JPH03292303A - Production of porous particle - Google Patents

Abstract

PURPOSE:To obtain porous particles excellent in pressure resistance, etc., by dissolving a polyoxyethylene compound having a double bond on each end, a polyfunctional crosslinking agent and a (meth)acrylic acid derivative in an inert organic solvent, dispersing the resulting solution in water containing a specified dispersion stabilizer, and subjecting the resulting dispersion to suspension polymerization. CONSTITUTION:A polyoxyethylene compound having a polymerizable double bond on each end, represented by formula I (wherein R<1> and R<2> are each CH2=CR<3>-X-; R<3> is H or methyl; X is -CO-,-CO-NH-CO- or the like; and n is 14-45), a polyfunctional crosslinking agent of formula II, III, IV and/or V (wherein R<4> is hydroxyl, methyl or the like; R<5> is H or methyl; Y is a group of formula VI; and m is 1-4) and a (meth) acrylic acid derivative of formula VII (wherein R<6> is H or methyl) and R<7> is hydroxy- lower-alkoxy or the like) are dissolved in an inert organic solvent in which the formed polymer is insoluble. The formed solution is dispersed in water containing polyvinyl alcohol of a degree of saponification of 60-80mol% and a degree of polymerization of 500-2000 or a water-soluble cellulose ether in which the hydroxyl groups of the cellulose are substituted by 1-4C (hydroxy)alkoxy groups, and the resulting dispersion is subjected to suspension polymerization to obtain porous particles.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a method for producing porous particles that can be used, for example, in the separation and purification of physiologically active substances such as sugars, proteins, and enzymes used in pharmaceuticals, foods, etc. More specifically, the porous particles, which are completely porous hydrophilic spherical particles with excellent pressure resistance and can immobilize various functional substances by introducing surface functional groups, have a particle size of 3.0 to 3.0. It relates to a manufacturing method that allows for arbitrary preparation within the range of 1000 μm.

[Prior Art and Problems to be Solved by the Invention] As a method for producing fine resin particles, a method is known in which a polymerization composition containing a water-soluble monomer is subjected to suspension polymerization in an aqueous dispersion system. In methods that utilize suspension polymerization, water-soluble monomers are dissolved in an aqueous medium, resulting in gelation or agglomeration of the polymerization product, resulting in truly spherical particles. The disadvantage was that it was difficult to obtain.

Therefore, in order to eliminate such drawbacks, we have developed two methods: 1. Adding a hydrophobic substance together with a water-soluble monomer to an aqueous dispersion system to reduce the affinity of the polymerization product to the aqueous medium; 2. By dissolving inorganic salts such as sodium phosphate at a high concentration in the water, it is possible to prevent the water-soluble monomer from dissolving in the aqueous solution, and also to impart an ionic charge to the generated particles to prevent them from agglomerating. There are known methods for preventing this.

However, method (2) has the disadvantage that the materials used for formulation design are limited to styrene, n-butyl (meth)acrylate, etc., and the resulting particles are hydrophobic, so it is difficult to purify and separate proteins. There is a drawback in that proteins are non-specifically adsorbed when used in the method (2) above, and in addition, the method (2) has the drawback that it takes time to wash and remove the inorganic salts remaining in the obtained particles. .

Furthermore, such conventional suspension polymerization in water has the drawback that the physical properties and surface condition of the obtained particles vary widely, making it impossible to maintain constant quality.

Additionally, a method is known in which particles are formed using a so-called water-in-oil polymerization system in which the water in the water dispersion system is replaced with an organic solvent. There are disadvantages in that there are few solvents (void constituents) and dispersion stabilizers that can be used to suppress the agglomeration of formed particles, and large amounts of organic solvents are used in the particle manufacturing process. The drawback was that it was subject to numerous restrictions in terms of safety and health management of the process.

The purpose of the present invention is to be able to obtain completely porous, hydrophilic, true spherical particles with excellent pressure resistance in a constant quality with no variation in physical properties or surface condition, and in addition, to be able to obtain them safely without a complicated cleaning process. An object of the present invention is to provide a method for producing porous particles that is easy to maintain hygiene.

[Means for Solving the Problems] The method for producing porous particles of the present invention includes the following components (A), (
A mixed solution of B) and (C) dissolved in the inert organic solvent shown below (D) is dispersed in water containing the dispersion stabilizer shown below (E), and the components (A), (B) and It is characterized by subjecting (C) to suspension polymerization.

(A) Following formula (I) R'-0-+CH--(IJI2-Ohr R"
(I) [In formula (I), R1 and R8 are each CH, = CR3-X-(R'' represents a hydrogen atom or hamethyl group, x is -CO-1-(:0-NH −
GO= or -CO-0-CHx-CH2-NH-CO-
), where n is an integer from 14 to 45. A polyoxyethylene compound having a polymerizable double bond at both ends.

(B) The following formula (n) R'-(:R2-C-+cn2-o-co-cR' =
Hz) s (II) [In formula (11),
R4 is a hydroxyl group, a methyl group, or -0-GO-CR' =
CH, and R6 represents a hydrogen atom or a methyl group] A polyfunctional crosslinking agent represented by the following formula (■): CH,-0-Y-GO-CR' = CHxCH-0-
Y-Go-CR'=CH2CH, -0-Y-CO-CR'=CH, (III
) [In formula (III), R5 is the same as above, Y represents →CH, -CH2-0 h, and m is 1 to
represents an integer of 4], a polyfunctional crosslinking agent represented by the following formula (
TV) C-4-CH2-0-Y-GO-CR'= CH214
(rV) [In formula (IV), Y and R1' are the same as above] and/or the following formula (V): [In formula (V), Y and R8 are the same as above] A polyfunctional crosslinking agent represented by [same as].

(C) The following formula (■): CH, = CR'-CO-R' (
Vl ) [In formula (Vl), R6 represents a hydrogen atom or a methyl group, R7 represents a hydroxy lower alkoxy group or a bar N [R") (represents a hydrogen atom or a lower alkyl group)] (meth)acrylic acid derivatives.

(D) All of the above components (A) to (C) are dissolved, but
An inert organic solvent that does not dissolve the polymerization products.

(E) Saponification degree 60-80 mol%, polymerization degree 500-20
A water-soluble cellulose ether in which part or all of the hydroxyl groups of 00 polyvinyl alcohol or cellulose are substituted with an alkoxy group or hydroxyalkoxy group having 1 to 4 carbon atoms.

The present invention will be explained in detail below.

Component (A) The polyoxyethylene compound represented by the formula (1) used in the present invention has polymerizable double bonds at both ends, and the number of chains of ethyleneoxy groups (formula % formula %). If the chain number of the groups is less than 14 or more than 45, the resulting porous particles are not preferred because, when used for protein separation and purification, for example, proteins will adsorb to the porous particles.

Examples of the polyoxyethylene compound used in the present invention include polyoxyethylene diacrylate, polyoxyethylene dimethacrylate, polyoxyethylene dimethacryloyl carbamate, and polyoxyethylene dimethacryloyloxyethyl carbamate.

Component (B) Examples of the polyfunctional crosslinking agent represented by the formulas (II) to (V) used in the present invention include 1,1゜1-1-limethylbroban trimethacrylate, 1.1.1- Trimethylpropane triacrylate, tetramethylolmethane triacrylate, tetramethylolmethane tetraacrylate, dipentaerythritol hexaacrylate, polyoxyethylene dipene querythritol hexaacrylate, polyoxyethylene glycerol ether triacrylate, polyoxyethylene pentaerythritol ether tetraacrylate etc. can be mentioned. Among these, preferred are polyoxyethylene dipene erythritol hexaacrylate, polyoxyethylene glycerol ether triacrylate, polyoxyethylene pentaerythritol ether tetraacrylate, and dipentaerythritol hexaacrylate having a polyoxyethylene moiety.

These multifunctional crosslinking agents increase the crosslinking density of porous particles and improve their mechanical strength.

Component (C) The (meth)acrylic acid derivative represented by the formula (VI) used in the present invention includes 2,3-dihydroxypropyl methacrylate, 2-hydroxyethyl methacrylate, (meth)acrylamide, and methyl (or ethyl) acrylamide. , dimethyl (or ethyl) acrylamide, and the like.

The blending ratio of the components (A), (B) and (C) is as follows:
The ratio of component (B) to the content of A) and (C) [100
-xB/(A0C)] is 20 to 100% by weight, preferably 30 to 50% by weight, and component (A) and C
The ratio of component (C) to the content of B) [100x C/
(A0B)] is 70 to 150% by weight, preferably 9
It is 0 to 120% by weight. In addition, [100XB/ (A
+C)] is 20% by weight ungrooved, the mechanical strength of the obtained porous particles may decrease;
When the amount exceeds 100%, the hydrophobicity of the obtained porous particles increases, and when the porous particles are used for purification and separation of proteins,
Proteins may be non-specifically adsorbed. Also, [10
0xC/(A+B)] is 70% by weight ungrooved,
The amount of functional groups introduced into the porous particles may be insufficient, making it difficult to immobilize functional substances.
When the temperature exceeds λ, the mechanical strength of the obtained porous particles may decrease.

Component (D) As the inert organic solvent used in the present invention, the above-mentioned component (A
) to (C) are all dissolved, but components (A) and (B)
There is no particular restriction as long as it is an inert organic solvent that does not dissolve the polymerization product of (C). For example, benzene, toluene,
Examples include chlorobenzene, -dichlorobenzene, m-dichlorobenzene, and p-dichlorobenzene.

Among them, preferred is cyclobenzene.

Note that these inert organic solvents can be used alone or in any combination of two or more.

The amount of the inert organic solvent used is 50 to 700 parts by weight, preferably 100 to 45 parts by weight, based on 100 parts by weight of the total solid content.
It is 0 parts by weight. In addition, when the amount used is less than 50 parts by weight, the pore volume of the obtained porous particles becomes small, and porous particles having sufficient separation performance may not be obtained. Sometimes, the mechanical strength of the resulting porous particles decreases, and when such porous particles are used as a column packing material, it may not be possible to increase the flow rate of the mobile phase.

Component (E) Polyvinyl alcohol (hereinafter referred to as PVA) used as a dispersion stabilizer in the present invention has a saponification degree of 60 to 8.
0 mol%, preferably 65 to 77 mol%.

The "saponification degree" referred to in the present invention is defined by JIS K672
6.4 (2). When the degree of saponification is less than 6 mol %, PVA exhibits poor solubility in water, making it impossible to obtain a uniformly transparent aqueous solution and making it impossible to obtain truly spherical particles. In addition, when it exceeds 80 mol%, the hydrophilicity of PVA increases, forming a hydrated phase together with the water-soluble monomer, and as a result, the hydrate covers the surface of the obtained porous particles. Because of the coating, completely porous particles cannot be obtained.

Furthermore, the PVA used in the invention has a degree of polymerization of 500 to 200.
It is 0. In addition, when the degree of polymerization is less than 500, the dispersibility of the formed porous particles becomes poor, and when it exceeds 2000, the solubility of PVA in water decreases.
It becomes difficult to obtain a uniform and transparent aqueous solution.

The water-soluble cellulose ether used as a dispersion stabilizer in the present invention is one in which part or all of the hydroxyl groups of cellulose are etherified, and is an alkoxy ether having 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. It is a water-soluble cellulose ether in which the hydroxyl group is substituted with a group or a hydroxyalkoxy group. Among them, water-soluble cellulose ethers having a degree of substitution of 1.3 to 2 are preferred.

The amount of the dispersion stabilizer used is 1 to 10 parts by weight, preferably 2 to 7 parts by weight, based on 100 parts by weight of the total solid content.

Suspension polymerization The method for producing porous particles of the present invention involves combining components (
A mixed solution of A), (B) and (C) dissolved in a predetermined amount of component (D) in an inert organic solvent is added to a predetermined amount of component (E).
The components (A), (B), and (C) are suspension polymerized in a so-called oil-in-water dispersion system in which the components (A), (B), and (C) are dispersed in water containing a dispersion stabilizer.

The blending ratio of the mixed solution of components (A), (B.) and (C) dissolved in component (D) and water is 10 to 40 parts by weight per 100 parts by weight of water. .

The polymerization initiator used in suspension polymerization is not particularly limited, and known radical polymerization initiators such as organic peroxides and azo compounds can be used, such as benzoyl peroxide,
Examples include 2.2'-azobisisobutyronitrile and 2.2'-azobis(2,4-dimethylvaleronitrile).

The amount of the polymerization initiator used is 0.1 to 5 parts by weight based on 100 parts by weight of the total solid content.

The suspension polymerization conditions are not particularly limited as long as the polymerization is oil-in-ice type polymerization, but the polymerization temperature is preferably 60 to 100°C, and the polymerization time is preferably 2 to 8 hours.

The surface roughness coefficient of the porous particles thus obtained [(
Roughness Factor = BET
Specific surface area/rigid surface area] (hereinafter referred to as RF value) is
20 or more, and the average pore radius is 50 to 500 pores.

[Example] (Example 1) A homogeneous mixed solution with the following composition was added to a solution in which 2.25 g of PVA with a degree of saponification of 77 mol% and a degree of polymerization of 500 was dissolved in 682 g of deionized water. -M type) at a rotation speed of 3000 rpm.
Atomization treatment was carried out for 0 minutes.

Warm/Cold Jl [1 Commandment Polyoxyethylene dimethacrylate (polyoxyethylene chain number 23)...15g Dipentaerythritol hexaacrylate...15g2.3-
Dihydroxypropyl methacrylate: 30g Chlorobenzene: 90g Benzoyl peroxide: 1.8g Next, pour the atomized liquid into a 1i cylinder. The average particle size of the copolymer particles produced in the reaction solution was placed in a separable flask and heated at 82°C for 5 hours with gentle stirring for suspension polymerization.
It was m.

The resulting copolymer particles were washed with acetone, then thoroughly with methanol, and then further washed with deionized water.

The obtained copolymer particles had a hydroxyl group content of 3.6 mm
oQ/g, the average pore radius was 87, and the RF value was 27.6.

The obtained copolymer particles were examined using a scanning electron microscope (hereinafter referred to as SE).
As shown in FIG. 1, the particle surface was completely porous and no film formation was observed.

(Example 2) Suspension polymerization was carried out in the same manner as in Example 1 except that PVA having a saponification degree of 62 mol % and a polymerization degree of 590 was used to obtain copolymer particles.

The obtained copolymer particles had an average particle size of 12.1 LLm.
The amount of hydroxyl groups was 33 mmol2/g, the average pore radius was 78, and the RF value was 23.3.

When the obtained copolymer particles were observed by SEM, the particle surfaces were completely porous and no film formation was observed.

(Example 3) Suspension polymerization was carried out in the same manner as in Example 1 except that a uniform mixed solution having the following composition was used to obtain copolymer particles.

Mixture J mouth [1-component polyoxyethylene dimethacrylate (polyoxyethylene chain number 23)...15g dipentaerythritol hexaacrylate...25g2.3-
Dihydroxypropyl methacrylate: 30g Chlorobenzene: 105g Benzoyl peroxide: 2.1g The obtained copolymer particles were:
The average particle size is 12.7 μm, and the average pore radius is 1
There were 27 people, and the RF value was 62.5.

When the obtained copolymer particles were examined using SEM, the particle surfaces were completely porous and no film formation was observed.

(Example 4) Suspension polymerization was carried out in the same manner as in Example 1 except that a uniform mixed solution having the following composition was used to obtain copolymer particles.

L bean i ball dish difference polyoxyethylene dimethacrylate (polyoxyethylene chain number 23)...15g tetramethylolmethanetetraacrylate...15g2.3-
Dihydroxypropyl methacrylate: 30g Chlorobenzene: 90g Benzoyl peroxide: 18g The obtained copolymer particles had an average particle size of , 12.5 μm, and the average pore radius is 92
It was crowded and the RF value was 20.7.

When the obtained copolymer particles were observed with SEM, the particle surface was completely porous and no film formation was observed.6 (Example 5) In place of PVA, methoxy and hydroxyethoxy group substituted Water-soluble cellulose ether [Metrose 65SH
-50 (manufactured by Shin-Etsu Chemical Co., Ltd.)] 2.25 g was used, but suspension polymerization was carried out in the same manner as in Example 1 to obtain copolymer particles.

The obtained copolymer particles had an average particle diameter of 21.1 μm, a hydroxyl group content of 2.9 mmoβ/g, an average pore radius of 75 mm, and an RF value of 32.3. Met.

When the obtained copolymer particles were observed by SEM, the particle surfaces were completely porous and no film formation was observed.

(Example 6) In place of PVA, a methoxy group-substituted water-soluble cellulose ether [Metrose 5M-100 (manufactured by Shin-Etsu Chemical Co., Ltd.)]
]2.25g was used, but suspension polymerization was carried out in the same manner as in Example 1 to obtain copolymer particles.

The obtained copolymer particles had an average particle diameter of 28.2 μm, an average pore radius of 70 μm, and an RF value of 33.
．． It was 2.

When the obtained copolymer particles were observed by SEM, the particle surfaces were completely porous and no film formation was observed.

(Example 7) Suspension polymerization was carried out in the same manner as in Example 1, except that 30 g of dimethyl acrylamide was used in place of 23-dihydroxypropyl methacrylate in the mixed solution composition used in Example 1, and a copolymer was obtained. Particles were obtained.

The obtained copolymer particles had an average particle diameter of 13.6 μm, an average pore radius of 115 μm, and an RF value of 2.
It was 6.0.

When the obtained copolymer particles were observed by SEM, the particle surfaces were completely porous and no film formation was observed.

(Comparative Example 1) A homogeneous mixed solution having the same composition as in Example 1 was heated to a degree of saponification of 89.
2.25 g of PVA with a mole % degree of polymerization of 500 and 10.2 g of sodium sulfate were added to a solution in 682 g of deionized water, and suspension polymerization was carried out in the same manner as in Example 1 to form copolymer particles.

The copolymer particles obtained by using inorganic salts in this way have an average particle size of 126 μm and a hydroxyl group content of 3.2 μm.
mmo! , the average pore radius is 242, and R
The F value was 2.8.

When the obtained copolymer particles were observed with SEM, it was found that the second
As shown in the figure, a thin film was observed on the particle surface.

(Comparative Example 2) In place of PVA used in Example 1, saponification degree of 89 mol%
, polymerization degree 500(7), except that 2.25 gt of PVA was used. Suspension polymerization was carried out in the same manner as in Example 1 to obtain copolymer particles.

The obtained copolymer particles had an average particle diameter of 12.9 am and a hydroxyl group content of 3.3 mmo! ! , the average pore radius was 150, and the RF value was 1.7.

When the obtained copolymer particles were observed by SEM, a thin film was observed on the particle surface.

(Example 8) Copolymer particles were separately manufactured five times under the same conditions as Example 1, and each of the obtained copolymer particles was subjected to RF
The average value and coefficient of variation were calculated.

The results are shown in Table 1.

(Comparative Example 3) Copolymer particles were separately produced five times under the same conditions as Comparative Example 1, and each of the obtained copolymer particles was subjected to RF
The average value and coefficient of variation were calculated.

The results are shown in Table 2.

Tojo Go 24° 26° 4 23° 24° Table 2 6 8 7 4 0 (Evaluation) In Examples 1 to 8, the RF value was 20 or more, and the particles obtained in Comparative Examples 1 to 3 This indicates that the particles are highly porous compared to .

Furthermore, as is clear from the coefficient of variation of the RF values shown in Example 8 and Comparative Example 3, the particles obtained in Examples had extremely small variations in surface condition between lots.

Furthermore, as a dispersion stabilizer, fully saponified PVA (saponification degree: 98 to 99 mol%) and commercially available partially saponified PV
When PVA with a saponification degree exceeding 80 mol%, such as A (saponification degree = 81 to 98 mol%), is used (Comparative Examples 1 to 3), a film is formed on almost the entire surface of the obtained particles. The porous structure of the particles was hidden by the film. Further, on the particle surface, film defects, which were thought to have been caused by collisions during polymerization, were partially observed, and the porous internal structure was exposed from the defects (see Figure 2).

On the other hand, water-soluble PVA with a saponification degree of 60 to 80 mol% and a polymerization degree of 500 to 2000 or in which the hydrogen group value in the glucose ring unit is substituted with an alkoxyl group having 1 to 4 carbon atoms. When cellulose ether was used as a dispersion stabilizer (Examples 1 to 8), no film formation was observed at all, and numerous pores were observed over almost the entire surface of the particles (see Figure 1). ).

[Effects of the Invention] The method for producing porous particles of the present invention provides the following effects.

(1) Since aggregation of copolymer particles generated in the suspension polymerization solution can be suppressed, hydrophilic true spherical particles can be obtained.

(2) Since the surface of the copolymer particles produced is not covered with a film, completely porous particles can be obtained;
In addition, it is possible to reduce variations in the physical properties and surface condition of the particles, making it possible to obtain particles of stable quality.

(3) Since particles can be produced without using highly concentrated inorganic salts or large amounts of organic solvents, the particle production process can be simplified and the safety and health management of the production process can be facilitated.

[Brief explanation of the drawing]

FIG. 1 is a scanning electron micrograph of porous particles obtained in Example 1. FIG. 2 is a scanning electron micrograph of porous particles obtained in Comparative Example 1. Engraving of drawings (no changes to content)

Claims (1)

[Claims] (1) The following ingredients (A), (B) and (C) are combined into the following (D)
A mixed solution of component (A) dissolved in an inert organic solvent is dispersed in water containing the dispersion stabilizer described below (E).
A method for producing porous particles, which comprises carrying out suspension polymerization of (B) and (C). (A) The following formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In formula (I), R^1 and R^2 are each CH_
2=CR^3-X- (R^3 represents a hydrogen atom or a methyl group, and X is -CO-, -CO-NH-CO- or -CO-O-CH_2-CH_2-NH-CO- ), and n represents an integer of 14 to 45] A polyoxyethylene compound having a polymerizable double bond at both ends. (B) Following formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In formula (II), R^4 is a hydroxyl group, a methyl group, or -O-
CO-CR^5=CH_2, R^5 represents a hydrogen atom or a methyl group] A polyfunctional crosslinking agent represented by the following formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III ) [In formula (III), R^5 is the same as above, and Y is
▲There are mathematical formulas, chemical formulas, tables, etc.▼, and m is 1
representing an integer of ~4], a polyfunctional crosslinking agent represented by the following formula (IV)
: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) A polyfunctional crosslinking agent represented by [In formula (IV), Y and R^5 are the same as above] and/or the following formula (V): ▲ There are mathematical formulas, chemical formulas, tables, etc.▼(V) A polyfunctional crosslinking agent represented by [In formula (V), Y and R^5 are the same as above]. (C) Following formula (VI): CH_2=CR^6-CO-^7 (VI) [In formula (VI), R^6 represents a hydrogen atom or a methyl group, and R^7 represents hydroxy lower alkoxy group or -N(
R^8) (R^9), and R^8 and R^9 each represent a hydrogen atom or a lower alkyl group]. (D) All of the above components (A) to (C) are dissolved, but
An inert organic solvent that does not dissolve the polymerization products. (E) Water-soluble cellulose ether in which part or all of the hydroxyl groups of polyvinyl alcohol or cellulose with a degree of saponification of 60 to 80 mol% and a degree of polymerization of 500 to 2000 are substituted with an alkoxy group or hydroxyalkoxy group having 1 to 4 carbon atoms. .