Hydrophilic membranes for filtration

Abstract

This disclosure provides porous membranes capable of removing extremely fine particles from liquid compositions. In some embodiments, such porous membranes comprise poly(tetrafluoroethylene), wherein the membrane is at least partially coated with a polymer prepared by a free radical reaction of olefinic unsaturated monomers, wherein such monomers include monomers having amide moieties. In particular embodiments, such membranes are capable of removing microbial particles such as bacteria by filtration, thereby making the resulting liquid composition substantially sterile.

Description

Technical Field

[0001] The present disclosure generally relates to hydrophilically modified porous membranes (eg, filter membranes) and methods of using such membranes to remove very small particles and / or microbial species from liquid compositions. Prior Art

[0002] Filters are used to remove unwanted materials from useful liquid solution streams and have become a crucial feature in a variety of technologies. Liquid solutions treated to remove unwanted materials include water, liquid industrial solvents and process fluids, industrial gases used in manufacturing or processing, and liquids with medical or pharmaceutical applications. Unwanted materials removed from fluids include impurities and contaminants, such as particles, microorganisms, and dissolved chemical species. Specific examples of filter applications include their use with liquid materials used in semiconductor and microelectronic device manufacturing, as well as for sterile filtration of liquid solutions intended for introduction into the human body.

[0003] Filters can remove unwanted materials in a variety of ways, such as through particle size selection or through chemical and / or physical interactions with the material. Some filters are defined by a structural material that provides the filter with a porous structure, capable of trapping particles too large to pass through the pores. Some filters are defined by the ability of the filter's structural material, or chemicals associated with the structural material, to bind and interact with materials passing through the filter. For example, the chemical properties of the filter may be capable of binding to unwanted materials in a stream passing through the filter, trapping them through interactions such as ionic, coordination, chelation, or hydrogen bonding. Some filters utilize both particle size selection and chemical interaction properties to remove materials from the filter stream.

[0004] In some cases, to perform the filtration function, the filter includes a filter membrane responsible for removing unwanted materials from the fluid passing therethrough. The filter membrane can optionally be in the form of a flat sheet, which can be wound (e.g., spirally), flat, pleated, or disc-shaped. The filter membrane can alternatively be in the form of a hollow fiber. The filter membrane can be contained in a housing or otherwise supported so that the fluid to be filtered enters through the filter inlet and passes through the filter membrane before passing through the filter outlet.

[0005] Certain filters are capable of removing very small particulate matter and microbial contaminants (e.g., bacteria), thereby rendering the filtered liquid solution essentially sterile. In such applications, it is also important that the filter media or membrane be operated so that very low amounts of extractable or leachable material are observed to seep through the filter, which could otherwise contaminate the filtered liquid solution. Furthermore, in the case of sterile filtration, it is also important that the filter not excessively retain the desired components of the liquid composition, such as the active pharmaceutical ingredient (API). Summary of the Invention

[0006] In summary, the present disclosure provides porous membranes capable of removing very small particles from liquid compositions. In certain embodiments, the porous membrane comprises poly(tetrafluoroethylene), wherein a) the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, wherein the monomers include monomers having an amide moiety; b) the membrane exhibits a wettability of at least about 80 dynes / cm; and c) the membrane exhibits a 60% isopropyl alcohol visualized bubble point greater than about 21 psi.

[0007] In certain embodiments, the membrane has an average pore size of about 0.1 µm to about 0.2 µm. In certain embodiments, the membrane is capable of removing microbial particles (e.g., bacteria) by filtration, thereby rendering the resulting liquid composition substantially sterile. Also in certain embodiments, the coating on the porous membrane allows for filtration of the liquid composition without excessive retention of the active pharmaceutical ingredient contained therein, particularly active pharmaceutical ingredients having ionizable nitrogen groups (e.g., quaternary ammonium groups). Simple diagram description

[0008] FIG1 is a graph comparing the wettability (dynes / cm) of a membrane of the present disclosure (A) and a commercial membrane (B) (i.e., Cobetter hydrophilic PTFE with a pore size of 0.2 μm).

[0009] FIG. 2 compares the visualized bubble point (in psi) of a membrane of the present disclosure (A) versus a commercial membrane (B) (i.e., Cobetter hydrophilic PTFE with a pore size of 0.2 μm) at 60% isopropyl alcohol.

[0010] FIG3 is a comparison of deionized water (DIW) flow time for a membrane of the present disclosure (A) and a commercial membrane (B) (i.e., Cobetter hydrophilic PTFE with a pore size of approximately 0.2 μm).

[0011] 4 is a plot of NVR (non-volatile residue) data for a membrane of the present disclosure (A) versus a commercial membrane (B) (i.e., Cobetter hydrophilic PTFE with a pore size of approximately 0.2 μm).

[0012] 5 is a drawing of an exemplary filter device including a membrane of the present disclosure. Implementation Method

[0013] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. As used in this specification and the appended claims, the term "or" is generally employed in its sense including "and / or" unless the context clearly dictates otherwise.

[0014] The term "about" generally refers to a range of values ​​that are considered equivalent to the recited value (e.g., having the same function or result). In many cases, the term "about" can include values ​​that are rounded to the nearest significant figure.

[0015] The recitation of numerical ranges using endpoints includes all numbers subsumed within that range (eg, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[0016] In a first aspect, the present disclosure provides a porous membrane comprising poly(tetrafluoroethylene), wherein a) the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, wherein the monomers include monomers having an amide moiety; b) the membrane exhibits a wettability of at least about 80 dynes / cm; and c) the membrane exhibits a 60% isopropyl alcohol visualized bubble point greater than about 21 psi.

[0017] In certain embodiments, the membranes of the present disclosure exhibit deionized water flow times of about 200 to about 400 seconds per 500 ml, about 200 to about 350 seconds per 500 ml, about 250 to about 400 seconds per 500 ml, or any and all ranges therebetween.

[0018] In certain embodiments, the porous membranes of the present disclosure are from about 0.1 μm to about 0.2 μm or from about 0.15 μm to about 0.22 μm.

[0019] The membranes disclosed herein are capable of removing very small contaminants from various solutions. Example contaminants include particulates and microbial species, such as bacteria. In one embodiment, the membrane has an average pore size of no greater than approximately 0.22 μm. In other embodiments, the membrane has an average pore size of from about 0.1 to about 0.22 μm, or from about 0.15 to about 0.22 μm, or any and all ranges therebetween.

[0020] The membranes of the present disclosure can be used in any type of process requiring high-purity liquid materials. Thus, the membranes of the present disclosure can be used in a variety of applications, including, for example, liquids for semiconductor photolithography, diagnostic applications (e.g., sample preparation and / or diagnostic lateral flow devices), inkjet applications, filtering fluids for the pharmaceutical industry, filtering fluids for medical applications (e.g., intravenous applications, such as blood (e.g., leukocyte removal)), filtering fluids for the electronics and semiconductor industries, filtering fluids for the food and beverage industry, and clarifying and filtering fluids containing antibodies and / or proteins.

[0021] In one embodiment, the membranes of the present disclosure can be used to remove microbial contaminants, such as bacteria, from various solutions.

[0022] Exemplary solutions where bacterial removal is necessary and desirable include those pharmaceutical formulations designed to be administered directly to a patient (i.e., in vivo), such as via subcutaneous, intramuscular, or intravenous injection. Typically, such solutions are primarily aqueous in nature and composition, but may contain materials such as pharmaceutically acceptable carriers and / or diluents in addition to the active pharmaceutical ingredient (API) (e.g., parenteral antibiotics).

[0023] Thus, in another aspect, the present disclosure provides a method for filtering a liquid, comprising passing the liquid through a membrane of the present disclosure. In certain embodiments, the present disclosure includes a method for removing bacteria from a liquid comprising at least one active pharmaceutical ingredient (API) and one or more diluents, comprising passing the liquid solution through a membrane of the present disclosure.

[0024] In general, pharmaceutically acceptable carriers and / or diluents include any material that is generally inert, i.e., has no therapeutic effect itself, but is sufficiently non-toxic in the amounts employed in a formulation containing the active pharmaceutical ingredient. Exemplary solvents, suspending media, dispersants, carriers, and diluents are described in U.S. Patent No. 10,137,132, which is incorporated herein by reference in its entirety.

[0025] Such carriers and / or diluents include materials such as ethanol, water, glycerol, propylene glycol, glycerol, diethylene glycol, monoethyl ether, vitamin A and vitamin E oils, mineral oil, PPG2 myristyl propionate, magnesium carbonate, potassium phosphate, silicon dioxide, vegetable oils (e.g., castor oil and its derivatives), vegetable gum, gelatin, animal oil, solketal, calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, polydextrose, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar, etc.

[0026] In other embodiments, the membranes of the present disclosure can be used to filter liquid compositions used in microelectronic device fabrication, such as in photolithography. In these applications, the liquid composition includes solvents such as n-butyl acetate, isopropyl alcohol, 2-ethoxyethyl acetate, xylene, cyclohexanone, ethyl lactate, isopentyl ether, methyl 2-hydroxyisobutyrate, methyl isobutyl carbinol, methyl isobutyl ketone, isopentyl acetate, undecane, propylene glycol methyl ether, propylene glycol monomethyl ether acetate (PGMEA), and a 7:3 mixture of propylene glycol monomethyl ether and PGMEA.

[0027] As described above, porous membranes are capable of serving as sterilization membranes (i.e., bacteria removal) without excessively retaining the desired API in solution. Generally speaking, the membranes, rendered relatively hydrophilic by the coatings described herein, also offer utility in sterile filtration of aqueous liquids while not excessively retaining certain active pharmaceutical ingredients, particularly those containing ionizable nitrogen groups (e.g., quaternary ammonium groups). This hydrophilicity characteristic is quantified herein by listing the membrane's wettability. In specific embodiments, the membrane exhibits a wettability of at least about 80 dynes / cm, for example, from about 82 to about 89 dynes / cm.

[0028] As described above, the films of the present disclosure include a coating prepared from the free-radical polymerization of ethylenically unsaturated monomers, wherein the monomers include monomers having amide moieties. In certain embodiments, the incorporation of a hydrophilic coating having amide moieties is performed to provide a coating having an amide density (AD) of about 0.008 to about 0.014, or about 0.01 to about 0.013. In this regard, the amide density (AD) of the coated films of the present disclosure can be defined as AD = (number of amide moieties / monomer unit / molecular weight of monomer unit).

[0029] Exemplary monomers include those acrylates, methacrylates, and vinyl esters having an amide moiety, including, for example, ethylacrylamide, butylacrylamide, N,N-dimethylaminopropylmethacrylamide, acrylamide, methacrylamide, ethylformamide, N-(2-methoxyacrylamido-ethyl)ethylene urea, N,N-methylenebisacrylamide, and dimethylacrylamide. In other embodiments, at least about 90 mol% of the monomers have an amide moiety. In certain embodiments, the monomers are selected from N,N-methylenebisacrylamide and dimethylacrylamide, or a combination thereof. In other embodiments, the coating thus formed on the film of the present disclosure is prepared from N,N-methylenebisacrylamide and dimethylacrylamide and is used in a weight ratio of about 1:1 to about 1:4, or about 1:2.5.

[0030] As a result of sterile filtering liquid compositions containing active pharmaceutical ingredients, the porous membranes of the present disclosure are believed to be effective in retaining only a small proportion of the active pharmaceutical ingredients, particularly those containing ionizable nitrogen functional groups (e.g., quaternary ammonium groups). At the same time, the membranes of the present disclosure also produce very low amounts of extractable material from the membrane.

[0031] The membranes disclosed herein can be prepared by coating a poly(tetrafluoroethylene) membrane with an amide-functional polymer (e.g., prepared by the free radical reaction of ethylenically unsaturated monomers, at least some of which contain amide functional groups or moieties). Advantageously, one of the amide-functional monomers, a dialkylacrylamide (e.g., dimethylacrylamide), can be used in combination with a difunctional amide-functional monomer (e.g., N,N-methylenebisacrylamide). In this manner, the N,N-methylenebisacrylamide acts as a crosslinker. Generally, a monomer mixture and a free radical polymerization initiator are dissolved in an inert solvent and contacted with the poly(tetrafluoroethylene) membrane, thereby forming a polymeric coating having amide functional groups on the surface of the various poly(tetrafluoroethylene) membranes. The monomers are used in solution at a concentration of about 1 to about 20% by weight of the reactant solution. The polymerization initiator is typically present in an amount of about 0.25 to about 2.5% by weight of the reactant solution. Suitable initiators are well known and include conventional free radical initiators such as azobisisobutyronitrile (AIBN) or photoinitiators such as Irgacure 2959 (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone). Alternatively, the membrane can be immersed in the reaction solution mentioned above and exposed to ultraviolet radiation to initiate the polymerization reaction and thus the coating of the membrane.

[0032] With this coating, a hydrophobic poly(tetrafluoroethylene) membrane becomes hydrophilic through the coating process. If it is desired to reduce the proportion of amide-functional groups in the coating, other ethylenically unsaturated monomer species can be used in conjunction with the amide-functional monomer. In certain embodiments, greater than 90% of the monomers used to form the coating contain amide-functional groups or portions thereof.

[0033] The porous membranes of the present disclosure can be characterized with respect to one or more properties or performance characteristics of the membrane, such as pore size, 60% isopropyl alcohol visualized bubble point, wettability, retention of active pharmaceutical ingredients, and extractable material produced by the membrane.

[0034] The pore size can be measured by conventional techniques, such as mercury intrusion porosimetry (MP), scanning electron microscopy (SEM), liquid displacement porosimetry (LLDP), or atomic force microscopy (AFM).

[0035] Regarding the 60% isopropyl alcohol visual bubble point, this property can be measured as follows: First, a 47 mm membrane specimen is placed on a holder and the membrane is moistened with 60% IPA in water. Air pressure is then applied to the membrane until bubbles are visible from the top of the holder. This pressure is recorded as the visual bubble point (VBP). This observable VBP is related to the pore size of the membrane. In some embodiments, the VBP is greater than approximately 21 psi, 22 psi, 23 psi, 24 psi, 25 psi, or 26 psi, 27 psi, 28 psi, 29 psi, or 30 psi.

[0036] Wettability can be measured by preparing solutions corresponding to different surface tensions: 20%, 22%, 24%, 26%, and 28% NaCl solutions, and 30%, 32%, 34%, 36%, 38%, 40%, and 42% CaCl₂ solutions. Each solution corresponds to a different surface tension. Using a pipette, several drops of a solution of a specific concentration are applied to the membrane surface. If the droplets wet the membrane surface within 10 seconds, the membrane is considered wettable in the solution corresponding to the specific surface tension. In one embodiment, the membrane exhibits a wettability of at least about 80 dynes / cm, for example, from about 82 to about 89 dynes / cm.

[0037] The effectiveness of the porous membrane of the present disclosure in removing bacteria was tested according to ASTM FM838-20, a bacterial challenge test.

[0038] In the case of sterile filtration of liquid solutions designed for in vivo use, it is also important that the membrane not retain the active pharmaceutical ingredient in the liquid solution, as such a tendency would be self-defeating.

[0039] The porous membranes of the present disclosure may have any desired geometric configuration suitable for filtering liquid solutions, such as circular, semicircular, elliptical, semi-elliptical, or polygonal (e.g., square, rectangular, hexagonal, or octagonal) shapes. The porous membranes may be in the form of flat sheets, corrugated sheets, pleated sheets, hollow fibers, etc.

[0040] The porous membrane of the present disclosure can be associated with a support structure, a housing, or both. For example, the membrane can be supported by a frame, brackets, clips, a net, a mesh, a cage, and the like. In some embodiments, at least a portion of the support structure is the housing; in other embodiments, the porous membrane is unsupported.

[0041] Embodiments of the present disclosure include filtration devices and methods for removing contaminants from a liquid, wherein the liquid passes through a membrane of the present disclosure. As shown in FIG. 5 , the present disclosure provides a filter.

[0100] , which includes a porous membrane

[0102] Filter

[0100] May have a housing

[0104] , which is a filter

[0100] Provides structure and fluid sealing to the interior of the filter.

[0104] It can be of any shape and size, such as cylindrical, polygonal, etc.

[0042] A portion of the filter may include an inlet port

[0106] , to receive the liquid composition to be filtered. Inlet port

[0106] can be configured to connect to a fluid supply line. Thus, the inlet port

[0106] Valves, gaskets, etc. (not shown) may be included to facilitate connection to a fluid supply. The liquid composition to be filtered may be located at the arrow

[0116] Flow through the inlet port in the direction indicated

[0106] , and enter the filter

[0100] Head space

[0114] , the top space is such as a porous membrane Input-facing surface

[0124] ,case Inner surface and inlet port

[0106] In embodiments, the filter may be constructed so that the volume of the headspace is a desired percentage of the total internal volume of the filter.

[0043] The inner portion of the filter may include a porous membrane in any suitable arrangement or configuration, wherein FIG5 shows a porous membrane.

[0102] Porous membrane with a disc-shaped structure (cross-sectional view shown).

[0102] side

[0122] (e.g. the outer circumference of the membrane) can be connected to the housing

[0104] Internal surface contact. Porous membrane

[0102] It may also have a surface facing the input that first contacts the liquid and the surface facing the output

[0126] , the treated liquid with reduced amount of particles or bacteria flows out from the surface facing the output. The shape of the filter can be based on the porous membrane Input-facing surface

[0124] is described by the ratio range of the surface area to volume or the ratio of the surface area to thickness of the filter.

[0044] Filter

[0100] It may also include supporting a porous membrane in the filter

[0102] One or more features. Any configuration for supporting the filter may be used and may include one or more discrete structural features such as a frame, bracket, clip, net, mesh, cage, and the like, or a material such as an adhesive may be used to support the membrane. A combination of adhesives and structural support features may be used. In an embodiment and with reference to FIG5 , the filter includes a frame portion having

[0110] and

[0112] The framework, the framework part

[0110] With the housing

[0104] The inner surface contacts and is attached to the part Part Can be with porous membrane Output-facing surface

[0126] Contact and provide support for the membrane during filtration. Frame portion

[0112] It can have a grid-like structure to allow the filtered liquid to freely enter the back space of the filter

[0120] , while still providing structural support for the porous membrane under increased fluid pressure.

[0045] In use, liquid passes through the inlet port

[0106]

[0116] Enter the filter in the direction indicated and then fill the filter

[0100] Head space inside

[0114] Sufficient fluid pressure is applied to move the fluid through the porous membrane at the desired flow rate.

[0046] Example-

[0047] Example 1

[0048] This example demonstrates how a porous polytetrafluoroethylene (PTFE) membrane can be surface modified using a hydrophilic coating of a polymerized monomer having amide groups.

[0049] A surface modification monomer solution was prepared, comprising: 0.3% Irgacure 2959 (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone); 10% methanol; 1.71% dimethylacrylamide (DMAM); 0.69% N,N-methylenebisacrylamide (MBAM); and 87.3% deionized water.

[0050] A hydrophilic PTFE membrane was prepared using the following method. First, a 47 mm disc of porous PTFE membrane (60 μm thick, 0.15-0.2 μm pore size) was wetted with an isopropyl alcohol (IPA) solution for 25 seconds. The membrane was then rinsed with an exchange solution containing 10% hexylene glycol and 90% water to remove the IPA. The porous membrane disc was then introduced into a surface-modifying monomer solution and kept submerged for 2 minutes. The porous membrane disc was removed from the surface-modifying monomer solution and placed between transparent polyethylene sheets. Any excess solution was removed by rolling a rubber roller over the polyethylene / membrane disc / polyethylene sandwich while it lay flat on a table. The polyethylene sandwich was then bonded to a transport unit that transported the assembly through a Fusion Systems broadband UV exposure lab unit emitting at wavelengths between 200 and 600 nm. Exposure time was controlled by the speed at which the assembly moved through the UV unit. In this example, the assembly moved through the UV chamber at 10 ft / min. After exiting the UV unit, the membrane was removed from the sandwich and immediately placed in DI water, where it was immersed for 5 minutes. The treated membrane sample was then transferred to methanol and allowed to soak for 5 minutes. Following this soaking procedure, the membrane was dried on a holder in an oven operated at 50°C for 10 minutes. The water flow time for the membrane modified as described above was 300 seconds per 500 mL. The resulting membrane was hydrophilic and spontaneously wetted when immersed in DI water.

[0051] Bacterial challenge test

[0052] The bacterial retention test is based on ASTM FM838-20.

[0053] The pressure vessel and upstream connecting pipes do not require autoclaving, but should be thoroughly cleaned, disinfected, and rinsed with sterile water before testing. The vessel can be disinfected with a 0.005% sodium hypochlorite solution prepared by diluting a 1:999 5% sodium hypochlorite solution, or with 70% ethanol, drained, and thoroughly rinsed with sterile water. Two sets of membranes of the present disclosure were installed in a test analytical filter assembly and then autoclaved at 121°C for 30 minutes. One set was used as is, while the other set was treated with the test product liquid at 38°C for 18 hours.

[0054] The pre-test bubble point of the membrane was collected using an automated integrity tester. Sterile 0.9% NaCl solution was added to the pressure vessel to wet the test membrane. Then, 20-50 mL of filtrate was collected downstream through the analytical membrane, which served as a negative control.

[0055] For the positive control test, a 0.45 μm positive control filter element (filter membrane or filter assembly) was tested for bacterial retention at a challenge level of no less than 1 × 107 cfu / cm2. The positive control sample was collected downstream of the control analytical filter assembly using an analytical membrane. The membranes of the present disclosure were subjected to bacterial retention using a 0.9% sterile NaCl solution inoculated with Brevundimonas diminuta at room temperature. The test sample was collected downstream of the test filter assembly using an analytical membrane. After the test challenge, the analytical membranes were aseptically transferred to PCA plates and incubated at 30 ± 2°C. Colony counts were then recorded at 72 hours and 7 days for the negative control analytical membranes, 48 ​​hours and 7 days for the test analytical membranes, and 48 hours for the positive control analytical membranes. The post-test membranes were then autoclaved at 121°C for 30 minutes. The membrane bubble point was then measured using an automated integrity tester as the post-test bubble point.

[0056] Table 1 below summarizes the average membrane bacterial challenge test results and shows that all tested membranes of the present disclosure can retain a Brevundimonas parvum challenge at a level of >10 7 cfu / cm 2 EFA after one autoclave cycle at 121° C. for 30 minutes.

[0057] Table 1 Examples Pressure test conditions (bar) flow rate (2-4 mL / min / cm2) Bacterial concentration Pass / Fail 1 2.0 2.35 1.3 × 10 8 pass 2.0 2.34 1.3 × 10 8 pass 2.0 3.02 1.3 × 10 8 pass 2 2.0 3.11 1.3 × 10 8 pass 2.0 2.65 1.3 × 10 8 pass 2.0 2.54 1.3 × 10 8 pass 3 2.0 3.16 1.3 × 10 8 pass 2.0 3.46 1.3 × 10 8 pass 2.0 3.08 1.3 × 10 8 pass 4 2.0 2.49 1.3 × 10 8 pass 2.0 3.11 1.3 × 10 8 pass 2.0 3.96 1.3 × 10 8 pass

[0058] Wettability test

[0059] Solutions corresponding to different surface tensions were prepared: 20%, 22%, 24%, 26%, and 28% NaCl solutions, and 30%, 32%, 34%, 36%, 38%, 40%, and 42% CaCl₂ solutions. Each solution corresponds to a different surface tension, as listed in Table 2 below. A pipette was used to deposit several drops of a solution of a specific concentration onto the membrane surface. If the droplet wetted the membrane surface within 10 seconds, the membrane was considered wettable in the solution corresponding to the specific surface tension. Figure 1 shows that the wettability of the membrane of the present disclosure (A) is greater than that of a commercial membrane (B), a Cobetter hydrophilic PTFE membrane with a pore size of 0.2 µm. As can be seen, the membrane of the present disclosure can have a wettability of at least approximately 80 dynes / cm⁻¹.

[0060] Table 2 % NaCl Dyne / cm 1.46 73 4.12 74 6.78 75 9.48 76 12.11 77 14.77 78 17.43 79 20.09 80 22.75 81 25.42 82 26.5 83 %CaCl 2 Dyne / cm 32.18 87 33.4 88 34.6 89 35.9 90 38.44 92 42.25 95 42.47 96 44 100

[0061] 60% IPA visual BP test

[0062] First, a 47 mm membrane specimen was placed on a holder and the membrane was moistened with 60% IPA (isopropyl alcohol) in water. Air pressure was then applied to the membrane until bubbles could be seen from the top of the holder. This pressure was recorded as the visual bubble point (VBP). Figure 2 shows that the 60% IPA VBP of the membrane of the present disclosure (A) is less than that of the Cobetter hydrophilic PTFE membrane with a pore size of approximately 0.2 μm (B). As can be seen, the membrane of the present disclosure can have a 60% IPA VBP greater than approximately 21 psi.

[0063] Water flow time test

[0064] Deionized water (DIW) flow time is measured in a DIW flow tester, which records the time it takes for 500 mL of DIW to flow through a 47 mm membrane specimen. Figure 3 shows that the membranes of the present disclosure exhibit DIW flow times greater than those of a commercially available PTFE membrane, namely, Cobetter hydrophilic PTFE membrane with a pore size of 0.2 µm. As can be seen, the membranes of the present disclosure can exhibit DIW flow times ranging from approximately 200 to approximately 400 seconds per 500 ml.

[0065] Extractable Materials Testing

[0066] The membrane was placed in a drum and extracted in 50% ethanol at 80°C for 24 hours while stirring with a magnetic stir bar at 50 rpm. The extractable test results, illustrated in Table 3 below, include non-volatile residue (NVR), UV, pH, LC, GC-MS, and ICP-MS measurements. In Table 3, NMT means not more than.

[0067] NVR of membranes A and B, each measuring 30 cm x 30 cm, was extracted in 250 mL of 100% isopropyl alcohol for 24 hours. The membrane of the present disclosure (A) showed a lower NVR (0.15 mg / g) compared to membrane B (0.26 mg / g).

[0068] Table 3 Extraction solution Extraction conditions Test items data Acceptance Criteria in conclusion 50% ethanol in water 80℃, 24 hours, stirring at 50 rpm NVR 53.2 mg / pc For reference NA pH changes 0.54 NMT 2 pass UV The wavelength is between 210 and 300 nm, and the maximum absorbance is 0.65 Au For reference NA Elemental compounds, by ICP-MS Max 0.00003 µg / g NMT 0.1 µg / day pass Organic compounds, by HPLC, LC-MS, GC-MS Compounds with suspected genotoxic risk Max 0.01 µg / day NMT 1.5 µg / day pass Compounds without genotoxicity risk Max 0.5 µg / day NMT 50 µg / day pass Unknown compound Based on its matching spectra, it was identified as non-genotoxic. Max 0.7 µg / day NMT 50 µg / day pass

[0069] Attitude

[0070] In a first aspect, the present disclosure provides a porous membrane comprising poly(tetrafluoroethylene), wherein a) the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, wherein the monomers include monomers having an amide moiety; b) the membrane exhibits a wettability of at least about 80 dynes / cm; and c) the membrane exhibits a 60% isopropyl alcohol visualized bubble point greater than about 21 psi.

[0071] In a second aspect, the present disclosure provides the porous membrane of the first aspect, wherein the membrane exhibits a deionized water flow time of about 200 to about 400 seconds per 500 ml.

[0072] In a third aspect, the present disclosure provides the porous membrane of the first aspect, wherein the average pore size of the membrane is from about 0.1 μm to about 0.2 μm.

[0073] In a fourth aspect, the present disclosure provides the porous membrane of the first or second aspect, wherein the average pore size of the membrane is from about 0.15 μm to about 0.22 μm.

[0074] In a fifth aspect, the present disclosure provides the film of any one of the first to fourth aspects, wherein the film exhibits a wettability of about 82 to about 89 dynes / cm.

[0075] In a sixth aspect, the present disclosure provides the film of any one of the first to fifth aspects, wherein the coating has an amide density (AD) of about 0.008 to about 0.014.

[0076] In a seventh aspect, the present disclosure provides the membrane of any one of the first to sixth aspects, wherein the monomers having an amide moiety are selected from the group consisting of ethylacrylamide, butylacrylamide, N,N-dimethylaminopropylmethacrylamide, acrylamide, methacrylamide, ethylformamide, N-(2-methoxyacrylamido-ethyl)ethylene urea, N,N-methylenebisacrylamide, dimethylacrylamide, and combinations thereof.

[0077] In an eighth aspect, the present disclosure provides the membrane of any one of the first to seventh aspects, wherein the monomers having an amide moiety are selected from the group consisting of N,N-methylenebisacrylamide, dimethylacrylamide, and combinations thereof.

[0078] In a ninth aspect, the present disclosure provides the membrane of any one of the first to eighth aspects, wherein at least about 90 mol% of the monomers have an amide moiety.

[0079] In a tenth aspect, the present disclosure provides the film of the eighth aspect, wherein the N,N-methylenebisacrylamide and dimethylacrylamide are used in a weight ratio of about 1:1 to about 1:4.

[0080] In an eleventh aspect, the present disclosure provides the film of any one of the first to tenth aspects, wherein the coating has an amide density (AD) of about 0.010 to about 0.013.

[0081] In a twelfth aspect, the present disclosure provides a filter comprising the membrane of any one of the first to eleventh aspects.

[0082] In a thirteenth aspect, the present disclosure provides a method of filtering a liquid, comprising passing the liquid through the membrane of any one of the first to eleventh aspects or the filter of the twelfth aspect.

[0083] In a fourteenth aspect, the present disclosure provides the method of the thirteenth aspect, wherein the liquid comprises one or more of the following: n-butyl acetate, isopropyl alcohol, 2-ethoxyethyl acetate, xylene, cyclohexanone, ethyl lactate, isopentyl ether, methyl 2-hydroxyisobutyrate, methyl isobutyl carbinol, methyl isobutyl ketone, isopentyl acetate, undecane, propylene glycol methyl ether, propylene glycol monomethyl ether acetate, and a mixed solution of propylene glycol monomethyl ether and propylene glycol monomethyl ether acetate.

[0084] In a fifteenth aspect, the present disclosure provides a method for removing bacteria from a liquid comprising at least one active pharmaceutical ingredient and one or more carriers and / or diluents, comprising passing the liquid through the membrane of any one of the first to eleventh aspects or the filter of the twelfth aspect.

[0085] In a sixteenth aspect, the present disclosure provides the method of the fifteenth aspect, wherein the liquid comprises water.

[0086] In a seventeenth aspect, the present disclosure provides the method of the sixteenth aspect, wherein the liquid further comprises one or more glycols or alcohols.

[0087] In an eighteenth aspect, the present disclosure provides the method of the seventeenth aspect, wherein the liquid further comprises one or more of propylene glycol, glycerol, a C 1 -C 4 alcohol, or a combination thereof.

[0088] In a nineteenth aspect, the present disclosure provides the method of the eighteenth aspect, wherein the liquid comprises water and at least one glycol selected from propylene glycol and glycerin.

[0089] Having thus described several illustrative embodiments of the present disclosure, one skilled in the art will readily understand that still other embodiments may be made and used within the scope of the appended claims. The many advantages of the present disclosure encompassed herein have been explained in the foregoing description. However, it should be understood that this disclosure is, in many aspects, merely illustrative. The scope of the present disclosure is, of course, defined by the language expressing the appended claims.

[0090] 100:Filter 102:Porous membrane 104: Shell 106: Entry Port 110:Framework 112:Frame part / part 114: Headspace 116: Arrow 120: back space 122: Side 124: Input-facing surface 126: Output-facing surface

Claims

1. A porous membrane for removing microbial particles, the porous membrane comprising poly(tetrafluoroethylene), wherein: a) The porous membrane is at least partially directly coated with a polymer prepared by a free radical reaction of an alkenyl unsaturated monomer, wherein the monomers include monomers having an amide moiety; b) The porous membrane exhibits a wettability of at least about 80 dynes / cm; and c) The porous membrane exhibits a visible bubble point of 60% isopropanol greater than about 21 psi, wherein the average pore size of the porous membrane is about 0.1 µm to about 0.22 µm, wherein the amide moiety is a combination of monomeric N,N-methylenebisacrylamide and dimethacrylamide, and wherein the N,N-methylenebisacrylamide and dimethacrylamide are used in a weight ratio of about 1:1 to about 1:

4.

2. The porous membrane of claim 1, wherein the porous membrane exhibits a deionized water flow time of approximately 200 to approximately 400 seconds / 500 ml.

3. The porous membrane of claim 1, wherein the average pore size of the porous membrane is about 0.15 µm to about 0.22 µm.

4. The porous membrane of claim 1, wherein the porous membrane exhibits wettability of about 82 to about 89 dynes / cm.

5. A porous membrane as claimed in any of claims 1 to 4, wherein at least about 90 mol% of the monomers have an amide moiety.

6. A filter comprising a porous membrane as claimed in any one of claims 1 to 5.

7. A method of filtering a liquid, comprising passing the liquid through a porous membrane as claimed in any one of claims 1 to 5.

8. The method of claim 7, wherein the liquid comprises one or more of the following: n-butyl acetate, isopropanol, 2-ethoxyethyl acetate, xylene, cyclohexanone, ethyl lactate, isopentyl ether, methyl-2-hydroxyisobutyrate, methyl isobutyl methanol, methyl isobutyl ketone, isopentyl acetate, undecane, propylene glycol methyl ether, propylene glycol monomethyl ether acetate, and a mixture of propylene glycol monomethyl ether and propylene glycol monomethyl ether acetate.

9. A method for removing bacteria from a liquid containing at least one active pharmaceutical ingredient and one or more carriers and / or diluents, the method comprising passing the liquid through a porous membrane as claimed in any one of claims 1 to 5.

10. The method of claim 9, wherein the liquid comprises water.

11. The method of claim 10, wherein the liquid further comprises one or more alcohols.

12. The method of claim 10, wherein the liquid further comprises one or more of propylene glycol, glycerol, C1-C4 alcohols or combinations thereof.

13. The method of claim 10, wherein the liquid comprises water and at least one alcohol selected from propylene glycol and glycerol.

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