Preparation method of MOFs / copolymer composite material blood purification adsorbent

Abstract

The invention relates to a preparation method of an MOFs / copolymer composite material. The preparation method comprises the following steps: (1) mixing styrene, divinylbenzene, acrylic acid, a pore-forming agent and an initiator to obtain an oil phase; a dispersant and water are mixed as a water phase; (2) injecting the oil phase into the water phase to carry out copolymerization reaction, and after the reaction is finished, cleaning to remove the pore-foaming agent to obtain a PS-DVB-AA precursor; (3) adding the PS-DVB-AA precursor into a zinc-containing aqueous solution for a chelating reaction, adding a 2-methylimidazole aqueous solution after the reaction is finished, and filtering to obtain compound particles; and (4) after the reaction is completed, washing and drying the obtained compound microparticles for multiple times to obtain the MOFs / copolymer composite material. When the composite material is applied to a blood perfusion adsorbent, not only is the toxin adsorption capacity of the adsorbent material improved, but also the stability of the adsorbent material is improved.

Description

Technical Field

[0001] The present invention relates to the field of molecular sieve composite materials, and provides a preparation method of a composite adsorbent that can be used for blood purification. Background Art

[0002] Hemoperfusion adsorbents play an important role in the treatment of clinical hemoperfusion diseases. Hemoperfusion adsorbents remove harmful substances in blood such as uremic toxins, bilirubin, endotoxin, sedative drugs, etc. through electrostatic interaction, hydrogen bond and other ways, so as to purify the patient's blood.

[0003] Metal-organic framework materials (MOFs), also known as porous coordination polymers, are a class of crystalline porous materials with a repeated network structure formed by the self-assembly connection of metal ions or metal ion clusters and bridging organic ligands. Due to their characteristics such as high porosity, high specific surface area, adjustable structure, and good chemical and thermal stability, MOFs materials have been widely used in the fields of catalysis, adsorption, drug loading, light-emitting devices, etc. in recent years. However, MOFs generally have the disadvantages of low mechanical strength and poor chemical stability, which limit their application fields and effects. In order to make up for these defects, MOFs are compounded with other materials to obtain new composite materials, which make up for the defects of MOFs and are thus used in a wider range of technical fields. Common MOFs composite materials include MOFs / carbon, MOFs / silica, MOFs / polymer, etc.

[0004] Polymers have advantages such as thermal stability and chemical stability. Ultra-high cross-linked polystyrene resin polymers are currently commonly used blood purification adsorbents, but their preparation is cumbersome and has problems of biological toxicity. The improvement of hemoperfusion adsorbents is a current research hotspot in technology. New materials produced by the hybridization of polymers and MOFs exhibit unique properties that are difficult to achieve individually by each component.

[0005] CN118994451A discloses a biological polyphenol macroporous resin. Its preparation method includes the following steps: Step S1, preparing an oil phase substance and an aqueous phase substance respectively; Step S2, continuously stirring the aqueous phase substance, introducing nitrogen protection into the heating device, and dropping the oil phase substance into the aqueous phase substance. After the dropping is completed, a mixture is obtained; Step S3, heating the mixture to a second temperature, stirring and keeping warm for a first period of time to obtain a solid-liquid mixture; Step S4, separating the solid product in the solid-liquid mixture, washing the solid product to obtain a biological polyphenol-based macroporous resin. Its preparation method is environmentally friendly and can reduce the harm caused by material preparation to the human body and the environment.

[0006] CN115449006A discloses a highly crosslinked macroporous resin for adsorbing medium and large molecular toxins. Its preparation method includes: (1) Mixing styrene monomers, polyvinyl crosslinking agents, pore-forming agents and initiators as the oil phase, and mixing dispersants, surfactants, salts and pure water as the water phase. Under stirring conditions, disperse the oil phase in the water phase to form an O / W emulsion, raise the temperature for suspension polymerization reaction to obtain polystyrene-based white balls, wash, extract and dry; (2) Swell the polystyrene-based white balls, then add aliphatic aldehydes and Lewis acid catalysts for reaction, and wash and dry the product. The highly crosslinked macroporous resin has a large specific surface area and excellent biocompatibility, and can adsorb medium and large molecular toxins such as protein-bound toxins in the blood. Its preparation method is green and environmentally friendly. Summary of the Invention

[0007] In view of the problems existing in the existing polymer blood perfusion adsorbents, the present invention first proposes a preparation method for a novel MOFs / olefin copolymer composite material. By optimizing the pore-forming agent, the pore size of the copolymer is increased, which is beneficial to the formation of MOFs by MOFs; introducing acrylic acid monomers into the olefin copolymer can significantly improve the stability and adsorption performance of the MOFs / olefin copolymer composite material. As a blood perfusion adsorbent, this composite material improves the toxin adsorption capacity and the stability of the adsorption material.

[0008] One aspect of the present invention discloses a preparation method for a MOFs / copolymer composite material, including the following steps:

[0009] (1) Mix styrene, divinylbenzene, acrylic acid, pore-forming agent and initiator to obtain the oil phase; mix the dispersant and water as the water phase;

[0010] (2) Inject the oil phase into the water phase for copolymerization reaction. After the reaction is completed, wash to remove the pore-forming agent to obtain the PS-DVB-AA precursor;

[0011] (3) Add the PS-DVB-AA precursor to an aqueous solution containing zinc for chelation reaction. After the reaction is completed, add an aqueous solution of 2-methylimidazole and filter to obtain composite particles;

[0012] (4) After the reaction is completed, wash the obtained composite microparticles multiple times and dry to obtain the MOFs / copolymer composite material.

[0013] In step (1), the mass ratio of styrene to divinylbenzene is 10 - 90:10 - 90, and the mass ratio of the sum of the masses of styrene and divinylbenzene to acrylic acid is 80 - 90:10 - 20; the mass ratio of the pore-forming agent to the sum of the masses of styrene, divinylbenzene, and acrylic acid is 1 - 5:100; the mass ratio of the initiator to the sum of the masses of styrene, divinylbenzene, and acrylic acid is 0.2 - 2:100; in step (1), the mass ratio of the oil phase to the water phase is 1:1.5 - 3; the dispersant is one of polyvinyl alcohol or gelatin; the mass concentration of the dispersant is 1 - 5%.

[0014] In step (1), the pore-forming agent is an organic ammonium salt with alkyl substituents that are not completely the same, the number of carbon atoms of the alkyl group is 1 - 8, more preferably 1 - 4; preferably, the pore-forming agent is one of trimethylethylammonium hydroxide, methyldiethylammonium hydroxide, methy tributylammonium hydroxide, trimethylpropylammonium hydroxide, triethylpropylammonium hydroxide, triethylbutylammonium hydroxide, tripropylmethylammonium hydroxide, tripropylethylammonium hydroxide.

[0015] In step (1), the initiator is one of azobisisobutyronitrile, azobisisoheptonitrile, benzoyl peroxide, tert-butyl peroxy-2-ethylhexanoate, tert-amyl peroxy-2-ethylhexanoate.

[0016] In step (2), the copolymerization reaction temperature is 30 - 80°C, preferably 50 - 60°C, the reaction time is 8 - 24 h, more preferably 10 - 16 h; the cleaning uses an acetic acid solution, and the acetic acid concentration is 0.1 - 0.5 mol / L.

[0017] In step (3), the mass-volume ratio of the PS-DVB-AA precursor to the zinc-containing aqueous solution is 1 g:10 - 50 ml; the concentration of zinc in the zinc-containing aqueous solution is 0.05 - 0.2 mol / L, and the concentration of the 2-methylimidazole aqueous solution is 0.1 - 0.5 mol / L; the molar ratio of zinc ions to 2-methylimidazole is 2 - 5.

[0018] In step (4), ultrasonic cleaning is used, and the cleaning uses ethanol or ethylene glycol, the cleaning time is 10 - 60 min; the drying temperature is 120 - 200°C, and the drying time is 1 - 6 h.

[0019] In another aspect of the present invention, a MOFs / copolymer composite material prepared by the method is disclosed, and the particle size of the MOFs / copolymer composite material is 100 - 1000 μm, more preferably 300 - 500 μm.

[0020] The adsorption rate of the MOFs / copolymer composite material for parathyroid hormone (PTH) is greater than 95%, more preferably greater than 97%; the adsorption rate for β2-microglobulin (β2-MG) is greater than 85%, more preferably greater than 86%.

[0021] Another aspect of the present invention discloses the application of the MOFs / copolymer composite material prepared by the method in whole blood perfusion adsorption.

[0022] The obtained MOFs / copolymer composite material of the present invention has an improved hierarchical pore structure. The pore-forming agent is preferably used to generate a pore structure with a pore diameter more suitable for embedding MOFs crystal grains. In addition, the carboxyl groups in the resin material have strong hydrophilic properties, which are beneficial to the formation of hydrogen bonds between MOFs crystal grains and resin macromolecules, thereby generating a composite material with stable chemical properties. The hierarchical pore structure of the composite material is beneficial for harmful small molecule substances in the blood, such as bilirubin, endotoxin, uremic toxins, etc., to enter the composite adsorbent material, so as to purify the patient's blood.

[0023] The technical effects of the present invention: The present invention improves the composition of the resin polymerization monomer, adds an acrylic acid monomer with better hydrophilicity, and improves the stability of the composite formed by MOFs and resin. The MOFs in the composite material can efficiently adsorb harmful small molecules in the blood. The composite material has low hemolysis and anticoagulation properties and can be used as a safe and efficient whole blood perfusion adsorbent. Specific embodiments

[0024] The following examples are used to further illustrate the present invention, but do not limit the present invention accordingly.

[0025] Example 1:

[0026] The preparation of the MOFs / copolymer composite material includes the following steps:

[0027] (1) Styrene, divinylbenzene, acrylic acid, pore-forming agent trimethylethylammonium hydroxide, and initiator azobisisobutyronitrile are mixed in a mass ratio of 50:40:15:3:1 to obtain an oil phase; dispersant polyvinyl alcohol and water are mixed to obtain a 2 wt% solution as the water phase;

[0028] (2) The oil phase is injected into the water phase at a mass ratio of oil phase: water phase of 1:2 and reacted at 50 °C for 12 h. After the reaction, the polymer product is filtered and washed, and a 0.1 mol / L acetic acid solution is added to remove the pore-forming agent to obtain a PS-DVB-AA precursor;

[0029] (3) The PS-DVB-AA precursor was added to an aqueous zinc solution with a concentration of 0.1 mol / L at a ratio of 1 g:20 ml for chelation reaction. After the reaction, an aqueous 2-methylimidazole solution with a concentration of 0.25 mol / L was added according to the dosage of 1 g:20 ml of 2-methylimidazole aqueous solution per 1 g of the PS-DVB-AA precursor, and the composite particles were obtained by filtration.

[0030] (4) After the reaction was completed, the obtained composite microparticles were washed ultrasonically with ethanol multiple times and dried at 150 °C for 3 h to obtain the MOFs / copolymer composite material.

[0031] Example 2:

[0032] Preparation of the MOFs / copolymer composite material includes the following steps:

[0033] (1) Styrene, divinylbenzene, acrylic acid, pore-forming agent methyltriethylammonium hydroxide, and initiator azodiisooctanenitrile were mixed in a mass ratio of 40:50:10:3:0.5 to obtain the oil phase; dispersant polyvinyl alcohol and water were mixed to obtain a 3 wt% solution as the water phase.

[0034] (2) The oil phase was injected into the water phase at an oil phase:water phase mass ratio of 1:2.5 and reacted at 70 °C for 12 h. After the reaction, the polymer product was filtered and washed, and a 0.1 mol / L acetic acid solution was added to remove the pore-forming agent to obtain the PS-DVB-AA precursor.

[0035] (3) The PS-DVB-AA precursor was added to an aqueous zinc solution with a concentration of 0.1 mol / L at a ratio of 1 g:20 ml for chelation reaction. After the reaction, an aqueous 2-methylimidazole solution with a concentration of 0.25 mol / L was added according to the dosage of 1 g:20 ml of 2-methylimidazole aqueous solution per 1 g of the PS-DVB-AA precursor, and the composite particles were obtained by filtration.

[0036] (4) After the reaction was completed, the obtained composite microparticles were washed ultrasonically with ethanol multiple times and dried at 120 °C for 3 h to obtain the MOFs / copolymer composite material.

[0037] Example 3:

[0038] Preparation of the MOFs / copolymer composite material includes the following steps:

[0039] (1) Styrene, divinylbenzene, acrylic acid, pore-forming agent triethylbutylammonium hydroxide, and initiator azodiisobutyronitrile were mixed in a mass ratio of 40:40:15:2:1 to obtain the oil phase; dispersant gelatin and water were mixed to obtain a 4 wt% solution as the water phase.

[0040] (2) Inject the oil phase into the water phase at a mass ratio of oil phase: water phase of 1:3 and react at 60 °C for 8 h. After the reaction, filter and wash the polymer product, and add 0.1 mol / L acetic acid solution to remove the pore-forming agent to obtain the PS-DVB-AA precursor;

[0041] (3) Add the PS-DVB-AA precursor at a ratio of 1 g: 30 ml to an aqueous zinc solution with a concentration of 0.1 mol / L for chelation reaction. After the reaction, add an aqueous 2-methylimidazole solution with a concentration of 0.25 mol / L according to the dosage of 1 g: 30 ml of 2-methylimidazole aqueous solution for the PS-DVB-AA precursor, and filter to obtain composite particles;

[0042] (4) After the reaction is completed, wash the obtained composite microparticles with ethanol by ultrasonic wave for multiple times and dry them at 170 °C for 1 h to obtain the MOFs / copolymer composite material.

[0043] Comparative Example 1:

[0044] Other steps are the same as those in Example 1, except that the polymerization monomers are styrene and divinylbenzene mixed at a mass ratio of 50:40.

[0045] Comparative Example 2:

[0046] Other steps are the same as those in Example 1, except that toluene is used as the pore-forming agent.

[0047] Comparative Example 3:

[0048] Other steps are the same as those in Example 1, except that the preparation method does not include step (3) and the copolymer does not contain MOFs.

[0049] Perform hemoperfusion purification tests on the adsorbents obtained in the examples and comparative examples. The test uses human plasma as the adsorption environment. Add parathyroid hormone with a concentration of 200 pmol / mL and β2-microglobulin with a concentration of 5000 ng / mL to the human plasma. Take 0.5 g of the adsorbent, moisten it with normal saline, add 10 mL of the above plasma, and adsorb it at a constant temperature of 37 °C for 1 h. Take the plasma and detect the concentrations of parathyroid hormone and β2-microglobulin in it. The results are shown in Table 1.

[0050] Table 1

[0051] Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 MTH adsorption rate 95.8％ 95.3％ 97.1％ 83.3％ 88.6％ 75.1％ β2-MG adsorption rate 85.1％ 85.6％ 86.3％ 70.3％ 75.2％ 60.5％

[0052] Judging from the plasma adsorption results of the examples and comparative examples, the adsorbent described in this application has better blood toxin adsorption ability.

[0053] Those skilled in the art should clearly understand that the above embodiments are only used to exemplarily illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the protection scope of the present invention.

Claims

1. A method for preparing a MOFs / copolymer composite material, comprising the following steps: (1) styrene, divinylbenzene, acrylic acid, a pore-forming agent, and an initiator are mixed to obtain an oil phase; a dispersant and water are mixed to obtain an aqueous phase; (2) injecting the oil phase into the water phase for copolymerization, and washing and removing the porogen after the reaction to obtain a PS-DVB-AA precursor; (3) PS-DVB-AA precursor is added to an aqueous solution containing zinc for chelation reaction, and after the reaction, a 2-methylimidazole aqueous solution is added, and the composite particles are obtained by filtration; (4) After the reaction is completed, the obtained composite microparticles are washed multiple times and dried to obtain a MOFs / copolymer composite material.

2. The method according to claim 1, characterized in that In step (1), the mass ratio of styrene to divinylbenzene is 10-90:10-90, and the mass ratio of the sum of the mass of styrene and divinylbenzene to the mass ratio of acrylic acid is 80-90:10-20; the mass ratio of the pore-forming agent to the sum of the mass of styrene, divinylbenzene and acrylic acid is 1-5:100; the mass ratio of the initiator to the sum of the mass of styrene, divinylbenzene and acrylic acid is 0.2-2:100; the mass ratio of the oil phase to the water phase in step (1) is 1:1.5-3; the dispersant is one of polyvinyl alcohol or gelatin; and the mass concentration of the dispersant is 1-5%.

3. The method according to claim 1, characterized in that The pore-forming agent in step (1) is an organic ammonium salt having alkyl substituents that are not completely the same, and the number of carbon atoms of the alkyl group is 1-8, and more preferably 1-4; preferably, the pore-forming agent is one of trimethylethylammonium hydroxide, methyltriethylammonium hydroxide, methyltributylammonium hydroxide, trimethylpropylammonium hydroxide, triethylpropylammonium hydroxide, triethylbutylammonium hydroxide, tripropylmethylammonium hydroxide, and tripropylethylammonium hydroxide.

4. The method according to claim 1, characterized in that The initiator in step (1) is one of azobisisobutyronitrile, azobisisoheptanenitrile, benzoyl peroxide, tert-butyl peroxy-2-ethylhexanoate, and tert-amyl peroxy-2-ethylhexanoate.

5. The method according to claim 1, characterized in that Step (2) The copolymerization reaction temperature is 30-80°C, preferably 50-60°C, and the reaction time is 8-24h, more preferably 10-16h; the cleaning uses an acetic acid solution with an acetic acid concentration of 0.1-0.5mol / L.

6. The method according to claim 1, characterized in that In step (3), the mass volume ratio of the PS-DVB-AA precursor and the zinc-containing aqueous solution is 1g:10-50ml; the concentration of zinc in the zinc-containing aqueous solution is 0.05-0.2mol / L, and the concentration of the 2-methylimidazole aqueous solution is 0.1-0.5mol / L; the molar ratio of the zinc ion to the 2-methylimidazole is 2-5.

7. The method according to claim 1, characterized in that In step (4), ultrasonic cleaning is adopted, ethanol or ethylene glycol is used for cleaning, and the cleaning time is 10-60 minutes; the drying temperature is 120-200° C., and the drying time is 1-6 hours.

8. A MOFs / copolymer composite material prepared by the method according to any one of claims 1 to 7, characterized in that The particle size of the MOFs / copolymer composite material is 100-1000 μm, more preferably 300-500 μm.

9. The composite material according to claim 8, characterized in that The adsorption rate of the MOFs / copolymer composite material to parathyroid hormone (PTH) is greater than 95%, more preferably greater than 97%; the adsorption rate to β2-microglobulin (β2-MG) is greater than 85%, more preferably greater than 86%.

10. Use of the MOFs / copolymer composite material prepared by the method according to any one of claims 1 to 7 in whole blood perfusion adsorption.