Hydrophilic Membranes for Filtration

Abstract

The present disclosure provides a porous membrane that can remove very small particulates from a liquid composition. In certain embodiments, the porous membrane comprises poly(tetrafluoroethylene), and the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, the monomers being composed of monomers having amide moieties. In certain embodiments, the membrane can remove microbial particles such as bacteria by filtration, thus making the resulting liquid composition essentially sterile.

Description

[Technical field]

[0001] FIELD OF THE DISCLOSURE This disclosure relates generally to hydrophilically modified porous membranes, such as filter membranes, and methods of using such membranes for the removal of very small particulate and / or microbial species from liquid compositions. [Background technology]

[0002] Filters are used to remove unwanted materials from streams of useful liquid solutions and are an important feature in a wide variety of technologies. Liquid solutions that are 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 uses. Undesirable materials removed from fluids include impurities and contaminants such as particles, microorganisms, and dissolved chemical species. Specific examples of filter applications include the sterile filtration of liquid solutions intended for introduction into the human body, as well as use with liquid materials for semiconductor and microelectronic device manufacturing.

[0003] Filters can remove unwanted materials by a variety of different methods, such as by size exclusion or by chemical and / or physical interaction with materials. Some filters are defined by the structural material that provides the filter with a porous structure, and the filter can capture particles that are too large to pass through the pores. Some filters are defined by the structural material of the filter, or the ability of the chemical properties associated with the structural material to bind and interact with substances passing over the filter. For example, the chemical characteristics of the filter can allow for association with unwanted materials from the stream passing over the filter, and capture those unwanted materials, for example, by ionic, coordination, chelating, or hydrogen bonding interactions. Some filters can utilize both size exclusion and chemical interaction characteristics to remove materials from the stream being filtered.

[0004] In some cases, to perform the filtering function, the filter includes a filter membrane, which serves to remove undesirable materials from the fluid passing through. The filter membrane may be in the form of a flat sheet, which may be wound (e.g., spirally wound), flat, pleated, or disk-shaped, as appropriate. Alternatively, the filter membrane may be in the form of a hollow fiber. The filter membrane may be contained within a housing or otherwise supported such that the fluid being filtered is required to enter through the filter inlet, pass through the filter membrane, and then pass through the filter outlet.

[0005] Certain filters are capable of removing very small particulate matter and microbial contaminants such as bacteria, thus rendering the filtered liquid solution essentially sterile. In such applications, it is also essential that the filter media or membrane perform such that very small amounts of extractable or leachable materials are found to leach out of the filter, which could otherwise contaminate the filtered liquid solution. Furthermore, in the case of sterile filtration, it is also essential that the filter does 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 a porous membrane that can remove very small particulates from liquid compositions.In certain embodiments, the porous membrane comprises poly(tetrafluoroethylene), a) the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, the monomers being composed of monomers having amide moieties; b) the membrane exhibits a wettability of at least about 80 Dynes / cm; and c) the membrane exhibits a 60% isopropanol visual bubble point of 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 can remove microbial particles such as bacteria by filtration, thus rendering the resulting liquid composition essentially 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(s) contained therein, particularly active pharmaceutical ingredient(s) having an ionizable nitrogen group such as a quaternary ammonium group. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 is a plot of wettability (Dynes / cm) comparing a membrane of the present disclosure (A) versus a commercially available membrane (B) Covetter hydrophilic PTFE with 0.2 μm pore size. [Diagram 2] FIG. 1 is a comparison of 60% isopropanol visual bubble point (psi (pounds per square inch)) for a membrane of the present disclosure (A) versus a commercially available membrane (B) Covetter hydrophilic PTFE with 0.2 μm pore size. [Diagram 3] FIG. 1 is a comparison of deionized water (DIW) flow time of a membrane of the present disclosure (A) versus a commercially available membrane (B) Coveter hydrophilic PTFE with a pore size of about 0.2 μm. [Figure 4] FIG. 1 shows NVR (non-volatile residue) data for a membrane of the present disclosure (A) versus a commercially available membrane (B) Covetter hydrophilic PTFE with pore size of about 0.2 μm. [Diagram 5] FIG. 1 is a diagram of an exemplary filter device comprising a membrane of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise.

[0010] The term "about" generally refers to a range of numbers that are considered equivalent to the stated value (e.g., having the same function or result). In many cases, the term "about" may include numbers that are rounded to the nearest significant figure.

[0011] Numeric ranges expressed using endpoints include all numbers subsumed within that range (eg, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[0012] In a first aspect, the disclosure provides a porous membrane comprising poly(tetrafluoroethylene), where a) the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, the monomers being composed of monomers having amide moieties; b) the membrane exhibits a wettability of at least about 80 Dynes / cm; and c) the membrane exhibits a 60% isopropanol visual bubble point of greater than about 21 psi.

[0013] In certain embodiments, the membranes of the present disclosure exhibit deionized water flux 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.

[0014] 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.

[0015] The membranes of the present disclosure are capable of removing extremely small contaminants from a variety of solutions. Exemplary contaminants include particulates and microbial species such as bacteria. In one embodiment, the average pore size of the membrane is about 0.22 μm or less. In other embodiments, the average pore size of the membrane is about 0.1 to about 0.22 μm or about 0.15 μm to about 0.22 μm or any range therebetween.

[0016] The membranes of the present disclosure are useful in any type of process that requires high purity liquid materials.Thus, the membranes of the present disclosure are useful in a variety of applications, including, for example, liquids used in semiconductor photolithography, diagnostic applications (e.g., sample preparation and / or diagnostic lateral flow devices), inkjet applications, filtration of fluids for the pharmaceutical industry, filtration of fluids for medical applications, intravenous applications such as blood (e.g., removal of white blood cells), filtration of fluids for the electronics and semiconductor industries, filtration, clarification of fluids for the food and beverage industry, and filtration of antibody and / or protein-containing fluids.

[0017] In one embodiment, the membranes of the present disclosure are useful for removing microbial contaminants, such as bacteria, from a variety of solutions.

[0018] Exemplary solutions in which removal of bacteria is necessary and desirable include pharmaceutical formulations designed to be administered directly to a patient (i.e., in vivo), for example, by subcutaneous, intramuscular, or intravenous injection. Often, these solutions are primarily aqueous in nature and composition, but may also contain materials such as pharma- ceutical acceptable carriers and / or diluents in addition to the active pharmaceutical ingredient (API) (such as a parenteral antibiotic).

[0019] Thus, in a further aspect, the present disclosure provides a method of filtering a liquid, the method comprising passing the liquid through a membrane of the present disclosure. In certain embodiments, the present disclosure includes a method of removing bacteria from a liquid comprising at least one active pharmaceutical ingredient (API) and one or more diluents, the method comprising passing the liquid solution through a membrane of the present disclosure.

[0020] In general, pharma- ceutically acceptable carriers and / or diluents include any material that is generally inert, i.e., has no therapeutic effect by itself, but is sufficiently non-toxic in the amounts employed in formulations containing active pharmaceutical ingredients. Exemplary solvents, suspension media, dispersants, carriers and diluents, etc., can be found in U.S. Patent No. 10,137,132, the entirety of which is incorporated herein by reference.

[0021] Such carriers and / or diluents include materials such as ethanol, water, glycerol, propylene glycol, glycerin, diethylene glycol, monoethyl ether, vitamin A and vitamin E oils, mineral oil, PPG2 myristyl propionate, magnesium carbonate, potassium phosphate, silicon dioxide, vegetable oils such as castor oil and its derivatives, vegetable gums, gelatin, animal oils, solketal, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextran, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugars, and the like.

[0022] In other embodiments, the membranes of the present disclosure are useful for filtering liquid compositions used in the manufacture of microelectronic devices, such as photolithography. In such applications, the liquid compositions include 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, isoamyl acetate, undecane, propylene glycol methyl ether, propylene glycol monomethyl ether acetate (PGMEA), and a mixture of propylene glycol monomethyl ether and PGMEA (7:3).

[0023] As noted above, the porous membrane can function as a sterilizing membrane (i.e., bacteria removal) without undue retention of the desired API in solution. In general, the membrane is rendered relatively hydrophilic by the coatings described herein, thus also rendering it useful for the sterile filtration of aqueous-based liquids without undue retention of certain active pharmaceutical ingredients, particularly those containing ionizable nitrogen groups such as quaternary ammonium groups. This hydrophilic property is quantified herein by a description of the wettability of the membrane. In certain embodiments, the membrane exhibits a wettability of at least about 80 Dynes / cm, e.g., from about 82 to about 89 Dynes / cm.

[0024] As described above, the membrane of the present disclosure includes a coating prepared from free radical polymerization of ethylenically unsaturated monomers, the monomers including 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 membrane of the present disclosure can be defined as AD=(number of amide moieties per monomer unit per molecular weight of the monomer unit).

[0025] Exemplary monomers include acrylic acid esters, methacrylic acid esters, and vinyl esters having an amide moiety, such as ethylacrylamide, butylacrylamide, N,N-dimethylaminopropylmethacrylamide, acrylamide, methacrylamide, ethylformamide, N-(2-methoxyacrylamido-ethyl)ethyleneurea, N,N-methylenebisacrylamide, and dimethylacrylamide. In other embodiments, at least about 90 mole percent of the monomers have an amide moiety. In certain embodiments, the monomers are selected from N,N-methylenebisacrylamide and dimethylacrylamide, or combinations thereof. In other embodiments, the coating so formed on the membrane of the present disclosure is prepared from N,N-methylenebisacrylamide and dimethylacrylamide, used in a weight ratio of about 1:1 to about 1:4, or about 1:2.5.

[0026] As a result of the sterile filtration of liquid compositions containing active pharmaceutical ingredients, the porous membranes of the present disclosure are believed to be effective in retaining only small percentages of such active pharmaceutical ingredients, especially those containing ionizable nitrogen functional groups such as quaternary ammonium groups, while also producing very small amounts of extractable material from the membrane.

[0027] The membranes of the present disclosure can be prepared by coating a poly(tetrafluoroethylene) membrane with an amide-functional polymer, such as one prepared by free radical reaction of ethylenically unsaturated monomers, at least some of which contain amide functionality or moieties. Advantageously, one such amide-functional monomer, such as a dialkylacrylamide, such as dimethylacrylamide, may be utilized in conjunction with a difunctional amide-functional monomer, such as N,N-methylenebisacrylamide. Thus, in this manner, the N,N-methylenebisacrylamide serves the function of a crosslinker. Generally, a mixture of monomers is dissolved in an inert solvent along with a free radical polymerization initiator and contacted with the poly(tetrafluoroethylene) membrane, thereby forming a polymer coating having amide functionality on the various surfaces of the poly(tetrafluoroethylene) membrane. The monomers are generally utilized in solution at a concentration of about 1 to about 20 percent (by weight) of the reactant solution. The polymerization initiator is generally present in an amount of about 0.25 to about 2.5 percent (by weight) of the reactant solution. Suitable initiators are well known and include common 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 and irradiated with ultraviolet light to initiate the polymerization reaction and thus the coating of the membrane.

[0028] This coating renders the hydrophobic poly(tetrafluoroethylene) membrane hydrophilic through this coating process. If it is desired to reduce the proportion of amide functionality on the coating, other ethylenically unsaturated monomer species may be utilized along with the amide functional monomers. In certain embodiments, greater than 90% of the monomers utilized to form the coating are monomers that contain amide functionality or moieties.

[0029] The porous membranes of the present disclosure may be characterized with reference to one or more attributes or performance properties of the membrane, such as pore size, 60% isopropanol visual bubble point, wettability, retention of active pharmaceutical ingredient(s), and extractable materials produced by the membrane.

[0030] Pore ​​size can be measured by known techniques such as mercury polysometry (MP), scanning electron microscopy (SEM), liquid displacement spectroscopy (LLDP), or atomic force microscopy (AFM).

[0031] With regard to 60% isopropanol visual bubble point, this property can be measured in the following manner: First, a 47 mm membrane coupon is placed in a holder and the membrane is wetted with a 60% IPA aqueous solution. Air pressure is then applied to the membrane until air bubbles are visible from the top of the holder. The pressure is recorded as the visual bubble point (VBP). This observable VBP correlates with the pore size of the membrane. In some embodiments, the VBP is greater than about 21 psi, 22 psi, 23 psi, 24 psi, 25 psi, or 26 psi, 27 psi, 28 psi, 29 psi, or 30 psi.

[0032] Regarding wettability, this property can be measured in the following way: with different surface tensions 20%, 22%, 24%, 26%, 28% NaCl solutions, and with 30%, 32%, 34%, 36%, 38%, 40%, 42% CaCl 2 Solutions corresponding to the solutions are prepared. Each solution corresponds to a different surface tension. Using a transfer pipette, a few drops of the solution of a particular concentration are placed on the surface of the membrane. If the drop wets the membrane surface within 10 seconds, the membrane was considered to be 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, about 82 to about 89 Dynes / cm.

[0033] The effectiveness of the porous membrane of the present disclosure in aiding in the removal of bacteria is measured using a bacterial challenge test according to ASTM FM838-20.

[0034] Also important in the case of sterile filtration of liquid solutions designed for in vivo use is the ability of the membrane not to retain the active pharmaceutical ingredient in the liquid solution, and such tendency is self-limiting.

[0035] The porous membranes of the present disclosure can be of any desired geometric configuration suitable for filtering liquid solutions, for example, circular, semicircular, elliptical, semi-elliptical, or polygonal, such as square, rectangular, hexagonal, or octagonal. The porous membranes can be in the form of flat sheets, corrugated sheets, pleated sheets, hollow fibers, and the like.

[0036] The porous membranes of the present disclosure can be associated with a support structure, a housing, or both. For example, the membranes can be supported by a frame, brackets, clips, webs, nets, cages, etc. In some embodiments, at least a portion of the support structure is a housing. In other embodiments, the porous membranes are unsupported.

[0037] One embodiment of the present disclosure includes a filter device and method for removing contaminants from a liquid, the liquid passing through a membrane of the present disclosure. As shown in FIG. 5, the present disclosure provides a filter 100 including a porous membrane 102. The filter 100 can have a housing 104 that provides structure to the filter 100 and fluidically seals the interior portion of the filter. The housing 104 can be of any shape and size, such as cylindrical, polygonal, etc.

[0038] A portion of the filter can include an inlet port 106 for receiving a liquid composition to be filtered. The inlet port 106 can be configured to be connected to a fluid supply line. Thus, the inlet port 106 can include a valve, gasket, or the like (not shown) to facilitate connection to a fluid supply. The liquid composition to be filtered can flow through the inlet port 106 in the direction indicated by arrow 116 and into a headspace 114 of the filter 100, which is defined by the input-facing surface 124 of the porous membrane 102, the inner surface of the housing 104, and the inlet port 106. In an embodiment, the filter can be constructed such that the headspace has a volume that is a desired percentage of the total internal volume of the filter.

[0039] The interior portion of the filter can include a porous membrane in any suitable arrangement or configuration, and FIG. 5 illustrates a porous membrane 102 having a disk-like structure (cross-section shown). A side 122 of the porous membrane 102, such as the membrane's periphery, can be in contact with the inside surface of the housing 104. The porous membrane 102 can also have an input-facing surface 124 that first contacts the liquid, and an output-facing surface 126 through which the treated liquid flows out having a reduced amount of particulate or bacterial flux. Embodiments of the filter can optionally be described in terms of a range of ratios of the surface area of ​​the input-facing surface 124 to the volume of the porous membrane 102, or a range of ratios of the surface area to the thickness of the filter.

[0040] The filter 100 may also include one or more features that support the porous membrane 102 within the filter. Any configuration for supporting the filter may be used, and one or more separate structural features such as frames, brackets, clips, webs, nets, cages, and the like, or materials such as adhesives may be used to support the membrane. A combination of adhesives and structural support features may be used. In one embodiment, referring to FIG. 5, the filter includes a frame having frame portions 110 and 112, where the frame portion 110 is in contact with the inner surface of the housing 104 attached to the portion 112. The portion 112 may be in contact with the output-facing surface 124 of the porous membrane 102 and may support the membrane during filtration. The frame portion 112 may have a grid-like structure that provides structural support to the porous membrane under increased fluid pressure while allowing filtered liquid to pass freely into the backspace 120 of the filter.

[0041] In use, liquid enters the filter through inlet port 106 in the direction indicated by arrow 116 and then fills the headspace 114 within filter 100. Sufficient fluid pressure is applied to move the fluid through the porous membrane at a desired flow rate. EXAMPLES

[0042] Example 1

[0043] This example demonstrates how a porous polytetrafluoroethylene (PTFE) membrane can be surface modified with a hydrophilic coating having polymerized monomers with amide groups.

[0044] Prepare a surface modification monomer solution containing: 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.

[0045] Hydrophilic PTFE membranes were made in the following manner. First, a 47 mm disk of PTFE porous membrane (60 um thick, pore size 0.15-0.2 μm) was wetted with an isopropanol (IPA) solution for 25 seconds. The membrane was then rinsed using an exchange solution containing 10% hexylene glycol and 90% water to remove the IPA. The porous membrane disk was then introduced into the surface modification monomer solution and left submerged for 2 minutes. The porous membrane disk was removed from the surface modification monomer solution and placed between clear polyethylene sheets. The polyethylene / membrane disk / polyethylene sandwich was placed flat on a table and any excess solution was removed by rolling a rubber roller over the sandwich. The polyethylene sandwich was then taped to a transport unit and the assembly was transported into a Fusion Systems broadband UV exposure lab unit emitting light at wavelengths from 200 to 600 nm. The speed at which the assembly moved through the UV unit controlled the time of exposure. In this example, the assembly moved through the UV chamber at 10 feet per minute. After emerging from the UV unit, the membrane was removed from the sandwich and immediately placed in DI water and allowed to soak 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 allowed to dry for 10 minutes on a holder in an oven operating at 50 °C. The water flow time for the membrane modified as above was 300 seconds / 500 mL. The resulting membrane was hydrophilic and spontaneously wetted when submerged in deionized water.

[0046] Bacterial challenge test

[0047] The bacterial retention test is based on ASTM FM838-20.

[0048] The pressure vessel and upstream connecting tubing do not need to be autoclaved, but should be thoroughly cleaned, disinfected, and flushed with sterile pure water before testing. The vessel may be disinfected with 5% sodium hypochlorite solution or 0.005% sodium hypochlorite solution made of 1:999 dilution of 70% ethanol, drained, and thoroughly rinsed with sterile pure water. Two groups of membranes of the present disclosure were placed in a test analytical filter assembly and then autoclaved at 121°C for 30 minutes. One group was used as is, and the other group was treated with test product liquid at 38°C for 18 hours.

[0049] The pre-test bubble points of the membranes were 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 from downstream by the analytical membrane as a negative control analytical membrane.

[0050] For the positive control test, a bacterial retention test should be performed on a 0.45 μm positive control filter cartridge (filter membrane or filter assembly) with a loading level of 1 × 10 7 cfu / cm 2 It should be equal to or greater than 100%. A positive control sample was collected from the downstream control analytical filter assembly using the analytical membrane. At room temperature, the membrane of the present disclosure was subjected to bacterial retention using a sterile 0.9% NaCl solution inoculated with B. diminuta. A test sample was collected from the downstream test filter assembly using the analytical membrane. After test loading, the analytical membrane was aseptically transferred to a PCA plate and incubated at 30±2°C. The colony count of the negative control analytical membrane was then recorded at 72 hours and 7 days, the colony count of the test analytical membrane was recorded at 48 hours and 7 days, and the colony count of the positive control analytical membrane was recorded at 48 hours. The post-test membrane was then autoclaved at 121°C for 30 minutes. The bubble point of the test membrane was then measured as the post-test bubble point using an automatic integrity tester.

[0051] Table 1 below summarizes the average membrane bacterial challenge test results, showing that after one autoclave cycle at 121° C. for 30 minutes, all test membranes of the present disclosure survived 10% to 20% of B. diminuta. 7 cfu / cm 2 This shows that it is possible to maintain an EFA level load of over 1000 mg / kg.

[0052] Table 1 TIFF2025517348000002.tif71170

[0053] Wettability Test

[0054] Different surface tensions of 20%, 22%, 24%, 26%, 28% NaCl solutions and 30%, 32%, 34%, 36%, 38%, 40%, 42% CaCl 2 Prepare solutions corresponding to the specific surface tensions. Each solution corresponds to a different surface tension, as listed in Table 2 below. Using a transfer pipette, several drops of the solution of a particular concentration were dropped onto the surface of the membrane. If the drop wets the membrane surface within 10 seconds, the membrane was considered to be 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 the commercially available membrane (B) Coveter 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 about 80 Dynes / cm.

[0055] Table 2 TIFF2025517348000003.tif122170

[0056] 60% IPA Visual BP Test

[0057] First, a 47 mm membrane coupon was placed in a holder and the membrane was wetted with 60% IPA (isopropanol) water solution. Air pressure was applied to the membrane until air bubbles were visible from the top of the holder. The pressure was recorded as visual bubble point (VBP). Figure 2 shows that the 60% IPA VBP of the membrane of the present disclosure (A) is smaller than the Coveter hydrophilic PTFE membrane (B) with a pore size of about 0.2 μm. As can be seen, the membrane of the present disclosure can have a 60% IPA VBP of more than about 21 psi.

[0058] Water flow time test

[0059] The flow time of deionized water (DIW) was tested with a DIW flow tester that records the time to flow 500 mL of DIW through a 47 mm membrane coupon. Figure 3 shows that the DIW flow time of the membrane of the present disclosure is longer than that of a commercial PTFE membrane Coveter hydrophilic PTFE membrane with a pore size of 0.2 μm. As can be seen, the membrane of the present disclosure can have a DIW flow time in the range of about 200 to about 400 seconds per 500 ml.

[0060] Extractable Material Testing

[0061] The membranes were placed in a cartridge device and extracted in 50% ethanol at 80° C. for 24 hours with stirring at 50 rpm using a magnetic stir bar. The extractable test results shown in Table 3 below include non-volatile residue (NVR), UV, pH, LC, GC-MS and ICP-MS measurements. In Table 3, "NMT" means "no more than."

[0062] The NVR test of membranes A and B with a size of 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).

[0063] Table 3

[0064] TIFF2025517348000004.tif85170

[0065] Aspects

[0066] In a first aspect, the disclosure provides a porous membrane comprising poly(tetrafluoroethylene), where a) the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, the monomers being composed of monomers having amide moieties; b) the membrane exhibits a wettability of at least about 80 Dynes / cm; and c) the membrane exhibits a 60% isopropanol visual bubble point of greater than about 21 psi.

[0067] In a second aspect, the present disclosure provides a porous membrane of the first aspect, wherein the membrane exhibits a deionized water flux time of about 200 to about 400 seconds per 500 ml.

[0068] In a third aspect, the present disclosure provides a porous membrane of the first aspect, wherein the membrane has an average pore size of from about 0.1 μm to about 0.2 μm.

[0069] In a fourth aspect, the present disclosure provides a 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.

[0070] In a fifth aspect, the present disclosure provides a membrane of any one of the first to fourth aspects, wherein the membrane exhibits a wettability of about 82 to about 89 Dynes / cm.

[0071] In a sixth aspect, the present disclosure provides the membrane 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.

[0072] In a seventh aspect, the present disclosure provides the membrane of any one of the first to sixth aspects, wherein the monomer having an amide moiety is selected from the group consisting of ethylacrylamide, butylacrylamide, N,N-dimethylaminopropylmethacrylamide, acrylamide, methacrylamide, ethylformamide, N-(2-methoxyacrylamido-ethyl)ethyleneurea, N,N-methylenebisacrylamide, dimethylacrylamide, and combinations thereof.

[0073] In an eighth aspect, the present disclosure provides the membrane of any one of the first to seventh aspects, wherein the monomer having an amide moiety is selected from the group consisting of N,N-methylenebisacrylamide, dimethylacrylamide, and combinations thereof.

[0074] In a ninth aspect, the present disclosure provides the membrane of any one of the first to eighth aspects, wherein at least about 90 mole percent of the monomers have an amide moiety.

[0075] In a tenth aspect, the present disclosure provides the membrane of the eighth aspect, wherein N,N-methylenebisacrylamide and dimethylacrylamide are used in a weight ratio of about 1:1 to about 1:4.

[0076] In an eleventh aspect, the present disclosure provides the membrane 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.

[0077] In a twelfth aspect, the present disclosure provides a filter comprising the membrane of any one of the first to eleventh aspects.

[0078] 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.

[0079] In a fourteenth aspect, the present disclosure provides the method of the thirteenth aspect, wherein the liquid comprises one or more of n-butyl acetate, isopropyl alcohol, 2-ethoxyethyl acetate, xylene, cyclohexanone, ethyl lactate, isopentyl ether, methyl-2-hydroxyisobutyrate, methyl isobutyl carbinol, methyl isobutyl ketone, isoamyl 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.

[0080] 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, the method comprising passing the liquid through the membrane of any one of the first to eleventh aspects or the filter of the twelfth aspect.

[0081] In a sixteenth aspect, the present disclosure provides a method of the fifteenth aspect, wherein the liquid comprises water.

[0082] 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.

[0083] In an eighteenth aspect, the present disclosure provides a method for the preparation of a glycerol-based ... 1 ~C 4 The method of the seventeenth aspect is provided, further comprising one or more of: an alcohol; or a combination thereof.

[0084] 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 glycerol.

[0085] Having thus described several exemplary embodiments of the present disclosure, those skilled in the art will readily appreciate that still other embodiments may be made and used within the scope of the appended claims. Numerous advantages of the present disclosure to which this document is directed have been set forth in the foregoing description. It will be understood, however, that the present disclosure is in many respects merely illustrative. The scope of the present disclosure will, of course, be expressed in the language in which the appended claims are expressed.

Claims

1. 1. A porous membrane comprising poly(tetrafluoroethylene), a) the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, the monomers being comprised of monomers having an amide moiety; b) the membrane exhibits a wettability of at least about 80 Dynes / cm; and c) the film exhibits a 60% isopropanol visual bubble point of greater than about 21 psi; Porous membrane.

2. 10. The porous membrane of claim 1, wherein the membrane exhibits a deionized water flux time of about 200 to about 400 seconds per 500 ml.

3. 3. The porous membrane of claim 1 or 2, wherein the average pore size of the membrane is from about 0.1 μm to about 0.2 μm.

4. 3. The porous membrane of claim 1 or 2, wherein the average pore size of the membrane is from about 0.15 μm to about 0.22 μm.

5. 5. The membrane of any one of claims 1 to 4, wherein the membrane exhibits a wettability of about 82 to about 89 Dynes / cm.

6. The membrane of any one of claims 1 to 5, wherein the coating has an amide density (AD) of about 0.008 to about 0.

014.

7. 7. The membrane of claim 6, wherein the coating has an amide density (AD) of about 0.010 to about 0.

013.

8. 8. The membrane of any one of claims 1 to 7, wherein the monomer having an amide moiety is selected from the group consisting of ethylacrylamide, butylacrylamide, N,N-dimethylaminopropylmethacrylamide, acrylamide, methacrylamide, ethylformamide, N-(2-methoxyacrylamido-ethyl)ethyleneurea, N,N-methylenebisacrylamide, dimethylacrylamide, and combinations thereof.

9. 8. The membrane of any one of claims 1 to 7, wherein the monomer having an amide moiety is selected from the group consisting of N,N-methylenebisacrylamide and dimethylacrylamide, and combinations thereof.

10. 10. The membrane of claim 9, wherein N,N-methylenebisacrylamide and dimethylacrylamide are used in a weight ratio of about 1:1 to about 1:

4.

11. 11. The membrane of claim 1, wherein at least about 90 mole percent of the monomers have an amide moiety.

12. A filter comprising a membrane according to any one of claims 1 to 11.

13. 13. A method for filtering a liquid comprising passing the liquid through a membrane according to any one of claims 1 to 11 or a filter according to claim 12.

14. 14. The method of claim 13, wherein the liquid comprises one or more of n-butyl acetate, isopropyl alcohol, 2-ethoxyethyl acetate, xylene, cyclohexanone, ethyl lactate, isopentyl ether, methyl-2-hydroxyisobutyrate, methyl isobutyl carbinol, methyl isobutyl ketone, isoamyl 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.

15. A method for removing bacteria from a liquid comprising at least one active pharmaceutical ingredient and one or more carriers and / or diluents, the method comprising passing the liquid through a membrane according to any one of claims 1 to 11 or a filter according to claim 12.

16. The method of claim 15 , wherein the liquid comprises water.

17. The method of claim 16 , wherein the liquid further comprises one or more glycols or alcohols.

18. The liquid is propylene glycol, glycerol, C １ ~C ４ 20. The method of claim 17, further comprising one or more of: an alcohol; or a combination thereof.

19. 20. The method of claim 18, wherein the liquid comprises water and at least one glycol selected from propylene glycol and glycerol.

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