Hydrophilic membrane for filtration

Abstract

The present disclosure provides a porous membrane capable of removing very small particulates from a liquid composition. In certain embodiments, the porous membrane comprises poly (tetrafluoroethylene), where the membrane is at least partially coated with a polymer prepared from a free radical reaction of ethylenically unsaturated monomers, where the monomers comprise monomers having amide moieties. In particular embodiments, the membrane is capable of removing microbial particles (e.g., 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 the same to remove very small particulates and / or microbial species from liquid compositions. Background Art

[0002] Filters are used to remove unwanted materials from useful liquid solution streams and have become an important feature in many technologies. Liquid solutions treated to remove unwanted materials include water, liquid industrial solvents and processing fluids, industrial gases for manufacturing or processing, and liquids with medical or pharmaceutical uses. Unwanted materials removed from fluids include impurities and contaminants, such as particles, microorganisms, and dissolved chemical species. Specific examples of filter applications include its use with liquid materials manufactured by semiconductors and microelectronic devices and for the sterilization filtration of liquid solutions intended to be introduced into the human body.

[0003] Filters can remove unwanted materials in a variety of different ways, such as by particle size screening or by chemical and / or physical interaction with the material. Some filters are defined by a structural material that provides a porous framework for the filter, and the filter is able to trap particles of a size that cannot 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 material passing through the filter. For example, the chemical characteristics of the filter may be able to bind to unwanted materials in the flow passing through the filter, trapping those unwanted materials through interactions such as ions, coordination, chelation, or hydrogen bonding. Some filters may utilize both particle size screening and chemical interaction characteristics to remove materials from the filter flow.

[0004] In some cases, to perform the filtering function, the filter includes a filter membrane responsible for removing unwanted materials from the liquid passing through. The filter membrane may be in the form of a flat plate as needed, which may be wound (e.g., spiral), flat, pleated, or disc-shaped. The filter membrane may alternatively be in the form of a hollow fiber. The filter membrane may be contained in a housing or otherwise supported so that the filtered fluid enters through the filter inlet and needs to pass 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 substantially sterile. In such applications, it is also important that the filter media or membrane be operated so that very low amounts of extractable or filterable leachable materials are found to seep from the filter, which otherwise could contaminate the filtered liquid solution. Additionally, in the case of sterile filtration, it is also important that the filter does not excessively retain the desired components of the liquid composition, such as an active pharmaceutical ingredient (API). Summary of the invention

[0006] In summary, the present disclosure provides a porous membrane capable of removing very small particles from a liquid composition. 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 comprise 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% isopropanol visualized 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 is capable of removing microbial particles (e.g., bacteria) by filtration, thereby rendering the resulting liquid composition substantially sterile. Additionally, in certain embodiments, the coating on the porous membrane allows filtration of the liquid composition without excessive retention of the active pharmaceutical ingredients contained therein, particularly those having ionizable nitrogen groups (e.g., quaternary ammonium groups). BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 A graph comparing the wettability (dynes / cm) of a membrane of the present disclosure (A) to a commercially available membrane (B) (i.e., Cobetter hydrophilic PTFE with a pore size of 0.2 μm).

[0009] Figure 2 Comparison of the 60% isopropanol visualized bubble point (expressed in psi) of the membrane of the present disclosure (A) and a commercial membrane (B), namely Cobite hydrophilic PTFE with a pore size of 0.2 μm.

[0010] Figure 3 Comparison of deionized water (DIW) flow time of the membrane of the present disclosure (A) and a commercial membrane (B) (ie, Cobite hydrophilic PTFE with a pore size of about 0.2 μm).

[0011] Figure 4 Plot of NVR (non-volatile residue) data for membranes of the present disclosure (A) versus commercial membranes (B), namely Cobbert hydrophilic PTFE with a pore size of about 0.2 μm.

[0012] Figure 5 is a drawing of an exemplary filter device including a membrane of the present disclosure. DETAILED DESCRIPTION

[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 used 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 (eg, 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) wherein the membrane exhibits a 60% isopropanol visualized bubble point greater than about 21 psi.

[0017] In certain embodiments, 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 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 no greater than about 0.22 μm. 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 and all ranges therebetween.

[0020] The membranes of the present disclosure can be used in any type of process requiring a high purity liquid material. Thus, the membranes of the present disclosure can be used in a variety of applications, including, for example, liquids for semiconductor lithography, 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, clarifying and filtering fluids containing antibodies and / or proteins.

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

[0022] Exemplary solutions where the removal of bacteria is required and desired 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, these 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 disclosure provides a method of filtering a liquid comprising passing the liquid through a membrane of the disclosure. In certain embodiments, the disclosure includes a method of 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 disclosure.

[0024] In general, pharmaceutically acceptable carriers and / or diluents include any material that is generally inert, that is, it has no therapeutic effect itself, while being sufficiently non-toxic in the amount utilized in the formulation containing the active pharmaceutical ingredient. Exemplary solvents, suspending media, dispersants, carriers, and diluents, etc. can be found in U.S. Pat. No. 10,137,132, which is incorporated herein by reference in its entirety.

[0025] The carrier and / or diluent 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 manufacturing (e.g., in photolithography). In such applications, the liquid composition includes solvents such as n-butyl acetate, isopropanol, ethyl 2-ethoxyacetate, xylene, cyclohexanone, ethyl lactate, isoamyl 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 mixed solution of propylene glycol monomethyl ether and PGMEA (7:3).

[0027] As described above, the porous membrane is capable of acting as a sterilization membrane (i.e., bacterial removal) without over-retaining the desired API in solution. In general, the membrane is rendered relatively hydrophilic by the coatings described herein, thereby also providing utility in sterile filtration of water-based liquids, while not over-retaining certain active pharmaceutical ingredients, particularly those containing ionizable nitrogen groups (e.g., quaternary ammonium groups). This hydrophilicity characteristic is quantified herein by reciting the wettability of the membrane. In a particular embodiment, the membrane exhibits a wettability of at least about 80 dynes / cm, e.g., about 82 to about 89 dynes / cm.

[0028] As described above, the membrane of the present disclosure comprises a coating prepared from free radical polymerization of ethylenically unsaturated monomers, wherein the monomers comprise monomers having amide moieties. In certain embodiments, the introduction 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 may 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, and include, for example, ethyl acrylamide, butyl acrylamide, N,N-dimethylaminopropyl methacrylamide, acrylamide, methacrylamide, ethyl formamide, N-(2-methoxyacrylamido-ethyl)ethylene urea, N,N-methylenebisacrylamide, and dimethylacrylamide. In other embodiments, at least about 90 mole % 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 so 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 a liquid composition containing an active pharmaceutical ingredient, it is believed that the porous membranes of the present disclosure are effective in retaining only a small proportion of the active pharmaceutical ingredient, especially those containing ionizable nitrogen functional groups (e.g., quaternary ammonium groups). At the same time, the membranes of the present disclosure also generate very small amounts of extractable materials from the membrane.

[0031] The membranes of the present disclosure may 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 functional groups or moieties. Advantageously, one of the amide-functional monomers, a dialkylacrylamide, such as dimethylacrylamide, may be utilized in conjunction with a difunctional amide-functional monomer, such as N,N-methylenebisacrylamide. In this manner, the N,N-methylenebisacrylamide thereby acts as a crosslinking agent. Generally, a monomer mixture and a free radical polymerization initiator are dissolved in an inert solvent and contacted with a poly(tetrafluoroethylene) membrane, thereby forming a polymeric coating having amide functional groups on the surface of the various poly(tetrafluoroethylene) membranes. The monomers are utilized 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, the hydrophobic poly(tetrafluoroethylene) membrane is rendered hydrophilic by this coating process. If it is desired to reduce the proportion of amide functional groups on the coating, other ethylenically unsaturated monomer species can be used together with the amide functional monomer. In certain embodiments, greater than 90% of the monomers used to form the coating are monomers containing amide functional groups or moieties.

[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% isopropanol visualized bubble point, wettability, retention of active pharmaceutical ingredients, and extractable materials produced by the membrane.

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

[0035] Regarding the 60% isopropanol visual bubble point, this property can be measured in the following manner: First, a 47 mm film specimen is placed on a holder and the film is wetted with 60% IPA in water. Air pressure is then applied to the film until bubbles can be seen from the top of the holder. The pressure is recorded as the visual bubble point (VBP). This observable VBP is related to the pore size of the film. 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.

[0036] Regarding wettability, this property can be measured in the following manner: prepare solutions corresponding to different surface tensions, namely 20%, 22%, 24%, 26%, 28% NaCl solutions and 30%, 32%, 34%, 36%, 38%, 40%, 42% CaCl2 solutions. Each solution corresponds to a different surface tension. Use a pipette to drop a few drops of a solution of a specific concentration onto the membrane surface; if the drop wets the membrane surface within 10 seconds, then the membrane is 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, such as about 82 to about 89 dynes / cm.

[0037] The porous membranes of the present disclosure are used for the removal of bacteria according to ASTM FM838-20, also known as the bacterial challenge test.

[0038] In the case of sterile filtration of liquid solutions designed for in vivo use, also important is the ability of the membrane to 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), etc. The porous membranes may be in the form of flat plates, corrugated plates, pleated plates, 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, a bracket, a clip, 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 of removing contaminants from a liquid wherein the liquid passes through a membrane of the present disclosure. Figure 5As shown in , the present disclosure provides a filter 100 that includes a porous membrane 102. Porous membrane 102. The filter 100 may have a housing 104 that provides structure to the filter 100 and fluidly seals the interior portion of the filter. The housing 104 may be any shape and size, such as cylindrical, polygonal, etc.

[0042] One portion of the filter may include an inlet port 106 to receive a liquid composition to be filtered. The inlet port 106 may be configured to connect to a fluid supply line. Thus, the inlet port 106 may include a valve, a gasket, etc. (not shown) to facilitate connection to a fluid supply. The liquid composition to be filtered may flow through the inlet port 106 in the direction indicated by arrow 116 and enter the head space 114 in the filter 100, as 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 embodiments, the filter may be constructed so that the volume of the head space 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 Figure 5 The porous membrane 102 is shown to have a disc-shaped architecture (a cross-sectional view is shown). A side 122 of the porous membrane 102 (e.g., the outer circumference of the membrane) can be in contact with the inner 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 from which the treated liquid with a reduced amount of particulates or bacteria flows out. Aspects of the filter can optionally be described according to a range of surface area to volume ratios of the input-facing surface 124 of the porous membrane 102 or a ratio of the surface area to thickness of the filter.

[0044] The filter 100 may also include one or more features that support the porous membrane 102 within the filter. Any configuration that supports the filter may be used and may include one or more discrete structural features, such as frames, frames, brackets, clips, nets, meshes, and 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 the embodiments and with reference to Figure 5 , the filter includes a frame having frame portions 110 and 112, wherein frame portion 110 contacts the inner surface of housing 104 and is attached to portion 112. Portion 112 may contact output-facing surface 124 of porous membrane 102 and provide support for the membrane during filtration. Frame portion 112 may have a grid-like structure to allow filtered liquid to freely enter the back space 120 of the filter while still providing structural support for the porous membrane under increased fluid pressure.

[0045] In use, liquid enters the filter through inlet port 106 in the direction indicated by arrow 116 and then fills head space 114 within filter 100. 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, which included: 0.3% of Ingard 2959 (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone); 10% of methanol, 1.71% of dimethylacrylamide (DMAM), 0.69% of N,N-methylenebisacrylamide (MBAM), and 87.3% of deionized water.

[0050] Hydrophilic PTFE membrane is prepared by the following method.First, 47mm disc-shaped PTFE porous membrane (60um thick, 0.15-0.2μm pore size) is wetted with isopropyl alcohol (IPA) solution for 25 seconds.Then, the membrane is rinsed and IPA is removed using an exchange solution comprising 10% hexylene glycol and 90% water.Then the porous membrane disc is introduced into the surface modification monomer solution and kept immersed for 2 minutes.The porous membrane disc is taken out from the surface modification monomer solution and placed between transparent polyethylene sheets.When the polyethylene / membrane disc / polyethylene sandwich structure is laid flat on the table, any excess solution is removed by rolling a rubber roller thereon.Then the polyethylene sandwich structure is bonded to a transmission unit, which transports the assembly through a broadband UV exposure laboratory unit of Fusion Systems, Inc., which is emitted at a wavelength of 200 to 600nm.The exposure time is controlled by the speed of the assembly moving through the UV unit.In this example, the assembly moves through the UV chamber at 10 feet / minute. After leaving the UV unit, the membrane was removed from the sandwich and immediately placed in DI water, where it was soaked for 5 minutes. Then, the treated membrane sample was transferred to methanol and allowed to soak for 5 minutes. After this soaking procedure, the membrane was dried on a holder in an oven operated at 50°C for 10 min. The water flow time of the membrane modified as described above was 300sec / 500mL. The resulting membrane was hydrophilic and wetted spontaneously when immersed in deionized water.

[0051] Bacterial challenge test

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

[0053] The pressure vessel and upstream connecting pipe do not need to be autoclaved, but should be thoroughly cleaned, disinfected and rinsed with sterile pure water before testing. The container can be disinfected with a 0.005% sodium hypochlorite solution made from a 1:999 dilution of a 5% sodium hypochlorite solution or 70% ethanol, drained and rinsed thoroughly with sterile pure water. Two sets of membranes of the present disclosure were installed in the test analytical filter assembly and then autoclaved at 121°C for 30 min. One set was used as is and 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 is collected using an automated integrity tester. Sterile 0.9% NaCl solution is added to the pressure vessel to wet the test membrane. Then, 20-50 mL of filtrate is collected downstream through the analytical membrane as a negative control analytical membrane.

[0055] For positive control testing, a bacterial retention test of a 0.45 μm positive control filter (filter membrane or filter assembly) should be performed and the challenge level should be no less than 1×10 7 cfu / cm 2 . The positive control sample was collected from the downstream of the control analytical filter assembly using an analytical membrane. The membrane of the present disclosure was subjected to bacterial retention using a 0.9% sterile NaCl solution inoculated with B. diminuta at room temperature. The test sample was collected from the downstream of the test filter assembly using an analytical membrane. After the test challenge, the analytical membrane was aseptically transferred to a PCA plate and incubated at 30±2°C. Then, the colony counts of the negative control analytical membrane were recorded at 72 hours and 7 days, the colony counts of the test analytical membrane were recorded at 48 hours and 7 days, and the colony counts of the positive control analytical membrane were recorded at 48 hours. The post-test membrane was then autoclaved at 121°C for 30 min. The bubble point of the membrane was then measured using an automatic 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 >10 7 cfu / cm 2 EFA levels of Brevundimonas parvum challenge.

[0057] Table 1

[0058]

[0059] Wettability test

[0060] Solutions corresponding to different surface tensions were prepared, namely 20%, 22%, 24%, 26%, 28% NaCl solutions and 30%, 32%, 34%, 36%, 38%, 40%, 42% CaCl2 solutions. Each solution corresponds to a different surface tension, as listed in Table 2 below. A pipette was used to drop a few drops of a solution of a specific concentration onto the membrane surface; if the drop wetted the membrane surface within 10 seconds, the membrane was considered wettable in the solution corresponding to the specific surface tension. Figure 1 The membrane (A) of the present disclosure is shown to have a wettability greater than that of a commercially available membrane (B), namely a Cobetex hydrophilic PTFE membrane having 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.

[0061] Table 2

[0062]

[0063] 60% IPA Visual BP Test

[0064] First, a 47 mm membrane specimen was placed on a holder and the membrane was wetted 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. The pressure was recorded as the Visual Bubble Point (VBP). Figure 2 The membrane of the present disclosure (A) is shown to have a 60% IPA VBP less than the Cobetex hydrophilic PTFE membrane (B) having a pore size of about 0.2 μm. As can be seen, the membrane of the present disclosure can have a 60% IPA VBP greater than about 21 psi.

[0065] Water flow time test

[0066] Deionized water (DIW) flow time was tested 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 The DIW flow time of the membrane of the present disclosure is shown to be greater than that of a commercially available PTFE membrane, namely a Cobetex hydrophilic PTFE membrane having 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 / 500 ml.

[0067] Extractable Materials Testing

[0068] The membrane was placed in a cartridge and extracted in 50% ethanol at 80°C for 24 hours while stirring at 50 rpm using a magnetic stir bar. 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.

[0069] The NVR test of membranes A and B with a size of 30 cm x 30 cm was extracted in 250 mL 100% isopropanol 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).

[0070] Table 3

[0071]

[0072] aspect

[0073] 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) wherein the membrane exhibits a 60% isopropanol visualized bubble point greater than about 21 psi.

[0074] 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 / 500 ml.

[0075] 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.

[0076] 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.

[0077] In a fifth aspect, the present disclosure provides the membrane of any one of the first to fourth aspects, wherein the membrane exhibits a wettability of about 82 to about 89 dynes / cm.

[0078] 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.

[0079] In a seventh aspect, the present disclosure provides the film of any one of the first to sixth aspects, wherein the monomer having an amide moiety is selected from the group consisting of ethyl acrylamide, butyl acrylamide, N,N-dimethylaminopropyl methacrylamide, acrylamide, methacrylamide, ethylformamide, N-(2-methoxyacrylamido-ethyl)ethylene urea, N,N-methylenebisacrylamide, dimethylacrylamide, and combinations thereof.

[0080] In an eighth aspect, the present disclosure provides the film 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.

[0081] 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 % of the monomers have an amide moiety.

[0082] 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.

[0083] 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.

[0084] In a twelfth aspect, the present disclosure provides a filter comprising the membrane of any one of the first to eleventh aspects.

[0085] 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.

[0086] 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, isopropanol, ethyl 2-ethoxyacetate, 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.

[0087] In a fifteenth aspect, the present disclosure provides a method of 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.

[0088] In a sixteenth aspect, the present disclosure provides the method of the fifteenth aspect, wherein the liquid comprises water.

[0089] 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.

[0090] 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 C1-C4 alcohol, or a combination thereof.

[0091] 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.

[0092] Having thus described several illustrative embodiments of the disclosure, it will be readily understood by those skilled in the art that still other embodiments may be made and used within the scope of the appended claims. Many of the advantages of the disclosure encompassed by this document have been explained in the foregoing description. However, it should be understood that this disclosure is merely illustrative in many respects. The scope of the disclosure is of course defined in the language in which the appended claims are expressed.

Claims

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

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

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

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

5. The film of any preceding claim, wherein the film exhibits a wettability of about 82 to about 89 dynes / cm.

6. The membrane of any preceding claim, wherein the coating has an amide density (AD) of about 0.008 to about 0.

014.

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

013.

8. The film of any preceding claim, wherein the monomer having an amide moiety is selected from the group consisting of ethyl acrylamide, butyl acrylamide, N,N-dimethylaminopropyl methacrylamide, acrylamide, methacrylamide, ethylformamide, N-(2-methoxyacrylamido-ethyl)ethylene urea, N,N-methylenebisacrylamide, dimethylacrylamide, and combinations thereof.

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

4.

11. A membrane according to any preceding claim wherein at least about 90 mole % of the monomers have an amide moiety.

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

13. A method of 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. The method according to claim 13, wherein the liquid comprises one or more of the following: n-butyl acetate, isopropyl alcohol, ethyl 2-ethoxyacetate, 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.

15. A method of 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 method of claim 17, wherein the liquid further comprises one or more of propylene glycol, glycerol, a C1-C4 alcohol, or a combination thereof.

19. 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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