CN117205764B - Cellulose membrane for virus removal, preparation method and filtering membrane component - Google Patents
Cellulose membrane for virus removal, preparation method and filtering membrane component Download PDFInfo
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- CN117205764B CN117205764B CN202311483088.2A CN202311483088A CN117205764B CN 117205764 B CN117205764 B CN 117205764B CN 202311483088 A CN202311483088 A CN 202311483088A CN 117205764 B CN117205764 B CN 117205764B
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- 239000003795 chemical substances by application Substances 0.000 claims description 10
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
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Abstract
The invention provides a cellulose membrane for virus removal, a preparation method and a filtering membrane component. The cellulose membrane for virus removal is suitable for removing viruses from a protein solution, has diffraction peaks at 2θ=16.5° in an XRD pattern, and has a crystallinity at the 2θ=16.5° of 5 to 25% of the overall crystallinity to improve the protein passing performance of the cellulose membrane. The cellulose membrane for virus removal provided by the invention has excellent protein passing performance. The preparation method provided by the invention is used for preparing the cellulose membrane for virus removal. The filtering membrane component provided by the invention comprises a plurality of layers of the cellulose membranes.
Description
Technical Field
The invention relates to the technical field of virus-removing filter membranes, in particular to a virus-removing cellulose membrane, a preparation method thereof and a filter membrane component.
Background
The virus removal filter membrane is used for intercepting viruses based on the effect of physical filtration, viruses meeting a specific size can be intercepted by the filter membrane with a specific pore diameter, and the interception effect is hardly influenced by the differences of physical and chemical properties and the differences of operating conditions of different viruses. Moreover, since the virus removal filter membrane is based on the action of physical filtration to retain viruses, it does not cause changes in the physical and chemical properties of viruses and useful proteins in the filtered solution. Therefore, the virus removal filter membrane can remove the virus content in the filtrate while collecting the useful protein filtrate, and has important application in the field of biological preparations.
The hydrophilic and hydrophobic properties of the virus removal filtration membrane have an important influence on the filtration performance of the filtration membrane. The virus removal filter membrane with poor hydrophilicity can adsorb proteins due to hydrophobic adsorption, so that the filter membrane is easy to block, the service time of the virus removal filter membrane is influenced, and the trafficability characteristic and the yield of the proteins are poor. For example, in US20200238221A1, a disclosure of which is filed by the company saidolis, in one embodiment, the filtering membrane is made of PES (polyethersulfone), and the poor hydrophilic property of PES is liable to cause the blocking of the membrane due to hydrophobic adsorption when the membrane is applied to the filtration of protein feed liquid, so that the filtering membrane made of PES is difficult to be applied to the filtration of medium and high concentration protein feed liquid.
Cellulose has a better hydrophilic property than PES, and is widely favored in the field of biological preparations. For example, patent publication No. CN105980038B, available from Asahi chemical industries, ltd., discloses a cellulose-based virus-removing film having an ability to capture colloidal gold particles of 20 nm. As shown by the spectrum measurement result, the position of capturing the colloidal gold is in a region of more than 25% and less than 85% of water entering the membrane, and the wide region ensures that the membrane has excellent virus removal capability. However, cellulose has a better hydrophilic property than PES, but is limited by the crystalline phase structure of cellulose itself, and the performance of protein passing performance of the cellulose membrane in the prior art is still poor when filtering high-concentration protein feed liquid.
In view of this, a new technical solution is necessary to overcome the drawbacks of the prior art.
Disclosure of Invention
The present invention has been made to solve the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a cellulose membrane which is suitable for removing viruses from a protein solution and has excellent protein-passing performance.
In order to achieve the above purpose, the present invention is realized by the following technical scheme:
a cellulose membrane for virus removal suitable for removing viruses from a protein solution, wherein the cellulose membrane has a diffraction peak at 2θ=16.5° in an XRD pattern, and has a crystallinity at the 2θ=16.5° of 5 to 25% of the overall crystallinity to enhance protein passing performance of the cellulose membrane.
The diffraction peak of the cellulose film existing at 2θ=16.5° in the XRD pattern can reflect the crystallization condition of the cellulose skeleton structure. The inventor finds that the crystallinity of the cellulose skeleton structure influences the hydrophilic performance of the cellulose membrane, and the hydrophilic performance of the cellulose membrane can be improved by reducing the crystallinity of the cellulose skeleton structure.
The preparation method comprises the steps of solidifying a cellulose film in a coagulating bath containing a water-soluble strong-polarity non-solvent, changing the crystallinity of the cellulose film at 2θ=16.5 degrees in an XRD pattern, and controlling the crystallinity to be 5-25% of the whole crystallinity so as to improve the protein passing performance of the cellulose film.
Further, the cellulose film has a crystallinity at 2θ=16.5° in the XRD pattern of 15 to 20% of the overall crystallinity. When the crystallinity of the cellulose membrane at 2θ=16.5° is high compared with the overall crystallinity, the overall hydrophobic effect of the cellulose membrane is obvious, and blockage can occur due to the hydrophobic adsorption effect when filtering the protein solution; when the above-mentioned ratio is low, the whole skeleton of the cellulose appears as a less regular body, resulting in poor tensile strength of the cellulose film, which is unfavorable for use in production processing and filtration. Thus, preferably, the crystallinity of the cellulose film at 2θ=16.5° in the XRD pattern is controlled to be 15 to 20% of the overall crystallinity.
Further, the mass ratio of carbon, nitrogen and oxygen elements of the cellulose film is as follows: the carbon-oxygen ratio is 0.8-1.2, the carbon-nitrogen ratio is 4-8, and the oxygen-nitrogen ratio is 5-10. The cellulose membrane is prepared by solidifying the cellulose membrane in a coagulating bath containing a water-soluble strong-polarity non-solvent, and elements in the water-soluble strong-polarity non-solvent are reflected in the prepared cellulose membrane, so that carbon, nitrogen and oxygen elements of the cellulose membrane are changed, and the cellulose membrane has unique element content and microstructure.
Further, the cellulose membrane has a porosity of 60% to 80%. The cellulose membrane obtained by changing the crystallinity has higher porosity, better filtration flux and better protein trafficability.
Further, the cellulose membrane comprises a porous liquid inlet surface and a porous liquid outlet surface, wherein the average pore diameter of the porous liquid inlet surface is 50-700nm, and the average pore diameter of the porous liquid outlet surface is 10-50nm. Further, the thickness of the cellulose membrane is 80-100 μm, and the PMI average pore diameter thereof is 22-45nm. The cellulose film is prepared by curing in a coagulating bath containing a water-soluble strong-polarity non-solvent, so that the hydrogen bonding action in cellulose is weakened in the phase-splitting film forming process of the cellulose film in the coagulating bath, and thus, the cellulose film prepared by the method has relatively large pores.
Further, the average pore diameter of the cellulose film varies by not more than 3nm/μm in the thickness direction of the cellulose film. From the analysis of the cross-section structure, the liquid surface was extracted from the porous liquid inlet surface to the porous liquid outlet surface according to the pore diameter calculation of SEM, the average pore diameter variation of the membrane was not more than 3nm/μm, and the pore size had high uniformity.
Further, the peak region of the cellulose membrane capturing colloidal gold having a diameter of 20nm in a wet state is within a region of 2 to 8 μm from below the porous liquid inlet surface. The 20nm colloidal gold completes most interception within the distance of 2-8 mu m of the liquid inlet surface, so that more than 90% area of the membrane is an interception area.
Further, the water flux of the cellulose membrane is 100-160L/(m) 2 H) @30psi. The cellulose membrane of the application has higher water flux.
Further, the contact angle of water entering the liquid surface of the cellulose film is 10-22 degrees, and the contact angle of water exiting the liquid surface is 15-25 degrees.
Further, the immunoglobulin solution with a protein content of 30g/L is filtered at 30psi, the protein passage performance of the cellulose membrane is 500-650L/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Filtering an immunoglobulin solution having a protein content of 50g/L at 30psi, said cellulose membrane having a protein passage property of 300-400L/m 2 . The cellulose membrane of the present application exhibits excellent protein passage performance in filtering a feed solution having a high concentration of protein content.
Further, the cellulose in the cellulose membrane is cellulose II type. The cellulose membrane is cellulose II type regenerated cellulose and has better stability.
The invention is also realized by the following technical scheme:
a method of preparing a cellulose membrane for virus removal, the method comprising:
preparing a casting solution, and placing the casting solution on a carrier plate;
placing the carrier plate into a coagulating bath for curing, wherein the coagulating bath contains a water-soluble strong-polarity non-solvent; and
hydrolyzing to obtain cellulose membrane.
The cellulose membrane is prepared by solidifying the cellulose membrane in a coagulating bath containing a water-soluble strong-polarity non-solvent, so that the crystallinity of the cellulose skeleton structure is changed, specifically, the specific gravity of the crystallinity of the cellulose skeleton structure to the whole crystallinity is reduced, and the protein passing performance of the cellulose membrane is improved.
Further, the water-soluble, strongly polar non-solvent in the coagulation bath comprises urea or thiourea. Urea or thiourea has strong polarity, biological safety and is easy to obtain, and is suitable for adding and applying in the coagulating bath for preparing the virus-removing film.
Further, the coagulation bath comprises 10-60% of water, 20-80% of non-solvent and 5-20% of the water-soluble strong polar non-solvent by weight ratio.
Further, the non-solvent in the coagulation bath comprises methanol, ethanol or isopropanol.
Further, the casting film solution comprises 12-30% of film forming polymer, 20-30% of volatile solvent, 15-30% of conventional non-volatile solvent, 0-5% of pore-forming agent A and 15-30% of pore-forming agent B in weight ratio.
Further, the film-forming polymer in the casting solution comprises cellulose acetate; the pore-forming agent A in the casting film liquid comprises polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) or water, and the pore-forming agent B comprises acetamide; the volatile solvent in the casting film liquid comprises acetone; the conventional nonvolatile solvents include N-methylpyrrolidone (NMP), dimethylacetamide (DMAC), dimethylformamide (DMF), or Dimethylsulfoxide (DMSO).
Further, the cellulose film produced by the production method has a diffraction peak at 2θ=16.5° in the XRD pattern, and its crystallinity at the 2θ=16.5° is 5 to 25% of the overall crystallinity. The inventor finds that the crystallinity of the cellulose skeleton structure influences the hydrophilic performance of the cellulose membrane, and the hydrophilic performance of the cellulose membrane can be improved by reducing the crystallinity of the cellulose skeleton structure. The preparation method comprises the steps of solidifying a cellulose film in a coagulating bath containing a water-soluble strong-polarity non-solvent, changing the crystallinity of the cellulose film at 2θ=16.5 degrees in an XRD pattern, and controlling the crystallinity to be 5-25% of the whole crystallinity so as to improve the protein passing performance of the cellulose film.
The invention is also realized by the following technical scheme: a filtration membrane module having a plurality of cellulosic membranes in a stacked arrangement, the cellulosic membranes being as described above, wherein the filtration membrane module has a virus removal LRV value of greater than 4. The filtration membrane component is formed by laminating a plurality of cellulose membranes, and the formed filtration membrane component has an LRV value greater than 4 and can meet the virus interception requirement.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following brief description of the drawings of the embodiments will make it apparent that the drawings in the following description relate only to some embodiments of the present invention and are not limiting of the present invention.
FIG. 1 is a scanning electron micrograph of a longitudinal section of an embodiment of a virus-removing cellulose membrane according to the present invention at a magnification of 10K.
FIG. 2 is a scanning electron microscope image of the meniscus of an embodiment of a cellulose membrane for virus removal according to the present invention, at a magnification of 10K.
FIG. 3 is a scanning electron microscope image of the liquid surface of an embodiment of the virus-removing cellulose membrane of the present invention, which has a magnification of 10K.
Figure 4 is an XRD pattern for one embodiment of a virally-eliminating cellulose membrane of the present invention.
FIG. 5 is a graph of colloid Jin Jieliu of one embodiment of a virus-resistant cellulose membrane of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings. The components of the embodiments of the present invention generally described and illustrated in the figures herein may be arranged and designed in a wide variety of different configurations. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It should be noted that: like reference numerals and letters denote like items in the following figures, and thus once an item is defined in one figure, no further definition or explanation thereof is necessary in the following figures.
Unless defined otherwise, technical or scientific terms used in this patent document should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs. The terms "first," "second," and the like in the description and in the claims, do not denote any order, quantity, or importance, but rather are used to distinguish one element from another. Likewise, the terms "a," "an," or "the" and similar terms do not denote a limitation of quantity, but rather denote the presence of at least one. The word "comprising" or "comprises", and the like, is intended to mean that elements or items that are present in front of "comprising" or "comprising" are included in the word "comprising" or "comprising", and equivalents thereof, without excluding other elements or items. "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", "far", "near", etc. are used merely to denote relative positional relationships, which may also change accordingly when the absolute position of the object being described is changed, merely to facilitate description of the invention and simplify description, and do not indicate or imply that the apparatus or elements being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus should not be construed as limiting the invention.
Some embodiments of the present invention are described in detail below with reference to the accompanying drawings.
Referring to fig. 1 to 5, the present invention discloses a cellulose membrane for virus removal, which is suitable for removing viruses from a protein solution, the cellulose membrane being prepared by solidifying in a coagulation bath containing a water-soluble strongly polar non-solvent, the cellulose membrane having a diffraction peak at 2θ=16.5° in an XRD pattern, and having a crystallinity at 2θ=16.5° of 5 to 25% of the overall crystallinity to improve the protein passing performance of the cellulose membrane.
The diffraction peak of the cellulose film existing at 2θ=16.5° in the XRD pattern can reflect the crystallization condition of the cellulose skeleton structure. The inventor finds that the crystallinity of the cellulose skeleton structure influences the hydrophilic performance of the cellulose membrane, and the hydrophilic performance of the cellulose membrane can be improved by reducing the crystallinity of the cellulose skeleton structure. The preparation method comprises the steps of solidifying a cellulose film in a coagulating bath containing a water-soluble strong-polarity non-solvent, changing the crystallinity of the cellulose film at 2θ=16.5 degrees in an XRD pattern, and controlling the crystallinity to be 5-25% of the whole crystallinity so as to improve the protein passing performance of the cellulose film.
Wherein the XRD pattern is obtained by X-ray diffraction test. Specifically, cu kα rays (λ=1.5406 a) are used as targets, the acceleration voltage is 40 kV, the current is 30 mA, the scanning range 2θ=10-30 °, and the scanning speed is 2 °/min. The overall crystallinity of cellulose is the ratio of the area of the crystalline diffraction peak in the XRD pattern to the total area of the XRD pattern; the crystallinity of cellulose at 2θ=16.5° is the ratio of the area of the diffraction peak at 2θ=16.5° in the XRD pattern to the total area of the XRD pattern. The peaks indicated by the three broken lines P1, P2 and P3 in FIG. 4 are peak-splitting diagrams of three diffraction peaks in the XRD pattern of cellulose, and the 2 theta values corresponding to the peaks of the three diffraction peaks from left to right are about 16.5 degrees, about 20.5 degrees and about 22.5 degrees in sequence, which correspond to the cellulose crystal structures respectivelyDiffraction of the (110) and (020) facets. XRD was used to calculate the crystallinity of the polymerThe crystallinity of cellulose can be determined by a peak height method, a deconvolution method, and a standard method based on the test results of XRD, a common method. The crystallinity calculation method used in the present application is a deconvolution integration method, and the applicant calculates the crystallinity of cellulose by a peak height method, and from the results, although the results are not completely consistent, the crystallinity at 2θ=16.5° still accounts for about 5-25% of the overall crystallinity.
Preferably, the cellulose film has a crystallinity of 15-20% of the overall crystallinity at 2θ=16.5° in the XRD spectrum. When the crystallinity of the cellulose membrane at 2θ=16.5° is high compared with the overall crystallinity, the overall hydrophobic effect of the cellulose membrane is obvious, and blockage can occur due to the hydrophobic adsorption effect when filtering the protein solution; when the above-mentioned ratio is low, the whole skeleton of the cellulose appears as a less regular body, resulting in poor tensile strength of the cellulose film, which is unfavorable for use in production processing and filtration. Thus, preferably, the crystallinity of the cellulose film at 2θ=16.5° in the XRD pattern is controlled to be 15 to 20% of the overall crystallinity.
The cellulose membrane is prepared by solidifying the cellulose membrane in a coagulating bath containing a water-soluble strong-polarity non-solvent, and elements in the water-soluble strong-polarity non-solvent are reflected in the prepared cellulose membrane, so that carbon, nitrogen and oxygen elements of the cellulose membrane are changed, and the cellulose membrane has unique element content and microstructure. In some embodiments, the cellulose film has a carbon, nitrogen, oxygen element mass ratio that satisfies: the carbon-oxygen ratio is 0.8-1.2, the carbon-nitrogen ratio is 4-8, and the oxygen-nitrogen ratio is 5-10.
The porosity of the cellulose membrane is 60% -80%. The cellulose membrane obtained by changing the crystallinity has higher porosity, better filtration flux and better protein trafficability. The cellulose membrane comprises a porous liquid inlet surface and a porous liquid outlet surface, wherein the average pore diameter of the porous liquid inlet surface is 50-700nm, and the average pore diameter of the porous liquid outlet surface is 10-50nm. Further, the thickness of the cellulose membrane is 80-100 μm, and the PMI average pore diameter thereof is 22-45nm. The cellulose film of the present application is cured in a coagulation bath containing a water-soluble strongly polar non-solvent such that the cellulose film is in the coagulation bathThe hydrogen bonding in cellulose is weakened during the phase separation film forming process, so that the cellulose film prepared by the method has relatively large pores. The cellulose membrane has higher water flux, and the water flux of the cellulose membrane is 100-160L/(m) through experiments 2 H) @30psi. From the analysis of the cross-section structure, the liquid surface was extracted from the porous liquid inlet surface to the porous liquid outlet surface according to the pore diameter calculation of SEM, the average pore diameter variation of the membrane was not more than 3nm/μm, and the pore size had high uniformity. The change in average pore size of the membrane can be calculated as follows: dividing the section into 20-30 parts according to the thickness, calculating and counting the pore diameter in each part, and calculating the average pore diameter in each part to obtain the average pore diameter change rate from the liquid inlet surface to the liquid outlet surface.
As is apparent from the 20nm colloidal gold retention curve shown in FIG. 5, the pulse signal of the colloidal gold content at the position 2-8 μm from the inlet level is stronger from the porous inlet level to the porous outlet level, reflecting that the gold content reaches the peak value at the position, and the gold content is almost consistent at the rest positions. That is, the peak region of the colloidal gold having a diameter of 20nm captured by the cellulose membrane in the wet state is in the region of 2 to 8 μm from below the porous liquid inlet surface, particularly in the region of 4 to 6 μm. This indicates that the 20nm colloidal gold completes most of the entrapment within a distance of 2-8 μm from the liquid inlet surface, and more than 90% of the area of the membrane is the entrapment zone.
Immunoglobulin solutions having a protein content of 30g/L were filtered at 30psi using some examples of the cellulose membranes of the present application having protein passage properties of 500-650L/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Filtering an immunoglobulin solution having a protein content of 50g/L at 30psi, said cellulose membrane having a protein passage property of 300-400L/m 2 . As can be seen, the cellulose membranes of the present application exhibit excellent protein passage properties in filtering feed solutions of high protein content.
The cellulose membrane is cellulose II type regenerated cellulose and has better stability.
The invention also provides a preparation method of the cellulose membrane for virus removal, which comprises the following steps:
preparing a casting solution, and placing the casting solution on a carrier plate;
placing the carrier plate into a coagulating bath for curing, wherein the coagulating bath contains a water-soluble strong-polarity non-solvent; and
hydrolyzing to obtain cellulose membrane.
The cellulose membrane is prepared by solidifying the cellulose membrane in a coagulating bath containing a water-soluble strong-polarity non-solvent, so that the crystallinity of the cellulose skeleton structure is changed, specifically, the specific gravity of the crystallinity of the cellulose skeleton structure to the whole crystallinity is reduced, and the protein passing performance of the cellulose membrane is improved.
In some embodiments, the casting solution comprises 12-30% film forming polymer, 20-30% volatile solvent, 15-30% conventional non-volatile solvent, 0-5% porogen A, and 15-30% porogen B by weight. Specifically, in some embodiments, the film-forming polymer in the casting solution comprises cellulose acetate; the pore-forming agent A in the casting film liquid comprises polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) or water, and the pore-forming agent B comprises acetamide; the volatile solvent in the casting film liquid comprises acetone; the conventional nonvolatile solvents include N-methylpyrrolidone (NMP), dimethylacetamide (DMAC), dimethylformamide (DMF), or Dimethylsulfoxide (DMSO).
In some embodiments, the water-soluble, strongly polar non-solvent in the coagulation bath comprises urea or thiourea. Urea or thiourea is strongly polar and readily available and is suitable for additive application in coagulation baths. Specifically, in some embodiments, the coagulation bath comprises 10-60% water, 20-80% non-solvent, and 10-20% of the water-soluble, strongly polar non-solvent by weight; in some embodiments, the non-solvent in the coagulation bath comprises methanol, ethanol, or isopropanol.
The preparation of the casting solution, the film forming and the hydrolysis can be specifically performed as follows.
Preparing a casting solution: mixing cellulose acetate with weight ratio of 12-30%, pore-forming agent A (PVP or PEG or water) with weight ratio of 0-5%, volatile solvent (acetone) with weight ratio of 20-30% and conventional non-volatile solvent (NMP and DMAc or DMF or DMSO etc.) with weight ratio of 15-30% at 40-80 deg.C, stirring thoroughly pore-forming agent B (such as acetamide) with weight ratio of 15-30%, defoaming, standing and cooling to room temperature.
Film forming: uniformly scraping the defoamed casting film liquid onto a glass plate by using a scraper with a certain thickness, and immediately immersing the glass plate into a coagulating bath for solidification. The coagulation bath in this step comprises between 10% and 60% by weight of water, between 20% and 80% of a non-solvent and between 10% and 20% of a water-soluble, strongly polar non-solvent. The non-solvent in the coagulation bath system is one of methanol, ethanol and isopropanol. The water-soluble, strongly polar non-solvent in the coagulation bath system may be urea or thiourea.
Hydrolysis: and (3) placing the cellulose acetate membrane in an alkaline solution for hydrolysis to form the regenerated cellulose membrane. The concentration of the alkaline solution used for hydrolysis ranges from 0.01mol/L to 1mol/L, and the higher the concentration is, the shorter the time required for obtaining regenerated cellulose is; the hydrolysis temperature is in the range of 30-80 ℃, and the higher the hydrolysis temperature is, the shorter the time for obtaining regenerated cellulose is. The final characterization means of the hydrolysis is that the final characterization means is verified by infrared until the carbonyl peak of the cellulose acetate completely disappears, and the complete regenerated cellulose is obtained.
The cellulose film produced by the above-described production method has a diffraction peak at 2θ=16.5° in the XRD spectrum, and its crystallinity at the 2θ=16.5° is 5 to 25% of the overall crystallinity. By the preparation method, the crystallinity of the cellulose film at 2θ=16.5 degrees in the XRD spectrum is changed, the crystallinity is controlled to be 5-25% of the whole crystallinity, and the protein passing performance of the cellulose film is improved.
The properties of cellulose films prepared using the present application and the preparation method are shown below in some specific examples and comparative examples. In the following examples and comparative examples, the raw materials and equipment used are commercially available as they are, unless otherwise specified. The test methods involved therein are briefly described below.
Average pore size test: the pore size distribution tester PMI is used for testing, a certain size of membrane is cut, ethanol with different concentrations is used for wetting the membrane, then a solvent with low surface tension (such as the surface tension of 15.6 mN/m) is used for wetting the membrane (provided by PMI equipment manufacturer in America), the membrane is placed in a testing groove, and finally the average pore size and the starting bubble pore size are obtained through a dry-wet line.
Flow rate: the test is carried out by using a Millipore virus sm ax test device and a stainless steel exchangeable membrane filter with the thickness of 25mm (the device is used for protein transmittance experiments and virus filtration experiments), and the effective filtration area is 4.1cm 2 The filtration test was carried out using ultra-pure water at a temperature of 25℃and a pressure control of 30psi (2 bar).
Virus retention experimental test: using polyclonal antibody IgG as an antibody solution, 5% of MVM murine parvovirus and BVDV bovine viral diarrhea virus were added to the obtained antibody solution, and the mixture was thoroughly stirred to obtain an antibody solution containing the virus. The test was performed using a Millipore virus max test unit plus a 25mm stainless steel membrane change filter. Meanwhile, permeation and top washing are tested, wherein the top washing is to simulate the process interruption of the virus removal membrane in a real application scene, so that the virus is ensured not to leak through brownian motion.
The parameter lrv=log10 (C0/CF) characterizing the viral retention properties of the virus-removal membrane; wherein C0 represents the infectious titer of the stock solution containing the antibody against the virus, and CF represents the infectious titer in the filtrate after the virus removal filtration membrane using regenerated cellulose.
Elemental analysis: the elemental analysis of the film was performed using EDS in a scanning electron microscope.
Colloid Jin Guolv: the purchased 20nm colloidal gold solution was filtered at 30psi. The membrane area used was 0.00035m 2 。
Colloidal gold test: and (3) carrying out liquid nitrogen embrittlement and freeze-drying on the membrane subjected to the colloidal gold filtration, scanning the gold element of the whole membrane by using an EDS of a scanning electron microscope, and determining the interception position of the membrane main body according to the gold content of the whole membrane.
Example 1
S1, preparing casting film liquid: preparing 120g of total materials of casting film liquid, wherein 12% of Cellulose Acetate (CA), 1% of polyvinylpyrrolidone K30 (as a pore-forming component A), 29.5% of acetamide (as a pore-forming component B), 29.5% of conventional volatile solvent acetone and 28% of conventional nonvolatile solvent dimethylacetamide are uniformly mixed at 40 ℃ to obtain the casting film liquid;
s2, film forming: uniformly coating the casting solution on a glass plate by using a scraper with the thickness of 350 mu m, immersing the casting solution scraped on the glass plate in a coagulating bath which is a water solution of 60% water, 20% ethanol and 20% urea at 24 ℃, and stopping for 60 seconds to obtain a cellulose acetate solidified film;
s3, hydrolysis: hydrolyzing the cellulose acetate solidified film obtained in the step S2 in sodium hydroxide aqueous solution with concentration of 0.02mol/L and temperature of 50 ℃ for 5-10 hours, then adopting infrared verification, wherein the infrared spectrum shows carbonyl peak 1740cm of cellulose acetate -1 The position completely disappears, and a complete regenerated cellulose membrane is obtained;
s4, post-processing: and cleaning the hydrolyzed finished film, soaking the cleaned regenerated cellulose film in a 20% glycerol aqueous solution, moisturizing, and finally drying.
Examples 2 to 8
Examples 2 to 8 differ from example 1 mainly in the content of the components of the casting solution and the coagulation bath, as shown in tables 1 and 2 below. Other operating steps and conditions were carried out with reference to example 1.
Comparative examples 1 to 5
The content of each component of the casting solutions in comparative examples 1 to 5 was the same as in examples 2 to 6, and the coagulation bath did not contain a water-soluble strongly polar non-solvent, as shown in tables 1 and 2 below. Other operating steps and conditions were carried out with reference to example 1.
The basic properties of the cellulose films obtained in examples 1 to 8 and comparative examples 1 to 5 described above were tested, and experimental data were obtained as shown in Table 3 below.
As shown in table 3, examples 1 to 8 produced cellulose films having reduced diffraction peak ratios at 2θ=16.5° in the range of approximately 5% -25% due to the addition of water-soluble strongly polar non-solvent urea or flowing urea in the coagulation bath; the cellulose films prepared in comparative examples 1 to 5, in which no water-soluble strongly polar non-solvent was added to the coagulation bath, had a diffraction peak ratio at 2θ=16.5° of 26% or more. The overall PMI average pore diameter, the liquid inlet average pore diameter, and the liquid outlet average pore diameter of the cellulose membranes produced in examples 1 to 8 are larger than those of comparative examples 1 to 5, and the liquid inlet water contact angle of the cellulose membranes produced in examples 1 to 8 is about 10 ° to 22 °, and the liquid outlet water contact angle is about 15 ° to 25 °. The cellulose films produced in examples 1 to 8 were different in the ratio of carbon, nitrogen, and oxygen elements as compared with comparative examples 1 to 5.
The cellulose membranes obtained in examples 1 to 8 and comparative examples 1 to 5 above were tested for virus retention and protein passage properties, and experimental data were obtained as shown in Table 4 below.
As shown in Table 4, the cellulose membrane bilayers prepared in examples 1-8 have an LRV of greater than 4 when used, meeting the virus retention requirements. Meanwhile, the cellulose membranes prepared in examples 1 to 8 were significantly higher in water flux than comparative examples 1 to 5, and the protein passing performance was significantly higher than comparative examples 1 to 5. The protein passage performance is expressed in terms of protein load, which in this application refers to the amount of protein that passes through a unit area of cellulose membrane.
Wherein, the data of the protein load is obtained by the following test, and the cellulose membrane double-layer filtration in examples 1-8 of the application is used for testing, and the test process is as follows: the polyclonal antibody IgG immunoglobulin antibody solution is used as protein filtering feed liquid to be filtered, and is respectively diluted into 30g/L and 50g/L; the test was performed using a Millipore virus max test unit plus a 25mm stainless steel membrane change filter, the filtration volume at this time was recorded every 20min and the current protein filtration throughput was calculated until final passageThe counting was stopped at 25% of the initial protein throughput, resulting in the protein load data in table 4. As can be seen, the protein loading of the cellulose membrane was about 500-650L/m by filtering an immunoglobulin solution having a protein content of 30g/L at 30psi 2 While comparative examples 1-5 were in an amount of about 60-90L/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Filtering an immunoglobulin solution having a protein content of 50g/L at 30psi, said cellulose membrane having a protein loading of about 300-400L/m 2 While the amounts of comparative examples 1 to 5 were about 35 to 55L/m 2 . It is evident that the cellulose membranes of the present application exhibit excellent protein passage properties in filtering feed solutions of high protein content. The performance of the entrapped virus was reduced compared to the bilayer, whereas the protein loading performance was comparable to the bilayer, when tested on a single-layered cellulose membrane. In order to ensure the virus interception performance, in a practical application, a filtration membrane component is formed by laminating a plurality of cellulose membranes. That is, the present invention also provides a filtration membrane module having a plurality of layers of the cellulose membrane as described above stacked, wherein the filtration membrane module is formed to have a virus-free LRV value of greater than 4. The filtration membrane module may comprise 2, 3 or more layers of cellulose membranes.
As can be seen from the above description, the virus-removing cellulose membrane and the method for preparing the same according to the present invention, by adjusting the components of the coagulation bath, changes the final structure of regenerated cellulose, and the prepared virus-removing cellulose membrane has a unique structure, thereby bringing about superior hydrophilic properties; as can be seen from the scanning electron microscope of the longitudinal section of the cellulose film, the cellulose film has ultrahigh symmetry; it can be seen from experimental data that the regenerated cellulose virus-removing membrane prepared by the method has a uniform pore size distribution. The high uniformity and the super-excellent hydrophilicity of the pore size distribution of the regenerated cellulose membrane provided by the application enable the regenerated cellulose membrane to show super-high protein loading in the field of filtering high-concentration proteins, namely, the regenerated cellulose membrane has excellent protein passing performance and can be applied to the filtration of antibodies with different aggregation degrees and different concentrations, various immunoglobulins and other solutions.
The present invention is not limited to the above embodiments, and any changes or substitutions that can be easily understood by those skilled in the art within the technical scope of the present invention are intended to be included in the scope of the present invention. Therefore, the protection scope of the invention is subject to the protection scope of the claims.
Claims (21)
1. A virus-removing cellulose membrane adapted to remove viruses from a protein solution, characterized in that:
the cellulose membrane has a diffraction peak at 2θ=16.5° in the XRD pattern, and has a crystallinity at the 2θ=16.5° of 5 to 25% of the overall crystallinity to enhance protein passing performance of the cellulose membrane;
wherein the cellulose film is prepared by solidifying in a coagulating bath containing a water-soluble strongly polar non-solvent, and the water-soluble strongly polar non-solvent in the coagulating bath comprises urea or thiourea.
2. The virus-removing cellulose membrane according to claim 1, wherein the cellulose membrane has a crystallinity of 15 to 20% of the overall crystallinity at 2Θ=16.5° in the XRD pattern.
3. The virus-removing cellulose membrane according to claim 1, wherein the cellulose membrane has a mass ratio of carbon, nitrogen, and oxygen elements such that: the carbon-oxygen ratio is 0.8-1.2, the carbon-nitrogen ratio is 4-8, and the oxygen-nitrogen ratio is 5-10.
4. The virus-removing cellulose membrane according to claim 1, wherein the cellulose membrane has a porosity of 60% to 80%.
5. The virus-removing cellulose membrane according to claim 1, wherein the cellulose membrane comprises a porous liquid inlet surface and a porous liquid outlet surface, the porous liquid inlet surface has an average pore size of 50 to 700nm, and the porous liquid outlet surface has an average pore size of 10 to 50nm.
6. The virus-removing cellulose membrane according to claim 5, wherein the cellulose membrane has an average pore diameter which varies by not more than 3nm/μm in the thickness direction of the cellulose membrane.
7. The virus-removing cellulose membrane according to claim 5, wherein a peak region of colloidal gold having a diameter of 20nm captured by the cellulose membrane in a wet state is within a region of 2 to 8 μm from below the porous liquid inlet surface.
8. The virus-removing cellulose membrane according to claim 1, wherein the cellulose membrane has a thickness of 80 to 100 μm and a PMI average pore diameter of 22 to 45nm.
9. The virus-removing cellulose membrane according to claim 1, wherein the water flux of the cellulose membrane is 100 to 160L/(m) 2 ·h）@30psi。
10. The virus-removing cellulose film according to claim 1, wherein the cellulose film has a liquid inlet contact angle of 10 ° to 22 ° and a liquid outlet contact angle of 15 ° to 25 °.
11. The virus-removing cellulose membrane according to claim 1, wherein the protein passage performance of the cellulose membrane is 500 to 650L/m by filtering an immunoglobulin solution having a protein content of 30g/L at 30psi 2 。
12. The virus-removing cellulose membrane according to claim 1, wherein the protein passage performance of the cellulose membrane is 300 to 400L/m by filtering an immunoglobulin solution having a protein content of 50g/L at 30psi 2 。
13. The virus-removing cellulose membrane according to claim 1, wherein the cellulose in the cellulose membrane is cellulose type ii.
14. A method for producing a cellulose membrane for virus removal according to any one of claims 1 to 13, comprising:
preparing a casting solution, and placing the casting solution on a carrier plate;
placing the carrier plate into a coagulating bath for curing, wherein the coagulating bath contains a water-soluble strong-polarity non-solvent; and
hydrolyzing to obtain cellulose membrane.
15. The method of claim 14, wherein the coagulation bath comprises 10-60% water, 20-80% non-solvent, and 5-20% of the water-soluble, strongly polar non-solvent by weight.
16. The method of claim 15, wherein the non-solvent in the coagulation bath comprises methanol, ethanol, or isopropanol.
17. The method of claim 14, wherein the casting solution comprises, by weight, 12-30% film-forming polymer, 20-30% volatile solvent, 15-30% conventional non-volatile solvent, and 0-5% porogen a and 15-30% porogen B.
18. The method of claim 17, wherein,
the film-forming polymer in the film casting liquid comprises cellulose acetate;
the pore-forming agent A in the casting film liquid comprises polyvinylpyrrolidone, polyethylene glycol or water, and the pore-forming agent B comprises acetamide;
the volatile solvent in the casting film liquid comprises acetone;
the conventional nonvolatile solvent includes N-methylpyrrolidone, dimethylacetamide, dimethylformamide or dimethylsulfoxide.
19. A filtration membrane module having a plurality of cellulosic membranes in a stacked arrangement, wherein the cellulosic membranes are the cellulosic membranes of any one of claims 1 to 13, wherein the filtration membrane module has a virus removal LRV value greater than 4.
20. The filtration membrane module of claim 19, wherein the protein passage performance of the filtration membrane module is 500-650L/m when the immunoglobulin solution having a protein content of 30g/L is filtered at 30psi 2 。
21. The filtration membrane module of claim 19, wherein the protein passage performance of the filtration membrane module is 300-400L/m when the immunoglobulin solution having a protein content of 50g/L is filtered at 30psi 2 。
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| JP2023110805A (en) * | 2022-01-28 | 2023-08-09 | 日本特殊膜開発株式会社 | Hole diffusion porous cellulose composite film and manufacturing method thereof |
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| JP5526392B2 (en) * | 2007-05-26 | 2014-06-18 | ザ・リサーチ・ファウンデーション・フォー・ザ・ステイト・ユニヴァーシティ・オブ・ニューヨーク | High flux fluid separation membrane containing cellulose or cellulose derivatives |
| US11253821B2 (en) * | 2015-03-18 | 2022-02-22 | Nvigorea Ab | Preparation and use of cellulose nanofiber membrane |
| US11884751B2 (en) * | 2017-05-14 | 2024-01-30 | Washington State University | Environmentally friendly cellulose waste recycling |
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| US6013182A (en) * | 1996-04-19 | 2000-01-11 | Teijin Limited | Selectively permeable hollow fiber membrane and process for producing same |
| WO2015142159A1 (en) * | 2014-03-17 | 2015-09-24 | Universiti Kebangsaan Malaysia | A method for preparing a cellulose based material |
| CN105980038A (en) * | 2014-04-11 | 2016-09-28 | 旭化成医疗株式会社 | Virus removal membrane |
| JP2023110805A (en) * | 2022-01-28 | 2023-08-09 | 日本特殊膜開発株式会社 | Hole diffusion porous cellulose composite film and manufacturing method thereof |
| CN116943428A (en) * | 2023-07-24 | 2023-10-27 | 杭州科百特过滤器材有限公司 | Nylon porous membrane for virus removal prefiltration and preparation method thereof |
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