CN117679962A - Cellulose virus-removing filter membrane and preparation process and application thereof - Google Patents
Cellulose virus-removing filter membrane and preparation process and application thereof Download PDFInfo
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- CN117679962A CN117679962A CN202410153002.8A CN202410153002A CN117679962A CN 117679962 A CN117679962 A CN 117679962A CN 202410153002 A CN202410153002 A CN 202410153002A CN 117679962 A CN117679962 A CN 117679962A
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- Prior art keywords
- cellulose
- filter membrane
- flux
- virus
- membrane
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- Granted
Links
- 239000012528 membrane Substances 0.000 title claims abstract description 653
- 229920002678 cellulose Polymers 0.000 title claims abstract description 188
- 239000001913 cellulose Substances 0.000 title claims abstract description 179
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 230000004907 flux Effects 0.000 claims abstract description 374
- 239000007788 liquid Substances 0.000 claims abstract description 307
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 231
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 231
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 158
- 238000001914 filtration Methods 0.000 claims abstract description 134
- 230000014759 maintenance of location Effects 0.000 claims abstract description 17
- 238000005266 casting Methods 0.000 claims description 193
- 239000000243 solution Substances 0.000 claims description 162
- 239000011148 porous material Substances 0.000 claims description 160
- 239000002904 solvent Substances 0.000 claims description 101
- 238000004132 cross linking Methods 0.000 claims description 89
- 238000006460 hydrolysis reaction Methods 0.000 claims description 88
- 230000007062 hydrolysis Effects 0.000 claims description 87
- 239000003431 cross linking reagent Substances 0.000 claims description 73
- 238000011069 regeneration method Methods 0.000 claims description 67
- 230000008929 regeneration Effects 0.000 claims description 62
- 238000000034 method Methods 0.000 claims description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 54
- 230000001112 coagulating effect Effects 0.000 claims description 54
- 239000004627 regenerated cellulose Substances 0.000 claims description 50
- 239000007787 solid Substances 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 45
- 230000008569 process Effects 0.000 claims description 42
- 229920000642 polymer Polymers 0.000 claims description 36
- 238000004519 manufacturing process Methods 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 230000007774 longterm Effects 0.000 claims description 22
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 19
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 16
- 239000012527 feed solution Substances 0.000 claims description 16
- 238000007711 solidification Methods 0.000 claims description 16
- 230000008023 solidification Effects 0.000 claims description 16
- 239000012982 microporous membrane Substances 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 14
- 238000005345 coagulation Methods 0.000 claims description 14
- 230000015271 coagulation Effects 0.000 claims description 14
- QKSIFUGZHOUETI-UHFFFAOYSA-N copper;azane Chemical compound N.N.N.N.[Cu+2] QKSIFUGZHOUETI-UHFFFAOYSA-N 0.000 claims description 14
- AOBIOSPNXBMOAT-UHFFFAOYSA-N 2-[2-(oxiran-2-ylmethoxy)ethoxymethyl]oxirane Chemical compound C1OC1COCCOCC1CO1 AOBIOSPNXBMOAT-UHFFFAOYSA-N 0.000 claims description 13
- 230000008859 change Effects 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- 238000005191 phase separation Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 229920001747 Cellulose diacetate Polymers 0.000 claims description 7
- 229920000875 Dissolving pulp Polymers 0.000 claims description 7
- 239000004677 Nylon Substances 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 7
- 239000012510 hollow fiber Substances 0.000 claims description 7
- 229920001778 nylon Polymers 0.000 claims description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 230000001172 regenerating effect Effects 0.000 claims description 6
- 238000010345 tape casting Methods 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002033 PVDF binder Substances 0.000 claims description 5
- 238000004140 cleaning Methods 0.000 claims description 5
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- 229920002284 Cellulose triacetate Polymers 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- SYEWHONLFGZGLK-UHFFFAOYSA-N 2-[1,3-bis(oxiran-2-ylmethoxy)propan-2-yloxymethyl]oxirane Chemical compound C1OC1COCC(OCC1OC1)COCC1CO1 SYEWHONLFGZGLK-UHFFFAOYSA-N 0.000 claims description 3
- SEFYJVFBMNOLBK-UHFFFAOYSA-N 2-[2-[2-(oxiran-2-ylmethoxy)ethoxy]ethoxymethyl]oxirane Chemical compound C1OC1COCCOCCOCC1CO1 SEFYJVFBMNOLBK-UHFFFAOYSA-N 0.000 claims description 3
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 3
- UGZICOVULPINFH-UHFFFAOYSA-N acetic acid;butanoic acid Chemical compound CC(O)=O.CCCC(O)=O UGZICOVULPINFH-UHFFFAOYSA-N 0.000 claims description 3
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 claims description 3
- AVMNFQHJOOYCAP-UHFFFAOYSA-N acetic acid;propanoic acid Chemical compound CC(O)=O.CCC(O)=O AVMNFQHJOOYCAP-UHFFFAOYSA-N 0.000 claims description 3
- 229920005994 diacetyl cellulose Polymers 0.000 claims description 3
- 229920001451 polypropylene glycol Polymers 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000005057 Hexamethylene diisocyanate Substances 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 238000013329 compounding Methods 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims description 2
- 238000009826 distribution Methods 0.000 claims description 2
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002608 ionic liquid Substances 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229920000098 polyolefin Polymers 0.000 claims description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 229940014800 succinic anhydride Drugs 0.000 claims description 2
- 229940005605 valeric acid Drugs 0.000 claims description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims 1
- 229920008347 Cellulose acetate propionate Polymers 0.000 claims 1
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 claims 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 claims 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims 1
- 229920006218 cellulose propionate Polymers 0.000 claims 1
- 241000700605 Viruses Species 0.000 abstract description 88
- 239000000706 filtrate Substances 0.000 abstract description 3
- 101001065501 Escherichia phage MS2 Lysis protein Proteins 0.000 abstract 1
- 239000010410 layer Substances 0.000 description 49
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- 241001441571 Hiodontidae Species 0.000 description 1
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- 241000702623 Minute virus of mice Species 0.000 description 1
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Landscapes
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
The application relates to a cellulose virus-removing filter membrane and a preparation process and application thereof, wherein the filter membrane comprises a porous main body, and the porous main body is provided with a liquid inlet surface for the feed liquid containing protein to enter and a liquid outlet surface for the feed liquid containing protein to flow out; water flux T of the filter membrane Water and its preparation method 30-85 LMH@30psi; stable flux T of filter membrane to 50g/L protein feed liquid 240 Not lower than 7LMH@30psi; the retention capacity of the filter membrane for PP7 phage satisfied LRV > 4. The application further discloses a preparation process of the filter membrane and application of the filter membrane in virus removal and filtration in feed liquid with concentration of more than 20 g/L. The filters of the present application, while having a relatively low water flux, often have a low water flux as compared to commonly recognized filtersThe lower protein filtrate flux is different, and the filter membrane has unexpectedly high flux when applied to the high-concentration protein preparation with the protein concentration of more than 20 g/L.
Description
Technical Field
The application relates to the field of membrane separation technology, in particular to a cellulose virus-removing filter membrane and a preparation process and application thereof.
Background
For various biological agents, whether endogenous viruses carried by the original cell line or exogenous viruses accidentally carried in the production process, the risk of virus contamination of the biological agents is caused, and the virus contamination can have serious consequences in clinic, so that the virus safety of various biological agents is necessarily ensured. This is also an important reason why higher requirements are put on the viral safety of biological agents in relevant documents such as the "chinese pharmacopoeia" of 2020 edition and the "biotechnology product-viral safety evaluation" of ICH Q5A.
The membrane separation technology has the advantages of no need of additional reagent, no phase change process in the separation process, normal temperature operation, low energy consumption and the like, is particularly suitable for separating heat-sensitive substances and bioactive substances, and is widely applied to virus removal steps in the preparation process of various biological agents because of replacing some traditional common virus inactivation modes such as organic solvent inactivation, detergent inactivation, low pH inactivation and the like.
The conventional virus removal filter membranes comprise PVDF virus removal membranes, PES virus removal membranes and cellulose virus removal membranes, wherein the PES virus removal membranes have high filtration efficiency and good virus filtration effect, but the PES material has poor hydrophilicity, and the conventional commercial PES virus removal membranes subjected to hydrophilic modification still have poor hydrophilicity and are easy to adsorb active proteins (main active ingredients in biological agents) in feed liquid. PVDF virus removal membranes also have similar problems as PES virus removal membranes. Compared with PVDF material and PES material, cellulose material has obviously better hydrophilicity, and has lower specific adsorption to active protein in feed liquid, so that the cellulose material has higher protein yield.
However, cellulose virus-removing membranes have the defect of too low flux when filtering feed liquid with high protein concentration, and even lose practical industrial application value. Such as the document "Effect of antibody solution conditions on filter performa" by the Japanese Xudi chemical company in Wiley Online Library, 3 months of 2010nce for virus removal filter Planova 20N' it is explicitly stated that the conditions of the antibody solution (e.g.antibody concentration, ionic strength, pH etc.) have an influence on the filtration performance of the virus removal filtration process, and that Planova produced by this company TM IgG concentration is 10-20mg/mL under the optimal application condition of the 20N cellulose virus removal membrane, and when the IgG concentration in the filtering feed liquid reaches 40mg/mL or even 50mg/mL, the Planova is used TM The average flux of the 20N cellulose virus removal membrane is as low as 10L/m 2 /h or even 4L/m 2 And/h or less. It should be noted that if the filtration time is too long, the penetration probability of the virus increases, and the virus retention reliability cannot be guaranteed, so that too low flux means almost no production feasibility and cannot match the actual mass production requirements.
However, in addition to the biological agents such as immunoglobulin with higher concentration, increasing the concentration of various low-concentration biological agents has become an important trend for technology update iteration in the field of biological agents, for example, in recent years, the total obtained antibody preparation is relatively high with the obtained high-concentration monoclonal antibody preparation. The reason is that the current administration mode of various biological agents is subcutaneous injection, and the maximum dosage of subcutaneous administration is generally controlled to be less than 2mL, and the therapeutic dosage of monoclonal antibody is higher, so that the biological agents of single subcutaneous injection must contain higher concentration of active protein to ensure curative effect. In addition, high concentration formulations often mean higher production efficiency, lower production costs. Based on various advantages, high concentration formulations are a current trend, but this also presents more serious challenges to the production process.
For example, for PES virus removal membranes having poor hydrophilicity and high protein adsorption rate, a higher protein concentration tends to mean a higher probability of protein adsorption, and a large amount of adsorbed proteins easily cause clogging of the virus removal membrane pore structure, thereby leading to a rapid decrease in lifetime and an unavoidable increase in production cost. More importantly, higher protein adsorption means lower protein yields, while the high production costs of active proteins make the disadvantage of high protein losses unacceptable to manufacturers. For the cellulose material virus-removing membrane with good hydrophilicity and low protein adsorption rate, the protein loss is low because of high protein yield due to good hydrophilicity, but the too low flux when filtering high-concentration protein feed liquid makes it difficult to cope with the virus-removing requirement of high-concentration protein feed liquid.
Obviously, for high-concentration protein preparations with concentration of more than 20mg/mL (20 g/L), the low breakthrough possibility of viruses is guaranteed, and meanwhile, high flux and high protein yield can be realized, so that the technical problems which are difficult to realize at present but are still to be solved urgently are solved.
Disclosure of Invention
The application provides a cellulose virus-removing filter membrane and a preparation process and application thereof, wherein the filter membrane has relatively low water flux, but has unexpectedly high flux when being applied to a high-concentration protein preparation with the protein concentration of more than 20g/L, unlike the commonly-recognized filter membrane with low water flux which often also has low protein filtrate flux; in addition, the lower water flux also means high-efficiency interception of viruses in feed liquid, and the good hydrophilicity of cellulose material ensures that the filter membrane has good virus interception effect, higher flux and higher protein yield, so that the filter membrane is particularly suitable for virus removal filtration of high-concentration protein preparations with concentration of more than 20 g/L.
In a first aspect, the present application provides a cellulose virus-removing filter membrane, which adopts the following technical scheme:
a cellulose virus-removing filter membrane comprises a porous main body, wherein the porous main body is provided with a liquid inlet surface for feeding liquid and a liquid outlet surface for discharging the feeding liquid;
the water flux T of the filter membrane Water and its preparation method Not higher than 85LMH@30psi and not lower than 30LMH@30psi;
stabilized flux T of the filter membrane 240 Not lower than 7LMH@30psi, said stable flux T 240 Flux data of the filter membrane when the concentration n of protein in the filter liquid is 50g/L and the filtering time t is 240 min;
the trapping capacity of the filter membrane for PP7 phage meets LRV > 4@ (0.1 g/L, IVIG).
By adopting the technical scheme, as before, the common cellulose virus removal membrane such as the commercially available Planova TM The 20N cellulose virus removal membrane has good virus interception capability and lower protein loss when filtering medium-low concentration protein feed liquid with the protein concentration not higher than 20 g/L; however, when the high-concentration protein feed liquid with the protein concentration of more than 20g/L is filtered, the flux of the filter membrane is rapidly reduced along with the continuous increase of the protein concentration in the feed liquid, and when the protein concentration in the feed liquid reaches 50g/L, the flux of the filter membrane is already approaching to 0, so that the possibility of actual production adaptation is lost.
Generally, the water flux performance of the filter membrane can well represent the transmembrane resistance of the filter membrane to the filtered feed liquid, because the higher the water flux of the filter membrane is, the lower the transmembrane resistance of the filter membrane to deionized water is, and the deionized water can pass through the filter membrane quickly; likewise, when the filter liquor is changed from deionized water to protein liquor containing protein, the resistance of the filter membrane to the protein liquor should also be low, so that the filter membrane should also have good flux when used for filtering the protein liquor; i.e. the water flux should have a certain positive correlation with the protein feed liquid flux. Of course, protein feed has a higher viscosity than deionized water, and higher viscosity means greater transmembrane resistance, and therefore, the absolute value of the flux of protein feed is generally lower than the water flux.
Based on the conventional knowledge, for the conventional cellulose virus removal membrane, if the flux of the cellulose virus removal membrane for filtering high-concentration protein feed liquid is to be improved, the general practice is to further improve the water flux of the filter membrane, ensure that the filter membrane has low resistance to the feed liquid, and further ensure that the filter membrane receives lower resistance to the filter membrane when filtering the high-concentration protein feed liquid with the protein concentration of more than 20g/L, so that the high flux is achieved.
However, the inventors of the present application have unexpectedly found that when a filter membrane is used for filtering a high concentration protein feed solution having a protein concentration of more than 20g/L, the control filter membrane has a lower water flux,rather, it is quite unexpected to be able to make the filter membrane have a high protein feed liquid flux against common sense. The inventor of the application can achieve at least not lower than 6LMH@30psi by controlling the water flux of the filter membrane to be not higher than 85LMH@30psi and LRV not less than 5, when the filter membrane filters feed liquid with high protein concentration (50 g/L, IVIG solution) even when the filtering duration is longer 240 min. When the high-concentration protein feed solution is filtered in the same manner, PLANOVA is commercially available at present TM The flux of the 20N cellulose virus removal membrane has been approaching 0, with no production match possibility. This result is quite unexpected as the current perceived water flux is greater, the greater the protein feed filtration flux is not the same.
This is probably due to the fact that the filtration mode of dead-end filtration is adopted in the virus-removing filtration membrane in the present application, and compared with the filtration mode of tangential flow filtration adopted by the common ultrafiltration membrane, the filtration mode of dead-end filtration is complete membrane-spanning filtration of feed liquid, so that the filtration membrane is often subjected to larger pressure. According to the modified Mooney equation, it is generally believed that the viscosity tends to increase exponentially as the concentration of protein in the feed solution increases. Higher viscosity tends to mean that the feed solution is subjected to higher flow resistance through the filter membrane during virus removal filtration, and the filter membrane itself will also be subjected to higher pressure. When the protein concentration in the feed liquid is not higher than 20g/L (the concentration of IVIG is not described later), the viscosity of the feed liquid can be kept at a relatively low level, and when the protein concentration in the feed liquid is higher than 20g/L, even up to 50g/L or higher, the viscosity of the feed liquid is increased rapidly, and the pressure born by the filter membrane is also increased rapidly. Since cellulosic materials have the disadvantage of being relatively soft in texture (which is why Planova in the aforementioned documents TM One of the important reasons for the official guidelines of the filtration pressure of the 20N cellulose virus removal membrane is 98 kPa), when the filter membrane is subjected to a large pressure, the collapse problem of the pore structure of the filter membrane using a cellulose material with softer texture as a film forming substance easily occurs, thereby causing the phenomenon that the undesired flux of the filter membrane is remarkably reduced.
Thus, if conventional modifications are used to further increase the water flux performance of the filter, while the filter does have a lower resistance to deionized water, a higher water flux tends to mean that the filter has a higher porosity and/or a larger pore size. For the working condition of lower viscosity (such as deionized water or low-concentration protein feed liquid), the pressure applied to the filter membrane is lower, the pore structure of the filter membrane is not easy to deform under pressure, and the higher porosity and/or the larger pore size have lower resistance to the feed liquid, so that the flux is higher. However, for high concentration protein feed solutions with protein concentration greater than 20g/L, the viscosity of the feed solution is increased sharply, the pressure to which the filter membrane is subjected is increased sharply, the porous main body with higher porosity is combined with the cellulose film forming material with softer texture, so that the filter membrane is easy to collapse when bearing higher pressure, and once the membrane pores collapse, the porosity, pore diameter and the like of the filter membrane are reduced greatly (the collapsed membrane structure becomes quite compact), and the collapsed pore structure and the feed solution with higher viscosity enable the filter membrane to have lower flux for the high concentration protein feed solution. Thus, as the water flux of the filter membrane increases, the filtration flux of the high-concentration protein feed liquid of the filter membrane decreases as a result of the reverse common sense.
The specific choice of the filter membrane with water flux not higher than 85LMH@30psi and LRV not less than 5 in the application means that the filter membrane has certain resistance to deionized water, but also has relatively low porosity and/or smaller pore size, so that the filter membrane has higher strength and self-supporting performance. When high-concentration protein feed liquid is filtered, the filter membrane with higher self-supporting performance is not easy to deform even if bearing higher pressure, and is not easy to collapse of a pore structure; thus, it actually has a higher porosity and/or larger pore size during filtration than the collapsed membrane, and thus a higher flux of high concentration protein feed solution filtration.
Of course, the water flux of the filter membrane is not too low, if the water flux of the filter membrane is lower than 30lmh@30psi, although the strength of the filter membrane can be further improved to have better self-supporting properties, too low water flux tends to mean that the filter membrane has too low porosity and/or too small pore size and thus has a higher resistance to deionized water. When the filter membrane is used for filtering high-concentration protein feed liquid, even if the pore structure of the filter membrane does not deform, the filtering resistance of the filter membrane to the high-concentration protein feed liquid is larger, and the flux of the filter membrane for filtering the high-concentration protein feed liquid is lower due to a small amount of deformation which is difficult to avoid and the feed liquid with higher viscosity.
In summary, for the special working condition of virus removal and filtration of high-concentration protein feed liquid, the flux of the high-concentration protein feed liquid of the filter membrane is continuously improved along with the improvement of the water flux, and then the flux is reduced rather than being continuously improved along with the improvement of the water flux, so that the filter membrane with the water flux of 30-85 LMH@30psi is specially selected and used in the method, and the high flux of the filter membrane during filtration of the high-concentration protein feed liquid can be ensured.
It should be noted that Planova is commercially available TM The official nominal filtration pressure for a 20N cellulose virus-removing membrane is about 14psi, and thus, although the test pressure in the foregoing document is not 30psi, it is expected that, since 30psi is far beyond the nominal filtration pressure for the commercial cellulose virus-removing membrane, the membrane is likely to undergo excessive pore structure collapse under the conditions of a filtration pressure of 30psi and a higher viscosity of high-concentration protein feed, which means further blockage of the feed flow passage in the membrane, the flux thereof will be further reduced, more toward 0.
It is understood that the water flux data test conditions of the filter membrane in the present application are that the filter membrane is placed in a filtration area of 4.1cm 2 In a stainless steel metal holder (e.g. Millipore Virusmax test device with an effective filtration area of 4.1 cm) 2 A stainless steel replaceable membrane filter, or other flux testing device conventional in the art) using deionized water as the test fluid. The water flux T of the filter membrane referred to in the present application Water and its preparation method Not higher than 85LMH@30psi, namely, the filter membrane is subjected to flux test by the testing device, the test pressure is controlled to be 30psi during the flux test, and the test result is not higher than 85LMH; wherein LMH means L/(h.m) 2 ）。
The high-concentration protein feed liquid flux data testing conditions of the filter membrane are the same as the water flux testing conditions, and the difference is only that IVIG solution with the concentration of 50g/L is adopted as the testing liquid.
The virus interception capability test condition of the filter membrane in the application is that the relevant virus interception test condition in PDA TR41 is referred, the model virus is PP7 phage, the model protein is IVIG, the concentration of IVIG is 0.1g/L, the titer of the PP7 phage before and after filtering the feed liquid is respectively tested, and the interception data LRV of the filter membrane to the PP7 phage can be calculated.
Alternatively, the stable flux T of the filter membrane 240 Not lower than 8LMH@30psi, the water flux T of the filter membrane Water and its preparation method Not higher than 83LMH@30psi.
Alternatively, the stable flux T of the filter membrane 240 Not lower than 9LMH@30psi, the water flux T of the filter membrane Water and its preparation method Not higher than 82LMH@30psi.
Optionally, the interception capability of the filter membrane for PP7 phage meets the requirement that LRV is more than or equal to [email protected] g/L (IVIG); further alternatively, the interception capacity of the filter membrane for PP7 phage meets LRV not less than [email protected] g/L (IVIG); furthermore, the interception capability of the filter membrane for PP7 phage meets the requirement that LRV is more than or equal to [email protected] g/L (IVIG).
Alternatively, the water flux T of the filter membrane Water and its preparation method Not higher than 80LMH@30psi and not lower than 35LMH@30psi;
stabilized flux T of the filter membrane 240 Not less than 10LMH@30psi;
the interception capability of the filter membrane for PP7 phage meets the requirement that LRV is more than or equal to 5.5@L (0.1 g/L, IVIG).
Alternatively, the water flux T of the filter membrane Water and its preparation method Not higher than 75lmh@30psi and not lower than 40lmh@30psi; further alternatively, the water flux T of the filter membrane Water and its preparation method Not higher than 70LMH@30psi and not lower than 50LMH@30psi.
Alternatively, the stable flux T of the filter membrane 240 Not lower than 12LMH@30psi; further alternatively, the stabilizing flux T of the filter membrane 240 Not less than 14LMH@30psi.
Optionally, the interception capacity of the filter membrane for PP7 phage meets the requirement that LRV is more than or equal to [email protected] g/L (IVIG); further alternatively, the retention capacity of the filter membrane for PP7 phage meets LRV not less than [email protected] g/L (IVIG).
By adopting the technical scheme, on the basis that the water flux of the filter membrane is not higher than 85LMH@30psi, the water flux of the filter membrane is further controlled to be not higher than 75 and even not higher than 70LMH@30psi, and with the further reduction of the water flux of the filter membrane, when the filter membrane filters high-concentration protein feed liquid with the protein concentration of 50g/L, the flux which is further preferable to be not lower than 10 and even not lower than 12LMH@30psi can be obtained. In the whole, the stable flux of the filter membrane under the working condition of high-concentration protein can be further controlled by further controlling the water flux performance of the filter membrane. For example, when controlling the water flux T of the filter membrane Water and its preparation method Stable flux T of filter membrane not higher than 84LMH@30psi 240 Not lower than 7LMH@30psi; when controlling the water flux T of the filter membrane Water and its preparation method Stable flux T of filter membrane not higher than 83LMH@30psi 240 Not less than 8LMH@30psi; when controlling the water flux T of the filter membrane Water and its preparation method A stable flux T of the filter membrane of not higher than 82LMH@30psi 240 Not lower than 9LMH@30psi. The water flux of the filter membrane is further controlled, so that the stable flux T of the filter membrane can be realized 240 Not less than 10LMH@30psi and even not less than 12LMH@30psi. This approach to improve the steady flux of the filter under high protein concentration conditions by further reducing the water flux is quite unexpected.
This may be due to the fact that, unlike filtration of low viscosity feed, the flux performance of a filter membrane is affected by a combination of factors when the filter membrane is used to filter high viscosity feed. Lower water flux and higher virus retention means lower porosity and/or smaller pore size, which tends to result in an increase in the membrane resistance to feed; however, lower porosity and/or smaller pore size also means a further improvement in pressure resistance, self-supporting properties of the filter membrane, and thus smaller pore structure variations in filtering high viscosity feed streams.
With a gradual decrease in the water flux of the filter membrane (e.g., from 85 to 84, 83, 82, 80, or even 75, 70lmh@30 psi), the filter flux effect on the high viscosity feed liquid of the filter membrane may be greater than the pressure resistance of the filter membrane, rather than the resistance of the membrane pores themselves to the feed liquid. Because the reduction of the water flux of the filter membrane is accompanied by the improvement of the feed liquid resistance, the improvement of the feed liquid resistance is relatively slow, and the influence is small; however, the reduction of the water flux of the filter membrane is accompanied by the rapid improvement of the pressure resistance of the filter membrane, so that the deformation of the filter membrane is rapidly reduced when the filter membrane is subjected to a larger pressure, and the smaller deformation means that the filter membrane has higher porosity and/or pore diameter in the actual filtration process, so that the high-viscosity feed liquid filtration flux of the filter membrane is further improved. With further reduction of the water flux of the filter membrane, although the pressure resistance of the filter membrane is further improved, the further improvement of the pressure resistance has a marginal decreasing effect on the filter membrane with smaller deformation, the deformation of the filter membrane can be really further reduced, but the improvement is smaller; while further reduction of the porosity and/or pore size of the filter membrane means a further increase of the membrane resistance to the feed liquid, which makes it difficult to obtain a higher flux even with smaller deformation amounts when the filter membrane filters high concentration protein feed liquid. Therefore, the flux of the high-concentration protein feed liquid of the filter membrane is reduced along with the low water flux, and the change trend of gradually increasing and gradually decreasing is shown, so that the higher the water flux of the filter membrane is, the better the higher the water flux of the filter membrane is, and the lower the water flux of the filter membrane is, the better the water flux of the filter membrane is. In the present application, the water flux of the filter membrane may be more preferably not less than 40 or even not less than 50lmh@30psi, so that the filter membrane obtains even more preferable high-concentration protein feed liquid filtration flux performance under the influence of various influencing factors such as feed liquid resistance and pressure resistance.
It should be noted that when the feed liquid is ultrapure water or low-concentration protein feed liquid, the porosity and/or pore diameter of the filter membrane when the filter membrane is not pressed are not greatly different from those of the filter membrane when the filter membrane is actually used because the pressure born by the filter membrane is small and the structural variation of the pore structure of the filter membrane is small. This results in a higher water flux for the filter, which also tends to mean that the filter has a higher flux when filtering low concentration protein feed streams.
When the feed liquid is high-protein feed liquid with the protein concentration of more than 20g/L, the flux of the filter membrane is directly influenced, and the porosity and/or the pore diameter of the filter membrane are not the porosity and/or the pore diameter of the filter membrane when the filter membrane is not pressed, but the porosity and/or the pore diameter of the filter membrane are subjected to larger pressure and deformed (namely, the filter membrane is in actual application). Thus, the higher porosity and/or pore size of the filter membrane when not under pressure does not represent that the filter membrane still has higher porosity and/or pore size after being subjected to greater pressure; indeed, the inventors of the present application found that a suitable reduction in the water flux of the filter membrane means that the filter membrane has a suitably reduced porosity and/or pore size and thus a higher pressure resistance, thereby reducing the amount of deformation of the filter membrane after being subjected to a larger pressure, but rather a higher porosity and/or pore size in actual use. This makes it quite unexpected that the flux of the filter membrane increases with decreasing water flux when filtering high concentration protein feed liquid.
Optionally, the liquid outlet surface is distributed with a plurality of liquid outlet holes, the average pore diameter of the liquid outlet holes is not more than 40nm, and the distribution density of the liquid outlet holes is not less than 100/mu m 2 。
By adopting the technical scheme, the common virus-removing filter membrane adopts a dead-end filtering mode, so that a prefilter area with larger pore diameter is usually arranged on the side, close to the upstream, of the filter membrane, and a interception area with smaller pore diameter is usually arranged on the side, close to the downstream, of the filter membrane. The prefilter region with larger aperture plays a role in intercepting impurities such as solid large particles, protein polymers and the like with larger size in the feed liquid, and the interception region with smaller aperture plays a role in intercepting target intercepted viruses in the feed liquid and improving the virus safety. When the feed liquid flows in the filter membrane, the three-dimensional pore structure in the filter membrane is a flow channel of the feed liquid, and the size (flow channel area) of the flow channel is determined to a great extent by the aperture of the pore structure. For example, if the pore structure is considered to be a standard circle, the size of the flow channel and the square of the pore diameter of the pore structure are in positive correlation (pi r 2 ) This means that if the pore size of the pore structure is reduced by half, the size of the flow channel will be reduced by a factor of four, and therefore the larger influence on the water flux in the filter membrane is the smaller pore size trapping area in the filter membrane.
The application controls the liquid outlet surface of the filter membrane to have a special structure with small pore diameter (the pore diameter is not more than 40 nm) and large pore density (the pore density is not less than 100/mu m) 2 ) Cellulose filter membrane capable of making soft texture although havingThe water flux is lower, but the water flux has high flux performance of the reverse general knowledge when the water flux is used under the working condition of high protein concentration. This is probably due to the fact that the aperture of the liquid outlet hole of the filter membrane is smaller, so that the flow passage area formed by the liquid outlet hole is correspondingly smaller, even if the hole density of the liquid outlet hole is larger, the density of the liquid outlet surface of the filter membrane is still higher, and the single flow passage area and the total flow passage area with smaller liquid outlet surface are difficult to avoid causing the filter membrane to have lower water flux.
However, the smaller aperture and higher density of the liquid outlet hole mean that the filter membrane has higher self-supporting performance, and particularly the interception area of the filter membrane is not easy to generate compression deformation. As mentioned above, when the filter membrane is applied to the working condition of high protein concentration, the high viscosity feed liquid is applied to the filter membrane with larger filtering resistance and larger acting force, and naturally, collapse and deformation of the pore structure are easier to occur for the cellulose material with softer texture. Particularly, if the interception area with smaller pore diameter and larger feed liquid flow resistance in the filter membrane is subjected to further collapse and deformation of the pore structure, the filter membrane is further caused to have larger feed liquid flow resistance, so that flux is reduced.
The smaller pore diameter of the liquid outlet pore structure in the application means that the supporting acting force required by the liquid outlet pore structure is obviously reduced, the interception area of the filter membrane is less prone to compression deformation, and the pore structure of the interception area of the filter membrane can be ensured to have larger pore diameter (compared with the collapsed pore structure) under the working condition of high-concentration protein feed liquid with high compression; the smaller deformation quantity of the liquid outlet holes is matched with the higher hole density of the liquid outlet holes, so that the liquid outlet surface/interception area of the filter membrane can be ensured to have higher total area of a flow passage under the working condition of high-concentration protein liquid under high pressure, and the high flux performance under the working condition of high-concentration protein liquid with reverse common sense is realized on the basis of lower water flux.
It should be noted that for a filter with a lower flux at high protein concentration conditions (e.g., PLANOVA 20N, etc.), it is generally believed that to increase the flux performance of the filter (whether water flux or flux at high protein concentration conditions), it is often desirable to appropriately increase the pore size and/or porosity of the rejection region of the filter that is most affected by flux. Since the interception area of the filter membrane is positioned at the downstream side of the filter membrane, the liquid outlet holes of the pore structure of the interception area of the filter membrane should have larger pore diameters to a certain extent, and the liquid outlet surface of the filter membrane has larger liquid flow passage area (larger single flow passage area and total flow passage area) along with the increase of the pore diameters and the decrease of the pore densities of the liquid outlet holes, so that the filter membrane has higher water flux and protein flux. Considering that the flow passage area is reduced to one fourth after the aperture of the liquid outlet surface of the filter membrane is halved, even if the density of the liquid outlet holes is improved, the liquid outlet surface of the filter membrane still has lower flow passage area of feed liquid, and the water flux and protein flux of the filter membrane are always lower. Therefore, in order to increase the flux of the filter membrane, a method of reducing the pore size of the liquid outlet surface pore structure is not generally adopted.
The pore diameter and pore density of the liquid surface can be measured by computer software (such as Matlab, NIS-Elements and the like) or manually after the morphology of the membrane structure is characterized by using a scanning electron microscope, and corresponding calculation is performed. In practice, the surface of the film can be characterized by electron microscopy to obtain a corresponding SEM image, and a certain area, such as 1 μm, can be selected because the pores on the surface of the film are substantially uniform 2 (1 μm by 1 μm) or 25 μm 2 (5 mu m multiplied by 5 mu m), the specific area is determined according to the actual situation, the pore diameters, the pore number and the like of all the holes on the area are measured by corresponding computer software or manually, and then calculation is carried out to obtain the shape parameters such as the average pore diameter, the pore density and the like of the surface; of course, the person skilled in the art can also obtain the above parameters by other measuring means, which are only used as reference.
Optionally, the average pore diameter of the liquid outlet hole is 15-35 nm, the pore diameter of the liquid outlet hole is larger than 40nm and is a flux hole, and the proportion of the flux hole is 2-20%.
By adopting the technical scheme, compared with the pore structure which is generally used for obtaining higher uniformity at present, the inventor of the application finds that aiming at the special working condition of high-concentration protein feed liquid, the liquid outlet hole has certain non-uniformity, and can enable the filter membrane to have further higher protein flux.
As described above, the filter membrane of the application selects a special small-aperture macroporous density liquid surface outlet structure based on a special high-concentration protein liquid working condition, the liquid surface outlet structure has higher liquid flow resistance in the interception area of the filter membrane due to the fact that the smaller aperture of the liquid surface is difficult to avoid, and the liquid flow resistance in the interception area of the filter membrane can be obviously reduced by introducing flux holes with larger aperture (more than 40 nm) and controlling the number of the flux holes to be not lower than 2%, because the flux holes with larger aperture have obviously larger flow passage area. The average pore diameter of the liquid outlet holes is controlled to be not more than 35nm, the number of the flux holes is controlled to be not more than 20%, the positions near the flux holes with larger pore diameters can be ensured to be supported by a sufficient number of relatively compact structures, so that the positions near the flux holes become weak stress positions, and collapse of the pore structures caused by compression near the flux holes is avoided. Therefore, by further preferably controlling the number of the flux holes to be a ratio, the filter membrane can be further provided with a higher protein flux in combination with the average pore diameter control of the liquid outlet holes.
Optionally, the aperture of the liquid outlet hole is not more than 25nm and is a interception hole, and the ratio of the interception hole is 40-85%.
By adopting the technical scheme, the holes with smaller pore diameters (not more than 25 nm) in the liquid outlet holes are interception holes, so that the virus interception capacity of the filter membrane is greatly determined by the interception holes on one hand, and the liquid flow resistance and the self-supporting formation of the interception area of the filter membrane are greatly determined on the other hand. The interception pore structure with the ratio not lower than 40% ensures that the interception area of the filter membrane obtains good virus interception performance through lamination of pore structures in the thickness direction of the membrane, and ensures high virus interception robustness; the retention hole structure accounts for not more than 80% to ensure that the retention area of the filter membrane does not have excessively high feed liquid flow resistance, and at the moment, even if the retention area of the filter membrane does not collapse or deform, the larger flow resistance can not be avoided, so that the filter membrane has lower water flux and lower protein flux.
Optionally, the hardness coefficient of the virus-removing filter membrane is not lower than 8, the hardness coefficient is the A type Shore hardness measured after n layers of filter membranes are laminated, and the number of the filter membrane layers n is 20 when in test.
Optionally, the hardness coefficient of the virus-removing filter membrane is not lower than 10; further, the hardness coefficient of the virus-removing filter membrane is not lower than 12.
By adopting the technical scheme, the hardness coefficient of the filter membrane is not standard hardness data, but can represent the strength of the filter membrane to a large extent, and represents the deformation resistance of the filter membrane after being subjected to large feed liquid acting force under the special high-concentration protein feed liquid working condition. By controlling the hardness coefficient of the filter membrane after 20 layers are laminated to be not lower than 8, more preferably not lower than 10 and even not lower than 12, the filter membrane can be ensured to have enough self-supporting performance, the deformation amount of the filter membrane after being pressed is reduced, and thus higher protein flux is obtained.
In the application, the LX-AM type Shore hardness tester is used for hardness test, and the 20 layers of filter membranes are laminated in a mode of liquid surface upwards and then used as test samples for hardness test, wherein the samples are kept in a wet state during the hardness test, and the hardness test is carried out for 3-5 times and an average value is obtained, so that the hardness coefficient is obtained. It should be noted that although LX-AM type shore hardness tester is used to perform national standard GB/T531.1-2008, and it is clearly specified in the standard that no more than 3 layers should be laminated, for a virus-removing filter membrane of smaller thickness, the result obtained by testing in a defined lamination manner has a higher positive correlation with the membrane hardness, although not the national standard specified hardness data.
Optionally, the top wash LRV retention of the filter membrane is not less than 0.85.
Optionally, the LRV retention of the filter membrane is not less than 0.9.
By adopting the technical scheme, for the specific working condition of the high-concentration protein feed liquid in the application, even if the membrane forming material of the filter membrane is a cellulose raw material with good hydrophilicity, the small interception of the filter membrane and the adsorption of protein in the feed liquid are difficult to avoid, and as mentioned above, the high production cost of the active protein makes the protein feed liquid have to have higher recovery rate. Therefore, after virus removal filtration using a filter membrane, the proteins in the filter membrane need to be further eluted and recovered, a process called top washing.
In order to ensure that the protein in the filter membrane is sufficiently eluted to improve the recovery rate of the protein, after the virus removal filtration/virus challenge test of the filter membrane is finished (when the flux of the filter membrane is reduced to 25% or challenge liquid filtration is regarded as filtration is finished when only a small amount of the residual bottom part is left), the pressure on the feed liquid side is required to be removed, and after the Buffer is added on the feed liquid side, the process is carried out for a period of time under normal pressure (generally, the process is carried out for 15min, the operation such as filtration is not carried out at the stage), so that the protein trapped by the filter membrane is released by movement and diffusion for a sufficient time, or is released again due to the change of the structure of the membrane hole; and after the process is stopped, pressurizing again to perform virus filtration/virus challenge test after the process is stopped, and independently collecting filtrate obtained by the test, performing virus titer measurement and calculating the LRV after the process is stopped.
Since not only the proteins are eluted due to the kinetic diffusion and the membrane pore structure change and re-release during the process residence stage, the viruses trapped by the filter membrane are eluted due to the kinetic diffusion and the membrane pore structure change and re-release, and therefore the LRV after the general process residence is smaller than the LRV measured by the normal virus challenge test. The ratio of the LRV data after process retention to the LRV data measured by the normal virus challenge test is the LRV retention. The higher LRV retention indicates that the filter releases less virus during the residence phase of the process.
Obviously, the main factors influencing the LRV retention rate of the filter membrane are the motion diffusion of the virus itself and the degree of membrane structure change of the filter membrane, and it is generally considered that the virus and the protein both carry out disordered brownian motion, and the main influencing factors of the brownian motion are the particle size and the temperature of the particles; in addition, the larger the deformation recovery amount of the filter membrane after the pressure of the feed liquid is removed, the more protein and virus are released. The method is characterized in that the filter membrane subjected to compression deformation can recover deformation after the pressure of feed liquid is removed, and in the process of recovering deformation, an acting force is given to proteins and viruses trapped/adsorbed in the filter membrane, the acting force can promote the release of the proteins and the viruses from the membrane pore structure, the higher the possibility of subsequent elution is, the naturally and subsequently decreasing LRV of top washing is, and therefore the LRV retention rate of the filter membrane is reduced. Thus, the higher the pressure resistance of the filter membrane, the higher the LRV rejection tends to be.
The LRV retention rate of the filter membrane is not lower than 0.85, which means that the filter membrane has good pressure resistance, and the water flux of the filter membrane is not higher than 85LMH@30psi and LRV is not less than 5@ (0.1 g/L, IVIG) by cooperative matching, so that the filter membrane can have the further preferable high-concentration protein feed liquid filtration flux.
Optionally, the long-term average flux of the filter membrane is 8-30 LMH@30psi, and the long-term average flux is the flux average value of the filter membrane in the filtration time t of 100-300 min when the protein concentration of the filter membrane in the filtration feed liquid is 50 g/L.
Optionally, the filter membrane has a long-term average flux of 10-30 LMH@30psi; further optionally, the filter membrane has a long term average flux of 12-30 lmh@30psi.
By adopting the technical scheme, when the filter membrane filters high-concentration protein feed liquid, the membrane pore structure of the filter membrane can be blocked by trapped viruses, and can be blocked due to a small amount of protein adsorbed by the filter membrane. If the dirt-receiving space of the filter membrane after being deformed under pressure is too small, a small amount of trapped viruses and adsorbed proteins can form serious blockage to the pore structure of the filter membrane, so that the flux of the filter membrane is quickly attenuated.
It is generally believed that the higher the water flux of the filter membrane, the higher the porosity and/or pore size, and naturally the larger the fouling space, the less prone to pore structure blockage. However, it is also unexpected that the filter membranes of the present application can maintain a higher average filtration flux over a longer filtration time, albeit with a lower water flux, when filtering high concentration protein feed.
The long-term flux average value refers to that the filtering flux data of the filter membrane is recorded every 5min with the filtering time of 100min as a starting point and the filtering time of 300min as an ending point (of course, the recording frequency can be properly increased or decreased according to actual needs, but the recording frequency should not be greater than 10 min/time so as not to introduce excessive errors), and the average flux data of the filter membrane in the period is calculated through the recorded data.
Optionally, the protein flux attenuation coefficient X of the filter membrane 50 At 100min not higher than 85%, the protein flux attenuation coefficient X of the filter membrane 50 @100min is obtained by:
Xn=（1-T t /T water and its preparation method ）×100%；
In the formula, xn is the protein flux attenuation coefficient when the protein concentration in the feed liquid is n, T t The unit is LMH for flux data of the filter membrane when the concentration of protein in the filter feed liquid is n and the filtering time is t; x is X 50 The @100min is the protein flux attenuation coefficient when the protein concentration n in the feed liquid is 50g/L and the filtration time t is 100 min.
By adopting the technical scheme, the protein flux attenuation coefficient X of the filter membrane in the application 50 And @100min is not higher than 85%, which means that the filter membrane is used for filtering the feed liquid with the protein concentration of 50g/L and the flux attenuation rate when the filtering time is 100min, compared with the water flux data. For example, if the water flux of the filter membrane is 100LMH, and the flux for filtering a feed solution having a protein concentration of 50g/L for a filtration time of 100min is 20LMH, the protein flux attenuation coefficient of the filter membrane is 80%. The larger the flux attenuation coefficient, the more attenuation the flux of the filter membrane is compared with the water flux of the filter membrane when the filter membrane is used for filtering high-concentration protein feed liquid.
The water flux of the filter membrane is controlled to be not higher than 85LMH@30psi, LRV is not less than 5@ (0.1 g/L, IVIG), and the flux attenuation coefficient of the filter membrane is cooperatively matched with the filter membrane, so that the filter membrane has smaller flux difference with the water flux when filtering high-concentration protein feed liquid.
The reason why flux data when the filtration time of the filter membrane is 100min is specifically selected for calculating the protein flux attenuation coefficient is that for the virus removal membrane adopting dead-end filtration, when the filter membrane is used for virus removal filtration, the flux can be obviously reduced at first, and when the filtration time reaches 100min, the filter membrane is not in the rapid flux reduction stage, so that the method has a reference value.
Alternatively, the protein flux attenuation coefficient X of the filter membrane 50 At 100min no more than 80%, said filteringT of film 100 Not less than 12LMH@30psi.
By adopting the technical scheme, the flux attenuation coefficient of the filter membrane is not higher than 80 percent, the water flux of the matched filter membrane is not higher than 85LMH@30psi, LRV is not less than 5@ (0.1 g/L, IVIG), the higher flux of the filter membrane when the filter membrane filters high-concentration protein feed liquid can be further ensured, and the T of the filter membrane 100 Not less than 12LMH@30psi has multiple flux enhancement compared with the currently marketed cellulose virus removal membranes.
Optionally, the relative deviation of the medium-term flux of the filter membrane is not higher than 20%, and the relative deviation of the medium-term flux is the relative deviation of flux data when the filter membrane is used for filtering the feed liquid and the time is 200min when the protein concentration n in the filter liquid is 50g/L and the filtering time t is 100 min.
Through adopting above-mentioned technical scheme, because the filter membrane in this application is the cellulose class filter membrane that hydrophilicity is good, the protein adsorption is lower, consequently, when the filter membrane was used for filtering deionized water or low concentration protein feed liquid, the membrane pore structure of filter membrane often was difficult for by the jam of protein feed liquid. When the filter membrane is used for filtering high-concentration protein feed liquid, even if the protein adsorption rate of the filter membrane is low, the absolute value of the protein adsorbed and trapped by the filter membrane is inevitably high due to the high protein concentration in the feed liquid. Therefore, as the filtration time of the virus is prolonged, the amount of protein trapped in the filter membrane is increased, and part of the pore structure is inevitably blocked, which inevitably leads to the decrease of the flux of the filter membrane.
In the application, the relative deviation of the medium-term flux of the filter membrane is not higher than 20%, so that the filter membrane can be ensured to have more stable and higher flux when filtering high-concentration protein feed liquid. This is probably because as the membrane pore structure of the filter membrane is gradually blocked, which means that the filter membrane is further increased in terms of feed liquid resistance, naturally receives a greater feed liquid pressure, and therefore, as the filtration process proceeds, the pressure to which the filter membrane is subjected is gradually increased. If the filter membrane is difficult to bear gradually increased pressure, the membrane pore structure of the filter membrane gradually collapses along with the extension of the filtering time, and the combination of the filter membrane with the membrane pore structure is higher in protein retention, so that the flux of the filter membrane is quickly reduced. The medium term flux deviation of the filter membrane is not higher than 20%, which means that although the flux of the filter membrane is reduced with the increase of the filtering time, the reduction is lower, and the filter membrane has enough pressure resistance to ensure that no significant collapse of the pore structure occurs with the increase of the bearing pressure of the filter membrane, thereby having relatively high and stable flux.
In the present application, the average value refers to the average value of flux data at a filter time of 100min and flux data at a filter time of 200min, and the measured value refers to the flux data at a filter time of 100min or the flux data at a filter time of 200 min.
Optionally, the relative deviation of the long-term flux of the filter membrane is not higher than 30%, and the relative deviation of the long-term flux is the relative deviation of flux data when the filter membrane is used for filtering the feed liquid and the time is 300min when the protein concentration n in the filter feed liquid is 50g/L and the filtering time t is 100 min.
By adopting the technical scheme, the relative deviation of the long-term flux of the filter membrane is controlled to be not higher than 30% similar to the relative deviation of the medium-term flux of the filter membrane, so that the filter membrane can still ensure that no obvious collapse phenomenon of the membrane pore structure occurs when the filtering time reaches 300min even when the filter membrane filters high-concentration protein feed liquid with the concentration of 50g/L, thereby having relatively high and stable flux.
In the present application, the long-term flux relative deviation=i measured value-average value i/average value x 100%, where the average value refers to the average value of flux data when the filtration time of the filter membrane is 100min and flux data when the filtration time is 300min, and the measured value refers to the flux data when the filtration time of the filter membrane is 100min or the flux data when the filtration time is 300 min.
Optionally, the long-term flux change gradient of the filter membrane is not more than 3LMH/100min, and the long-term flux change gradient is the ratio of the difference between flux data when the filtering time t is 100min and flux data when the filtering time is 300min when the protein concentration n of the filter membrane in the filtering feed liquid is 50 g/L.
By adopting the technical scheme, the factors influencing the flux of the filter membrane are more, such as the pressure resistance of the filter membrane, the adsorption rate of the filter membrane to protein in feed liquid and the like, and the long-term flux change gradient of the filter membrane can comprehensively represent the influences of the factors such as the pressure resistance of the filter membrane, the adsorption rate of the protein and the like on the flux attenuation speed of the filter membrane to a certain extent. The low long-term flux change gradient of the filter membrane is matched with low water flux data of the filter membrane, which means that the filter membrane not only has low protein adsorption rate, but also has good pressure resistance, so that the filter membrane can be ensured to have stable and high flux even when being used for filtering high-concentration protein feed liquid with the protein concentration of up to 50 g/L.
It is understood that the gradient of the long-term capacity change of the filter membrane is not more than 3LMH/100min, which means that the difference between the flux data at the time of 100min and the flux data at the time of 300min is not more than 6LMH (the total elapsed time is 200 min).
Alternatively, when the protein concentration in the filtered feed solution is 50g/L, the flux decays 75% for not less than 360min, and the T of the filter membrane 360 Not less than 8LMH@30psi.
By adopting the above technical scheme, it is generally considered that when the flux of the filter membrane is attenuated by 75% (flux retention 25%) in the virus removal filtration, the filtration endpoint is performed. The filtration endpoint time of the filter membrane in the application is not less than 360min, and when the filtration time is 360min, the flux of the filter membrane can still be kept not less than 8LMH@30psi, which indicates that along with the progress of filtration, the membrane pore structure of the filter membrane is not obviously blocked, and the flux of the filter membrane is higher than that of a commercially available cellulose virus removal membrane.
Optionally, the PMI average pore size of the filter membrane is not more than 30nm and not less than 15nm, and the SEM average pore size of the liquid inlet surface is larger than the SEM average pore size of the liquid outlet surface.
Optionally, the PMI average pore size of the filter membrane is not more than 25nm; further optionally, the PMI average pore size of the filter membrane is not greater than 23nm; still further optionally, the PMI average pore size of the filter membrane is not greater than 22nm.
By adopting the technical scheme, as the flux of the existing cellulose virus removal membrane is lower when the membrane is used for filtering high-concentration protein feed liquid, in order to improve the flux of the filter membrane, the general method is to improve the PMI average pore diameter of the filter membrane, and although the improvement of the PMI average pore diameter often leads to the reduction of the virus interception capability of the filter membrane, the flux of the filter membrane is expected to be improved.
However, the inventors of the present application have unexpectedly found that, for the specific high-concentration protein feed liquid filtering condition in the present application, compared with the general cognition of improving the PMI average pore size of the filter membrane, reducing the PMI average pore size of the filter membrane can not only ensure that the filter membrane has higher virus interception capability, but also enable the filter membrane to have higher flux under the specific condition. This is probably because a lower PMI average pore size tends to mean that the filter membrane has higher density, and in a certain range, the decrease in porosity of the filter membrane has an influence on the flux of the filter membrane due to the improvement of the pressure resistance of the filter membrane, and the influence on the flux of the filter membrane due to the increase in feed liquid resistance is larger than that due to the decrease in porosity of the filter membrane. Therefore, unlike the general knowledge, the application can control the PMI average pore diameter of the filter membrane to be not more than 30nm, more preferably not more than 25nm and even not more than 22nm, and can enable the filter membrane to have higher flux when being applied to filtering high-concentration protein feed liquid.
In summary, for the special working condition of virus removal and filtration of high-concentration protein feed liquid, the flux of the high-concentration protein feed liquid of the filter membrane is continuously improved along with the improvement of the PMI average pore diameter, and then is reduced; but not the general knowledge, increases continuously with the increase of the average pore size of the PMI. Therefore, the filter membrane with the PMI average pore diameter of 15-30 nm is specifically selected, so that higher flux can be ensured when the membrane filters high-concentration protein feed liquid.
In the application, the PMI average pore diameter of the filter membrane can be measured by a PMI pore diameter tester, and the used test liquid is a galwick standard test liquid with the surface tension of 15.9 dynes/cm.
Optionally, the porous body is composed of a cellulosic layer; or alternatively, the first and second heat exchangers may be,
the porous main body is obtained by compounding a cellulose layer and a supporting layer, and the surface of one side of the cellulose layer, which is away from the supporting layer, is a liquid outlet surface.
By adopting the technical scheme, the filter membrane can be a pure cellulose filter membrane composed of a cellulose layer, or a composite filter membrane which is obtained by compositing the cellulose layer and a supporting layer capable of further improving the strength of the filter membrane.
Optionally, the virus-removing filter membrane is obtained by hydrolysis and regeneration of cellulose ester compound, wherein the cellulose ester compound is at least one of diacetyl cellulose, triacetyl cellulose, propionic acid cellulose, phthalic acid acetic acid cellulose, acetic acid butyric acid cellulose and acetic acid propionic acid cellulose; or alternatively, the first and second heat exchangers may be,
the virus-removing membrane is obtained by dissolving cellulose in a solvent and regenerating the cellulose, wherein the solvent is one of copper ammonia solution, a lithium chloride and dimethylacetamide system, an ionic liquid solvent and N-methylmorpholine-N-oxide.
By adopting the technical scheme, two general technical routes exist for preparing the cellulose filter membrane, wherein one of the technical routes is to dissolve cellulose in a solvent to form a membrane casting solution, and then the cellulose in the membrane casting solution is regenerated into a solid membrane structure through a phase inversion method and post-treatment regeneration; the other is to dissolve cellulose ether or cellulose ester in solvent to form casting solution, and then to regenerate the cellulose derivative in the casting solution into solid film structure through phase inversion method and post-treatment regeneration.
The cellulose virus-removing filter membrane in the application can be obtained by hydrolysis and regeneration of cellulose derivatives, or can be obtained by dissolution and regeneration of cellulose.
In a second aspect, the present application provides a preparation process of a cellulose virus-removing filter membrane, which adopts the following technical scheme:
the preparation process of the cellulose virus-removing filter membrane comprises the following process steps:
s1, providing a regenerated cellulose base film, wherein the base film is obtained through hydrolysis and regeneration of cellulose ester compounds or is obtained through dissolution and regeneration of cellulose, and the water flux of the base film is not higher than 120LMH@30psi;
s2, crosslinking treatment, namely placing the regenerated cellulose base film into a crosslinking agent solution for crosslinking treatment to obtain a crosslinked film, wherein the crosslinking temperature is 20-80 ℃, the concentration of sodium hydroxide in the crosslinking agent solution is 0.05-1 mol/L, the crosslinking agent is at least one of polyglycidyl ether, epichlorohydrin, adipic acid, succinic anhydride, hexamethylene diisocyanate and maleic anhydride, the concentration of the crosslinking agent in the crosslinking agent solution is 0.5-2 mol/L, the crosslinking coefficient J is controlled to be 150-1500 min mol/L, and the crosslinking coefficient is the product of the concentration of the crosslinking agent in the crosslinking agent solution and the crosslinking time;
s3, post-treatment, namely cleaning the crosslinked membrane to obtain the cellulose virus-removing filter membrane.
By adopting the above technical scheme, it is generally considered that the base membrane is subjected to the crosslinking treatment, so that the filter membrane can have higher strength and self-supporting performance, however, the flux performance of the filter membrane is inevitably reduced due to the influence on the porosity, the pore diameter and the like of the filter membrane, and therefore, the flux performance of the filter membrane is not generally improved by adopting the crosslinking treatment. However, the inventors of the present application have unexpectedly found that by controlling a reasonable cross-linking process, although the water flux performance of the filter membrane is indeed reduced, the protein flux of the filter membrane under high concentration protein conditions (i.e. the protein flux of the filter membrane under high concentration protein conditions) is improved against common sense, which unexpected result is unexpected.
Of course, in order to ensure that the filter has good protein flux properties, the cross-linking process parameters of the filter should be reasonably controlled. The water flux of the base membrane is not higher than 120LMH, so that the filter membrane has no too high porosity and/or pore diameter before the cross-linking treatment, the porosity and/or pore diameter of the filter membrane is further reduced after the cross-linking treatment by a specific cross-linking treatment process, and the three-dimensional network structure of the filter membrane is further reinforced, so that the finally obtained filter membrane has further better strength and self-supporting performance. The choice of low water flux base membranes is quite specific, since in general knowledge, to achieve higher fluxes in feed solution conditions of high protein concentration, high water flux base membranes should be chosen to reduce the impact of crosslinking treatment on the flux performance of the filter membrane.
On the basis of selecting a low-water flux base film, the crosslinking temperature is controlled to be not lower than 20 ℃, the concentration of sodium hydroxide which plays a role in swelling a cellulose base film is not lower than 0.05mol/L, the concentration of a crosslinking agent is not lower than 0.5mol/L, and the crosslinking coefficient J is not lower than 150min & mol/L. The cellulose base film is well swelled and wetted at higher temperature and sodium hydroxide concentration, the acting force such as hydrogen bonds among molecular chains is reduced, the crosslinking modification accessibility of the cellulose molecular chains is greatly improved, and the cellulose molecular chains with high accessibility and crosslinking coefficient are matched, so that enough time and enough concentration of crosslinking agent molecules between the cellulose molecular chains with high accessibility and the crosslinking agent can be ensured to react, thereby strengthening the three-dimensional network structure of the filter film. In the application, the cross-linking coefficient is the product of the concentration of the cross-linking agent in the cross-linking agent solution and the cross-linking time, if the cross-linking coefficient is too low, the concentration of the cross-linking agent and/or the cross-linking time are often too low, and the three-dimensional network structure of the filter membrane does not obtain enough cross-linking strengthening modification, so that the water flux of the filter membrane is affected less, but the protein flux cannot be effectively improved.
Correspondingly, the crosslinking temperature is controlled to be not higher than 80 ℃, the concentration of sodium hydroxide playing a role in swelling the cellulose base film is not higher than 1mol/L, the concentration of the crosslinking agent is not higher than 2mol/L, and the crosslinking coefficient J is not higher than 1500 min.mol/L. This is because, although the strength of the cellulose material having a softer texture can be improved even further by increasing the degree of crosslinking in the present base film having a lower water flux, there is a marginal effect that the self-supporting performance of the filter film increases gradually with increasing degree of crosslinking, and the porosity and/or pore size of the filter film decreases further with increasing degree of crosslinking, which causes an undesirable decrease in the water flux and protein flux of the filter film.
Therefore, when polyglycidyl ether, epichlorohydrin, an organic acid or an organic acid anhydride or the like is specifically used as a crosslinking agent in the present application, it is possible to attach and crosslink on regenerated cellulose fibers, thereby reinforcing the fiber skeleton structure of the regenerated cellulose film to improve the strength of the produced virus-removing film. The improvement of the intensity of the virus-removing membrane is within a certain range, and the contribution to the improvement of the protein flux of the filter membrane is larger than the negative influence of the reduction of the pore size of the virus-removing membrane on the improvement of the protein flux, so that the virus-removing membrane has high protein flux beyond the common cognition.
It should be noted that, although it is a common method to crosslink and modify the base membrane in order to improve the self-supporting performance of the regenerated cellulose filter membrane, the pore structure of the filter membrane interception area is of smaller size in order to ensure high virus interception robustness of the virus-removing filter membrane. For example, if it is desired to entrap the model virus PP7 phage explicitly mentioned in PDA TR41, or to entrap viruses of about 20-30nm in size such as the common parvoviruses (e.g., murine parvovirus, etc.), the size of the pore structure of the entrapping region of the filter should be small. However, the cross-linking agent introduced into the filter membrane during the cross-linking modification inevitably leads to further reduction of the pore structure size of the filter membrane, particularly, the interception area of the pore structure with smaller size is formed, and further reduction of the pore diameter inevitably leads to further reduction of the flow passage area of the material liquid of the filter membrane, thereby further reducing the water flux of the filter membrane. Then, for the filter membrane with lower flux under the working condition of high protein concentration, further cross-linking treatment is carried out on the filter membrane, so that the filter membrane has lower water flux and flux under the working condition of high protein concentration. Therefore, it is generally impossible to crosslink the filter membrane to provide the filter membrane with a higher concentration of protein.
Optionally, the polyglycidyl ether is at least one of diethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether and glycerol triglycidyl ether;
in the step S2, the ambient pressure is kept at 0.5-0.8 bar in the crosslinking treatment process.
By adopting the technical scheme, the swelling degree, the molecular chain accessibility and the crosslinking reaction speed of cellulose are controlled by adjusting the concentration of sodium hydroxide in the crosslinking agent and the crosslinking temperature, and the crosslinking agent can better permeate into the pore structure of the regenerated cellulose membrane by applying proper small negative pressure during the crosslinking treatment, so that the sufficient crosslinking degree of the base membrane can be ensured without excessive crosslinking by matching proper concentration of the crosslinking agent and the crosslinking coefficient, and the sufficient crosslinking strengthening degree can be obtained without generating undesirable excessive reduction of the porosity and/or the pore diameter of the filter membrane. Thus, the cross-linking degree of the filter membrane is controlled in a region where the self-supporting performance of the filter membrane is rapidly increased and the porosity and/or the pore diameter are/is reduced slightly, so that the water flux of the filter membrane is reduced, but the protein flux is improved against common sense.
In addition, the inventors of the present application have unexpectedly found that a membrane having a further excellent protein flux performance can be obtained by specifically selecting a polyglycidyl ether such as diethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, glycerol triglycidyl ether, or the like as a crosslinking agent, as compared with a conventional crosslinking agent. This may be related to the crosslinking mechanism, where the polyglycidyl ether undergoes an etherification reaction with the hydroxyl groups on the cellulose molecules under alkaline conditions, and where each time the etherification reaction consumes one hydroxyl group on a cellulose molecule, one hydroxyl group is reintroduced, which means that the intrinsically good hydrophilicity of the filter membrane is not greatly affected even through the crosslinking reaction, thereby reducing the adsorption of proteins in the feed solution and reducing the probability of clogging the pore structure by proteins.
Optionally, the regenerated cellulose-based film is prepared by the following process:
s11, preparing a casting solution, wherein the casting solution comprises a cellulose film-forming polymer and a casting good solvent;
s12, extruding the casting film liquid to obtain a liquid film, and pretreating the liquid film through a pretreatment bath to obtain a pretreatment film, wherein the pretreatment bath comprises a pretreatment good solvent and a pretreatment non-solvent;
S13, solidifying, namely placing the pretreated film into a coagulating bath for phase separation and solidification to obtain a primary film;
and S14, regenerating, namely placing the primary membrane into a regeneration bath for treatment and regeneration, and cleaning to obtain the regenerated cellulose base membrane.
By adopting the technical scheme, the cellulose film-forming polymer is dissolved and then solidified into a film, and the film is regenerated into the regenerated cellulose base film, so that the base film with the required performance can be provided.
Optionally, in step S12, the mass ratio of the pretreatment non-solvent in the pretreatment bath is 5-20%, and the temperature of the pretreatment bath is 30-40 ℃.
Through adopting above-mentioned technical scheme, the dissolution characteristic of cellulose class material makes it very easily take place quick split-phase solidification when meetting the coagulating bath that has high concentration non-solvent to form the compact cortex structure of unexpected appearance on one side surface of liquid film, lead to the filter membrane to have too high feed liquid flow resistance. And pretreating the liquid film by a pretreatment bath with the mass ratio of the non-solvent not higher than 20% and controlling the temperature of the pretreatment bath to be 30-40 ℃. The pretreatment bath and the liquid film are subjected to mutual permeation and substance exchange to a certain extent at a higher temperature, on one hand, the pretreatment good solvent with higher concentration in the pretreatment bath has the dilution effect on partial areas of the liquid film, so that gradient difference of solid content is formed inside the liquid film; on the other hand, the lower concentration of the pretreatment non-solvent in the pretreatment bath promotes localized and slow pregelatinization/pre-phase separation of the liquid film. The liquid film with lower solid content after dilution is easy to form a pore structure with larger size on the surface under the condition of slower pre-phase separation speed, so that the possibility of generating a compact cortex structure due to rapid phase separation is reduced.
Optionally, the step S11 includes preparing a first casting solution and a second casting solution, where the first casting solution and the second casting solution both include a cellulose film-forming polymer and a casting good solvent; the solid content of the second film casting liquid is lower than that of the first film casting liquid, the solid content of the first film casting liquid is 15-30%, and the solid content of the second film casting liquid is 5-20%;
in the step S12, the first casting solution and the second casting solution are co-extruded to obtain a liquid film, and the second casting solution is located at a side of the liquid film, which is close to the pretreatment bath.
By adopting the technical scheme, compared with a single-layer casting process, the double-layer casting process controls the main membrane proportion of the membrane with a macroporous structure and the main membrane proportion of the membrane with a small pore structure in the filter membrane by controlling different solid contents, blade coating thickness and the like of two layers of casting membrane liquids. Through further pouring the second casting film liquid with lower solid content on the first casting film liquid, the second casting film liquid with lower solid content is matched with a proper pretreatment process, a porous film structure with larger pore diameter is easier to form, and the prefiltering effect on large-particle impurities in the liquid can be better formed, so that the method is more suitable for a complex system. Therefore, a single-layer casting process or a double-layer casting process can be selected according to actual requirements.
Optionally, the virus-removing filter membrane is hollow fiber, and in step S12, the first casting solution, the second casting solution and the pretreatment bath are extruded through an annular spinneret, the second casting solution is located at the radial inner side of the first casting solution, and the pretreatment bath is located as a core solution in the inner cavity of the second casting solution.
Through adopting above-mentioned technical scheme, hollow fiber form is comparatively common at present removes virus filter membrane form, extrudes the two-layer membrane casting liquid that the solid content is different jointly through annular spinneret to make the second membrane casting liquid that the solid content is lower be located the radial inboard of liquid film, consequently, with the membrane casting liquid coextrusion, lie in the second membrane casting liquid inside cavity and regard as the preliminary treatment bath of core liquid, when liquid film extrusion, carry out preliminary treatment promptly to the second membrane casting liquid that lies in radial inboard, thereby produce the great membrane pore structure of aperture at the internal surface of liquid film.
Of course, it can be understood that a single-layer casting solution extrusion film forming process can be selected according to actual needs, that is, a single casting solution and a pretreatment bath are used for coextrusion, and the pretreatment bath is used as a core solution to pretreat the inner surface of the casting solution, so that a film pore structure with larger pore diameter is generated on the inner surface of the liquid film.
Optionally, the virus-removing filter membrane is in a flat plate shape, and in step S12, the first casting solution and the second casting solution are sequentially poured onto the carrier to obtain a liquid membrane, the doctor-blading speed of the first casting solution is smaller than that of the second casting solution, the doctor-blading speed of the second casting solution is 1-3 m/min, and then the side, away from the carrier, of the liquid membrane is pretreated through a pretreatment bath.
By adopting the technical scheme, the flat plate-shaped filter membrane is also a common virus-removing filter membrane at present, at the moment, two layers of casting membrane liquid are poured on a carrier in the modes of extrusion, casting, knife coating and the like, and the carrier can be steel belt, roller and other equipment, release film and the like; and the second casting film liquid with lower solid content is controlled to be positioned on the air side so as to be convenient for the thickness pretreatment bath to pretreat the second casting film liquid, thereby forming a pore structure with larger pore diameter on the surface of the liquid film.
It should be noted that, when the flat-plate filter membrane is prepared by adopting the double-layer casting process, the inventor of the application finds that the doctor-blading speed of the first casting solution and the second casting solution has a certain influence on the performance of the finally prepared virus-removing membrane in the membrane preparation process. For example, in a certain range, the strength of the prepared virus-removing membrane can be improved by properly improving the membrane scraping speed, so that the deformation of the filter membrane when filtering high-concentration protein feed liquid is reduced, and higher flux is obtained.
This is probably due to the fact that the tensile strength and the elongation at break of the film are both greatly increased with the increase of the film scraping speed. This is because the macromolecular chains or segments and crystallites must exhibit different degrees of orientation under the influence of external forces. The external force applied by the scraping rod is in direct proportion to the scraping speed, and along with the increase of the scraping speed, the external force applied by the scraping rod is also increased, so that the orientation degree of the polymer material is increased, the number of chemical bonds in a unit section is obviously increased in the direction of a covalent bond connected molecular chain, and the tensile strength is greatly enhanced.
Optionally, in step S12, after casting the casting solution onto the carrier, a support layer is further covered on the casting solution to obtain a liquid film, where the support layer is one of a PVDF microporous membrane, a PES microporous membrane, a PTFE microporous membrane, a Nylon microporous membrane, a cellulose microporous membrane, a polyolefin microporous membrane, or a nonwoven substrate.
By adopting the technical scheme, the pressure resistance of the filter membrane can be further improved by introducing the microporous membrane supporting layer or the non-woven supporting layer, and the size of the pore structure of the microporous membrane supporting layer or the non-woven supporting layer is obviously larger than that of the cellulose layer formed by the casting solution, so that the influence of the introduction of the supporting layer on the flux of the filter membrane is small. Of course, although the introduction of the supporting layer can improve the overall pressure resistance of the filter membrane, if the strength of the cellulose layer in the filter membrane is too low, the cellulose layer itself may still be greatly deformed when the filter membrane is used for filtering high-concentration protein feed liquid.
Optionally, the regenerated cellulose base film is obtained by hydrolysis and regeneration of cellulose ester compounds, and the cellulose film-forming polymer is at least one of diacetyl cellulose, triacetyl cellulose, propionic acid cellulose, phthalic acid acetic acid cellulose, acetic acid butyric acid cellulose and acetic acid propionic acid cellulose.
Optionally, in the step S13, the coagulation bath includes a coagulation good solvent and a coagulation non-solvent;
the casting film good solvent, the pretreatment good solvent and the solidification good solvent are at least one of acetone, dioxane, N-dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid and valeric acid;
the pretreatment non-solvent and the solidification non-solvent are water or small molecular alcohol;
the temperature of the coagulating bath is not higher than 30 ℃, and the mass ratio of the coagulating non-solvent in the coagulating bath is 85-95%.
By adopting the technical scheme, the method and the device have the advantages that on the basis of preparing the membrane by adopting the cellulose derivative hydrolysis regeneration method, the low-temperature solidification phase-splitting technology is also adopted, and the strength of the prepared virus-removing membrane can be improved, so that the deformation of the filter membrane when the high-concentration protein feed liquid is filtered is reduced, and higher flux is obtained.
This is probably because the rising of the coagulation bath temperature accelerates the double diffusion rate between the casting solution and the coagulation bath, the solidification of the polymer is too strong, and the cellulose macromolecules are not yet crystallized and oriented, and are coagulated and molded, so that the finally prepared virus-removing membrane has lower crystallinity, disordered arrangement, loose network structure and low orientation degree, the virus-removing membrane has lower strength, excessive deformation occurs when high-concentration protein feed liquid is filtered, and the flux is greatly reduced.
Optionally, in step S14, the regeneration bath is a sodium hydroxide aqueous solution with a concentration of 0.01-1 mol/L, and the hydrolysis is performed first and then the secondary hydrolysis is performed, wherein the temperature of the regeneration bath is 60-80 ℃ during the primary hydrolysis, the time of the primary hydrolysis is 10-30 min, the temperature of the regeneration bath is 30-40 ℃ during the secondary hydrolysis, and the time of the secondary hydrolysis is 40-150 min.
By adopting the technical scheme, in the hydrolysis regeneration step, the process of hydrolyzing the cellulose film-forming polymer to obtain regenerated cellulose does not only occur; regenerated cellulose is easy to be subjected to alkaline hydrolysis and oxidative degradation under alkaline and high-temperature conditions, and low-molecular-weight cellulose is generated due to degradation reaction of glycosidic bond cleavage of cellulose molecular chains, so that the strength of the prepared virus-removing membrane is reduced. However, if the degree of hydrolysis of the cellulose-based film-forming polymer to regenerated cellulose is too low, it will affect the hydrophilic properties of the finally produced virus-free film and ultimately affect the protein yield of the virus-free film. Clearly, during the hydrolysis regeneration process, how to ensure that the cellulose-based film-forming polymer is sufficiently hydrolyzed to regenerated cellulose to ensure the hydrophilicity of virus removal, while regenerated cellulose is less hydrolyzed to low molecular weight cellulose is a more difficult problem to solve.
The inventor of the application finds that when the primary membrane obtained by split-phase solidification is subjected to hydrolysis regeneration, a special secondary hydrolysis process is adopted, and the filter membrane can have higher flux when being used for filtering high-concentration protein feed liquid by combining high-temperature primary hydrolysis for a lower time with low-temperature secondary hydrolysis for a higher time.
This is probably because, when the regenerated film is subjected to hydrolysis regeneration treatment, the reaction of hydrolyzing the cellulose-based film-forming polymer to obtain regenerated cellulose and the reaction of further hydrolyzing regenerated cellulose always tend to occur first, and the ease of hydrolyzing the cellulose-based film-forming polymer to obtain regenerated cellulose is not ensured to be the same as the ease of further hydrolyzing regenerated cellulose. In the initial stage of hydrolysis regeneration, the content of the cellulose film-forming polymer in the primary film is high, so that the reaction of hydrolyzing the cellulose film-forming polymer to obtain regenerated cellulose is more prone to occur first, and therefore, the cellulose film-forming polymer can be hydrolyzed at a high temperature once in a short time, and the rapid hydrolysis of the cellulose film-forming polymer to obtain regenerated cellulose can be ensured. While the ratio of regenerated cellulose in the primary membrane gradually increases as the hydrolysis reaction proceeds, if the alkaline and high-temperature reaction environment is maintained, the hydrolysis of the film-forming polymer to obtain regenerated cellulose proceeds, but further hydrolysis of the regenerated cellulose inevitably occurs, resulting in a decrease in the strength of the virus-free membrane produced. Based on this, after the primary hydrolysis is performed at a short time and a high temperature, the secondary hydrolysis is further performed at a specific long time and a low temperature, and by controlling the lower reaction temperature, the possibility of alkali hydrolysis and oxygen degradation of cellulose (the temperature is lower, but the hydrolysis of cellulose film-forming polymer into regenerated cellulose can still be performed) can be greatly reduced, and the high hydrolysis rate of cellulose film-forming polymer can be ensured, so that the finally prepared virus-removing agent not only has good hydrophilicity, but also has higher strength.
Optionally, the regenerated cellulose-based film is obtained by dissolving cellulose in a solvent and regenerating, wherein the cellulose-based film-forming polymer is cellulose, and the casting film good solvent is copper ammonia solution.
By adopting the technical scheme, the cuprammonium solution is one of common solvents for cellulose, and the cuprammonium solution is selected to dissolve cellulose and is subjected to regeneration treatment, so that the required regenerated cellulose base film can be obtained.
Optionally, inorganic salt is added into the casting solution, wherein the solid content of the casting solution is 7-10%, the copper content is 0.4-0.6 times of the solid content, and the inorganic salt content is 0.01-0.2 times of the solid content; the cation of the inorganic salt is one or more of sodium, potassium, calcium and magnesium, and the anion of the inorganic salt is one or more of sulfate radical, sulfite radical or carbonate.
By adopting the technical scheme, on the basis of selecting the cuprammonium solution as a solvent and using a dissolution regeneration method as a film making process, the ratio of the copper content to the solid content in the film casting solution is further controlled, so that the cuprammonium solution can be ensured to be capable of well dissolving cellulose, and higher solid content can be obtained. The addition of the inorganic salt can improve the phase separation performance of the casting solution by controlling the content of the inorganic salt in the casting solution to be 0.01-0.2 times of the solid content, but the addition amount of the inorganic salt is important. This is probably because copper ammonia ions in the copper ammonia solution generally exist in two forms, namely complex alkali and complex salt, and the complex alkali can play a role in dissolving cellulose, if excessive addition of inorganic salt is likely to promote the generation of complex salt, the content of complex alkali is reduced, so that cellulose which is not easy to dissolve is rapidly separated in a coagulating bath to form a relatively compact pore structure; on the other hand, if the amount of the inorganic salt added is too small, the effect on the formation and diffusion of the polymer-rich phase during the phase separation is insufficient, and the desired regenerated cellulose-based film is not easily formed.
Optionally, the coagulating bath comprises acetone and ammonia water, wherein the content of the acetone in the coagulating bath is 40-70wt% and the content of the ammonia in the coagulating bath is 0.1-0.4wt%;
the regeneration bath is an aqueous solution of an acid with the concentration of 1-10wt%, and the acid is at least one of acetic acid, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, citric acid and malic acid.
By adopting the technical scheme, the cellulose has a special high-strength intermolecular hydrogen bond, which is also an important reason that the cellulose is difficult to be dissolved by a common solvent, and is also a reason that a compact cortex structure is easier to generate when the cellulose is split-phase solidified in a coagulating bath. In addition, for the regenerated cellulose base film using natural cellulose as a film forming substance, the natural cellulose has uneven molecular weight and lower crystallinity, so that a film with uniform performance is not easy to prepare, and the phase separation speed is properly slowed down by controlling the ammonia content in the coagulating bath to be 0.1-0.4wt%, so that the phase separation uniformity of the liquid film can be improved everywhere, and the regenerated cellulose base film with more uniform mechanical strength is obtained.
In the further acidolysis regeneration procedure, the concentration of acid in the regeneration bath is controlled to be not more than 10wt%, and the uniformity of cellulose regeneration can be improved.
In a third aspect, the present application provides the use of the aforementioned cellulose virus-removing filter in a feed solution having a protein concentration of greater than 20 g/L.
In summary, the present application includes at least one of the following beneficial technical effects:
1. unlike the general recognition that the flux of the high-concentration protein feed liquid can be improved by improving the water flux of the filter membrane, the filter membrane in the application has lower water flux and higher virus interception capability through the control of the reverse general knowledge, and can have higher flux when filtering the high-concentration protein feed liquid;
2. the flux of the filter membrane in the application is less in the process of filtering high-concentration protein feed liquid than in the process of filtering deionized water, which shows that the membrane pore structure of the filter membrane with lower water flux is not excessively deformed even in the process of filtering high-concentration protein feed liquid with higher viscosity, so that the filter membrane can ensure higher flux in the process of filtering high-concentration protein feed liquid;
3. the filter membrane has lower middle-term flux relative deviation and lower long-term flux relative deviation by controlling, so that even if the filter membrane bearing pressure is further improved along with the extension of the filter time, no obvious pore structure collapse occurs, and therefore, the filter membrane has relatively higher and stable flux;
4. The filter membrane has smaller PMI average pore diameter through the control of the reverse general knowledge, and can be higher in flux when being applied to filtering high-concentration protein feed liquid.
Drawings
FIG. 1 is a graph showing the flux over time when the virus-removing membrane prepared in example 1 of the present application was used for filtering an IVIG solution having a protein concentration of 50 g/L.
FIG. 2 is a graph showing the flux over time when the virus-removing membrane prepared in example 2 of the present application was used for filtering an IVIG solution having a protein concentration of 50 g/L.
FIG. 3 is a graph showing the flux over time when the virus-removing membrane prepared in example 3 of the present application was used for filtering an IVIG solution having a protein concentration of 50 g/L.
FIG. 4 is a scanning electron microscope image of the liquid outlet surface of the virus-free film obtained in example 1 of the present application, and the magnification is 50K×.
FIG. 5 is a scanning electron microscope image of the virus-free film produced in example 1 of the present application, showing a cross section of the film near the liquid-exit surface, at a magnification of 50K.
FIG. 6 is a scanning electron microscope image of the cross-sectional area of the interface between the cellulose layer and the nylon support layer of the virus-free film prepared in example 1 of the present application, and the magnification is 5K×.
FIG. 7 is a scanning electron microscope image of the liquid outlet surface of the virus-free film obtained in example 2 of the present application, and the magnification is 50K×.
FIG. 8 is a scanning electron micrograph of a cross section of the virus-removing film obtained in example 2 of the present application on the side close to the liquid surface, at a magnification of 50K.
FIG. 9 is a scanning electron micrograph of an overall cross section of the virus-free film obtained in example 2 of the present application at a magnification of 1500X.
Detailed Description
The present application is described in further detail below with reference to fig. 1-9.
The embodiment of the application discloses a cellulose virus-removing filter membrane, and a preparation process and application thereof.
Example 1
The embodiment discloses a cellulose virus-removing filter membrane, the preparation process comprises the following process steps:
s11, preparing casting solutions, namely preparing a first casting solution and a second casting solution respectively, wherein the first casting solution and the second casting solution both comprise cellulose film-forming polymers and casting good solvents, in the embodiment, the cellulose film-forming polymers in the first casting solution and the second casting solution are the same, and are cellulose diacetate (or called cellulose diacetate and CA), and the casting good solvents in the first casting solution and the second casting solution are the same, and are N, N-dimethylacetamide; in addition, in this embodiment, the solid content of the first casting solution was 23wt%, and the solid content of the second casting solution was lower than that of the first casting solution, specifically, the solid content of the second casting solution was 12wt%.
S12, pouring to form a film, firstly, scraping the prepared first casting film liquid to a carrier in a scraping mode, wherein the carrier can be a steel belt, a roller and the like, or can be a film sheet such as a PET release film, and the like, in the embodiment, the steel belt is selected as the carrier, and the scraping speed of the first casting film liquid is 1.5m/min; and after the first casting film liquid is scraped and coated, the second casting film liquid is scraped and coated above the first casting film liquid, the scraping and coating speed of the second casting film liquid is 2m/min, and after the first casting film liquid and the second casting film liquid are sequentially poured onto a carrier, a nylon microporous film with the nominal aperture of 0.22 mu m and the thickness of 70 mu m is covered above the second casting film liquid, so that a liquid film is obtained.
The liquid film is placed in a pretreatment bath for pretreatment, the pretreatment time is 20s, the temperature of the pretreatment bath is kept at 35 ℃, and the pretreatment film is obtained after the pretreatment is completed; in this embodiment, the pretreatment bath is a mixed system of a good pretreatment solvent and a non-solvent for pretreatment, wherein the mass ratio of the non-solvent for pretreatment in the pretreatment bath is 13%, the non-solvent for pretreatment is deionized water, and the good pretreatment solvent for pretreatment is N, N-dimethylacetamide.
S13, solidifying, namely placing the pretreatment film into a coagulating bath until the pretreatment film is completely phase-separated and solidified to obtain a primary film, wherein the temperature of the coagulating bath is controlled to be 15 ℃, the coagulating bath comprises a good coagulating solvent and a non-coagulating solvent, the mass ratio of the non-coagulating solvent in the coagulating bath is 90%, the non-coagulating solvent is deionized water, and the good coagulating solvent is N, N-dimethylacetamide.
S14, hydrolysis regeneration, namely placing the primary membrane obtained after full split-phase solidification in a regeneration bath for hydrolysis treatment to obtain a regenerated cellulose membrane, and carrying out primary hydrolysis and secondary hydrolysis during hydrolysis, wherein the temperature of the regeneration bath is controlled to be 70 ℃ during primary hydrolysis, the primary hydrolysis time is controlled to be 20min, the temperature of the regeneration bath is controlled to be 35 ℃ during secondary hydrolysis, the secondary hydrolysis time is controlled to be 90min, and sodium hydroxide aqueous solution with the concentration of 0.5mol/L is selected as the primary hydrolysis bath and the secondary hydrolysis bath.
S2, crosslinking treatment, namely placing the regenerated cellulose membrane obtained after hydrolysis regeneration into a crosslinking agent solution for crosslinking treatment, wherein the concentration of the crosslinking agent polyethylene glycol diglycidyl ether in the crosslinking agent solution is 1.3mol/L, sodium hydroxide with the concentration of 0.5mol/L is also added into the crosslinking agent solution, the crosslinking coefficient J is controlled to 624min & mol/L, and the temperature of the crosslinking agent solution is controlled to 45 ℃. In order to promote better penetration of the cross-linking agent into the pore structure of the membrane, the environment in this example was controlled to be negative pressure, specifically, the ambient pressure was 0.65bar.
And S3, cleaning the crosslinked membrane to obtain the cellulose virus-removing filter membrane.
Example 2 to example 7
The main difference between examples 2-7 is that the casting solutions used for preparing the virus-free films are different and different film-making process parameters are adopted, and the details are shown in Table 1.
More specifically, the virus removal films in embodiment 2 and embodiment 4 have no supporting layer structure, so in step S12, only the first casting solution and the second casting solution are required to be poured onto the carrier in sequence, and the subsequent step of covering the supporting layer is not required. The virus-removing membranes of examples 3 and 5 to 7 each had a support layer structure, wherein the support layers used in examples 5 to 7 were nylon microporous membranes having a nominal pore size of 0.22 μm and a thickness of 70 μm, and the nonwoven fabric layers having a nominal pore size of 0.45 μm and a thickness of 60 μm were used in example 3, similarly to example 1.
Example 8 to example 9
The main difference between the embodiments 8-9 and the foregoing embodiments is that the embodiments 8-9 all adopt a single-layer casting process, i.e. in step S12, the liquid film is obtained only by casting the first casting solution onto the carrier, and the subsequent casting process of the second casting solution is not performed. In addition, the virus-removing membrane in example 8 had a support layer structure, and the support layer used was the same as that of example 1, and was a nylon microporous membrane having a nominal pore diameter of 0.22 μm and a thickness of 70 μm; whereas the virus removal membrane of example 9 had no support layer structure. The specific process parameters are shown in Table 1.
Example 10
The main difference between example 10 and example 1 is that the virus-removing membrane prepared in example 10 is a hollow fiber membrane, and specifically comprises the following process steps:
s11, preparing casting solutions, namely preparing a first casting solution and a second casting solution respectively, wherein the first casting solution and the second casting solution both comprise cellulose film-forming polymers and casting good solvents, in the embodiment, the cellulose film-forming polymers in the first casting solution and the second casting solution are the same, and are cellulose diacetate (or called cellulose diacetate and CA), and the casting good solvents in the first casting solution and the second casting solution are the same, and are N, N-dimethylacetamide; in addition, in this embodiment, the solid content of the first casting solution was 20wt%, and the solid content of the second casting solution was lower than that of the first casting solution, specifically, the solid content of the second casting solution was 10wt%.
S12, extruding the first casting solution, the second casting solution and the pretreatment bath through an annular spinneret, wherein the second casting solution is positioned at the radial inner side of the first casting solution, the pretreatment bath is used as a core liquid to be positioned in an inner cavity of the second casting solution, and the pretreatment bath is used for carrying out pretreatment on the inner surface of the second casting solution positioned at the radial inner side while the liquid film is extruded, so that the pretreatment film is obtained. The pretreatment bath is a mixed system of a good pretreatment solvent and a non-solvent for pretreatment, the mass ratio of the non-solvent for pretreatment in the pretreatment bath is 18%, the non-solvent for pretreatment is deionized water, the good pretreatment solvent for pretreatment is N, N-dimethylacetamide, the temperature of the pretreatment bath is 35 ℃, the pretreatment time is 15s (the time from liquid film extrusion to immersion in the coagulation bath is 15s, and the pretreatment bath serving as core liquid still plays a pretreatment role within a certain time after the liquid film is immersed in the coagulation bath).
S13, solidifying, namely placing the pretreatment film into a coagulating bath until the pretreatment film is completely phase-separated and solidified to obtain a primary film, wherein the temperature of the coagulating bath is controlled to be 20 ℃, the coagulating bath comprises a good coagulating solvent and a non-coagulating solvent, the mass ratio of the non-coagulating solvent in the coagulating bath is 90%, the non-coagulating solvent is deionized water, and the good coagulating solvent and the N, N-dimethylacetamide are used.
S14, hydrolysis regeneration, namely placing the primary membrane obtained after full split-phase solidification in a regeneration bath for hydrolysis treatment to obtain a regenerated cellulose membrane, and carrying out primary hydrolysis and secondary hydrolysis during hydrolysis, wherein the temperature of the regeneration bath is controlled to be 75 ℃ during primary hydrolysis, the primary hydrolysis time is controlled to be 20min, the temperature of the regeneration bath is controlled to be 30 ℃ during secondary hydrolysis, the secondary hydrolysis time is controlled to be 90min, and sodium hydroxide aqueous solution with the concentration of 0.5mol/L is selected as the primary hydrolysis bath and the secondary hydrolysis bath.
S2, crosslinking treatment, namely placing the regenerated cellulose membrane obtained after hydrolysis regeneration into a crosslinking agent solution for crosslinking treatment, wherein the concentration of the crosslinking agent polyethylene glycol diglycidyl ether in the crosslinking agent solution is 1.0mol/L, sodium hydroxide with the concentration of 0.5mol/L is also added into the crosslinking agent solution, the crosslinking coefficient J is controlled to be 600min & mol/L, and the temperature of the crosslinking agent solution is controlled to be 45 ℃. In order to promote better penetration of the cross-linking agent into the pore structure of the membrane, the environment in the cross-linking is controlled to be negative pressure in the embodiment, and specifically, the environment pressure is 0.6bar.
Example 11
The main difference between example 11 and example 10 is that example 11 uses a single layer casting solution and a pretreatment bath to co-extrude, so as to prepare a hollow fiber membrane, and specifically comprises the following process steps:
s11, preparing a casting solution, wherein the first casting solution comprises a cellulose film-forming polymer and a casting good solvent, and in the embodiment, the cellulose film-forming polymer is cellulose diacetate (or called cellulose diacetate and CA), and the casting good solvent is N, N-dimethylacetamide; in this example, the solid content of the first casting solution was 22wt%.
S12, extruding the first casting film liquid and the pretreatment bath through an annular spinneret, wherein the pretreatment bath is used as a core liquid to be positioned in an inner cavity of the first casting film liquid, and the pretreatment bath is used for pretreating the inner surface of the first casting film liquid while the liquid film is extruded, so that a pretreatment film is obtained. The pretreatment bath is a mixed system of a good pretreatment solvent and a non-solvent for pretreatment, the mass ratio of the non-solvent for pretreatment in the pretreatment bath is 11%, the non-solvent for pretreatment is deionized water, the good pretreatment solvent for pretreatment is N, N-dimethylacetamide, the temperature of the pretreatment bath is 35 ℃, the pretreatment time is 15s (the time from liquid film extrusion to immersion in the coagulation bath is 15s, and the pretreatment bath serving as core liquid still plays a pretreatment role within a certain time after the liquid film is immersed in the coagulation bath).
S13, solidifying, namely placing the pretreatment film into a coagulating bath until the pretreatment film is completely phase-separated and solidified to obtain a primary film, wherein the temperature of the coagulating bath is controlled to be 15 ℃, the coagulating bath comprises a good coagulating solvent and a non-coagulating solvent, the mass ratio of the non-coagulating solvent in the coagulating bath is 90%, the non-coagulating solvent is deionized water, and the good coagulating solvent and the N, N-dimethylacetamide are used.
S14, hydrolysis regeneration, namely placing the primary membrane obtained after full split-phase solidification in a regeneration bath for hydrolysis treatment to obtain a regenerated cellulose membrane, and carrying out primary hydrolysis and secondary hydrolysis during hydrolysis, wherein the temperature of the regeneration bath is controlled to be 70 ℃ during primary hydrolysis, the primary hydrolysis time is controlled to be 20min, the temperature of the regeneration bath is controlled to be 35 ℃ during secondary hydrolysis, the secondary hydrolysis time is controlled to be 90min, and sodium hydroxide aqueous solution with the concentration of 0.5mol/L is selected as the primary hydrolysis bath and the secondary hydrolysis bath.
S2, crosslinking treatment, namely placing the regenerated cellulose membrane obtained after hydrolysis regeneration into a crosslinking agent solution for crosslinking treatment, wherein the concentration of the crosslinking agent polyethylene glycol diglycidyl ether in the crosslinking agent solution is 1.0mol/L, sodium hydroxide with the concentration of 0.5mol/L is also added into the crosslinking agent solution, the crosslinking coefficient J is controlled to be 600min & mol/L, and the temperature of the crosslinking agent solution is controlled to be 45 ℃. In order to promote better penetration of the cross-linking agent into the pore structure of the membrane, the environment in the cross-linking is controlled to be negative pressure in the embodiment, and specifically, the environment pressure is 0.6bar.
Example 12
Example 12 differs from the previous examples mainly in that the regenerated cellulose-based film is regenerated by dissolving cellulose in a copper ammonia solution, specifically comprising the following process steps:
s11, preparing a casting solution, wherein the first casting solution comprises a cellulose film-forming polymer and a casting good solvent, and in the embodiment, the cellulose film-forming polymer is cellulose (cotton fiber), and the casting good solvent is copper ammonia solution; in the prepared first casting film liquid, the solid content of cellulose is 8.5%, the copper content is 0.5 times of the solid content, the content of inorganic salt is 0.1 times of the solid content, and the inorganic salt is sodium sulfate.
S12, pouring to form a film, scraping the prepared first casting film liquid onto a carrier in a scraping mode, wherein the carrier can be a steel belt, a roller or the like, or can be a film sheet such as a PET release film, the steel belt is selected as the carrier, the scraping speed of the first casting film liquid is 1.8m/min, and then a nylon microporous film with the nominal aperture of 0.22 mu m and the thickness of 70 mu m is covered above the second casting film liquid, so that a liquid film is obtained.
The liquid film is placed in a pretreatment bath for pretreatment, the pretreatment time is 10s, the temperature of the pretreatment bath is kept at 35 ℃, and the pretreatment film is obtained after the pretreatment is completed; in this embodiment, the pretreatment bath is a mixed system of a good pretreatment solvent and a non-solvent for pretreatment, wherein the mass ratio of the non-solvent for pretreatment in the pretreatment bath is 15%, the non-solvent for pretreatment is deionized water, and the good pretreatment solvent for pretreatment is N, N-dimethylacetamide.
S13, solidifying, namely placing the pretreatment film into a coagulating bath until the pretreatment film is completely phase-separated and solidified to obtain a primary film, wherein the temperature of the coagulating bath is controlled to be 15 ℃, the coagulating bath comprises acetone and ammonia water, the acetone content is 55wt%, and the ammonia content is 0.25wt%.
S14, acid washing regeneration, namely placing the primary membrane obtained after full phase separation solidification in a regeneration bath for acid washing treatment to obtain the regenerated cellulose membrane, wherein the regeneration bath used for acid washing is a sulfuric acid aqueous solution with the concentration of 6 wt%.
S2, crosslinking treatment, namely placing the regenerated cellulose membrane obtained after hydrolysis regeneration into a crosslinking agent solution for crosslinking treatment, wherein the concentration of the crosslinking agent polyethylene glycol diglycidyl ether in the crosslinking agent solution is 1.2mol/L, sodium hydroxide with the concentration of 0.5mol/L is also added into the crosslinking agent solution, the crosslinking coefficient J is controlled to be 660min & mol/L, and the temperature of the crosslinking agent solution is controlled to be 45 ℃. In order to promote better penetration of the cross-linking agent into the pore structure of the membrane, the environment in the cross-linking is controlled to be negative pressure in the embodiment, and specifically, the environment pressure is 0.6bar.
Example 13
The main difference between embodiment 13 and embodiment 12 is that the virus-removing film in embodiment 13 has no supporting layer structure, so in step S12, only the first casting solution needs to be poured onto the carrier, and the method specifically includes the following steps:
S11, preparing a casting solution, wherein the first casting solution comprises a cellulose film-forming polymer and a casting good solvent, and in the embodiment, the cellulose film-forming polymer is cellulose (cotton fiber), and the casting good solvent is copper ammonia solution; in the prepared first casting film liquid, the solid content is 10%, the copper content is 0.4 times of the solid content, the inorganic salt content is 0.02 times of the solid content, and the inorganic salt is sodium sulfate.
S12, pouring to form a film, and doctor-coating the prepared first casting film liquid on a carrier in a doctor-blade mode, wherein the carrier can be a steel belt, a roller or the like, or can be a film sheet such as a PET release film, and the like, in the embodiment, the steel belt is selected as the carrier, and the doctor-coating speed of the first casting film liquid is 1.6m/min, so that a liquid film is obtained.
The liquid film is placed in a pretreatment bath for pretreatment, the pretreatment time is 10s, the temperature of the pretreatment bath is kept at 35 ℃, and the pretreatment film is obtained after the pretreatment is completed; in this embodiment, the pretreatment bath is a mixed system of a good pretreatment solvent and a non-solvent for pretreatment, wherein the mass ratio of the non-solvent for pretreatment in the pretreatment bath is 10%, the non-solvent for pretreatment is deionized water, and the good pretreatment solvent for pretreatment is N, N-dimethylacetamide.
S13, solidifying, namely placing the pretreatment film into a coagulating bath until the pretreatment film is completely phase-separated and solidified to obtain a primary film, wherein the temperature of the coagulating bath is controlled to be 15 ℃, the coagulating bath comprises acetone and ammonia water, the acetone content is 70wt%, and the ammonia content is 0.4wt%.
S14, acid washing regeneration, namely placing the primary membrane obtained after full phase separation solidification in a regeneration bath for acid washing treatment to obtain the regenerated cellulose membrane, wherein the regeneration bath used for acid washing is a 10wt% sulfuric acid aqueous solution.
S2, crosslinking treatment, namely placing the regenerated cellulose membrane obtained after hydrolysis regeneration into a crosslinking agent solution for crosslinking treatment, wherein the concentration of the crosslinking agent polyethylene glycol diglycidyl ether in the crosslinking agent solution is 1.0mol/L, sodium hydroxide with the concentration of 0.5mol/L is also added into the crosslinking agent solution, the crosslinking coefficient J is controlled to be 550min & mol/L, and the temperature of the crosslinking agent solution is controlled to be 45 ℃. In order to promote better penetration of the cross-linking agent into the pore structure of the membrane, the environment in the cross-linking is controlled to be negative pressure in the embodiment, and specifically, the environment pressure is 0.6bar.
Example 14
The difference between the embodiment 14 and the embodiments 12 to 13 is that the virus-removing membrane prepared in the embodiment 14 is a hollow fiber membrane, and the hollow fiber membrane is prepared by adopting a mode of co-extrusion of a single-layer casting solution and a pretreatment bath, and specifically comprises the following process steps:
s11, preparing a casting solution, wherein the first casting solution comprises a cellulose film-forming polymer and a casting good solvent, and in the embodiment, the cellulose film-forming polymer is cellulose (cotton fiber), and the casting good solvent is copper ammonia solution; in the prepared first casting film liquid, the solid content is 7%, the copper content is 0.6 times of the solid content, the inorganic salt content is 0.2 times of the solid content, and the inorganic salt is sodium sulfate.
S12, extruding the first casting film liquid and the pretreatment bath through an annular spinneret, wherein the pretreatment bath is used as a core liquid to be positioned in an inner cavity of the first casting film liquid, and the pretreatment bath is used for pretreating the inner surface of the first casting film liquid while the liquid film is extruded, so that a pretreatment film is obtained. The pretreatment bath is a mixed system of a good pretreatment solvent and a non-solvent for pretreatment, the mass ratio of the non-solvent for pretreatment in the pretreatment bath is 11%, the non-solvent for pretreatment is deionized water, the good pretreatment solvent for pretreatment is N, N-dimethylacetamide, the temperature of the pretreatment bath is 35 ℃, the pretreatment time is 15s (the time from liquid film extrusion to immersion in the coagulation bath is 15s, and the pretreatment bath serving as core liquid still plays a pretreatment role within a certain time after the liquid film is immersed in the coagulation bath).
S13, solidifying, namely placing the pretreatment film into a coagulating bath until the pretreatment film is completely phase-separated and solidified to obtain a primary film, wherein the temperature of the coagulating bath is controlled to be 15 ℃, the coagulating bath comprises acetone and ammonia water, the acetone content is 40wt%, and the ammonia content is 0.1wt%.
S14, acid washing regeneration, namely placing the primary membrane obtained after full phase separation solidification in a regeneration bath for acid washing treatment to obtain the regenerated cellulose membrane, wherein the regeneration bath used for acid washing is 2wt% sulfuric acid aqueous solution.
S2, crosslinking treatment, namely placing the regenerated cellulose membrane obtained after hydrolysis regeneration into a crosslinking agent solution for crosslinking treatment, wherein the concentration of the crosslinking agent polyethylene glycol diglycidyl ether in the crosslinking agent solution is 1.5mol/L, sodium hydroxide with the concentration of 0.5mol/L is also added into the crosslinking agent solution, the crosslinking coefficient J is controlled to be 750min & mol/L, and the temperature of the crosslinking agent solution is controlled to be 45 ℃. In order to promote better penetration of the cross-linking agent into the pore structure of the membrane, the environment in the cross-linking is controlled to be negative pressure in the embodiment, and specifically, the environment pressure is 0.6bar.
Comparative example 1
Comparative example 1A commercially available type Planova from Asahi chemical Co., ltd TM 20N, and the membrane is a hollow cellulose virus-removing membrane.
Comparative example 2
Comparative example 2 is different from example 1 mainly in that the solid content of the casting solution is different and the secondary hydrolysis process is not adopted in the hydrolysis regeneration step, but a long-time hydrolysis process is adopted; in addition, a longer crosslinking time and a higher concentration of crosslinking agent were used in this comparative example to ensure that the produced virus-free film had good pressure resistance. The specific process parameters are shown in Table 1.
Comparative example 3
Comparative example 3 is different from example 1 mainly in that the solid content of the casting solution is different and the secondary hydrolysis process is not adopted in the hydrolysis regeneration step, but a long-time hydrolysis process is adopted; in addition, shorter crosslinking times and lower concentrations of crosslinking agents were employed in this comparative example to ensure low potential for blocking of the crosslinking agent to the virus-free membrane pore structure. The specific process parameters are shown in Table 1.
Comparative example 4
The difference between comparative example 4 and example 1 is mainly that the crosslinking process in step S2 is different, an excessive crosslinking coefficient J is adopted, and the other process parameters are the same as those in example 1, and are not repeated. Step S2 of this comparative example specifically comprises the following process steps:
s2, crosslinking treatment, namely placing the regenerated cellulose membrane obtained after hydrolysis regeneration into a crosslinking agent solution for crosslinking treatment, wherein the crosslinking agent solution contains 3mol/L of crosslinking agent polyethylene glycol diglycidyl ether, 1mol/L of sodium hydroxide, the crosslinking coefficient J is controlled to 2400min mol/L, and the temperature of the crosslinking agent solution is controlled to 60 ℃. In order to promote better penetration of the cross-linking agent into the pore structure of the membrane, the environment in this example was controlled to be negative pressure, specifically, the ambient pressure was 0.65bar.
Table 1 casting solutions and process parameters of examples and comparative examples
The performance parameters of the filter membranes prepared in each example and comparative example are shown in Table 2 and Table 3.
Table 2 various performance parameters of various examples, comparative examples
TABLE 3 Performance parameters for the examples, comparative examples
In tables 2 and 3, planova in comparative example 1 TM 20N is prepared by a copper ammonia process, and the official guidelines are rated to use a pressure of 14psi, so that the test pressure is 14psi and the water flux is converted to a theoretical flux of 30psi at 14 psi. The calculation mode is T 20N X30/14, where T 20N Refers to the water flux measured at 14psi for the filter. Similarly, examples 12-14, prepared with copper ammonia, were also run with a test pressure of 14psi, and converted as above.
In tables 2 and 3, the tensile strength at break of each example was measured by a universal tensile tester, and the ratio of the tensile strength at break of each example, comparative example and example 1 was calculated based on the tensile strength at break of example 1.
The morphology parameters of the filter membranes prepared in each example and comparative example are shown in Table 4:
table 4 morphology parameters of examples, comparative examples
Conclusion(s)
By comparing the technical schemes and performance parameters of example 1, comparative example 2 and comparative example 4, it is not difficult to find that, compared with example 1, in the case of adopting one thermal hydrolysis in comparative example 2, excessive crosslinking (the crosslinking coefficient J is 2000min mol/L), although the crosslinking can improve the self-supporting performance of the filter membrane to a certain extent, and reduce the strength decrease of the filter membrane caused by excessive hydrolysis, however, excessive crosslinking is difficult to avoid the excessive pore size influence on the filter membrane having the nano-scale pore structure, thereby leading to lower water flux and protein flux of the filter membrane. However, as in comparative example 4, the strength of the filter film was surely high even if the excessive crosslinking was performed without excessive hydrolysis (crosslinking coefficient J was 2400 min. Mol/L), but the pore size was affected too much, resulting in a lower water flux and protein flux of the filter film. Of course, the membrane produced in comparative example 4 had a lower water flux but a higher protein flux than comparative example 2, probably because comparative example 4 was not excessively hydrolyzed and thus had higher strength and better self-supporting properties, and thus deformation of the membrane pores did not occur under the high concentration protein condition.
By further comparing the technical solutions and performance parameters of example 1, comparative example 1 and comparative example 3, it was found that the filter membrane had a significantly higher water flux in the case of comparative example 3 having a smaller crosslinking coefficient (crosslinking coefficient J is 6 min. Mol/L). Considering that the cross-linking agent does not cause significant blocking of the pore structure of the filter membrane, it is believed that the filter membrane of comparative example 3 should have a higher protein flux, however, unexpectedly, the filter membrane prepared in comparative example 3 clearly has a lower protein flux, with substantially no industrial application possibilities. Similar to comparative example 3, comparative example 1 likewise exists, which, although having a higher water flux, likewise has an unexpectedly low protein flux.
By further comparing the technical schemes and performance parameters of comparative example 1 and examples 12-14, it is readily found that even if the filter membrane is prepared by the copper ammonia dissolution regeneration method as well (the commercial product in comparative example 1 is prepared by copper ammonia), the present application has a significantly better protein flux against common sense by employing a specific cross-linking treatment process, although it would result in a decrease in the water flux of the filter membrane.
By comparing the technical schemes and performance parameters of examples 1 and 3-7, it is not difficult to find that, for the virus-removing membrane with a supporting layer, the filtration flux of the high-concentration protein feed liquid of the virus-removing membrane shows a tendency of gradually rising and then falling with the increase of the water flux, which is quite unexpected.
By further comparing the technical schemes and performance parameters of example 1, example 3 and example 5, it can be found that, although example 5 has a water flux similar to that of example 3, the virus removal membrane of example 5 has a significantly lower stable flux and a higher flux attenuation coefficient, probably because the virus removal membrane of example 5 has a significantly higher hydrolysis degree than that of example 3, and a lower crosslinking degree than that of example 3, resulting in a decrease in the strength of the virus removal membrane, whether the hydrolysis degree is too high or the crosslinking degree is too low, thereby providing the virus removal membrane of example 5 with a non-preferred high concentration protein filtration flux than that of example 3. Therefore, when the water flux of the virus-removing membrane is high, it is advantageous to appropriately decrease the water flux of the virus-removing membrane for improving the high-concentration protein filtration flux of the virus-removing membrane.
By further comparing the technical schemes and performance parameters of example 6 and example 7, it is not difficult to find that, for the virus-removing membrane having the support layer, when the water flux of the virus-removing membrane is low, the high-concentration protein feed liquid filtration flux of the virus-removing membrane shows an upward trend with the increase of the water flux. This means that although the strength of the virus-removing membrane can be further improved by controlling the membrane-forming process parameters, the effect of the virus-removing membrane on the high-concentration protein filtration flux is a marginal decreasing effect as the strength of the virus-removing membrane is gradually improved, whereas the effect of the virus-removing membrane on the high-concentration protein filtration flux is improved as the resistance of the virus-removing membrane to the feed liquid is continuously improved, and therefore, when the water flux of the virus-removing membrane is low, it is advantageous to improve the water flux of the virus-removing membrane.
By comparing the technical schemes and performance parameters of example 2 and example 4, it is not difficult to find that, for the virus-removing membrane without the support layer, when the water flux of the virus-removing membrane is high, the filtration flux of the high-concentration protein feed liquid of the virus-removing membrane shows a decreasing trend with the increase of the water flux, which is quite unexpected. This may be related to the fact that the virus-free film of example 4 has a lower strength and is more prone to deformation (lower tensile strength at break) than the virus-free film of example 2. In addition, the virus removal membrane in example 4 has no support layer for reinforcement and has poor self-supporting performance, so that the flux of the virus removal membrane is obviously reduced along with the extension of the filtering time, which is shown by the long-term deviation of the virus removal membrane reaching 40.2 percent, and the flux gradient reaching 4.05LMH/100min. Therefore, it is advantageous to properly reduce the water flux of the filter membrane to improve the flux stability of the virus-removing membrane when filtering a high-concentration protein feed solution.
By comparing the technical schemes and performance parameters of example 8 and example 9, it is not difficult to find that, whether the virus-removing membrane obtained by single-layer casting is provided with a supporting layer or not, when the water flux of the virus-removing membrane is in a more preferable range, the protein flux attenuation coefficient is lower, and the flux of the high-concentration protein feed liquid is higher. And the introduction of the supporting layer reduces the attenuation coefficient of the protein flux of the virus removal membrane.
By further comparing the technical schemes and performance parameters of the embodiment 1 and the embodiment 8, it is not difficult to find that the virus-removing membrane obtained by single-layer casting has higher flux of excessive protein feed liquid in the membrane on the premise that the water flux of the two membranes is not great, which is probably because compared with the virus-removing membrane obtained by double-layer casting, the single-layer casting process has no second casting solution with lower solid content, so that the large-aperture membrane pore structure in the cellulose layer occupies less membrane pore structure and is less prone to local deformation. Example 2 also has a similar tendency to example 9.
By further comparing the technical schemes and performance parameters of examples 10 to 11, it was found that, similarly to the flat plate-like filter membrane, the hollow fiber-like filter membrane also had an abnormal phenomenon that the protein flux was decreased with the increase of the water flux within a certain range.
By further comparing the technical schemes and performance parameters of examples 12 to 14, it was found that, similarly to the filter membrane produced by the CA hydrolysis method, the filter membrane produced by the copper ammonia dissolution regeneration method also had an abnormal phenomenon that the protein flux was decreased with the increase of the water flux within a certain range.
The present embodiment is merely illustrative of the present application and is not intended to be limiting, and those skilled in the art, after having read the present specification, may make modifications to the present embodiment without creative contribution as required, but is protected by patent laws within the scope of the claims of the present application.
Claims (37)
1. A cellulose virus-removing filter membrane, characterized in that: the device comprises a porous main body, wherein the porous main body is provided with a liquid inlet surface for feeding liquid and a liquid outlet surface for discharging the feeding liquid;
the water flux T of the filter membrane Water and its preparation method Not higher than 85LMH@30psi and not lower than 30LMH@30psi;
stabilized flux T of the filter membrane 240 Not lower than 7LMH@30psi, said stable flux T 240 Flux data of the filter membrane when the concentration n of protein in the filter liquid is 50g/L and the filtering time t is 240 min;
the trapping capacity of the filter membrane for PP7 phage meets LRV > 4@ (0.1 g/L, IVIG).
2. A cellulose virus-removing filter according to claim 1, wherein: stabilized flux of the filter membraneT 240 Not lower than 8LMH@30psi, the water flux T of the filter membrane Water and its preparation method Not higher than 83LMH@30psi.
3. A cellulose virus-removing filter according to claim 1, wherein: stabilized flux T of the filter membrane 240 Not lower than 9LMH@30psi, the water flux T of the filter membrane Water and its preparation method Not higher than 82LMH@30psi.
4. A cellulose virus-removing filter according to claim 1, wherein:
the water flux T of the filter membrane Water and its preparation method Not higher than 80LMH@30psi and not lower than 35LMH@30psi;
Stabilized flux T of the filter membrane 240 Not less than 10LMH@30psi;
the interception capability of the filter membrane for PP7 phage meets the requirement that LRV is more than or equal to 5.5@L (0.1 g/L, IVIG).
5. A cellulose virus-removing filter according to claim 1, wherein: stabilized flux T of the filter membrane 240 Not less than 12LMH@30psi.
6. A cellulose virus-removing filter according to claim 1, wherein: stabilized flux T of the filter membrane 240 Not less than 14LMH@30psi.
7. A cellulose virus-removing filter according to claim 1, wherein: the liquid outlet surface is distributed with a plurality of liquid outlet holes, the average pore diameter of the liquid outlet holes is not more than 40nm, and the distribution density of the liquid outlet holes is not less than 100/mu m 2 。
8. The cellulose virus-removing filter of claim 7, wherein: the average pore diameter of the liquid outlet holes is 15-35 nm, the pore diameter of the liquid outlet holes is larger than 40nm, and the ratio of the flux holes is 2-20%.
9. The cellulose virus-removing filter of claim 7, wherein: the aperture in the liquid outlet hole is not more than 25nm and is a interception hole, and the proportion of the interception hole is 40-85%.
10. A cellulose virus-removing filter according to claim 1, wherein: the hardness coefficient of the virus-removing filter membrane is not lower than 8, the hardness coefficient is A type Shore hardness measured after n layers of filter membranes are laminated, and the number of layers of the filter membranes is 20 when tested.
11. A cellulose virus-removing filter according to claim 10, wherein: the hardness coefficient of the virus-removing filter membrane is not lower than 12.
12. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: the retention rate of the top washing LRV of the filter membrane is not lower than 0.85.
13. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: the long-term average flux of the filter membrane is 8-30 LMH@30psi, and the long-term average flux is the flux average value of the filter membrane in 100-300 min when the protein concentration of the filter membrane in the filter feed liquid is 50 g/L.
14. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein:
protein flux attenuation coefficient X of the filter membrane 50 At 100min not higher than 85%, the protein flux attenuation coefficient X of the filter membrane 50 @100min is obtained by:
Xn=（1-T t /T water and its preparation method ）×100%；
In the formula, xn is the protein flux attenuation coefficient when the protein concentration in the feed liquid is n, T t The unit is LMH for flux data of the filter membrane when the concentration of protein in the filter feed liquid is n and the filtering time is t; x is X 50 100min means in the feed solutionProtein flux attenuation coefficient at protein concentration n of 50g/L and filtration time t of 100 min.
15. A cellulose virus-removing filter according to claim 14, wherein: protein flux attenuation coefficient X of the filter membrane 50 At 100min no more than 80%, T of the filter membrane 100 Not less than 10LMH@30psi.
16. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: the relative deviation of the medium-term flux of the filter membrane is not higher than 20%, and the relative deviation of the medium-term flux is the relative deviation of flux data when the filter membrane is used for filtering the feed liquid and the time t is 100min and the flux data when the filter time t is 200min when the protein concentration n in the filter feed liquid is 50 g/L.
17. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: the relative deviation of the long-term flux of the filter membrane is not higher than 30%, and the relative deviation of the long-term flux is the relative deviation of flux data when the filtering time t is 100min and flux data when the filtering time t is 300min when the protein concentration n of the filter membrane in the filtering feed liquid is 50 g/L.
18. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: the long-term flux change gradient of the filter membrane is not more than 3LMH/100min, and the long-term flux change gradient is the ratio of the difference between flux data when the filter time t is 100min and flux data when the time is 300min when the protein concentration n of the filter membrane in the filter feed liquid is 50 g/L.
19. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: when the protein concentration in the filtered feed liquid is 50g/L, the flux decays 75% for not less than 360min, and the T of the filter membrane 360 Not less than 8LMH@30psi.
20. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: the PMI average pore diameter of the filter membrane is not more than 30nm and not less than 15nm, and the SEM average pore diameter of the liquid inlet surface is larger than the SEM average pore diameter of the liquid outlet surface.
21. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: the porous body is composed of a cellulosic layer; or alternatively, the first and second heat exchangers may be,
the porous main body is obtained by compounding a cellulose layer and a supporting layer, and the surface of one side of the cellulose layer, which is away from the supporting layer, is a liquid outlet surface.
22. The cellulose virus-removing filter according to any one of claims 1 to 11, wherein: the virus-removing filter membrane is obtained by hydrolysis and regeneration of cellulose ester compounds, wherein the cellulose ester compounds are at least one of cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate phthalate, cellulose acetate butyrate and cellulose acetate propionate; or alternatively, the first and second heat exchangers may be,
The virus-removing membrane is obtained by dissolving cellulose in a solvent and regenerating the cellulose, wherein the solvent is one of copper ammonia solution, a lithium chloride and dimethylacetamide system, an ionic liquid solvent and N-methylmorpholine-N-oxide.
23. The process for preparing the cellulose virus-removing filter membrane according to any one of claims 1 to 22, which is characterized in that: the method comprises the following process steps:
s1, providing a regenerated cellulose base film, wherein the base film is obtained through hydrolysis and regeneration of cellulose ester compounds or is obtained through dissolution and regeneration of cellulose, and the water flux of the base film is not higher than 120LMH@30psi;
s2, crosslinking treatment, namely placing the regenerated cellulose base film into a crosslinking agent solution for crosslinking treatment to obtain a crosslinked film, wherein the crosslinking temperature is 20-80 ℃, the concentration of sodium hydroxide in the crosslinking agent solution is 0.05-1 mol/L, the crosslinking agent is at least one of polyglycidyl ether, epichlorohydrin, adipic acid, succinic anhydride, hexamethylene diisocyanate and maleic anhydride, the concentration of the crosslinking agent in the crosslinking agent solution is 0.5-2 mol/L, the crosslinking coefficient J is controlled to be 150-1500 min mol/L, and the crosslinking coefficient is the product of the concentration of the crosslinking agent in the crosslinking agent solution and the crosslinking time;
s3, post-treatment, namely cleaning the crosslinked membrane to obtain the cellulose virus-removing filter membrane.
24. The process for preparing a cellulose virus-removing filter according to claim 23, wherein: the polyglycidyl ether is at least one of diethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether and glycerol triglycidyl ether;
in the step S2, the ambient pressure is kept at 0.5-0.8 bar in the crosslinking treatment process.
25. The process for preparing a cellulose virus-removing filter according to claim 24, wherein: the regenerated cellulose base film is prepared by the following process:
s11, preparing a casting solution, wherein the casting solution comprises a cellulose film-forming polymer and a casting good solvent;
s12, extruding the casting film liquid to obtain a liquid film, and pretreating the liquid film through a pretreatment bath to obtain a pretreatment film, wherein the pretreatment bath comprises a pretreatment good solvent and a pretreatment non-solvent;
s13, solidifying, namely placing the pretreated film into a coagulating bath for phase separation and solidification to obtain a primary film;
and S14, regenerating, namely placing the primary membrane into a regeneration bath for treatment and regeneration, and cleaning to obtain the regenerated cellulose base membrane.
26. The process for preparing a cellulose virus-removing filter according to claim 25, wherein: in the step S12, the mass ratio of the pretreatment non-solvent in the pretreatment bath is 5-20%, and the temperature of the pretreatment bath is 30-40 ℃.
27. The process for preparing a cellulose virus-removing filter according to claim 25, wherein: the step S11 comprises the steps of preparing a first casting solution and a second casting solution respectively, wherein the first casting solution and the second casting solution both comprise cellulose film-forming polymers and casting good solvents; the solid content of the second film casting liquid is lower than that of the first film casting liquid, the solid content of the first film casting liquid is 15-30%, and the solid content of the second film casting liquid is 5-20%;
in the step S12, the first casting solution and the second casting solution are co-extruded to obtain a liquid film, and the second casting solution is located at a side of the liquid film, which is close to the pretreatment bath.
28. The process for preparing a cellulose virus-removing filter according to claim 27, wherein: the virus-removing filter membrane is hollow fiber, and the step S12 is specifically to extrude the first casting solution, the second casting solution and the pretreatment bath through an annular spinneret, wherein the second casting solution is located at the radial inner side of the first casting solution, and the pretreatment bath is located as a core solution in the inner cavity of the second casting solution.
29. The process for preparing a cellulose virus-removing filter according to claim 27, wherein: the virus-removing filter membrane is in a flat plate shape, and the step S12 is specifically to sequentially pour a first casting solution and a second casting solution onto a carrier to obtain a liquid membrane, wherein the doctor-blading speed of the first casting solution is smaller than that of the second casting solution, the doctor-blading speed of the second casting solution is 1-3 m/min, and then the side, away from the carrier, of the liquid membrane is pretreated through a pretreatment bath.
30. The process for preparing a cellulose virus-removing filter according to claim 29, wherein: in the step S12, after casting the casting solution onto the carrier, a support layer is further covered on the casting solution to obtain a liquid film, where the support layer is one of a PVDF microporous membrane, a PES microporous membrane, a PTFE microporous membrane, a Nylon microporous membrane, a cellulose microporous membrane, a polyolefin microporous membrane, and a nonwoven substrate.
31. The process for preparing a cellulose virus-removing filter according to any one of claims 25 to 30, wherein: the regenerated cellulose base film is obtained by hydrolysis and regeneration of cellulose ester compounds, and the cellulose film-forming polymer is at least one of diacetyl cellulose, triacetyl cellulose, propionic acid cellulose, phthalic acid acetic acid cellulose, acetic acid butyric acid cellulose and acetic acid propionic acid cellulose.
32. The process for preparing a cellulose virus-removing filter according to claim 31, wherein: in the step S13, the coagulation bath includes a coagulation good solvent and a coagulation non-solvent;
the casting film good solvent, the pretreatment good solvent and the solidification good solvent are at least one of acetone, dioxane, N-dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid and valeric acid;
The pretreatment non-solvent and the solidification non-solvent are water or small molecular alcohol;
the temperature of the coagulating bath is not higher than 30 ℃, and the mass ratio of the coagulating non-solvent in the coagulating bath is 85-95%.
33. The process for preparing a cellulose virus-removing filter according to claim 31, wherein: in the step S14, the regeneration bath is a sodium hydroxide aqueous solution with the concentration of 0.01-1 mol/L, and the hydrolysis is carried out firstly and then is carried out secondarily, wherein the temperature of the regeneration bath is 60-80 ℃ during the primary hydrolysis, the time of the primary hydrolysis is 10-30 min, the temperature of the regeneration bath is 30-40 ℃ during the secondary hydrolysis, and the time of the secondary hydrolysis is 40-150 min.
34. The process for preparing a cellulose virus-removing filter according to claim 25, wherein: the regenerated cellulose-based film is obtained by dissolving cellulose in a solvent and regenerating the solvent, wherein the cellulose-based film-forming polymer is cellulose, and the casting film good solvent is copper ammonia solution.
35. The process for preparing a cellulose virus-removing filter according to claim 34, wherein: inorganic salt is also added into the casting film liquid, wherein the solid content of the casting film liquid is 7-10%, the copper content is 0.4-0.6 times of the solid content, and the inorganic salt content is 0.01-0.2 times of the solid content; the cation of the inorganic salt is one or more of sodium, potassium, calcium and magnesium, and the anion of the inorganic salt is one or more of sulfate radical, sulfite radical or carbonate.
36. The process for preparing a cellulose virus-removing filter according to claim 34, wherein: the coagulating bath comprises acetone and ammonia water, wherein the content of the acetone in the coagulating bath is 40-70wt% and the content of the ammonia in the coagulating bath is 0.1-0.4wt%;
the regeneration bath is an aqueous solution of an acid with the concentration of 1-10wt%, and the acid is at least one of acetic acid, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, citric acid and malic acid.
37. The use of a cellulose virus-free filter according to any one of claims 1 to 22 in virus-free filtration of feed solutions having a protein concentration of more than 20 g/L.
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| GB2086798A (en) * | 1980-11-07 | 1982-05-19 | Akzo Nv | Microporous cellulose membrane |
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| CN116236925A (en) * | 2022-12-14 | 2023-06-09 | 杭州科百特过滤器材有限公司 | Asymmetric regenerated cellulose virus-removing filter membrane and preparation process thereof |
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| GB2086798A (en) * | 1980-11-07 | 1982-05-19 | Akzo Nv | Microporous cellulose membrane |
| US20120305472A1 (en) * | 2010-03-09 | 2012-12-06 | Toyo Boseki Kabushiki Kaisha | Porous hollow fiber membrane for treatment of protein-containing liquid |
| US20150232506A1 (en) * | 2012-11-15 | 2015-08-20 | Toyobo Co., Ltd. | Porous hollow fiber membrane |
| CN107185416A (en) * | 2017-06-29 | 2017-09-22 | 河南省科学院能源研究所有限公司 | A kind of high temperature resistant separation furfural press filtration film, preparation method and applications |
| CN116236925A (en) * | 2022-12-14 | 2023-06-09 | 杭州科百特过滤器材有限公司 | Asymmetric regenerated cellulose virus-removing filter membrane and preparation process thereof |
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