CN114100588B - Nitrogen-containing functional group ultrahigh crosslinked adsorbent, preparation method thereof and blood perfusion device - Google Patents

Nitrogen-containing functional group ultrahigh crosslinked adsorbent, preparation method thereof and blood perfusion device Download PDF

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CN114100588B
CN114100588B CN202010896376.0A CN202010896376A CN114100588B CN 114100588 B CN114100588 B CN 114100588B CN 202010896376 A CN202010896376 A CN 202010896376A CN 114100588 B CN114100588 B CN 114100588B
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CN114100588A (en
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刘云鸿
彭新艳
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Quanzhou Normal University
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
    • B01J20/267—Cross-linked polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F212/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F212/02—Monomers containing only one unsaturated aliphatic radical
    • C08F212/04—Monomers containing only one unsaturated aliphatic radical containing one ring
    • C08F212/06—Hydrocarbons
    • C08F212/08—Styrene
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F212/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F212/02—Monomers containing only one unsaturated aliphatic radical
    • C08F212/04—Monomers containing only one unsaturated aliphatic radical containing one ring
    • C08F212/06—Hydrocarbons
    • C08F212/12—Monomers containing a branched unsaturated aliphatic radical or a ring substituted by an alkyl radical
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F212/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F212/34—Monomers containing two or more unsaturated aliphatic radicals
    • C08F212/36—Divinylbenzene
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
    • C08F8/32—Introducing nitrogen atoms or nitrogen-containing groups by reaction with amines

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  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

The invention discloses a nitrogen-containing functional group ultrahigh crosslinked adsorbent and a preparation method thereof. According to the preparation method, the use of carcinogenic chloromethyl methyl ether is avoided in the preparation process, so that the safety and environmental protection problems caused by the use of carcinogenic chloromethyl methyl ether in the traditional process are solved; the invention adopts a novel cross-linking agent system, realizes the post-crosslinking of the adsorbent resin and the functionalization of the nitrogen-containing group by a one-step method on the basis of polystyrene microspheres, and has simple reaction process; the preparation and development of the novel nitrogen-containing functional group ultrahigh crosslinked adsorbent are beneficial to improving the broad-spectrum toxin adsorption and removal functions of the adsorbent and reducing the medical cost of blood perfusion.

Description

Nitrogen-containing functional group ultrahigh crosslinked adsorbent, preparation method thereof and blood perfusion device
Technical Field
The invention relates to an adsorption resin, a preparation method and an application field thereof, in particular to a nitrogen-containing functional group ultrahigh crosslinked adsorbent, a preparation method thereof and a perfusion device using the adsorbent.
Background
The ultra-high crosslinked polystyrene resin is a polymer adsorbent with high crosslinking degree, complex internal structure and porous network structure. Compared with the traditional adsorbent activated carbon, the ultra-high crosslinked polystyrene resin has the advantages of high specific surface area, rigid framework, stable physical and chemical properties, adjustable pore diameter structure and easy regeneration and circulation, and is widely applied to the fields of blood perfusion technology, environmental pollution control, chemical analysis, medicine separation and purification and the like at present. Particularly in the field of blood perfusion, the ultra-high crosslinking resin has excellent adsorption performance, can remove endogenous or exogenous pathogenic factors in blood in an adsorption mode, such as uremic toxins, sedative hypnotic drugs, herbicide pesticides and the like, and plays an important role in the field of treating liver and kidney failure, acute drug poisoning and other diseases.
However, the ultra-high crosslinked polystyrene resin still has certain problems in production and use, such as the existing blood perfusion ultra-high crosslinked polystyrene resin is mainly prepared by chloromethylation and Friedel-Crafts post-crosslinking of macroporous low crosslinked polystyrene-divinylbenzene copolymer; the chloromethylation process uses toxic and carcinogenic chloromethyl ether and other chemical substances, and the chemical substances have strong carcinogenicity and low boiling point and volatility, so that the chemical substances cause great threat to the health of production operators, cause great pollution to the environment and have high preparation cost, thereby influencing the sustainable development of the whole industry and needing further technical optimization and improvement; in addition, the prepared ultra-high crosslinked polystyrene resin structure also contains a certain residual amount of chloromethyl, and in the storage and use processes of the hemoperfusion apparatus, the residual chloromethyl can undergo side reactions such as hydrolysis and the like, so that the pH value is reduced, and a certain potential safety hazard exists. In addition, the existing ultra-high crosslinked polystyrene resin IS mainly aimed at middle-large molecular toxins, but has no good adsorption and removal effects on protein-bound toxoids such as bilirubin, IS and PCS, charged toxins such as endotoxin and the like. The development of novel resin with higher broad-spectrum toxin adsorption and removal functions, the reduction of medical cost and the improvement of the treatment rate of patients become urgent clinical demands.
Therefore, the development of the novel ultra-high crosslinking adsorbent which avoids using chloromethyl ether as a raw material, has the advantages of green and environment-friendly preparation process method, controllable performance and higher broad-spectrum toxin adsorption and removal function is of great importance to the development of the ultra-high crosslinking adsorbent industry, the health of human beings and the development of the blood perfusion adsorbent resin industry.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the invention aims to provide the nitrogen-containing functional group ultrahigh crosslinking adsorbent, the preparation method thereof and the perfusion device using the adsorbent, wherein chloromethyl ether is not used as a raw material for the adsorbent material, and the preparation process method is environment-friendly and has controllable structure and performance;
in order to achieve the above object, the present invention adopts the following technical scheme;
the invention provides a nitrogen-containing functional group ultrahigh crosslinked adsorbent which is prepared by mixing polystyrene microspheres with a nitrogen-containing functional group crosslinking agent A, a crosslinking agent B and a swelling agent and performing crosslinking reaction under the condition of a catalyst;
the nitrogen-containing functional group cross-linking agent A is:
wherein R is 1 Is of the type-CH 3 、*—CH 2 CH 3 、*—CH 2 CH 2 CH 3 、*—CH 2 CH 2 CH 2 CH 3 、*—CH(CH 3 ) 2 One of (2) is provided;
R 2 is H, X-CH 3 、*—CH 2 CH 3 、*—OCH 3 、*—OCH 2 CH 3 、*—OCH(CH 3 ) 2 、*—OCH 2 CH 2 CH 2 CH 3 One of (2) is provided;
R 3 is: - (CH) 2 ) n -. SumOne of (2) is provided; wherein n is an integer of 0 to 18, and m is an integer of 0 to 18;
R 4 is one of a tertiary amine group structure, a secondary amine group structure, a primary amine group structure, a pyridine group structure, an aromatic amine group structure, a pyrrole group structure, an imidazole group structure, a morpholine group structure, a pyrimidine group structure, a naphthyridine group structure and a quaternary ammonium salt group structure;
wherein, represents the point of covalent attachment;
wherein R is 4 In the case of tertiary amine group structure, the nitrogen-containing functional group crosslinking agent A is preferably N, N-dimethylformamide dimethyl acetal, (dimethylamino) acetaldehyde formal, diethylaminoacetaldehyde dimethyl acetal, 1-dimethoxy-N, N-dimethylethylamine, 4-dimethylaminobutyraldehyde dimethyl acetal, dimethylaminoacetaldehyde diethyl acetal, 4-dimethyl acetalAmino butyraldehyde diethanol, 4-dimethylaminobutyraldehyde diethanol, diethylaminoacetaldehyde diethanol;
wherein R is 4 In the case of primary amine group structure, the nitrogen-containing functional group crosslinking agent A is preferably aminoacetaldehyde dimethyl acetal, 4-aminobutyraldehyde dimethyl acetal, aminoacetaldehyde diethyl acetal, 2-aminopropionaldehyde dimethyl acetal or 4-aminobutyraldehyde diethyl acetal;
wherein R is 4 In the case of secondary amine group structure, the nitrogen-containing functional group crosslinking agent A is preferably N-methylamino acetaldehyde dimethyl acetal, butylaminoacetal dimethyl acetal, methylamino acetaldehyde dimethyl acetal, phenethylamino acetaldehyde dimethyl acetal, N-benzylamino acetaldehyde dimethyl acetal, cyclododecyl-2-aminoacetal diethyl acetal;
wherein R is 4 In the case of imidazole group structure, the nitrogen-containing functional group crosslinking agent A is preferably 2- (dimethoxymethyl) -1H-imidazole, 1- [4- (2, 2-dimethoxy-ethoxy) -phenyl]-1H-imidazole, 5, 6-dimethoxybenzimidazole;
wherein R is 4 In the case of an aromatic amine group structure, the nitrogen-containing functional group crosslinking agent A is preferably 3- (dimethoxymethyl) aniline;
wherein R is 4 In the case of morpholine group structure, the nitrogen-containing functional group cross-linking agent A is preferably 4- (2, 2-dimethoxyethyl) morpholine;
wherein R is 4 In the case of pyrimidine group structure, the nitrogen-containing functional group crosslinking agent A is preferably 4- (dimethoxymethyl) pyrimidine;
wherein R is 4 In the case of naphthyridine group structure, the nitrogen-containing functional group crosslinking agent A is preferably [1,8 ]]Naphthyridine-2-carbaldehyde dimethyl acetal;
the cross-linking agent B is:
at least one of (2);
wherein R is 5 Is of the type-CH 3 、*—CH 2 CH 3 、*—CH 2 CH 2 CH 3 、*—CH 2 CH 2 CH 2 CH 3 、*—CH(CH 3 ) 2 One of (2) is provided;
k is an integer of 0 to 18;
R 6 is hydrogen, -CH 3 、*—CH 2 CH 3 、One of (2) is provided;
wherein, represents the point of covalent attachment;
the catalyst is at least one of Lewis acid and protonic acid;
the nitrogen-containing functional group ultrahigh crosslinked adsorbent is spherical particles with the particle size of 0.01-3 mm; the specific surface area of the nitrogen-containing functional group super-crosslinked adsorbent is 10-3500 m 2 /g；
The ion exchange capacity of the nitrogen-containing functional group super-high crosslinking adsorbent can be controlled to be 0.0001-5.0 mmol/ml.
The preparation method of the nitrogen-containing functional group ultrahigh crosslinked adsorbent comprises the following steps:
(1) Suspension polymerization for preparing polystyrene microsphere
The preparation method comprises the steps of forming an oil phase by using a styrene monomer, a pore-forming agent and an oily initiator, carrying out suspension polymerization on the oil phase in a water phase consisting of a dispersing agent, a dispersing aid and water, removing the pore-forming agent in the polymerized resin, purifying and drying to obtain the polystyrene microsphere.
The polystyrene microsphere is obtained by suspension polymerization of monomers, and the styrene monomer is at least one of a multi-vinyl aromatic monomer and a single-vinyl aromatic monomer in the monomers of suspension polymerization reaction; the polyvinyl aromatic monomers include a class of compounds consisting of divinylbenzene, mixtures of m-divinylbenzene and p-divinylbenzene, trivinylbenzene, divinylbenzene, divinylxylene, divinylnaphthalene, and derivatives thereof, for example, halides such as chlorodivinylbenzene, and the like. These compounds may be used singly or as a mixture of two or more. The polyvinyl aromatic monomer is preferably at least one of m-divinylbenzene and p-divinylbenzene; particularly preferred polyvinyl aromatic monomer mixtures consist of m-divinylbenzene and p-divinylbenzene. In the preparation of polystyrene-based microspheres by suspension polymerization in the step (1) of the invention, the amount of the polyvinyl aromatic monomer is calculated by dry weight of the copolymer; the monomer comprises at least 1wt% of a polyvinyl aromatic monomer; the amount of the polyvinyl aromatic monomer is preferably 1 to 80% by weight based on the dry weight of the copolymer.
In the suspension polymerization monomers, the monovinylaromatic monomers include, but are not limited to, for example, styrene and C 1 -C 4 Alkyl substituted styrenes such as ethyl styrene, m-ethyl styrene and p-ethyl styrene and mixtures thereof, derivatives, e.g. halides, such as chlorostyrene and chloroethyl styrene. These compounds may be used singly or in a mixture of two or more kinds; the monovinyl aromatic monomer is preferably at least one of styrene, m-ethyl styrene and p-ethyl styrene; particularly preferred mixtures are, for example, mixtures of m-and p-ethylstyrene and mixtures of styrene, m-and p-ethylstyrene. In the preparation of polystyrene-based microspheres by suspension polymerization in the step (1) of the invention, the amount of the monovinyl aromatic monomer is calculated by dry weight of the copolymer; the monomer comprises no more than 99wt% of a monovinylaromatic monomer; the amount of the monovinylaromatic monomer is preferably 20 to 99% by weight, based on the dry weight of the copolymer.
In an extreme embodiment, the monomers comprise the following monomers, based on dry weight of the copolymer: (a) Approximately 100wt% of at least one of m-divinylbenzene and p-divinylbenzene; and (b) at least one of styrene, m-ethyl styrene, p-ethyl styrene in an amount of almost 0wt%.
In an extreme embodiment, the monomers comprise the following monomers, based on dry weight of the copolymer: (a) Near 100wt% of at least one of styrene, m-ethyl styrene, p-ethyl styrene; and (b) about 0wt% of at least one of m-divinylbenzene and p-divinylbenzene.
In some cases, the polymerized monomers may also contain up to 20% by weight, preferably from 1 to 10% by weight, based on the dry weight of the copolymer, of copolymerized monomers, such as methyl methacrylate, methacrylic acid, acrylic acid, butyl acrylate, methyl acrylate, ethyl acrylate, isooctyl acrylate, 2-hydroxyethyl acrylate, ethyl methacrylate, butyl methacrylate, vinyl acetate, N-methylolacrylamide, acrylonitrile, acrylamide, 2-hydroxyethyl methacrylate, and the like.
The organic porogen used in the suspension polymerization is selected from at least one of organochlorine, hydrocarbon, alcohol; the organic chlorine is at least one of methylene dichloride, ethylene dichloride, propylene dichloride, chlorobenzene and chlorotoluene; the hydrocarbon is at least one of cyclohexane, methyl cyclohexane, ethyl cyclohexane, benzene, toluene, xylene and ethylbenzene; the alcohol is at least one of methyl isobutyl carbinol, diisobutyl carbinol and isooctyl alcohol;
the initiator used in the suspension polymerization is at least one of a peroxide and an azo compound; the peroxide is preferably dibenzoyl peroxide, tert-butyl 2-ethyl peroxy caproate and dilauryl peroxide; the azo compound is preferably azobisisobutyronitrile, 2' -azobis-2-methylbutyronitrile.
Suspension polymerization is carried out in a conventional manner, preferably in a continuous aqueous solution comprising suspension auxiliaries, such as dispersants, protective colloids and buffers, and then mixed with an organic phase solution comprising monomers, porogens and initiators, the monomers being copolymerized at a gradient-increasing temperature, the copolymer being in the form of pellets.
The mass ratio of the styrene monomer to the pore-forming agent to the oily initiator is preferably 1 (0.1-10): 0.001-0.1);
the mass ratio of the water, the dispersing agent and the dispersing auxiliary is preferably 1 (0.0001-0.1) (0-0.01);
the mass ratio of the oil phase to the water phase is preferably 1 (0.5-10);
the suspension polymerization reaction temperature is preferably 20-90 ℃, and the reaction time is preferably 1-24 h.
(2) Crosslinking reaction
And (3) in the presence of a swelling agent, a catalyst, a cross-linking agent A containing nitrogen functional groups and a cross-linking agent B, carrying out cross-linking reaction on the polystyrene microsphere, and purifying to obtain the ultra-high cross-linking adsorbent containing nitrogen functional groups.
The catalyst is at least one of ferric trichloride, aluminum trichloride, zinc chloride, sulfuric acid and phosphoric acid;
the swelling agent is at least one of dichloromethane, dichloroethane, propylene dichloride, chlorobenzene, chlorotoluene and nitrobenzene;
the mass ratio of the polystyrene microsphere to the swelling agent to the catalyst to the cross-linking agent A to the cross-linking agent B containing nitrogen functional groups is 1 (1-100) (0.1-10) (0-10);
the crosslinking reaction condition is reflux reaction for 2-80 h at the temperature of 40-130 ℃.
In the step (2), polystyrene-based microspheres and a swelling agent are mixed and swelled for 1-12 h at the temperature of 10-60 ℃; then adding a cross-linking agent A containing nitrogen functional groups, a cross-linking agent B and a catalyst respectively to carry out cross-linking reaction;
in the step (2), polystyrene microsphere can be mixed with swelling agent, nitrogen-containing functional group cross-linking agent A and cross-linking agent B, and swelled for 1-12 h at 10-60 ℃; then adding a catalyst to carry out a crosslinking reaction;
in the step (2), polystyrene microsphere, swelling agent and nitrogen-containing functional group cross-linking agent A can be mixed and swelled for 1-12 h at 10-60 ℃; then adding a cross-linking agent B and a catalyst respectively to carry out a cross-linking reaction;
in the step (2), the structure and the performance of the target product can be controlled by changing the adding sequence, the adding amount and other reaction conditions of the cross-linking agent A with the nitrogen-containing functional groups and the cross-linking agent B.
The invention also provides a preparation method of the super-high crosslinking adsorbent containing the quaternary ammonium salt group structure, namely, the super-high crosslinking adsorbent containing the quaternary ammonium salt group structure is obtained by carrying out crosslinking reaction on polystyrene microspheres in the presence of a swelling agent, a catalyst, a tertiary amine functional group crosslinking agent A and a crosslinking agent B, further carrying out quaternization reaction with a quaternizing agent and purifying. The quaternary amination reagent is at least one of haloalkane, organic acid, benzyl chloride, chlorohydrin, sulfate and the like; the quaternary amination reagent is preferably at least one of methyl chloride, benzyl chloride, chloroethanol, ethylene oxide, dimethyl sulfate and methyl bromide.
The crosslinking method in the step (2) can also be used for carrying out post-crosslinking reaction on the existing commercial polystyrene resin (white balls, etc.), such as polystyrene resins with different crosslinking degrees, so as to obtain the corresponding ultra-high crosslinking adsorbent.
In addition, the suspension polymerization reaction and crosslinking reaction conditions, including, for example, the kind and content of the added monomer, the degree of crosslinking, the presence or absence of a porogen and the kind, have an influence on the ion exchange capacity, surface area, pore volume and other properties of the product; post-crosslinking reaction conditions include, for example, the amount of catalyst, the kind and content of crosslinking agent, reaction time and reaction temperature, and the like. By properly changing the reaction conditions, the structure and the performance of the adsorbent can be effectively regulated and controlled, and the target product with ideal performance can be obtained.
The invention also provides a perfusion device for removing endogenous or exogenous poison or pathogenic substances in blood, which comprises the nitrogen-containing functional group super-crosslinked adsorbent or the nitrogen-containing functional group super-crosslinked adsorbent prepared by the preparation method. The adsorption resin for blood perfusion or the super-crosslinked adsorbent containing nitrogen functional groups prepared by the preparation method can be used for adsorbing endogenous or exogenous poison or pathogenic substances in human or animal bodies in blood perfusion, and particularly can be used in a perfusion device as an adsorbent.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. according to the preparation method, the use of carcinogenic chloromethyl methyl ether is avoided in the preparation process, so that the safety and environmental protection problems caused by the use of carcinogenic chloromethyl methyl ether in the traditional process are solved;
2. the invention adopts a novel cross-linking agent system, realizes the post-crosslinking of the adsorbent resin and the functionalization of the nitrogen-containing group by a one-step method on the basis of polystyrene microspheres, and has simple reaction process;
3. the preparation and development of the novel nitrogen-containing functional group ultrahigh crosslinked adsorbent are beneficial to improving the broad-spectrum toxin adsorption and removal functions of the adsorbent and reducing the medical cost of blood perfusion.
Drawings
FIG. 1 is a schematic diagram of the preparation principle of the ultra-high crosslinked porous resin in example 5;
FIG. 2 is an infrared spectrum of the ultra-high crosslinked polyporous resin in example 5;
FIG. 3 is an N1s spectrum of XPS of the ultra-high crosslinked polyporous resin in example 5;
FIG. 4 is an SEM image of the appearance of the ultra-high crosslinked porous resin of example 5;
FIG. 5 is an internal SEM image of the ultra-high crosslinked polyporous resin of example 5;
FIG. 6 is a schematic diagram of the preparation principle of the ultra-high crosslinked porous resin in example 6;
FIG. 7 is an infrared spectrum of the ultra-high crosslinked polyporous resin in example 6;
FIG. 8 is an N1s spectrum of XPS of the ultra-high crosslinked polyporous resin in example 6;
FIG. 9 is an N2 adsorption-desorption isotherm of the ultra-high crosslinked porous resin of example 6;
FIG. 10 is a pore size distribution of the ultra-high crosslinked polyporous resin in example 6;
FIG. 11 is an SEM image of the appearance of an ultra-high crosslinked porous resin of example 6;
FIG. 12 is an internal SEM image of an ultra-high crosslinked polyporous resin of example 6.
Detailed Description
Specific embodiments of the present invention will be described in further detail below with reference to the drawings and examples, but the embodiments of the present invention are not limited thereto.
Example 1
Uniformly stirring 20g of 55% divinylbenzene/45% ethylstyrene, 80g of styrene, 140g of toluene, 60g of isooctanol and 1.6g of benzoyl peroxide to form an oil phase; adding the oil phase into a pre-dissolved and uniform water phase consisting of 900g of deionized water and 5g of polyvinyl alcohol, starting stirring, heating the mixture to 60-80 ℃ in a gradient way, and keeping the temperature for 15 hours. And removing the pore-forming agent in the polymerized resin, and purifying to obtain the polystyrene-based microspheres.
Example 2
50g of 63% divinylbenzene/37% ethylstyrene, 50g of styrene, 5g of toluene, 195g of methylcyclohexane and 1g of benzoyl peroxide are stirred uniformly to form an oil phase; adding the oil phase into a pre-dissolved and uniform water phase consisting of 600g of deionized water and 25g of gelatin, stirring, and heating the mixture to 60-90 ℃ in a gradient way for 9 hours. And removing the pore-forming agent in the polymerized resin, and purifying to obtain the polystyrene-based microspheres.
Example 3
90g of 80% divinylbenzene/20% ethylstyrene, 10g of styrene, 100g of toluene, 100g of methyl isobutyl carbinol and 1.8g of azobisisobutyronitrile are uniformly stirred to form an oil phase; adding the oil phase into a pre-dissolved and uniform water phase consisting of 1000g of deionized water and 5g of gelatin, stirring, and heating the mixture to 50-75 ℃ in a gradient way for 12 hours. And removing the pore-forming agent in the polymerized resin, and purifying to obtain the polystyrene-based microspheres.
Example 4
100g of polystyrene-based microspheres prepared in example 1 are taken and mixed with 400g of dichloroethane, after swelling for 12 hours at room temperature, 200g of trimethyl orthoformate, 100g of N, N-dimethylformamide dimethyl acetal and 50g of ferric trichloride are added, reflux reaction is carried out for 120 hours under the gradient heating condition of 50-80 ℃, and the ultra-high crosslinked porous polymer resin is obtained after purification.
Example 5
100g of polystyrene-based microspheres prepared in example 1 are mixed with 500g of dichloroethane, 300g of aminoacetaldehyde dimethyl acetal and 300g of ferric trichloride, and subjected to reflux reaction for 24 hours at a gradient temperature rise condition of 50-80 ℃ and purified, so that the ultra-high crosslinked porous polymer resin is obtained.
FIG. 1 is a schematic diagram of the preparation principle of the ultra-high crosslinked porous resin in example 5;
FIG. 2 is an infrared spectrum of the ultra-high crosslinked polyporous resin in example 5;
FIG. 3 is an N1s spectrum of XPS of the ultra-high crosslinked polyporous resin in example 5; as can be seen from the figure, the surface of the prepared ultra-high crosslinked porous resin has XPS peaks of amino groups belonging to aminoacetaldehyde dimethyl acetal.
FIG. 4 is an SEM image of the appearance of the ultra-high crosslinked porous resin of example 5; as can be seen from the figure, the ultra-high crosslinked porous polymer resin prepared has a smooth surface.
FIG. 5 is an internal SEM image of the ultra-high crosslinked polyporous resin of example 5; it can be seen from the figure that the prepared ultra-high crosslinked porous resin has a remarkable porous structure inside.
Example 6
100g of polystyrene-based microspheres prepared in example 1 are taken and mixed with 300g of dichloroethane and 100g of N, N-dimethylformamide dimethyl acetal, after swelling for 12 hours at room temperature, 50g of ferric trichloride is added for mixing, reflux reaction is carried out for 120 hours under the gradient heating condition of 50-80 ℃, and the ultra-high crosslinked porous polymer resin is obtained after purification.
FIG. 6 is a schematic diagram of the preparation principle of the ultra-high crosslinked porous resin in example 6;
FIG. 7 is an infrared spectrum of the ultra-high crosslinked polyporous resin in example 6;
FIG. 8 is an N1s spectrum of XPS of the ultra-high crosslinked polyporous resin in example 6; from the graph, the surface of the prepared ultra-high crosslinked porous resin has XPS peak of tertiary amine belonging to N, N-dimethylformamide dimethyl acetal;
FIG. 9 is an N2 adsorption-desorption isotherm of the ultra-high crosslinked porous resin of example 6;
FIG. 10 is a pore size distribution of the ultra-high crosslinked polyporous resin in example 6; as can be seen from fig. 9 and 10, the prepared ultra-high crosslinked porous resin has an obvious nano-pore structure, and comprises mesopores and micropores;
FIG. 11 is an SEM image of the appearance of an ultra-high crosslinked porous resin of example 6; as can be seen from the figure, the ultra-high crosslinked porous polymer resin prepared has a smooth surface;
FIG. 12 is an internal SEM image of an ultra-high crosslinked polyporous resin of example 6; it can be seen from the figure that the prepared ultra-high crosslinked porous resin has a remarkable porous structure inside.
Example 7
100g of polystyrene-based microspheres prepared in example 2 are mixed with 2000g of chlorobenzene, 300g of 4-aminobutyraldehyde dimethyl acetal, 50g of 1, 1-dimethoxy acetone and 500g of ferric trichloride, and are subjected to reflux reaction for 120 hours under the gradient heating condition of 50-80 ℃ and purified, so that the ultra-high crosslinked porous polymer resin is obtained.
Example 8
100g of the polystyrene-based microspheres prepared in example 2 are mixed with 1000g of methylene dichloride, 50g of (dimethylamino) acetaldehyde formal, 50g of 1, 3-tetramethoxy propane and 1000g of zinc chloride, and the mixture is subjected to reflux reaction for 18 hours under the gradient heating condition of 50-80 ℃ and purified to obtain the ultra-high crosslinked porous polymer resin.
Example 9
100g of polystyrene microsphere prepared in example 3 is taken and mixed with 1000g of dichloroethane, 100g of 4-aminobutyraldehyde dimethyl acetal and 100g of dimethoxymethane, after swelling for 12 hours at room temperature, 200g of ferric trichloride is added, reflux reaction is carried out for 48 hours under the gradient heating condition of 40-120 ℃, and the ultra-high crosslinked porous resin is obtained after purification.
Example 10
100g of commercially available polystyrene-based microspheres (XAD 16) are mixed with 600g of dichloroethane, 10g of trimethyl orthoformate, 50g of (dimethylamino) acetaldehyde formal and 700g of ferric trichloride, and the mixture is subjected to reflux reaction for 1h at 80 ℃ and purified to obtain the ultra-high crosslinked porous polymer resin.
Example 11
100g of the ultra-high crosslinking porous resin prepared in example 6 is taken and mixed with 200g of dimethyl sulfoxide, 80g of benzyl chloride is added, and the mixture is subjected to reflux reaction for 12 hours at 120 ℃ and purified to obtain the ultra-high crosslinking porous resin containing quaternary amine groups.
The adsorbents obtained in the above examples were subjected to evaluation of physical and chemical parameters, evaluation of adsorption performance, evaluation of safety, and the like in this order, using the commercial resin AMBERLITE XAD16, and the commercial emitter resins HA130 and BS330 as reference samples.
(1) Evaluation of physicochemical parameters
And measuring the pore diameter and specific surface area data of the resin by adopting a specific surface area and pore space analyzer and an N2 adsorption-desorption method.
Mixing 5ml of adsorbent resin with 15ml of pure water solution, placing at 60 ℃ for 100 hours, and detecting the pH value of the solution to obtain the pH value of the preservation solution.
Table 1 physical and chemical evaluation data of examples and comparative examples
By comparing the examples with the comparative examples, it is known that adsorbents having different pore structures and chemical properties can be obtained by changing the conditions of the production process.
(2) The operation method for evaluating the adsorption performance is as follows:
10ml of a plasma solution containing Dimethoate, sodium pentobarbital, interleukin 6 (IL-6), tumor necrosis factor TNF-alpha, parathyroid hormone PTH, bilirubin, bile acid, p-cresol PCS sulfate, indoxylIS sulfate was added to 1ml of the adsorption resin obtained in the above examples and comparative examples, and after shaking at 37℃for 2 hours, the change of the adsorbed substances was measured, and the results are shown in tables 2 and 3 below.
Table 2 adsorption performance data for examples and comparative examples
As can be seen from the results in Table 2, the adsorbents prepared in examples 4 to 11 all have higher adsorption rates for parathyroid hormone (PTH), dimethoate, sodium pentobarbital, interleukin IL-6, and tumor necrosis factor TNF-a than the control samples.
TABLE 3 protein-bound toxin adsorption performance data for examples and comparative examples
As can be seen from the results in Table 3, the adsorbents prepared in examples 4 to 11 have better adsorption performance on protein-bound toxoids such as total bilirubin, total bile acid, indoxyl Sulfate (IS), and p-cresol sulfate (PCS), and are superior to the control samples.
(3) The blood compatibility and safety were evaluated as follows:
the haemolysis and platelet adhesion were mainly used, i.e. the tests were carried out according to GB/T16886.4-2003 and GB/T16175-1996 for blood compatibility and safety tests of the materials. The results are shown in Table 4 below.
Table 4 hemolysis and platelet adhesion evaluation data of examples and comparative examples
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As can be seen from the results in table 4, examples 4 to 11 have a lower hemolysis rate and platelet adhesion rate, showing a better blood compatibility. Meanwhile, the adsorbents of examples 4 to 11 of the present invention showed excellent biocompatibility results by performing the tests of cytotoxicity, thrombosis, coagulation, complement activation, immunity and other biocompatibility.
Finally, it should be emphasized that the foregoing is merely a preferred embodiment of the present invention, and is not intended to limit the invention, but rather that various changes and modifications can be made by those skilled in the art without departing from the spirit and principles of the invention, and any modifications, equivalent substitutions, improvements, etc. are intended to be included within the scope of the present invention.

Claims (8)

1. The application of the super-high crosslinking adsorbent containing nitrogen functional groups in a hemoperfusion apparatus is characterized in that: the nitrogen-containing functional group ultrahigh crosslinking adsorbent is prepared by mixing polystyrene microspheres with a nitrogen-containing functional group crosslinking agent A, a crosslinking agent B and a swelling agent, and performing crosslinking reaction under the condition of a catalyst;
the nitrogen-containing functional group cross-linking agent A is:
wherein R1 is-CH 3 、*—CH 2 CH 3 、*—CH 2 CH 2 CH 3 、*—CH 2 CH 2 CH 2 CH 3 、*—CH(CH 3 ) 2 One of (2) is provided;
r2 is H, -CH 3 、*—CH 2 CH 3 、*—OCH 3 、*—OCH 2 CH 3 、*—OCH(CH 3 ) 2 、*—OCH 2 CH 2 CH 2 CH 3 One of (2) is provided;
r3 is- (CH) 2 ) n -. SumOne of (2) is provided; wherein n is an integer of 0 to 18, and m is an integer of 0 to 18;
r4 is one of a tertiary amine group structure, a secondary amine group structure, a primary amine group structure, a pyridine group structure, an aromatic amine group structure, a pyrrole group structure, an imidazole group structure, a morpholine group structure, a pyrimidine group structure, a naphthyridine group structure and a quaternary ammonium salt group structure;
wherein, represents the point of covalent attachment;
the cross-linking agent B is:
at least one of (2);
wherein R5 is-CH 3 、*—CH 2 CH 3 、*—CH 2 CH 2 CH 3 、*—CH 2 CH 2 CH 2 CH 3 、*—CH(CH 3 ) 2 One of (2) is provided;
k is an integer of 0 to 18;
r6 is hydrogen, -CH 3 、*—CH 2 CH 3 、One of (2) is provided;
r7 is hydrogen, -CH 3 、*—CH 2 CH 3 、One of (2) is provided;
wherein, represents the point of covalent attachment;
the catalyst is at least one of Lewis acid and protonic acid;
the preparation method of the nitrogen-containing functional group ultrahigh crosslinked adsorbent comprises the following steps:
(1) Suspension polymerization for preparing polystyrene microsphere
The preparation method comprises the steps of (1) forming an oil phase by using a styrene monomer, a pore-forming agent and an oily initiator, carrying out suspension polymerization on the oil phase in a water phase consisting of a dispersing agent, a dispersing aid and water, removing the pore-forming agent in the polymerized resin, purifying and drying to obtain polystyrene microspheres;
the styrene monomer is at least one of a multi-vinyl aromatic monomer and a single-vinyl aromatic monomer; the oily initiator is at least one of peroxide and azo compound;
(2) Crosslinking reaction
Under the existence of a swelling agent, a catalyst, a cross-linking agent A containing nitrogen functional groups and a cross-linking agent B, carrying out cross-linking reaction on polystyrene microspheres, and purifying to obtain an ultrahigh cross-linking adsorbent containing nitrogen functional groups;
the catalyst is at least one of ferric trichloride, aluminum trichloride, zinc chloride, sulfuric acid and phosphoric acid;
the mass ratio of the styrene monomer to the pore-forming agent to the oily initiator is 1:0.1-10:0.001-0.1;
the mass ratio of the water to the dispersing agent to the dispersing auxiliary is 1:0.0001-0.1:0-0.01;
the mass ratio of the oil phase to the water phase is 1:0.5-10;
the suspension polymerization reaction temperature is 20-90 ℃ and the reaction time is 1-24 h.
2. The use of a nitrogen-containing functional group ultra-high crosslinking adsorbent in a hemodiayer according to claim 1, wherein: the nitrogen-containing functional group ultrahigh crosslinked adsorbent is spherical particles with the particle size of 0.01-3 mm; the specific surface area of the nitrogen-containing functional group super-crosslinked adsorbent is 10-3500 m 2 /g。
3. The use of a nitrogen-containing functional group ultra-high crosslinking adsorbent in a hemodiayer according to claim 1, wherein: in step (1), the organic porogen is selected from at least one of organochlorine, hydrocarbon, alcohol.
4. Use of a nitrogen-containing functional group ultra-high crosslinking adsorbent in a hemodiayer according to claim 3, characterized in that: the organic chlorine is at least one of methylene dichloride, ethylene dichloride, propylene dichloride, chlorobenzene and chlorotoluene;
the hydrocarbon is at least one of cyclohexane, methyl cyclohexane, ethyl cyclohexane, benzene, toluene, xylene, ethylbenzene, naphthene and alkane;
the alcohol is at least one of methyl isobutyl carbinol, diisobutyl carbinol and isooctyl alcohol.
5. The use of a nitrogen-containing functional group ultra-high crosslinking adsorbent in a hemodiayer according to claim 1, wherein: in the step (2), the swelling agent is at least one of dichloromethane, dichloroethane, propylene dichloride, chlorobenzene, chlorotoluene and nitrobenzene.
6. The use of a nitrogen-containing functional group ultra-high crosslinking adsorbent in a hemodiayer according to claim 1, wherein: in the step (2), the mass ratio of the polystyrene-based microspheres to the swelling agent to the catalyst to the cross-linking agent A containing nitrogen functional groups to the cross-linking agent B is 1:1-100:0.1-10:0.1-10.
7. The use of a nitrogen-containing functional group ultra-high crosslinking adsorbent in a hemodiayer according to claim 1, wherein: in the step (2), the crosslinking reaction condition is reflux reaction for 2-80 h at the temperature of 40-130 ℃.
8. A blood perfusion apparatus, characterized in that: the hemoperfusion cartridge comprises the nitrogen-containing functional group ultra-high crosslinking adsorbent of any one of claims 1 to 7.
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