified, and pretreatment is performed, that is, pre-phase separation is performed first, that is, the liquid film is put into the pre-phase separation solution, wherein the pre-phase separation solution is a mixture of the second organic solvent and the non-solvent.
  • the second organic solvent is miscible with the first organic solvent, and the second organic solvent can be the same as or different from the first organic solvent;
  • the non-solvent is water or ethanol, and the presence of the non-solvent can help the liquid film close to the air side to Phase separation.
  • the liquid film will slowly separate phases, thereby forming holes with larger diameters near the air side; due to the difference in the pre-phase separation liquid Different from the pre-phase separation time, the maximum pore diameter of the final filter membrane is at the first outer surface or close to the first outer surface; and since some holes with larger pore diameters have been formed during the pre-phase separation, then This makes it easier for the coagulation bath to invade into the liquid membrane near the carrier side, and the phase separation is more complete.
  • the final filter membrane will have a higher porosity, and thus a higher flux.
  • the film is placed in a sodium hydroxide solution for hydrolysis.
  • the hydrolysis temperature is 20-40°C and the hydrolysis time is 15-45 minutes; it is washed after hydrolysis to form a solid film.
  • the prepared cellulose filter membrane is hydrolyzed in a sodium hydroxide aqueous solution with a concentration of 0.005 mol/L-0.03 mol. After hydrolysis, it is washed with deionized water to form a solid membrane; the solid membrane after hydrolysis, It has better hydrophilicity and lower non-specific adsorption of proteins, thereby further increasing protein yield and improving economic benefits.
  • the asymmetric cellulose filter membrane for virus removal provided by the present invention includes a main body, one side surface of the main body is a first outer surface, the first outer surface is a macroporous surface, and the second outer surface It is a small pore surface with an average pore diameter of 15-40nm; the first outer surface is a large pore surface, and the average pore diameter of the first outer surface is at least 4 times the average pore diameter of the second outer surface; the main body includes a dirt-holding layer and a For the interception layer that intercepts viruses, the main body includes a pollution-retaining layer and a retention layer for retaining viruses.
  • One side of the pollution-retaining layer is the first outer surface, and one side of the retention layer is the second outer surface;
  • the other side and the other side of the interception layer are transitioned by continuous fibers, which shows that the filter membrane is only made of one casting liquid and does not require compounding.
  • the preparation process is relatively simple; the average pore size of the dirt-holding layer is larger than that of the interception layer.
  • the average pore size; and the average pore size change gradient of the dirt-holding layer is greater than the average pore size change gradient of the interception layer, and the pore size decelerates with the thickness, ensuring that the filter membrane has a strong interception effect on parvovirus, and can obtain a higher Protein yield, large flux, fast filtration speed, large loading capacity, long service life, meeting the needs of practical applications; especially suitable for the field of virus removal; in addition, the present invention also provides the preparation of the filter membrane The preparation method is convenient, fast, effective, simple to operate, green and environmentally friendly, and is suitable for large-scale promotion.
  • Figure 1 is a scanning electron microscope (SEM) image of the first outer surface of the filter membrane prepared in Example 1, where the magnification is 5K ⁇ ;
  • Figure 2 is a scanning electron microscope (SEM) image of the second outer surface of the filter membrane prepared in Example 1, where the magnification is 20K ⁇ ;
  • Figure 3 is a scanning electron microscope (SEM) image of the longitudinal section of the filter membrane prepared in Example 1, where the magnification is 2K ⁇ ;
  • Figure 4 is a further enlarged scanning electron microscope (SEM) image of the longitudinal section of the filter membrane prepared in Example 1, where the magnification is 20K ⁇ ;
  • Figure 5 is a scanning electron microscope (SEM) image of the cortical area closest to the first outer surface of the longitudinal section of the filter membrane prepared in Example 5, where the magnification is 10K ⁇ ;
  • Figure 6 is a scanning electron microscope (SEM) image of the longitudinal cross-section of the cortex area farthest from the first outer surface of the filter membrane prepared in Example 5, where the magnification is 10K ⁇ ;
  • Figure 7 is a scanning electron microscope (SEM) image of the longitudinal cross-section of the filter membrane prepared in Example 5, showing the dirt-holding layer (non-cortical area) away from the interception layer, with a magnification of 10K ⁇ ;
  • Figure 8 is a scanning electron microscope (SEM) image of the longitudinal section of the filter membrane prepared in Example 5 of the pollution-holding layer (non-cortical area) close to the interception layer, where the magnification is 10K ⁇ ;
  • Figure 9 is a scanning electron microscope (SEM) image of the longitudinal section of the filter membrane prepared in Example 5 away from the second outer surface, where the magnification is 10K ⁇ ;
  • Figure 10 is a scanning electron microscope (SEM) image of the longitudinal section of the filter membrane prepared in Example 5 near the second outer surface, where the magnification is 10K ⁇ ;
  • FIG 11 is a schematic diagram of the membrane flux testing device of the present invention.
  • Figure 12 is a schematic diagram of the test device when the filter membrane of the present invention uses colloidal gold to test the retention efficiency
  • Figure 13 is a scanning electron microscope (SEM) image of the cross-section of the multi-layer composite ultrafiltration membrane prepared by patent CN1759924B;
  • Figure 14 is a schematic diagram of the composite device used in patent CN1759924B to prepare multi-layer composite ultrafiltration membranes.
  • the raw materials and equipment used to prepare the filter membrane can be purchased through commercial channels.
  • a scanning electron microscope model S-5500 provided by Hitachi was used to characterize the structural morphology of the filter membrane.
  • Example 1 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • S1 Prepare a casting liquid and cast it onto a carrier to form a liquid film;
  • the casting liquid includes the following parts by weight: 12 parts of film-forming polymer; 17 parts of first organic solvent; 58 parts of pore-forming agent;
  • the film-forming polymer is cellulose diacetate; the first organic solvent is acetone; the pore-forming agent is ethanol; the temperature of the casting liquid is 34°C;
  • the liquid film is immersed in a coagulation bath for phase separation and solidification.
  • the temperature of the coagulation bath is 24°C and the duration is 32 seconds to form a film; the coagulation bath is water.
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore diameter of the region near the second outer surface; and in the dirt-holding layer, the average pore diameter change gradient of the region near the first outer surface is greater than the average pore diameter change of the region near the second outer surface of the dirt-holding layer Gradient; the average pore size in the retention layer becomes smaller continuously with thickness.
  • Example 2 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • the casting liquid includes the following parts by weight: 24 parts of film-forming polymer; 34 parts of first organic solvent; 34 parts of pore-forming agent;
  • the film-forming polymer is cellulose triacetate;
  • the first organic solvent is dioxane;
  • the pore-forming agent is formamide;
  • the temperature of the casting liquid is 18°C;
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore diameter of the region near the second outer surface; and in the dirt-holding layer, the average pore diameter change gradient of the region near the first outer surface is greater than the average pore diameter change of the region near the second outer surface of the dirt-holding layer Gradient; the average pore diameter in the retention layer basically remains unchanged with thickness.
  • Example 3 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • the casting liquid includes the following parts by weight: 20 parts of film-forming polymer; 28 parts of first organic solvent; 42 parts of pore-forming agent;
  • the film-forming polymer includes 10 parts of cellulose diacetate and 10 parts of cellulose triacetate;
  • the first organic solvent is dimethylacetamide;
  • the pore-forming agent is 2-pentanol;
  • the temperature of the casting liquid is 28°C;
  • the liquid film is immersed in a coagulation bath for phase separation and solidification.
  • the temperature of the coagulation bath is 34°C and the duration is 40 seconds to form a film; the coagulation bath is water.
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore size of the area close to the second outer surface; and in the dirt-holding layer, the average pore size change gradient of the area close to the first outer surface is basically the same as the average pore size change gradient of the area close to the second outer surface of the dirt-holding layer. The same; the average pore diameter in the interception layer first decreases and then increases with the thickness.
  • Example 4 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • the casting liquid includes the following parts by weight: 14 parts of film-forming polymer; 20 parts of first organic solvent; 50 parts of pore-forming agent ;
  • the film-forming polymer is cellulose diacetate;
  • the first organic solvent is N-methylpyrrolidone;
  • the pore-forming agent is ethanol; the temperature of the casting liquid is 32°C;
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore diameter of the region near the second outer surface; and in the dirt-holding layer, the average pore diameter change gradient of the region near the first outer surface is greater than the average pore diameter change of the region near the second outer surface of the dirt-holding layer Gradient; the average pore size in the retention layer becomes smaller continuously with thickness.
  • Example 5 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • the casting liquid includes the following parts by weight: 16 parts of film-forming polymer; 23 parts of first organic solvent; 62 parts of pore-forming agent ;
  • the film-forming polymer is cellulose diacetate; the first organic solvent is acetone; the pore-forming agent is diethylamine; the temperature of the casting liquid is 36°C;
  • the filter membrane includes a dirt-holding layer and a retention layer.
  • the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer;
  • the dirt-holding layer includes a cortex area, and the cortex area includes a first outer surface; in the dirt-holding layer (the first In the direction of the outer surface facing the second outer surface), the membrane pore size first increases and then decreases with the thickness; the average pore size in the retention layer becomes smaller continuously with the thickness.
  • Example 6 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • the casting liquid includes the following parts by weight: 21 parts of film-forming polymer; 30 parts of first organic solvent; 66 parts of pore-forming agent ;
  • the film-forming polymer is nitrocellulose;
  • the first organic solvent is dioxane;
  • the pore-forming agent is isopropyl alcohol;
  • the temperature of the casting liquid is 24°C;
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore diameter of the region near the second outer surface; and in the dirt-holding layer, the average pore diameter change gradient of the region near the first outer surface is greater than the average pore diameter change gradient of the region near the second outer surface of the dirt-holding layer;
  • the average pore size in the interception layer first decreases and then increases with thickness.
  • Example 7 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • the casting liquid includes the following parts by weight: 26 parts of film-forming polymer; 36 parts of first organic solvent; 36 parts of pore-forming agent ;
  • the film-forming polymer is cellulose triacetate; the first organic solvent is acetic acid; the pore-forming agent is 1-pentanol; the temperature of the casting liquid is 26°C;
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore size of the area close to the second outer surface; and in the dirt-holding layer, the average pore size change gradient of the area close to the first outer surface is basically the same as the average pore size change gradient of the area close to the second outer surface of the dirt-holding layer. The same; the average pore diameter in the interception layer basically remains unchanged with the thickness.
  • Example 8 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • S1 Prepare a casting liquid and cast it onto a carrier to form a liquid film;
  • the casting liquid includes the following parts by weight: 18 parts of film-forming polymer; 26 parts of first organic solvent; 70 parts of pore-forming agent ;
  • the film-forming polymer includes 10 parts of cellulose diacetate and 8 parts of cellulose triacetate;
  • the first organic solvent is valeric acid; the pore-forming agent is 1-propanol; the temperature of the casting liquid is 38°C;
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore size of the area close to the second outer surface; and in the dirt-holding layer, the average pore size change gradient of the area close to the first outer surface is basically the same as the average pore size change gradient of the area close to the second outer surface of the dirt-holding layer. The same; the average pore diameter in the interception layer becomes smaller with the continuous gradient of thickness.
  • Example 9 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • the casting liquid includes the following parts by weight: 28 parts of film-forming polymer; 38 parts of first organic solvent; 38 parts of pore-forming agent ;
  • the film-forming polymer is cellulose triacetate; the first organic solvent is dimethylacetamide;
  • the pore-forming agent is n-butanol; the temperature of the casting liquid is 20°C;
  • the second organic solvent is dimethylacetamide; the non-solvent is water;
  • the filter membrane includes a dirt-holding layer and a retention layer.
  • the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer;
  • the dirt-holding layer includes a cortex area, and the cortex area includes a first outer surface; in the dirt-holding layer (the first In the direction of the outer surface facing the second outer surface), the membrane pore size first increases and then decreases with the thickness; the average pore size in the retention layer basically remains unchanged with the thickness.
  • Example 10 A method for preparing an asymmetric cellulose filter membrane for virus removal, including the following steps:
  • S1 Prepare a casting liquid and cast it onto a carrier to form a liquid film;
  • the casting liquid includes the following parts by weight: 22 parts of film-forming polymer; 32 parts of first organic solvent; 46 parts of pore-forming agent ;
  • the film-forming polymer includes 10 parts of cellulose diacetate and 12 parts of cellulose triacetate;
  • the first organic solvent is N-methylpyrrolidone; the pore-forming agent is isopropyl alcohol; the temperature of the casting liquid is 30°C;
  • the second organic solvent is N-methylpyrrolidone; the non-solvent is water;
  • the filter membrane includes a dirt-holding layer and a retention layer.
  • the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer;
  • the dirt-holding layer includes a cortex area, and the cortex area includes a first outer surface; in the dirt-holding layer (the first In the direction of the outer surface facing the second outer surface), the membrane pore size first increases and then decreases with the thickness; the average pore size in the retention layer first decreases and then increases with the thickness.
  • Example 1 The pore-forming agent ethanol in Example 1 was replaced with polyvinylpyrrolidone, and the other conditions remained unchanged, and the preparation was carried out; after testing, it was found that there was a dense surface layer in the film, and its pore size was also very small, 20-30nm, but the The thickness of the dense surface layer is very small, about 1um, and has no load capacity at all, so it cannot form a virus-removing membrane that can be practically used.
  • a method for preparing an asymmetric cellulose filter membrane for virus removal including the following steps:
  • the casting liquid includes the following parts by weight: 26 parts of film-forming polymer; 20 parts of first organic solvent; 50 parts of pore-forming agent;
  • the membrane polymer is cellulose diacetate;
  • the first organic solvent is N-methylpyrrolidone;
  • the pore-forming agent is ethanol;
  • the temperature of the casting liquid is 30°C;
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore diameter of the region near the second outer surface; and in the dirt-holding layer, the average pore diameter change gradient of the region near the first outer surface is greater than the average pore diameter change gradient of the region near the second outer surface of the dirt-holding layer;
  • the average pore size in the retention layer becomes smaller with the continuous gradient of thickness;
  • a method for preparing an asymmetric cellulose filter membrane for virus removal including the following steps:
  • the casting liquid includes the following parts by weight: 28 parts of film-forming polymer; 24 parts of first organic solvent; 40 parts of pore-forming agent;
  • the membrane polymer is cellulose triacetate;
  • the first organic solvent is butyric acid;
  • the pore-forming agent is isopropyl alcohol;
  • the temperature of the casting liquid is 25°C;
  • the pre-phase separation liquid includes a second organic solvent and a non-solvent, and the content of the non-solvent is 10%;
  • the second organic solvent is Propionic acid;
  • non-solvent is water;
  • S3 Immerse the liquid film into a coagulation bath for phase separation and solidification.
  • the coagulation bath temperature is 20°C and the duration is 24s to form a film; the coagulation bath is water;
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore diameter of the region near the second outer surface; and in the dirt-holding layer, the average pore diameter change gradient of the region near the first outer surface is greater than the average pore diameter change gradient of the region near the second outer surface of the dirt-holding layer;
  • the average pore size in the retention layer decreases continuously with thickness.
  • a method for preparing an asymmetric cellulose filter membrane for virus removal including the following steps:
  • S1 Prepare a casting liquid and cast it onto a carrier to form a liquid film;
  • the casting liquid includes the following parts by weight: 30 parts of film-forming polymer; 22 parts of first organic solvent; 45 parts of pore-forming agent ;
  • the film-forming polymer includes 15 parts of cellulose diacetate and 15 parts of cellulose triacetate;
  • the first organic solvent is dioxane; the pore-forming agent is n-butanol; the temperature of the casting liquid is 30°C;
  • the pre-phase separation liquid includes a second organic solvent and a non-solvent, and the content of the non-solvent is 25%;
  • the second organic solvent is Propionic acid;
  • the non-solvent is water;
  • S3 Immerse the liquid film into a coagulation bath for phase separation and solidification.
  • the temperature of the coagulation bath is 20°C and the duration is 22 s to form a film; the coagulation bath is water;
  • the filter membrane includes a dirt-holding layer and a retention layer.
  • the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer;
  • the dirt-holding layer includes a cortex area, and the cortex area includes a first outer surface; in the dirt-holding layer (the first In the direction of the outer surface facing the second outer surface), the membrane pore size first increases and then decreases with the thickness; the average pore size in the retention layer becomes smaller continuously with the thickness.
  • a method for preparing an asymmetric cellulose filter membrane for virus removal including the following steps:
  • S1 Prepare a casting liquid and cast it onto a carrier to form a liquid film;
  • the casting liquid includes the following parts by weight: 27 parts of film-forming polymer; 18 parts of first organic solvent; 35 parts of pore-forming agent;
  • the membrane polymer includes 18 parts of cellulose diacetate and 9 parts of cellulose triacetate;
  • the first organic solvent is acetone; the pore-forming agent is 1-pentanol; the temperature of the casting liquid is 35°C;
  • the pre-phase separation liquid includes a second organic solvent and a non-solvent, and the content of the non-solvent is 10%;
  • the second organic solvent is Dimethylacetamide;
  • the non-solvent is ethanol;
  • S3 Immerse the liquid film into a coagulation bath for phase separation and solidification.
  • the temperature of the coagulation bath is 23°C and the duration is 23 seconds to form a film; the coagulation bath is water;
  • the filter membrane includes a dirt-holding layer and a retention layer, wherein the pore size change gradient of the dirt-holding layer is greater than the pore size change gradient of the retention layer; in the dirt-holding layer, the average pore size of the area close to the first outer surface is larger than the dirt-holding layer.
  • the average pore diameter of the region near the second outer surface; and in the dirt-holding layer, the average pore diameter change gradient of the region near the first outer surface is greater than the average pore diameter change gradient of the region near the second outer surface of the dirt-holding layer;
  • the average pore size in the retention layer decreases continuously with thickness.
  • Table 1 Structural characteristics and overall characteristics of the outer surface of the filter membrane
  • the filter membranes prepared in Examples 1-10 of the present invention all have an ideal membrane structure.
  • the filter membrane is formed into an integrated film without going through a composite process, and the process preparation is simple; and the filter membrane is an unconventional membrane.
  • the symmetrical membrane has a reasonable membrane structure, which not only ensures efficient virus interception, but also has high flux and loading capacity, long service life, and low protein adsorption, which is suitable for use in the field of virus removal;
  • the membrane flux is calculated as follows:
  • the operating conditions used for measuring the separation performance of the filter membrane in the present invention are: the feed liquid is deionized water, the operating pressure is 30 psi, the operating temperature is 25°C, and the solution pH is 7; the flux testing device is shown in Figure 11;
  • the filter membranes prepared in Examples 1-10 have excellent hydrophilicity, and their first contact angles are all small; they have high flux and high loading capacity, fast filtration speed, and long service life; and they also have high flux and high loading capacity. It has good tensile strength and elongation at break, and has high processing practicability; in addition, it can be seen that comparing Example 1 with Example 4, it can be seen that the filter membrane prepared in Example 4 has higher porosity and higher flux, which also shows that during preparation, it is preferable to perform pre-phase separation, that is, immerse the liquid film in the coagulation bath for phase separation and solidification before immersing the liquid film in the pre-phase separation liquid for pre-phase separation.
  • the first water contact angle of the film in the present invention is the average of the first water contact angles of the two outer surfaces.
  • virus retention test can be carried out according to the test method used in paragraph 114 of CN201010154974.7-Ultrafiltration membrane and its preparation method:
  • the virus used was murine parvovirus with a particle size of 20 nm;
  • the filter membrane of the present invention has a sufficient and sufficient interception effect for viruses with a particle size of 20 nm and above. ;
  • the protein yield of the filter membrane is not less than 98%; therefore, the filter membrane is particularly suitable for use in the field of virus removal.
  • the filter membrane prepared in Example 11 has an LRV of 5.9 for viral impurities with a particle size of 20 nm; the filter membrane prepared in Example 12 has an LRV of 6.4 for viral impurities with a particle size of 20 nm; and the filter membrane prepared in Example 13 has an LRV of 6.4 for viral impurities with a particle size of 20 nm.
  • the LRV of viral impurities with a diameter of 20nm is 7.1; the filter membrane prepared in Example 14 has an LRV of 6.7 for viral impurities with a particle size of 20nm; thus further demonstrating that the filter membrane of the present invention is very sufficient for viruses of 20nm and above interception effect.
  • Filtration accuracy test test the interception efficiency of the filter membrane obtained in each example; interception particles: colloidal gold with a particle size of 20nm;
  • Experimental equipment Tianjin Luogan particle counter KB-3; Experimental preparation: Assemble the experimental device according to Figure 12, ensure that the device is clean, and use ultrapure water to rinse the device; take a filter membrane with a diameter of 47mm and install it in a butterfly filter. Make sure the assembled filter is airtight.
  • n 0 The number of particles in the original solution, the average of 5 groups of counts, each;
  • n 1 The number of particles in the filtrate, the average of 5 groups of counts, each.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Manufacturing & Machinery (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)
  • Filtering Materials (AREA)

Abstract

L'invention concerne une membrane filtrante cellulosique asymétrique utilisée pour l'élimination de virus et son procédé de préparation. La membrane filtrante comprend un corps principal, une surface latérale du corps principal représentant une première surface externe, et l'autre surface latérale du corps principal représentant une seconde surface externe ; le diamètre moyen des pores de la seconde surface externe étant de 15 à 40 nm ; le diamètre moyen des pores de la première surface externe étant au moins 4 fois supérieur au diamètre moyen des pores de la seconde surface externe ; le corps principal comprenant une couche contenant de la saleté et une couche de piégeage, qui est conçue pour piéger des virus, un côté de la couche contenant de la saleté représentant la première surface externe, et un côté de la couche de piégeage représentant la seconde surface externe ; le diamètre moyen des pores de la couche contenant de la saleté étant supérieur au diamètre moyen des pores de la couche de piégeage ; et un gradient de changement du diamètre moyen des pores de la couche contenant de la saleté étant supérieur à celui du diamètre moyen des pores de la couche de piégeage. Le procédé de préparation de la membrane filtrante comprend les étapes suivantes : la préparation d'une solution de coulée de membrane, la coulée de la solution de coulée de membrane sur un support afin de former une membrane liquide, et l'immersion de la membrane liquide dans un bain de coagulation pour une solidification par séparation de phase.
PCT/CN2023/096735 2022-07-08 2023-05-29 Membrane filtrante cellulosique asymétrique utilisée pour l'élimination de virus et son procédé de préparation Ceased WO2024007767A1 (fr)

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