A pharmaceutical grade low-dissolution degassing hollow fiber membrane material and a preparation method thereof

Abstract

The application discloses a medical-grade low-dissolution degassing hollow fiber membrane material and a preparation method thereof, and belongs to the technical field of hollow fiber membrane materials. The base material of the material is formed by blending poly-4-methyl-1-pentene and polyvinylidene fluoride-hexafluoropropylene copolymer; the membrane wall of the hollow fiber membrane material is integrally formed into a continuous pore size gradient structure along a radial direction, and is sequentially divided into a liquid blocking zone, a transition zone and a gas transmission zone from outside to inside, and the pore sizes of the three zones are sequentially increased; the outer surface of the liquid blocking zone is provided with a double-scale rough morphology composed of a micron-level convex structure and a nanometer-level villus structure; and a fluorinated hydrophobic layer is covalently grafted to the surface of the double-scale rough morphology, and the fluorinated hydrophobic layer covers the surfaces of the micron-level convex structure and the nanometer-level villus structure.

Description

Technical Field

[0001] This application relates to the field of hollow fiber membrane materials technology, and more specifically, to a pharmaceutical-grade low-dissolution degassing hollow fiber membrane material and its preparation method. Background Technology

[0002] In the pharmaceutical industry, particularly in sterile injections, biopharmaceutical filling, and blood purification, hollow fiber membrane degassing components are widely used to remove dissolved gases from liquid media. This prevents air bubbles from forming during filling, which can affect product appearance and efficacy, and also reduces the oxidative impact of dissolved oxygen on active ingredients. Existing hollow fiber degassing membrane materials are mostly made from hydrophobic polyolefin membranes (such as polypropylene, poly4-methyl-1-pentene, etc.) through stretching-induced pore formation or thermal phase separation methods. While they possess good permeability, they still have the following shortcomings: Firstly, the membrane wall has a uniform pore size distribution, making it difficult to balance gas transmission resistance and liquid resistance: if the pore size is too large, wet-out is likely to occur; if the pore size is too small, the gas transmission efficiency will decrease. It is difficult to achieve optimal performance for both at the same pore size scale.

[0003] Secondly, the hydrophobicity of the membrane surface mainly depends on the substrate itself and the physical roughening treatment. Under the long-term repeated sterilization conditions of high temperature and high pressure steam above 121°C, the surface hydrophobicity will degrade, causing the membrane pores to gradually become wet, the degassing efficiency to decrease, and even leakage to occur, making it difficult to meet the reliability requirements of long-term repeated use of pharmaceutical-grade components.

[0004] Third, in order to improve processing fluidity and antistatic properties, plasticizers, antistatic agents and other additives are often added to the existing membrane material formulations. These additives are prone to dissolution and migration during long-term contact with the drug solution, which can lead to foreign substance contamination and safety hazards, and do not meet the strict requirements of pharmaceutical grade materials for low dissolution and biosafety.

[0005] Fourth, hydrophobic modification of membrane surfaces is mostly achieved through physical coating. The coating and the substrate are non-covalently bonded, and the coating is prone to peeling or migration under repeated high-temperature steam sterilization and fluid flushing conditions, making it difficult to guarantee long-term stability.

[0006] Therefore, how to ensure the gas transmission efficiency of hollow fiber membranes while also taking into account their liquid-blocking reliability, hydrophobic stability, and low leaching cleanliness has become a technical problem that urgently needs to be solved for pharmaceutical-grade degassing membrane materials. Summary of the Invention

[0007] In order to overcome a series of defects in the existing technology, the purpose of this application is to provide a pharmaceutical-grade low-dissolution degassing hollow fiber membrane material, wherein the substrate is a blend of poly(4-methyl-1-pentene) and polyvinylidene fluoride-hexafluoropropylene copolymer. The hollow fiber membrane material has a continuous pore size gradient structure integrally formed in the radial direction, which is divided into a liquid blocking region, a transition region and a gas transport region from the outside to the inside, with the pore size increasing in that order. The outer surface of the liquid-blocking region has a dual-scale rough morphology composed of a micron-level protrusion structure and a nano-level villous structure. The surface of the dual-scale rough morphology is also covalently grafted with a fluorinated hydrophobic layer, which covers the surface of the micron-scale protrusion structure and the nano-scale villous structure.

[0008] In some embodiments, the pore size of the liquid-blocking region is 0.02 μm to 0.05 μm, and the porosity is 30% to 40%; the pore size of the transition region gradually changes from 0.05 μm to 0.15 μm; and the pore size of the gas transport region is 0.2 μm to 0.5 μm, and the porosity is 60% to 75%.

[0009] In some embodiments, the protrusion size of the micron-scale protrusion structure is 1μm to 3μm, the size of the nano-scale villous structure is 50nm to 200nm, and the nano-scale villous structure is distributed between adjacent micron-scale protrusion structures.

[0010] In some embodiments, the fluorinated hydrophobic layer is formed by graft polymerization of a long-chain perfluoropolyether methacrylate monomer, wherein the long-chain perfluoropolyether methacrylate monomer has a molecular weight greater than 1000.

[0011] In some embodiments, the blending ratio of polyvinylidene fluoride-hexafluoropropylene copolymer in the substrate is 5% to 15%.

[0012] In some embodiments, the substrate does not contain plasticizers or antistatic additives.

[0013] In some embodiments, after the hollow fiber membrane material is subjected to at least 10 cycles of high-pressure steam sterilization at 121°C or above, the fluorinated hydrophobic layer remains covalently bonded to the dual-scale rough morphology surface.

[0014] This application also provides a method for preparing the above-mentioned pharmaceutical-grade low-dissolution degassing hollow fiber membrane material, including the following steps: The nascent fibers were obtained by extruding poly(4-methyl-1-pentene) and polyvinylidene fluoride-hexafluoropropylene copolymer after melt blending. The nascent fibers are subjected to high-temperature annealing treatment; Under radial temperature gradient control, the annealed fibers are subjected to low-temperature cold stretching and high-temperature hot stretching in sequence, so that the membrane wall is integrally formed with the pore size increasing from the outside to the inside in the liquid blocking zone, transition zone and gas transport zone, and then heat set to obtain hollow fibers. The outer surface of the liquid-blocking region of the hollow fiber is subjected to plasma etching and chemical micro-etching in sequence to form a dual-scale rough morphology that combines micron-scale protrusion structure and nano-scale villous structure. Low-temperature oxygen plasma activation treatment was performed on the surface with dual-scale rough morphology. Using long-chain perfluoropolyether methacrylate as a grafting monomer, grafting polymerization is carried out on the activated dual-scale rough morphology surface by surface-initiated atom transfer radical polymerization, so that the fluorinated hydrophobic segments are covalently covered on the dual-scale rough morphology surface to form a fluorinated hydrophobic layer. Hollow fiber membranes were purified by supercritical carbon dioxide extraction to obtain pharmaceutical-grade low-dissolution degassed hollow fiber membrane materials.

[0015] In some embodiments, the radial temperature gradient control is as follows: the outer layer region of the membrane wall corresponding to the liquid blocking region is stretched slowly at a relatively low temperature, while the inner layer region of the membrane wall corresponding to the gas transport region is stretched rapidly at a relatively high temperature.

[0016] In some embodiments, the plasma activation treatment is controlled to a depth of less than 100 nm on the surface to avoid affecting the intrinsic pore structure of the membrane.

[0017] Compared with the prior art, this application has the following beneficial effects: 1) By controlling the stretching process with radial temperature gradient, the membrane wall is integrally formed with a gradient structure of liquid blocking zone, transition zone and gas transport zone with continuously increasing pore size from the outside to the inside. This avoids the problem of poor bonding at the interface of multilayer composite membranes, while taking into account both liquid blocking reliability and gas transport efficiency. 2) A dual-scale rough morphology of micron-scale protrusions and nano-scale villous composite is constructed on the outer surface of the liquid-blocking region by combining plasma etching and chemical micro-etching. Long-chain perfluoropolyether methacrylate is covalently grafted onto the rough surface by surface-initiated atom transfer radical polymerization, so that the fluorinated hydrophobic layer is firmly bonded to the substrate surface. After at least 10 cycles of high-pressure steam sterilization at 121°C or above, it can still maintain excellent hydrophobic stability, effectively avoiding the problems of membrane pore wetting and leakage caused by repeated sterilization. 3) The substrate formulation does not contain plasticizers or antistatic additives, and combined with supercritical carbon dioxide extraction purification process, it significantly reduces the extractable / leached content of the membrane material, meeting the requirements of low dissolution and biosafety of pharmaceutical grade materials. Detailed Implementation

[0018] The technical solution of the present invention will be described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto. Unless otherwise specified, the raw materials used in the embodiments are all conventional commercially available products, and the equipment used is all conventional equipment in the art.

[0019] I. Raw Materials and Main Equipment Poly(4-methyl-1-pentene) (PMP): melt flow rate approximately 26 g / 10 min (260 °C / 5 kg); Polyvinylidene fluoride-hexafluoropropylene copolymer (PVDF-HFP): Hexafluoropropylene (HFP) molar content is approximately 8%–12%; Long-chain perfluoropolyether methacrylate (PFPEMA) grafted monomers: number average molecular weight approximately 1200–2000; Main equipment: twin-screw melt extruder, annular spinneret spinning unit, radial temperature gradient stretching device, radio frequency plasma treatment device, supercritical carbon dioxide extraction device, etc.

[0020] II. Performance Testing Methods 1. Pore size and porosity: The average pore size and porosity of the liquid-blocking region, transition region and gas transport region were determined by bubble point method (referring to ASTM F316 standard) combined with scanning electron microscopy (SEM) observation of membrane cross sections. 2. Surface micro- and nano-morphology: The size and distribution of the micron-scale protrusions and nano-scale villous structures on the outer surface of the liquid-blocking region were observed using field emission scanning electron microscopy (FE-SEM). 3. Water contact angle: Using a contact angle measuring instrument, the static water contact angle was measured at 5 different points on the membrane surface and the average value was taken; 4. Gas flux: Using nitrogen as the test medium, the gas flux per unit membrane area was measured under a transmembrane pressure difference of 0.1 MPa; 5. Carbon dioxide degassing efficiency: Using a simulated liquid containing saturated dissolved carbon dioxide as feed, the removal efficiency of the membrane module for dissolved carbon dioxide was measured under a gas-side vacuum of -0.09 MPa. 6. Total organic carbon (TOC) leaching: The total organic carbon content of the extract was determined by soaking the extract in purified water at 70°C for 72 hours, in accordance with the extract determination method in the general chapter of the Chinese Pharmacopoeia. 7. Stability against high-pressure steam sterilization: The membrane material was placed in a 121℃, 0.1MPa saturated steam sterilizer for 30 minutes as one sterilization cycle. After repeating the treatment 10 times, the change in water contact angle on the membrane surface was measured (characterized by contact angle retention rate).

[0021] III. Examples Example 1 (S1) (1) Weigh the raw materials according to the proportion of polyvinylidene fluoride-hexafluoropropylene copolymer of 8% (the balance is poly4-methyl-1-pentene), melt blend them in a twin-screw extruder at 260-280°C, and extrude them through an annular spinneret to obtain nascent hollow fibers; (2) Place the nascent fibers in a 150℃ hot air oven for annealing for 60 min; (3) Using a radial temperature gradient control device, the outer layer of the fiber corresponding to the liquid blocking region is cold stretched at 80°C at a speed of 5 mm / min, and then the inner layer of the fiber corresponding to the gas transport region is hot stretched at 150°C at a speed of 40 mm / min. The total stretching ratio is 2.5 times. Then, it is heat-set at 155°C for 10 min, so that the membrane wall is integrally formed with the liquid blocking region, transition region and gas transport region whose pore size increases from the outside to the inside, thus obtaining hollow fiber; (4) The hollow fiber was placed in a radio frequency plasma processing device and a mixed gas with an Ar / O2 volume ratio of 4:1 was introduced. The fiber was etched at 100W power for 90s. Then the fiber was immersed in a 5% potassium permanganate / sulfuric acid composite etching solution and treated at 40℃ for 3min. After washing and drying, a dual-scale rough morphology of micron-scale protrusion structure and nano-scale villous structure was formed on the outer surface of the liquid-blocking region. (5) The above-mentioned dual-scale rough morphology surface was subjected to low-temperature oxygen plasma activation treatment with a power of 50W and a treatment time of 20s, and the activation depth was controlled to be within 100nm on the surface. (6) Using long-chain perfluorinated polyether methacrylate with a number average molecular weight of about 1500 as the grafting monomer, the surface-initiated atom transfer radical polymerization (SI-ATRP) method was used to carry out the grafting polymerization reaction on the activated dual-scale rough morphology surface. The reaction temperature was 60℃ and the reaction time was 4h, so that the fluorinated hydrophobic segments were covalently covered on the dual-scale rough morphology surface to form a fluorinated hydrophobic layer. (7) The obtained hollow fiber membrane was placed in a supercritical carbon dioxide extraction device and extracted and purified for 2 hours at 35 MPa and 45 °C to obtain a pharmaceutical grade low-dissolution degassing hollow fiber membrane material, which was numbered S1.

[0022] Testing revealed that the S1 sample had a liquid-blocking zone pore size of approximately 0.030 μm and a porosity of 35%; the transition zone pore size gradually changed from 0.05 μm to 0.14 μm; the gas transport zone pore size was approximately 0.35 μm and the porosity was 68%; the outer surface of the liquid-blocking zone had micron-sized protrusions of approximately 2.0 μm and nano-sized villous structures of approximately 120 nm; the initial water contact angle was 152°, and after 10 cycles of steam sterilization at 121°C, the water contact angle was 146°, with a retention rate of 96.1%; the nitrogen flux was approximately 3200 L / (m²·h·0.1MPa); the carbon dioxide degassing efficiency of the simulated liquid was 92.5%; and the TOC dissolution was 0.35 mg / L.

[0023] Example 2 (S2) Based on Example 1, the blending ratio of polyvinylidene fluoride-hexafluoropropylene copolymer was adjusted to 12%; in step (3), the cold stretching temperature was adjusted to 75°C and the speed to 4 mm / min, the hot stretching temperature was adjusted to 155°C and the speed to 45 mm / min, and the total stretching ratio was adjusted to 2.8 times; in step (6), the SI-ATRP graft polymerization reaction time was extended to 5 h, and the remaining steps and conditions were the same as in Example 1, resulting in sample S2.

[0024] Testing revealed that the S2 sample had a liquid-blocking zone pore size of approximately 0.025 μm and a porosity of 32%; a transition zone pore size that gradually increased from 0.05 μm to 0.13 μm; a gas transport zone pore size of approximately 0.32 μm and a porosity of 65%; micron-sized protrusions of approximately 1.5 μm and nano-sized villous structures of approximately 90 nm; an initial water contact angle of 155°, which decreased to 150° after 10 cycles of steam sterilization at 121°C, maintaining a retention rate of 96.8%; a nitrogen flux of approximately 2950 L / (m²·h·0.1 MPa); a carbon dioxide degassing efficiency of 93.8%; and a TOC leaching amount of 0.28 mg / L.

[0025] Example 3 (S3) Based on Example 1, the blending ratio of polyvinylidene fluoride-hexafluoropropylene copolymer was adjusted to 5%; in step (4), the plasma etching power was adjusted to 80W, the etching time was adjusted to 120s, the mass fraction of chemical etching solution was adjusted to 4%, and the processing time was adjusted to 4min. The remaining steps and conditions were the same as in Example 1, and sample S3 was obtained.

[0026] Testing revealed that the S3 sample had a liquid-blocking zone pore size of approximately 0.045 μm and a porosity of 39%; a transition zone pore size that gradually decreased from 0.06 μm to 0.15 μm; a gas transport zone pore size of approximately 0.48 μm and a porosity of 73%; micron-sized protrusions of approximately 2.8 μm and nano-sized villous structures of approximately 180 nm; an initial water contact angle of 149°, which decreased to 141° after 10 cycles of steam sterilization at 121°C, maintaining a retention rate of 94.6%; a nitrogen flux of approximately 3650 L / (m²·h·0.1 MPa); a carbon dioxide degassing efficiency of 90.2%; and a TOC leaching amount of 0.41 mg / L.

[0027] Example 4 (S4) Based on Example 2, the grafting monomer in step (6) was replaced with a long-chain perfluoropolyether methacrylate with a number average molecular weight of about 2000. The SI-ATRP reaction temperature was adjusted to 65°C and the reaction time was adjusted to 6h. The remaining steps and conditions were the same as in Example 2, and sample S4 was obtained.

[0028] Testing revealed that the S4 sample had a liquid-blocking zone pore size of approximately 0.028 μm and a porosity of 33%; the transition zone pore size gradually increased from 0.05 μm to 0.13 μm; the gas transport zone pore size was approximately 0.30 μm and the porosity was 63%; the micron-sized protrusions were approximately 1.8 μm in size, and the nano-sized villous tissue was approximately 100 nm in size; the initial water contact angle was 158°, and after 10 cycles of steam sterilization at 121°C, the water contact angle remained at 154°, with a retention rate of 97.5%; the nitrogen flux was approximately 2800 L / (m³). 2 The carbon dioxide degassing efficiency was 94.6%; the TOC leaching amount was 0.22 mg / L, making it the sample with the best overall performance among the four examples.

[0029] IV. Comparative Examples Comparative Example 1 (D1, without dual-scale rough morphology and fluorinated hydrophobic layer) Hollow fiber membranes with the same substrate formulation (8% PVDF-HFP) and the same pore size gradient structure were prepared according to steps (1) to (3) of Example 1, but steps (4) plasma etching and chemical micro-etching, step (5) plasma activation and step (6) fluorination graft polymerization were skipped, and step (7) supercritical carbon dioxide extraction and purification were carried out directly to obtain the comparative membrane material, numbered D1.

[0030] Testing revealed that the pore size of the liquid-blocking region of sample D1 was approximately 0.030 μm with a porosity of 35%, while the pore size of the gas transport region was approximately 0.35 μm with a porosity of 68%, both largely consistent with S1, indicating that the pore size gradient structure was not affected by the surface treatment process. However, due to the lack of a two-scale rough morphology and the absence of a fluorinated hydrophobic layer grafted onto the outer surface of the liquid-blocking region, the initial water contact angle of sample D1 was only 108°. After 10 cycles of steam sterilization at 121°C, the water contact angle decreased to 89°, with a retention rate of only 82.4%. Furthermore, localized leakage occurred in the membrane module during the pressure resistance leakage test; the nitrogen flux decreased to 2400 L / (m³). 2 The pressure was 0.1 MPa (h), indicating that some channels were wetted; the carbon dioxide degassing efficiency dropped to 76.3%; the TOC leaching amount was 0.33 mg / L, similar to S1, indicating that the surface treatment process had little effect on the extractable content.

[0031] Therefore, under the premise of the same pore size gradient structure, the lack of dual-scale rough morphology and covalent fluorinated hydrophobic layer will result in significantly lower hydrophobic properties of the membrane material surface. Moreover, the hydrophobic stability will be significantly deteriorated after repeated high-pressure steam sterilization, making it easy for membrane pores to become wet and leak, and failing to meet the reliability requirements of long-term repeated sterilization of pharmaceutical-grade degassing components.

[0032] Comparative Example 2 (D2, substrate without PVDF-HFP) Following the process route of Example 2, the substrate was replaced with pure poly(4-methyl-1-pentene) (without adding polyvinylidene fluoride-hexafluoropropylene copolymer), and the remaining steps (annealing, radial temperature gradient stretching, dual-scale rough morphology construction, fluorination graft polymerization, supercritical carbon dioxide extraction and purification) and process conditions were exactly the same as in Example 2, resulting in a comparative membrane material, designated D2.

[0033] Testing revealed that due to the high crystallinity of the pure poly-4-methyl-1-pentene material, the deformation coordination between the outer and inner layers was poor during radial temperature gradient stretching, resulting in discontinuous transitions in the membrane pore size gradient and localized abrupt changes in pore size. The pore size distribution in the gas transport zone was uneven, ranging from 0.25 μm to 0.60 μm, with a porosity of only 58%. Similarly, the pore size distribution in the liquid blocking zone was also uneven, ranging from 0.030 μm to 0.080 μm, with a porosity of only 28%. The initial water contact angle of sample D2 was 150°, which decreased to 140° after 10 cycles of steam sterilization at 121°C, maintaining a retention rate of 93.3%, similar to Example 2. This indicates that the surface dual-scale roughness morphology and the fluorination grafting process itself were not affected; however, the nitrogen flux was only approximately 2650 L / (m²). 2 The carbon dioxide degassing efficiency was 85.1% (0.1 MPa), and the repeatability between different batches of samples was poor. Some batches showed local wetting points in the liquid-blocking area; the TOC dissolution amount was 0.31 mg / L.

[0034] Therefore, the addition of polyvinylidene fluoride-hexafluoropropylene copolymer helps to regulate the deformation coordination of the blend system during radial temperature gradient stretching, so that the pore size gradient structure is formed continuously and uniformly in the radial direction. If the substrate does not contain polyvinylidene fluoride-hexafluoropropylene copolymer, even if the surface roughening and fluorination grafting processes are exactly the same as in Example 2, the insufficient radial pore uniformity of the substrate itself will lead to a decrease in the gas transmission efficiency of the membrane material and a significant deterioration in batch stability.

[0035] V. Results Summary and Analysis For ease of comparison, the main structural parameters and performance test results of Examples 1-4 and Comparative Examples 1-2 are summarized and explained below.

[0036] Regarding the blending ratio of polyvinylidene fluoride-hexafluoropropylene copolymer, Example 1 (S1) is 8%, Example 2 (S2) is 12%, Example 3 (S3) is 5%, Example 4 (S4) is 12%, Comparative Example 1 (D1) is 8%, and Comparative Example 2 (D2) is 0% (excluding the copolymer).

[0037] Regarding the pore size and porosity of the liquid-blocking region, S1 is 0.030 μm and 35%, S2 is 0.025 μm and 32%, S3 is 0.045 μm and 39%, S4 is 0.028 μm and 33%, D1 is the same as S1 at 0.030 μm and 35%, while D2 exhibits a wide distribution range of 0.030 μm to 0.080 μm due to the non-uniformity of the pores, with a porosity of only 28%.

[0038] Regarding the pore size and porosity of the gas transport zone, S1 is 0.35 μm and 68%, S2 is 0.32 μm and 65%, S3 is 0.48 μm and 73%, S4 is 0.30 μm and 63%, D1 is the same as S1 at 0.35 μm and 68%, and D2 also exhibits a wide distribution range of 0.25 μm to 0.60 μm due to the non-uniformity of the pores, with a porosity of only 58%.

[0039] Regarding the micro-nano morphology size of the outer surface of the liquid-blocking region, S1 has a micron-scale protrusion of about 2.0 μm and a nano-scale villous texture of about 120 nm, S2 has about 1.5 μm and 90 nm respectively, S3 has about 2.8 μm and 180 nm respectively, and S4 has about 1.8 μm and 100 nm respectively; D1 does not have a dual-scale rough morphology because it has not undergone plasma etching and chemical micro-etching treatment; the surface morphology of D2 is similar to that of S2, about 2.0 μm and 120 nm respectively.

[0040] Regarding the water contact angle, S1 initially had a contact angle of 152°, which decreased to 146° after 10 sterilizations at 121°C, with a retention rate of 96.1%; S2 initially had a contact angle of 155°, which decreased to 150° after sterilization, with a retention rate of 96.8%; S3 initially had a contact angle of 149°, which decreased to 141° after sterilization, with a retention rate of 94.6%; S4 initially had a contact angle of 158°, which decreased to 154° after sterilization, with a retention rate of 97.5%; D1 initially had a contact angle of only 108°, which decreased to 89° after sterilization, with a retention rate of only 82.4%; D2 initially had a contact angle of 150°, which decreased to 140° after sterilization, with a retention rate of 93.3%.

[0041] In terms of nitrogen flux, S1 is approximately 3200 L / (m³). 2 •h•0.1MPa), S2 approximately 2950 L / (m 2 •h•0.1MPa), S3 approximately 3650 L / (m 2 •h•0.1MPa), S4 approximately 2800 L / (m 2 (·h·0.1MPa), D1 decreases to approximately 2400 L / (m 2 ·h·0.1MPa), D2 is approximately 2650 L / (m 2 (·h·0.1MPa).

[0042] In terms of carbon dioxide degassing efficiency, S1 is 92.5%, S2 is 93.8%, S3 is 90.2%, S4 is 94.6%, D1 decreases to 76.3%, and D2 is 85.1%.

[0043] In terms of total organic carbon (TOC) leaching, S1 was 0.35 mg / L, S2 was 0.28 mg / L, S3 was 0.41 mg / L, S4 was 0.22 mg / L, D1 was 0.33 mg / L, and D2 was 0.31 mg / L. All samples were at a low level.

[0044] Based on the data above, it can be seen that: (1) Comparing Examples 1-4 with Comparative Example 1 (D1), it can be seen that under the condition that the substrate formulation and pore size gradient structure are exactly the same, whether or not a dual-scale rough morphology is constructed and a fluorinated hydrophobic layer is covalently grafted is the key factor determining the initial hydrophobicity of the membrane material and its hydrophobic stability after repeated high-pressure steam sterilization: the samples of Examples 1-4 with dual-scale rough morphology and fluorinated hydrophobic layer have a contact angle retention rate of more than 94% after 10 times of 121°C steam sterilization, while the contact angle retention rate of Comparative Example 1 (D1) is only 82.4%, accompanied by a significant decrease in leakage and degassing efficiency.

[0045] (2) Comparing Example 2 and Comparative Example 2 (D2), it can be seen that under the condition that the surface treatment process is exactly the same, the introduction of polyvinylidene fluoride-hexafluoropropylene copolymer in the substrate plays an important role in the continuity, uniformity and batch stability of the pore size gradient structure: the pore size distribution of the Comparative Example 2 sample without the copolymer is obviously wider and less uniform, and the gas transmission efficiency and repeatability are significantly lower than those of Example 2.

[0046] (3) Within the range of Examples 1 to 4, as the blending ratio of polyvinylidene fluoride-hexafluoropropylene copolymer (within the range of 5% to 15%) and the molecular weight of graft monomer are adjusted, the pore size gradient structure, hydrophobic stability, gas removal efficiency and low dissolution performance of the membrane material can all achieve a good synergistic balance. Among them, Example 4 (blending ratio of 12% and graft monomer molecular weight of about 2000) has the best comprehensive performance in terms of hydrophobic stability (contact angle retention rate of 97.5%), carbon dioxide degassing efficiency (94.6%) and low dissolution performance (TOC dissolution amount of 0.22 mg / L), and is one of the preferred embodiments of the present invention.

[0047] In summary, this invention, through the synergistic design of an integrally formed continuous pore size gradient structure, a dual-scale rough morphology on the outer surface of the liquid-blocking region, and a covalently grafted fluorinated hydrophobic layer, combined with a substrate formulation free of plasticizers and antistatic agents and a supercritical carbon dioxide extraction purification process, enables the resulting hollow fiber membrane material to maintain excellent gas removal efficiency while possessing good liquid-blocking reliability, hydrophobic stability resistant to repeated high-pressure steam sterilization, and low dissolution cleanliness meeting pharmaceutical-grade requirements, thus demonstrating promising prospects for industrial applications.

[0048] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A pharmaceutical-grade low-dissolution degassing hollow fiber membrane material, characterized in that, The substrate is a blend of poly(4-methyl-1-pentene) and polyvinylidene fluoride-hexafluoropropylene copolymer; The hollow fiber membrane material has a continuous pore size gradient structure integrally formed in the radial direction, which is divided into a liquid blocking region, a transition region and a gas transport region from the outside to the inside, with the pore size increasing in that order. The outer surface of the liquid-blocking region has a dual-scale rough morphology composed of a micron-level protrusion structure and a nano-level villous structure. The surface of the dual-scale rough morphology is also covalently grafted with a fluorinated hydrophobic layer, which covers the surface of the micron-scale protrusion structure and the nano-scale villous structure.

2. The pharmaceutical-grade low-dissolution degassing hollow fiber membrane material according to claim 1, characterized in that, The pore size of the liquid-blocking region is 0.02μm to 0.05μm, and the porosity is 30% to 40%; the pore size of the transition region gradually changes from 0.05μm to 0.15μm; the pore size of the gas transport region is 0.2μm to 0.5μm, and the porosity is 60% to 75%.

3. The pharmaceutical-grade low-dissolution degassing hollow fiber membrane material according to claim 1, characterized in that, The protrusion size of the micron-scale protrusion structure is 1μm to 3μm, and the size of the nano-scale villous structure is 50nm to 200nm. The nano-scale villous structure is distributed between adjacent micron-scale protrusion structures.

4. The pharmaceutical-grade low-dissolution degassing hollow fiber membrane material according to claim 1, characterized in that, The fluorinated hydrophobic layer is formed by graft polymerization of long-chain perfluoropolyether methacrylate monomers, wherein the molecular weight of the long-chain perfluoropolyether methacrylate monomers is greater than 1000.

5. The pharmaceutical-grade low-dissolution degassing hollow fiber membrane material according to claim 1, characterized in that, The blending ratio of polyvinylidene fluoride-hexafluoropropylene copolymer in the substrate is 5% to 15%.

6. The pharmaceutical-grade low-dissolution degassing hollow fiber membrane material according to claim 1, characterized in that, The substrate does not contain plasticizers or antistatic additives.

7. The pharmaceutical-grade low-dissolution degassing hollow fiber membrane material according to claim 1, characterized in that, After the hollow fiber membrane material is subjected to at least 10 cycles of high-pressure steam sterilization at 121°C or above, the fluorinated hydrophobic layer is still maintained in the form of covalent bonds on the dual-scale rough morphology surface.

8. A method for preparing a pharmaceutical-grade low-dissolution degassing hollow fiber membrane material, used to prepare the pharmaceutical-grade low-dissolution degassing hollow fiber membrane material according to any one of claims 1-7, characterized in that, Includes the following steps: The nascent fibers were obtained by extruding poly(4-methyl-1-pentene) and polyvinylidene fluoride-hexafluoropropylene copolymer after melt blending. The nascent fibers are subjected to high-temperature annealing treatment; Under radial temperature gradient control, the annealed fibers are subjected to low-temperature cold stretching and high-temperature hot stretching in sequence, so that the membrane wall is integrally formed with the pore size increasing from the outside to the inside in the liquid blocking zone, transition zone and gas transport zone, and then heat set to obtain hollow fibers. The outer surface of the liquid-blocking region of the hollow fiber is subjected to plasma etching and chemical micro-etching in sequence to form a dual-scale rough morphology that combines micron-scale protrusion structure and nano-scale villous structure. Low-temperature oxygen plasma activation treatment was performed on the surface with dual-scale rough morphology. Using long-chain perfluoropolyether methacrylate as a grafting monomer, grafting polymerization is carried out on the activated dual-scale rough morphology surface by surface-initiated atom transfer radical polymerization, so that the fluorinated hydrophobic segments are covalently covered on the dual-scale rough morphology surface to form a fluorinated hydrophobic layer. Hollow fiber membranes were purified by supercritical carbon dioxide extraction to obtain pharmaceutical-grade low-dissolution degassed hollow fiber membrane materials.

9. The preparation method according to claim 8, characterized in that, The radial temperature gradient control is as follows: the outer layer of the membrane wall corresponding to the liquid blocking region is stretched slowly at a relatively low temperature, while the inner layer of the membrane wall corresponding to the gas transport region is stretched rapidly at a relatively high temperature.

10. The preparation method according to claim 8, characterized in that, The plasma activation treatment is controlled to a depth of less than 100 nm on the surface to avoid affecting the intrinsic pore structure of the membrane.