Method for producing porous particles, and method for producing carrier for purification or adsorption

Abstract

Provided are methods for efficiently producing porous particles and a carrier for purification or adsorption which have excellent antifouling properties or excellent carbon dioxide adsorption properties.　A method for producing porous particles includes steps (i) to (iii) mentioned below, wherein the water-based medium in step (iii) is a water-based medium such that the amount of a salt dissolved per unit mass is 10 parts by mass or more when the mass of the salt per unit mass in a saturated solution reached by dissolving the salt in the water-based medium under conditions of 23°C and 1 atm is 100.　(i) A step for preparing a hydrocolloid in a salt-containing water-based medium; (ii) a step for dispersing a liquid composition in a hydrocolloid-containing water-based medium prepared in step (i), the liquid composition containing a hydrophobe having a solubility in water at 25°C of 1.0×10-4g / L or less and one or more monomers that are different from the hydrophobe; and (iii) a step for subjecting the monomers dispersed in step (ii) to suspension polymerization in a water-based medium containing a hydrocolloid and a salt.

Description

Method for producing porous particles and method for producing purified or adsorbent carriers

[0001] The present invention relates to a method for producing porous particles and a method for producing a purifying or adsorption carrier.

[0002] Porous particles are widely used as carriers for purification and adsorption. For example, antibodies used in research reagents and antibody drugs are generally produced through affinity purification. Affinity purification is often performed using carriers to which immunoglobulin-binding proteins are bound. Furthermore, after affinity purification, ion exchange chromatography and hydrophobic interaction chromatography are often performed in combination to remove impurities, and porous particles are also used as carriers in these processes. In addition, technologies that directly adsorb, separate, and recover carbon dioxide from the air have attracted attention in recent years as an approach to decarbonization that differs from reducing carbon dioxide emissions, and the use of porous particles as carriers is also being studied in this field.

[0003] To improve the efficiency of impurity removal by affinity purification and ion exchange purification, techniques have been reported to enhance the antifouling properties of porous particles by making them hydrophilic. For example, known hydrophilic carriers include porous particles in which the inside of the pores is filled with a water-soluble polymer that does not have a crosslinking structure (Patent Document 1), solid carriers formed by reverse-phase suspension polymerization of hydrophilic monomers such as acrylamide monomers, and solid carriers obtained by polymerizing and deprotecting hydrophilic monomers after hydrophobizing them with a protecting group or the like (Patent Documents 2-4). In addition, a technique has been reported to introduce benzylamine units as structural units of the polymer constituting porous particles in order to efficiently adsorb carbon dioxide from the air (Patent Document 5).

[0004] Japanese Patent No. 5250985, Japanese Patent Publication No. 2003-511659, Japanese Patent Publication No. 2009-503203, Japanese Patent Publication No. 2006-111717, Japanese Patent Publication No. 2024-543146

[0005] However, when attempting to produce porous particles with high hydrophilicity and excellent antifouling properties for affinity purification or ion exchange purification, or when using monomers with a large amount of amino groups as the monomer composition or macromonomer, the hydrophilicity of the monomer composition also increases, making it easier for the monomer to leak into the aqueous phase during suspension polymerization, thus making efficient particle production difficult. The problem that the present invention aims to solve is to provide a method for efficiently producing porous particles and carriers for purification or adsorption that have excellent antifouling properties or excellent carbon dioxide adsorption properties.

[0006] The above problems were solved by the following means <1> to <16>. <1> A method for producing porous particles (hereinafter also referred to as "the method for producing porous particles of the present invention") comprising the following steps (i) to (iii), wherein the aqueous medium in step (iii) is an aqueous medium in which, when the mass of salt per unit mass in the saturated solution reached by dissolving salt in the aqueous medium at 23°C and 1 atm is set to 100 parts by mass, the amount of salt dissolved per unit mass is 10 parts by mass or more. (i) A step of producing hydrocolloids in a salt-containing aqueous medium (ii) In the hydrocolloid-containing aqueous medium obtained in step (i), a salt with a solubility in water at 25°C of 1.0 × 10 －４ (iii) A step of dispersing a liquid composition containing a hydrophobe in a concentration of g / L or less and one or more monomers different from the hydrophobe; (iii) A step of suspension polymerization of the monomer dispersed in step (ii) in an aqueous medium containing a hydrocolloid and a salt.

[0007] <2> The manufacturing method according to <1>, further including the following step (iv). (iv) A step of separating the particles obtained in step (iii) from the hydrocolloid. <3> The salt-containing aqueous medium used in step (i) uses at least water as the aqueous medium, and step (ii) is such that the ratio of the weight of the liquid composition to the weight of water contained in the hydrocolloid-containing aqueous medium [(weight of liquid composition) / (weight of water contained in hydrocolloid-containing aqueous medium) × 100] is 10 to 40. The manufacturing method according to <1> or <2>, which is a step of dispersing. <4> The content ratio of the hydrophobe is 0.05 to 20% by mass based on the total mass of the liquid composition used in step (ii). The manufacturing method according to any one of <1> to <3>. <5> The hydrophobe used in step (ii) has a solubility in water at 25°C of 1.0×10 －４ g / L or less of hydrocarbons, a solubility in water at 25°C of 1.0×10 －４ g / L or less of higher alcohols, and a solubility in water at 25°C of 1.0×10 －４ g / L or less of monomers, and is at least one hydrophobe selected from the group consisting of monomers. The manufacturing method according to any one of <1> to <4>.

[0008] <6> The manufacturing method according to any one of <1> to <5>, wherein the liquid composition used in step (ii) further contains a suspension stabilizer. <7> The manufacturing method according to <6>, wherein the suspension stabilizer has a solubility in water at 25°C of 1 to 100 g / L. <8> The manufacturing method according to <6>, wherein the suspension stabilizer is an alcohol having 5 to 10 carbon atoms. <9> As one or two or more monomers different from the hydrophobe used in step (ii), at least a monomer having a 1-octanol / water partition coefficient (log Pow) of 2 or less is used. The manufacturing method according to any one of <1> to <8>.

[0009] <10> The manufacturing method according to any one of <1> to <9>, wherein the average particle diameter of the porous particles is 20 to 500 μm. <11> The manufacturing method according to any one of <1> to <10>, wherein the porous particles are a carrier for purification or adsorption (hereinafter also referred to as "the manufacturing method for the carrier for purification or adsorption of the present invention." The manufacturing method for porous particles and the manufacturing method for the carrier for purification or adsorption of the present invention are also collectively referred to as "the manufacturing method of the present invention."). <12> A method for manufacturing an affinity purification carrier, wherein porous particles are obtained by the manufacturing method according to any one of <1> to <10>, and an affinity ligand is immobilized on the obtained porous particles (hereinafter also referred to as "the manufacturing method for the carrier for affinity purification of the present invention."). <13> The manufacturing method according to any one of <1> to <10>, wherein at least one monomer having an ion exchange group and a polymerizable unsaturated group is used as one or more monomers different from the hydrophobe used in step (ii), and the porous particles are a carrier for ion exchange purification. <14> A method for producing a carrier for ion exchange purification, comprising obtaining porous particles by a manufacturing method described in any of <1> to <10>, and introducing ion exchange groups into the obtained porous particles. <15> A method for producing a carrier for carbon dioxide adsorption, comprising using at least one or more monomers different from the hydrophobe used in step (ii), wherein monomers having an amino group and a polymerizable unsaturated group, and wherein the porous particles are a carrier for carbon dioxide adsorption. <16> A method for producing a carrier for carbon dioxide adsorption, comprising obtaining porous particles by a manufacturing method described in any of <1> to <10>, and introducing amino groups into the obtained porous particles.

[0010] According to the manufacturing method of the present invention, porous particles having excellent antifouling properties or excellent carbon dioxide adsorption properties, and carriers for purification or adsorption can be efficiently produced.

[0011] [Method for Producing Porous Particles] The method for producing porous particles of the present invention includes the following steps (i) to (iii), and the aqueous medium in step (iii) is an aqueous medium in which when the mass of the salt per unit mass in the saturated solution reached when the salt is dissolved in the aqueous medium under the conditions of 23°C and 1 atm is 100 parts by mass, the salt dissolved per unit mass is 10 parts by mass or more. (i) Step of producing a hydrocolloid in a salt-containing aqueous medium (ii) In the hydrocolloid-containing aqueous medium obtained in step (i), a liquid composition containing a hydrophobe having a solubility in water at 25°C of 1.0×10 －４ g / L or less and one or more monomers different from the hydrophobe are dispersed. (iii) Step of suspension-polymerizing the monomers dispersed in step (ii) in an aqueous medium containing a hydrocolloid and a salt. The salt in the "salt-containing aqueous medium" and the "aqueous medium containing a hydrocolloid and a salt" exists ionized in the aqueous medium.

[0012] (Step (i)) Step (i) is a step of producing a hydrocolloid in a salt-containing aqueous medium, but it is preferable to produce the hydrocolloid in a salt-containing aqueous medium having at least water as the aqueous medium.

[0013] In this specification, "hydrocolloid" refers to a colloid of an inorganic compound or polymer compound that disperses well in an aqueous medium. As the inorganic compound that yields the hydrocolloid, an inorganic salt is preferred. Examples of inorganic compounds that yield the hydrocolloid include metal hydroxides such as magnesium hydroxide, calcium hydroxide, aluminum hydroxide, and ferric hydroxide; inorganic salts (sulfates such as calcium sulfate and barium sulfate; carbonates such as calcium carbonate, barium carbonate, and magnesium carbonate; phosphates such as calcium phosphate); metal oxides such as titanium dioxide, aluminum oxide, and zinc oxide, as well as magnesium silicate, talc, bentonite, and silica. Examples of polymer compounds that yield the hydrocolloid include celluloses such as hydroxyethylcellulose and methylcellulose, as well as polyvinyl alcohol, polyethylene glycol, gellan gum, xanthan gum, guar gum, carrageenan, sodium alginate, and pullulan. Among hydrocolloids, hydrocolloids of poorly water-soluble metal salts, hydrocolloids of celluloses, and polyethylene glycol with a degree of polymerization of 2 to 500 are preferred in order to reduce monomer leakage into the aqueous medium (aqueous phase) during suspension polymerization and improve production efficiency. Hydrocolloids of metal hydroxides and hydrocolloids of celluloses are more preferred, hydrocolloids of metal hydroxides and hydrocolloids of hydroxyalkylcellulose are even more preferred, and hydrocolloids of magnesium hydroxide and hydrocolloids of hydroxyethylcellulose are particularly preferred. When the hydrocolloid is a hydrocolloid of a poorly water-soluble metal salt, it becomes easier to separate it from porous particles. Hydrocolloids may be used individually or in combination of two or more types.

[0014] The salt contained in the aqueous medium used in step (i) exists ionized within the aqueous medium. The salt may be any compound consisting of an anion and a cation, but in the present invention, step (i) is excluded when the salt contained in the aqueous medium used in step (i) and the inorganic compound that yields the hydrocolloid, the polyvalent metal salt described later, or the monovalent metal compound are of the same type. When using a colloid of an inorganic compound as the hydrocolloid, a salt that is not of the same type as the inorganic compound, the polyvalent metal salt, or the monovalent metal compound that yields it should be used. Examples of salts include inorganic salts, as well as organic salts such as citrates, tartrates, acetates (ammonium acetate, etc.), and trifluoroacetates (methylammonium trifluoroacetate, etc.). However, in order to reduce the leakage of monomers into the aqueous medium (aqueous phase) during suspension polymerization and improve production efficiency, inorganic salts are preferred, more preferably alkali metal halides, alkaline earth metal halides, even more preferably alkali metal halides, and particularly preferably alkali metal chlorides. Examples include sodium chloride, potassium chloride, magnesium chloride, and calcium chloride. Furthermore, in the case of hydrocolloids of inorganic compounds other than inorganic salts, or hydrocolloids of polymer compounds, phosphates such as potassium dihydrogen phosphate; sulfates such as sodium sulfate; and nitrates may be used. One of these may be used alone, or two or more may be used in combination.

[0015] The salt concentration of the aqueous medium used in step (i) should be such that the salt concentration of the aqueous medium in step (iii) is within the desired range (an aqueous medium in which, when the mass of salt per unit mass in a saturated solution is 100 parts by mass at 23°C and 1 atm, the amount of salt dissolved per unit mass is 10 parts by mass or more). For example, if step (ii) involves adding a liquid composition in which monomers are dissolved or dispersed in an aqueous medium to the hydrocolloid-containing aqueous medium obtained in step (i), the salt concentration of the aqueous medium used in step (i) should be determined such that the total salt concentration of the aqueous medium used in step (i) and the aqueous medium in the liquid composition is within the desired range (an aqueous medium in which, when the mass of salt per unit mass in a saturated solution is 100 parts by mass at 23°C and 1 atm, the amount of salt dissolved per unit mass is 10 parts by mass or more).

[0016] In this specification, "aqueous media" refers to water, ethanol, or a mixture of water and ethanol, but water is preferred. When dispersing the monomer in the hydrocolloid-containing aqueous media in step (ii), the monomer may be added directly to the hydrocolloid-containing aqueous media, or the monomer and other components may be added to an aqueous media other than the hydrocolloid-containing aqueous media in advance to form a monomer composition, and then the monomer composition may be added to the hydrocolloid-containing aqueous media.

[0017] The preparation of hydrocolloids can be carried out by appropriately combining known methods described in Japanese Patent Publication No. 2008-9092, Japanese Patent Publication No. 2018-59972, etc., except that the salt concentration of the aqueous medium in step (iii) is carried out in an aqueous medium with a salt concentration such that the salt concentration is within the desired range (when the mass of salt per unit mass in the saturated solution is set to 100 parts by mass at 23°C and 1 atm, the aqueous medium contains 10 parts by mass or more of dissolved salt per unit mass). For example, hydrocolloids of polymer compounds can be prepared by adding the polymer compound that gives the hydrocolloid to an aqueous medium with a salt concentration such that the salt concentration of the aqueous medium in step (iii) is within the desired range and stirring. Hydrocolloids of inorganic compounds (especially poorly water-soluble metal salts) can be prepared by stirring a polyvalent metal salt and a monovalent metal compound in an aqueous medium with a salt concentration such that the salt concentration of the aqueous medium in step (iii) is within the desired range. For example, the following methods can be used: adding a monovalent metal compound to an aqueous medium containing a polyvalent metal salt at a salt concentration such that the salt concentration of the aqueous medium in step (iii) is within a desired range, and stirring; adding a polyvalent metal salt to an aqueous medium containing a monovalent metal compound at a salt concentration such that the salt concentration of the aqueous medium in step (iii) is within a desired range, and stirring; adding an aqueous medium containing a monovalent metal compound to an aqueous medium containing a polyvalent metal salt at a salt concentration such that the salt concentration of the aqueous medium in step (iii) is within a desired range, and stirring; and adding an aqueous medium containing a polyvalent metal salt to an aqueous medium containing a monovalent metal compound at a salt concentration such that the salt concentration of the aqueous medium in step (iii) is within a desired range, and stirring. Note that hydrates of polyvalent metal salts may be used as the polyvalent metal salts. The stirring time when preparing hydrocolloids of polymer compounds or inorganic compounds is usually 1 to 60 minutes, preferably 5 to 30 minutes. The stirring temperature when preparing hydrocolloids of polymer compounds or inorganic compounds is usually 10 to 95°C, preferably 20 to 80°C.

[0018] The polyvalent metal salts mentioned above are preferably one or more selected from polyvalent metal halides and their hydrates, and more preferably one or more selected from magnesium halides, calcium halides, aluminum halides, iron halides and their hydrates. Examples include one or more selected from magnesium chloride, magnesium bromide, calcium chloride, calcium bromide, aluminum chloride, aluminum bromide, iron chloride, iron bromide and their hydrates.

[0019] As the monovalent metal compound mentioned above, alkali metal hydroxides are preferred, and one or more selected from sodium hydroxide, lithium hydroxide, and potassium hydroxide are more preferred, with sodium hydroxide being particularly preferred.

[0020] The amount of hydrocolloid produced in step (i), the amount of polyvalent metal salt used, and the amount of monovalent metal compound used should be determined so that the hydrocolloid content in the aqueous medium in step (iii) is the desired amount.

[0021] (Step (ii)) Step (ii) involves adding to the hydrocolloid-containing aqueous medium obtained in Step (i) a substance with a solubility in water at 25°C of 1.0 × 10⁻¹⁴. －４ This is a step of dispersing a liquid composition containing a hydrophobe of less than g / L and one or more monomers different from the hydrophobe (hereinafter also simply referred to as "non-hydrophobe monomers"). －４ By incorporating a hydrophob concentration of g / L or less into a liquid composition and dispersing it in a hydrocolloid-containing aqueous medium, monomer leakage into the aqueous medium (aqueous phase) during suspension polymerization is reduced. In particular, even when using highly hydrophilic monomers, monomer leakage into the aqueous medium (aqueous phase) during suspension polymerization is reduced. The reason for this effect is not clear, but the inventors surmise that it is due to an increase in osmotic pressure between the aqueous phase and the oil phase.

[0022] Here, in this specification, the "solubility in water at 25°C" refers to the solubility in water measured by a method in accordance with OECD GUIDELINE FOR THE TESTING OF CHEMICALS TEST No.105: Water Solubility at a temperature of 25°C. Also, in this specification, a "hydrophobe" refers to a compound with extremely high hydrophobicity (J. Jpn. Soc. Colour Mater., 83〔4〕, 171-177(2010)), and a compound with a solubility in water at 25°C of 1.0×10 －４ g / L or less is a hydrophobe because of its extremely high hydrophobicity. As for the solubility in water of the hydrophobe, in order to reduce the leakage of the monomer into the aqueous medium (aqueous phase) during suspension polymerization and improve the production efficiency, 1.0×10 －１３ to 1.0×10 －４ g / L is preferable, 1.0×10 －１２ to 1.0×10 －５ g / L is more preferable, 1.0×10 －１１ to 1.0×10 －６ g / L is still more preferable, and 1.0×10 －１０ to 1.0×10 －７ g / L is particularly preferable.

[0023] The hydrophobe may be a medium for suspension polymerization or a monomer that undergoes suspension polymerization together with the above monomer. As the hydrophobe, at least one hydrophobe selected from the group consisting of hydrocarbons with a solubility in water at 25°C of 1.0×10 －４ g / L or less, higher alcohols with a solubility in water at 25°C of 1.0×10 －４ g / L or less, and monomers with a solubility in water at 25°C of 1.0×10 －４ g / L or less is preferable, and at least one hydrophobe selected from the group consisting of hydrocarbons with a solubility in water at 25°C of 1.0×10 －４ g / L or less and higher alcohols with a solubility in water at 25°C of 1.0×10 －４ g / L or less is more preferable, and a solubility in water at 25°C of 1.0×10 －５Hydrocarbons with a concentration of less than g / L and a solubility in water at 25°C of 1.0 × 10⁻⁶ －５ A hydrophobe selected from the group consisting of higher alcohols at a concentration of g / L or less is even more preferable. When a hydrophobe selected from the group consisting of hydrocarbons and higher alcohols as described above is used, the antifouling properties are particularly improved. In this specification, "antifouling properties" refers to the resistance to nonspecific adsorption of impurities.

[0024] The above hydrocarbons are preferably saturated hydrocarbons having 10 or more carbon atoms, more preferably saturated hydrocarbons having 10 to 24 carbon atoms, and particularly preferably saturated hydrocarbons having 14 to 22 carbon atoms. The hydrocarbons may be linear or branched. For example, decane (solubility in water (25°C): 5.2 × 10⁻⁶) －５ g / L), hexadecane (solubility in water (25°C): 2.1 × 10 －８ g / L), octadecane (solubility in water (25°C): 6.0 × 10 －６ Examples include (g / L). Among these, hexadecane is preferred. As the higher alcohol, saturated monohydric alcohols having 16 or more carbon atoms are preferred, saturated monohydric alcohols having 16 to 24 carbon atoms are more preferred, and saturated monohydric alcohols having 16 to 22 carbon atoms are particularly preferred. The higher alcohol may be linear or branched. For example, 1-hexadecanol (solubility in water (25°C): 4.1 × 10⁻⁶ －５ g / L), stearyl alcohol (solubility in water (25°C): 1.1 × 10 －６ g / L), behenyl alcohol (solubility in water (25°C): 2.0 × 10 －５ Examples include g / L. Among these, 1-hexadecanol is preferred. Its solubility in water at 25°C is 1.0 × 10⁻⁶. －４ Examples of monomer species with a monomer concentration of g / L or less include (meth)acrylate monomers, (meth)acrylamide monomers, and alkylate vinyl monomers, but (meth)acrylate monomers are preferred. Such monomers have a solubility in water of 1.0 × 10⁻⁶ at 25°C. －４Examples include alkyl (meth)acrylates with a concentration of g / L or less. The alkyl group contained in this alkyl (meth)acrylate may be linear, branched, or cyclic. Preferably, the alkyl (meth)acrylate has 10 to 24 carbon atoms in the alkyl group, and more preferably, 12 to 22 carbon atoms in the alkyl group. An example of alkyl (meth)acrylate is dodecyl methacrylate (solubility in water (25°C): 3.0 × 10⁻⁶). －７ g / L), stearyl methacrylate (solubility in water (25°C): 1.0 × 10 －７ (g / L or less), behenyl acrylate (solubility in water (25°C): 1.5 × 10 －９ Examples include g / L. Among these, stearyl methacrylate is preferred. Hydrophobe may be used alone or in combination of two or more types.

[0025] The hydrophobe content in the liquid composition used in step (ii) is preferably 0.05% by mass or more, more preferably 0.1% by mass or more, and even more preferably 0.5% by mass or more, relative to the total mass of the liquid composition used in step (ii), in order to reduce monomer leakage into the aqueous medium (aqueous phase) during suspension polymerization and improve manufacturing efficiency. Furthermore, to facilitate obtaining the desired physical properties, the hydrophobe content is preferably 20% by mass or less, and more preferably 10% by mass or less, relative to the total mass of the liquid composition used in step (ii). Specifically, the range is preferably 0.05 to 20% by mass, more preferably 0.1 to 10% by mass, and even more preferably 0.5 to 10% by mass, relative to the total mass of the liquid composition used in step (ii). Manufacturing efficiency is particularly good when the hydrophobe content is 0.5% by mass or more.

[0026] The ratio of the weight of hydrophobe to the weight of non-hydrophobe monomers used in step (ii) [(weight of hydrophobe) / (weight of one or more monomers different from hydrophobe) × 100] is preferably 0.05 to 30, more preferably 0.1 to 25, and particularly preferably 1 to 20, in order to reduce the leakage of monomers into the aqueous medium (aqueous phase) during suspension polymerization, improve manufacturing efficiency, and make it easier to obtain the desired physical properties.

[0027] In step (ii), it is preferable to use at least a functional group-containing monomer as the monomer that is not hydrophob. The functional group contained in this monomer may be one that can be used for additional chemical reactions (such as reactions with ligands or crosslinking agents). Examples of functional groups include those selected from the group consisting of cyclic ether groups, carboxyl groups, -C(=O)-O-C(=O)-, succinimideoxycarbonyl groups, formyl groups, hydroxyl groups, amino groups, ion exchange groups, and isocyanate groups. Among these, when producing a carrier for affinity purification, cyclic ether groups, carboxyl groups, -C(=O)-O-C(=O)-, and isocyanate groups are preferred, and cyclic ether groups are more preferred. Furthermore, an amino group is preferred to enhance the carbon dioxide adsorption capacity of the porous particles, and an ion exchange group is preferred to enhance the ion exchange performance of the porous particles. Note that when monomers containing cyclic ether groups or hydroxyl groups as the above functional groups are used, amino groups or other ion exchange groups can be introduced after obtaining porous particles.

[0028] Here, the "cyclic ether group" is preferably a cyclic ether group having 3 to 7 atoms constituting the ring. The cyclic ether group may have an alkyl group as a substituent. Specific examples of cyclic ether groups include those represented by the following formulas (1) to (6), but the cyclic ether group represented by formula (1), (3), or (6) is preferred, and the cyclic ether group represented by formula (1) is more preferred.

[0029]

[0030] [In the formula, R 1 ~R4 Each of these independently represents a hydrogen atom or an alkyl group, and * represents a bond.

[0031] R 1 ~R 4 The number of carbon atoms in the alkyl group represented by is preferably 1 to 4, more preferably 1 or 2. The alkyl group may be linear or branched, and examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, etc. Also, R 1 ~R 4 A hydrogen atom is preferred as the element.

[0032] Examples of ion exchange groups include anion exchange groups such as amino groups and quaternary ammonium groups; and cation exchange groups. Examples of cation exchange groups include -SH and -S. － M ＋ , -S － , -C(=O)OH, -C(=O)O － M ＋ , -C(=O)O － , -S (=O) ２ OH, -S (=O) ２ O － M ＋ , -S (=O) ２ O － , -OP(=O)(OH) ２ , -OP(=O)(O － M ＋ ) ２ , -OP(=O)(O － ) ２ , -OP(=O)(OH)(O － M ＋ ), and -O-P(=O)(OH)(O － ) (M above) ＋ (Each of these represents a counterion) and may be one or more selected from these. ＋ Examples of counterions represented by include alkali metal ions such as sodium ions and potassium ions; alkaline earth metal ions such as magnesium ions and calcium ions; ammonium ions; and organic ammonium ions.

[0033] When producing a carrier for affinity purification, it is preferable to use at least a monomer having a ligand-binding functional group and a polymerizable unsaturated group as a non-hydrophobic monomer, and more preferably to use at least a monomer having a ligand-binding functional group and a polymerizable unsaturated group, and a monomer having a hydroxyl group and a polymerizable unsaturated group, in order to enhance antifouling properties. Examples of monomers having ligand-binding functional groups and polymerizable unsaturated groups include glycidyl (meth)acrylate, 3-oxyranylpropyl (meth)acrylate, 4-oxyranylbutyl (meth)acrylate, 5-oxyranylpentyl (meth)acrylate, 6-oxyranylhexyl (meth)acrylate, 7-oxyranylheptyl (meth)acrylate, 8-oxyranyloctyl (meth)acrylate, (3-methyloxyranyl)methyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate glycidyl ether, glycerin mono (meth)acrylate glycidyl ether, 3,4-epoxycyclohexylmethyl (meth)acrylate, and 3,4-epoxycyclohexylethyl (meth)acrylate. Examples include (meth)acrylate monomers having a cyclic ether group, such as phosphate, 3,4-epoxycyclohexylpropyl (meth)acrylate, α-(meth)acrylo-ω-glycidyl polyethylene glycol, and tetrahydrofurfuryl (meth)acrylate; allyl ether monomers having a cyclic ether group, such as allyl glycidyl ether; (meth)acrylate monomers having an isocyanate group, such as isocyanatoethyl (meth)acrylate; unsaturated dicarboxylic acid anhydride monomers, such as maleic anhydride, methyl maleic anhydride, and glutaconic anhydride; carboxyl group-containing vinyl monomers, such as (meth)acrylic acid and maleic acid; and 3,4-epoxy-1-butene and 3,4-epoxy-3-methyl-1-butene. These monomers can be used individually or in combination of two or more. Among these monomers, (meth)acrylate monomers having a cyclic ether group are preferred, and glycidyl (meth)acrylate is particularly preferred.

[0034] Monomers having a hydroxyl group and a polymerizable unsaturated group include non-crosslinkable monomers having a hydroxyl group and a polymerizable unsaturated group, and crosslinkable monomers having a hydroxyl group and a polymerizable unsaturated group. Examples of non-crosslinkable monomers having a hydroxyl group and a polymerizable unsaturated group include hydroxymethyl (meth)acrylate, hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, hydroxybutyl (meth)acrylate, glycerin mono(meth)acrylate, trimethylolethane mono(meth)acrylate, trimethylolpropane mono(meth)acrylate, butanetriol mono(meth)acrylate, diethylene glycol mono(meth)acrylate, polyethylene glycol mono(meth)acrylate, pentaerythritol mono(meth)acrylate, dipentaerythritol mono(meth)acrylate, inositol mono(meth)acrylate, and other (meth)acrylate monomers having a hydroxyl group. Crosslinkable monomers having hydroxyl groups and polymerizable unsaturated groups include glycerin di(meth)acrylate, trimethylolethane di(meth)acrylate, trimethylolpropane di(meth)acrylate, butanetriol di(meth)acrylate, pentaerythritol di(meth)acrylate, pentaerythritol tri(meth)acrylate, glucose di(meth)acrylate, glucose tri(meth)acrylate, glucose tetra(meth)acrylate, dipentaerythritol di( Examples include meth)acrylate, dipentaerythritol tri(meth)acrylate, dipentaerythritol tetra(meth)acrylate, dipentaerythritol penta(meth)acrylate, inositol di(meth)acrylate, inositol tri(meth)acrylate, inositol tetra(meth)acrylate, mannitol di(meth)acrylate, mannitol tri(meth)acrylate, mannitol tetra(meth)acrylate, mannitol penta(meth)acrylate, etc.

[0035] On the other hand, to enhance the carbon dioxide adsorption capacity of porous particles, it is preferable to use at least monomers having an amino group and a polymerizable unsaturated group as non-hydrophobic monomers. Examples of monomers having an amino group and a polymerizable unsaturated group include monomers obtained by reacting a monomer having a cyclic ether group and a polymerizable unsaturated group (for example, the (meth)acrylate monomer having the cyclic ether group or the allyl ether monomer having the cyclic ether group) with a polyhydric amine. Examples of polyhydric amines include diethylenetriamine, piperazine, N,N'-dimethylethylenediamine, ethylenediamine, tris(2-aminoethyl)amine, polyethyleneimine, etc. Note that monomers obtained by reacting a monomer having a cyclic ether group and a polymerizable unsaturated group with polyethyleneimine are macromonomers.

[0036] Furthermore, to improve the ion exchange performance of porous particles, it is preferable to use at least monomers having ion exchange groups and polymerizable unsaturated groups as non-hydrophobic monomers. Examples of monomers having ion exchange groups and polymerizable unsaturated groups include the above-mentioned monomers having amino groups and polymerizable unsaturated groups.

[0037] Furthermore, when introducing amino groups or other ion exchange groups after obtaining porous particles, it is preferable to use at least one or more monomers selected from monomers having a cyclic ether group and a polymerizable unsaturated group (for example, (meth)acrylate monomers having the cyclic ether group and allyl ether monomers having the cyclic ether group) and monomers having a hydroxyl group and a polymerizable unsaturated group as non-hydrophobic monomers. Monomers having a hydroxyl group and a polymerizable unsaturated group are the same as those described above.

[0038] The above-mentioned functional group-containing monomers can be used individually or in combination of two or more.

[0039] Furthermore, in step (ii), in addition to the functional group-containing monomers, the non-hydrophob monomer may also contain monomers other than functional group-containing monomers (hereinafter also referred to as other monomers). Other monomers are broadly classified into non-crosslinkable monomers and crosslinkable monomers, and either one or a combination of these may be used.

[0040] Examples of the above-mentioned non-crosslinkable monomers include (meth)acrylate-based non-crosslinkable monomers, (meth)acrylamide-based non-crosslinkable monomers, aromatic vinyl-based non-crosslinkable monomers, vinyl ketone-based non-crosslinkable monomers, (meth)acrylonitrile-based non-crosslinkable monomers, and N-vinylamide-based non-crosslinkable monomers. These can be used individually or in combination of two or more. Among the non-crosslinkable monomers, (meth)acrylate-based non-crosslinkable monomers and aromatic vinyl-based non-crosslinkable monomers are preferred.

[0041] Examples of the above (meth)acrylate-based non-crosslinkable monomers include methyl (meth)acrylate, ethyl (meth)acrylate, n-butyl (meth)acrylate, 4-tert-butyl (meth)acrylate, isobutyl (meth)acrylate, n-hexyl (meth)acrylate, n-octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, cyclohexyl (meth)acrylate, methoxymethyl (meth)acrylate, methoxyethyl (meth)acrylate, methoxypropyl (meth)acrylate, methoxybutyl (meth)acrylate, methoxypolyethylene glycol (meth)acrylate, N-[2-(dimethylamino)ethyl](meth)acrylate, and N-[2-(diethylamino)ethyl](meth)acrylate. These can be used individually or in combination of two or more.

[0042] Furthermore, the above (meth)acrylamide-based non-crosslinkable monomers include, for example, (meth)acrylamide, N-methyl(meth)acrylamide, dimethyl(meth)acrylamide, diethyl(meth)acrylamide, N-isopropyl(meth)acrylamide, hydroxyethyl(meth)acrylamide, N-methoxymethyl(meth)acrylamide, N-ethoxymethyl(meth)acrylamide, N-(2-aminoethyl)(meth)acrylamide, N-(3-aminopropyl)(meth)acrylamide, N-[2-(dimethylamino)ethyl](meth)acrylamide, N-[2-(diethylamino)ethyl](meth)acrylamide, Examples include N-[3-(dimethylamino)propyl](meth)acrylamide, N-[3-(diethylamino)propyl](meth)acrylamide, N-[4-(dimethylamino)butyl](meth)acrylamide, N-[4-(diethylamino)butyl](meth)acrylamide, N-[5-(dimethylamino)pentyl](meth)acrylamide, N-[5-(diethylamino)pentyl](meth)acrylamide, N-[6-(dimethylamino)hexyl](meth)acrylamide, N-[6-(diethylamino)hexyl](meth)acrylamide, (meth)acryloylmorpholine, diacetone(meth)acrylamide, etc. These can be used individually or in combination of two or more.

[0043] Examples of the above-mentioned aromatic vinyl non-crosslinkable monomers include styrenes such as styrene, α-methylstyrene, halogenated styrene, 4-methylstyrene, 2,4-dimethylstyrene, 2,4,6-trimethylstyrene, ethyl vinylbenzene, 4-isopropylstyrene, 4-n-butylstyrene, 4-isobutylstyrene, and 4-tert-butylstyrene. These can be used individually or in combination of two or more.

[0044] Examples of vinyl ketone-based non-crosslinkable monomers include ethyl vinyl ketone, propyl vinyl ketone, and isopropyl vinyl ketone. These can be used individually or in combination of two or more. Examples of (meth)acrylonitrile-based non-crosslinkable monomers include acrylonitrile and methacrylonitrile. These can be used individually or in combination of two or more. Examples of N-vinylamide-based non-crosslinkable monomers include N-vinylacetamide and N-vinylpropionamide. These can be used individually or in combination of two or more.

[0045] Examples of the above-mentioned crosslinkable monomers include (meth)acrylate-based crosslinkable monomers, aromatic vinyl-based crosslinkable monomers, and allyl-based crosslinkable monomers. These can be used individually or in combination of two or more. Furthermore, crosslinkable monomers with two to five functionalities are preferred, and crosslinkable monomers with two or three functionalities are more preferred. Among the crosslinkable monomers, (meth)acrylate-based crosslinkable monomers and aromatic vinyl-based crosslinkable monomers are preferred.

[0046] Examples of the above (meth)acrylate-based crosslinkable monomers include ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, tripropylene glycol di(meth)acrylate, tetrapropylene glycol di(meth)acrylate, polypropylene glycol di(meth)acrylate, 1,4-butanediol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, and the like. These can be used individually or in combination of two or more.

[0047] Examples of the above-mentioned aromatic vinyl crosslinkable monomers include divinylbenzene, trivinylbenzene, divinyltoluene, divinylxylene, and divinylethylbenzene. These can be used individually or in combination of two or more.

[0048] Furthermore, examples of the above-mentioned allyl crosslinkable monomers include allyl (meth)acrylate, diallyl phthalate, diallyl isophthalate, diallyl terephthalate, diallyl maleate, diallyl fumarate, diallyl itaconicate, diallyl trimellitate, triallyl trimellitate, triallyl cyanurate, diallyl isocyanurate, triallyl isocyanurate, pentaerythritol diallyl ether, pentaerythritol triallyl ether, pentaerythritol tetraallyl ether, and allylpentaerythritol (a mixture of pentaerythritol diallyl ether, pentaerythritol triallyl ether, and pentaerythritol tetraallyl ether). These can be used individually or in combination of two or more. In addition to the examples above, other crosslinkable monomers that can be used include dehydration condensation reaction products of amino alcohols such as diaminopropanol, trishydroxymethylaminomethane, and glucosamine with (meth)acrylic acid, and conjugated diolefins such as butadiene and isoprene.

[0049] Furthermore, as the non-hydrophobic monomer used in step (ii), monomers with a 1-octanol / water partition coefficient (log Pow) of 5 or less are preferred. Such monomers can be broadly classified into those with high hydrophilicity (log Pow of 2 or less, preferably -3 to 2, more preferably -0.2 to 2) and those with low hydrophilicity (log Pow of greater than 2, preferably greater than 2 and 5 or less, more preferably greater than 2 and 4 or less). However, even when at least highly hydrophilic monomers, such as monomers with a log Pow of 2 or less (preferably -0.2 to 2), are used as the non-hydrophobic monomers in the porous particle manufacturing method of the present invention, the monomers are less likely to leak into the aqueous medium (aqueous phase) during suspension polymerization, and porous particles can be manufactured efficiently.

[0050] For example, among the above monomers, glycidyl acrylate, glycidyl methacrylate (LogPOW: 0.81, solubility in water (25°C): 50 g / L), acrylic acid (LogPOW: 0.37, solubility in water (25°C): ≥100 g / L), methacrylic acid (LogPOW: 0.93, solubility in water (25°C): 89 g / L), methyl acrylate (LogPOW: 0.80, solubility in water (25°C): 52 g / L), methyl methacrylate (LogPOW: 1.61, solubility in water (25°C): 15 g / L), 2-hydroxyethyl methacrylate N-(Diethylamino)ethyl methacrylate (LogPOW: 0.60, Solubility in water (25°C): ≥100 g / L), Hydroxypropyl acrylate (LogPOW: 0.35, Solubility in water (25°C): ≥100 g / L), Hydroxypropyl methacrylate (LogPOW: 0.97, Solubility in water (25°C): 38.6 g / L), Glycerin monomethacrylate (LogPOW: -0.12, Solubility in water (25°C): 100 g / L), N-[2-(Diethylamino)ethyl]methacrylate (LogPOW: 1.95, Solubility in water (25°C): 11.32 g / L), N- [2-(dimethylamino)ethyl]acrylate (LogPOW: 0.68, solubility in water (25°C): ≥100 g / L), N-[2-(dimethylamino)ethyl]methacrylate (LogPOW: 1.13, solubility in water (25°C): ≥100 g / L), N-isopropylacrylamide (LogPOW: 0.57, solubility in water (25°C): 34.8 g / L), N-isopropylmethacrylamide (LogPOW: 0.491), N-[3-(dimethylamino)propyl]acrylamide (LogPOW: 0.06, solubility in water (25°C): N-[3-(dimethylamino)propyl]methacrylamide (LogPOW: 0.50, solubility in water (25°C): ≥100 g / L), diacetone acrylamide (LogPOW: 0.32), diethylene glycol diacrylate (LogPOW: 0.84, solubility in water (25°C): 7.1 g / L), diethylene glycol dimethacrylate (LogPOW: 1.93, solubility in water (25°C): 0.58 g / L), and macromonomers of polyethyleneimine and glycidyl methacrylate (LogPOW: -2.75) are,The monomer has high hydrophilicity (log Pow is 2 or less). In the porous particle manufacturing method of the present invention, in order to efficiently manufacture porous particles with excellent antifouling properties, it is preferable to use at least monomers with a log Pow of -3 to 2, more preferably monomers with a log Pow of -0.2 to 2, and particularly preferable monomers with a log Pow of 0 to 1.2 as non-hydrophobic monomers. When monomers with a log Pow of 0 to 1.2 are used at least, it becomes particularly easy to achieve both manufacturing efficiency and the antifouling properties of the porous particles.

[0051] On the other hand, among the above monomers, n-butyl methacrylate (LogPOW: 2.88, solubility in water (25°C): 0.36 g / L), 4-tert-butyl methacrylate (LogPOW: 2.54, solubility in water (25°C): 1.0 g / L), n-hexyl methacrylate (LogPOW: 4.34), 2-ethylhexyl methacrylate (LogPOW: 5.59, solubility in water (25°C): 5.9 × 10⁻¹⁰ －３ g / L), cyclohexyl methacrylate (LogPOW: 3.9, solubility in water (25°C): 1.3 × 10⁻⁶ －４ Monomers with low hydrophilicity (log POW greater than 2), such as styrene (Log POW: 2.95, solubility in water (25°C): 0.3 g / L), divinylbenzene (Log POW: 3.59, solubility in water (25°C): 0.053 g / L), diallyl phthalate (Log POW: 3.23), and allyl methacrylate (Log POW: 2.15), are low hydrophilic monomers (log POW greater than 2).

[0052] In this specification, the 1-octanol / water partition coefficient (log Pow) can be measured using a method in accordance with JIS Z7260-107:2000 or JIS Z7260-117:2006, depending on the magnitude of the partition coefficient.

[0053] Furthermore, non-hydrophobic monomers may be used individually or in combination of two or more.

[0054] In order to improve manufacturing efficiency, the content of non-hydrophobic monomers in the liquid composition used in step (ii) is preferably 1 to 99% by mass, more preferably 2 to 95% by mass, even more preferably 5 to 90% by mass, and particularly preferably 10 to 80% by mass, relative to the total mass of the liquid composition used in step (ii).

[0055] The amount of the highly hydrophilic monomer (specifically, monomers with log Pow of 2 or less) used is preferably 30% by mass or more, more preferably 40% by mass or more, even more preferably 50% by mass or more, and particularly preferably 60% by mass or more, relative to the total mass of monomer, in order to enhance antifouling properties. When attempting to produce particles with such amounts, the high hydrophilicity of the monomer composition makes it easy for the monomer to leak into the aqueous phase during suspension polymerization, making particle production generally difficult. However, according to the porous particle production method of the present invention, particles can be efficiently produced even with such amounts. In this specification, "total mass of monomer" refers to a monomer whose solubility in water at 25°C as a hydrophobe is 1.0 × 10⁻⁶. －４ When monomers of a concentration of g / L or less are used, this refers to the sum of the monomers used and the non-hydrophobic monomers. The amount of the low-hydrophilic monomers (specifically monomers with log Pow greater than 2) used is preferably 1 to 45% by mass, more preferably 2 to 40% by mass, even more preferably 3 to 35% by mass, and particularly preferably 5 to 30% by mass, relative to the total mass of monomers, in order to improve manufacturing efficiency.

[0056] The liquid composition used in step (ii) preferably further contains a suspension stabilizer and / or a polymerization initiator in addition to the above components, and more preferably further contains a suspension stabilizer and a polymerization initiator. When a suspension stabilizer is used, porous particles can be produced more efficiently.

[0057] As a suspension stabilizer, it is preferable to use one with a solubility in water of 1 to 100 g / L at 25°C, more preferably 1 to 80 g / L, and even more preferably 1 to 20 g / L, in order to reduce monomer leakage into the aqueous medium (aqueous phase) during suspension polymerization and improve manufacturing efficiency. Furthermore, it is preferable that the suspension stabilizer acts as a pologen. When a suspension stabilizer with a solubility in water of 1 to 20 g / L at 25°C is used, the manufacturing efficiency is particularly good.

[0058] As a suspension stabilizer, in order to reduce the leakage of monomers into the aqueous medium (aqueous phase) during suspension polymerization and improve production efficiency, at least one suspension stabilizer selected from the group consisting of alcohols with a solubility in water of 1 to 100 g / L at 25°C, polyhydric alcohols with a solubility in water of 1 to 100 g / L at 25°C, and ketones with a solubility in water of 1 to 100 g / L at 25°C is preferred, with alcohols with a solubility in water of 1 to 100 g / L at 25°C being particularly preferred.

[0059] The alcohols mentioned above may be linear or branched, but they are monohydric alcohols. To reduce monomer leakage into the aqueous medium (aqueous phase) during suspension polymerization and improve production efficiency, alcohols with 4 or more carbon atoms are preferred, alcohols with 5 or more carbon atoms are more preferred, alcohols with 5 to 10 carbon atoms are even more preferred, and alcohols with 5 to 7 carbon atoms are particularly preferred. Production efficiency is especially good when alcohols with 5 or more carbon atoms are used as suspension stabilizers. Furthermore, saturated alcohols are preferred. Examples of alcohols include butanol (solubility in water (25°C): 63.2 g / L), pentanol (solubility in water (25°C): 22 g / L), hexanol (solubility in water (25°C): 6 g / L), and heptanol (solubility in water (25°C): 1.67 g / L). Among these, hexanol is preferred.

[0060] Examples of the polyhydric alcohols mentioned above include 2-ethyl-1,3-hexanediol (solubility in water (25°C): 40 g / L). Examples of the ketones mentioned above include acetophenone (solubility in water (25°C): 6.13 g / L) and methyl butyl ketone (solubility in water (25°C): 14 g / L).

[0061] Furthermore, suspension stabilizers may be used individually or in combination of two or more types.

[0062] In order to improve manufacturing efficiency, the content of the suspension stabilizer in the liquid composition used in step (ii) is preferably 1 to 95% by mass, more preferably 2 to 90% by mass, even more preferably 5 to 85% by mass, and particularly preferably 10 to 80% by mass, relative to the total mass of the liquid composition used in step (ii).

[0063] As the polymerization initiator, a radical polymerization initiator is preferred. Examples of radical polymerization initiators include azo initiators, peroxide initiators, and redox initiators. More specifically, examples include azobisisobutyronitrile, methyl azobisisobutyrate, dimethyl azobisisobutyrate, azobis-2,4-dimethylvaleronitrile, benzoyl peroxide, di-tert-butyl peroxide, and benzoyl-dimethylaniline peroxide. The amount of polymerization initiator used is usually about 0.5 parts by mass to 5 parts by mass per 100 parts by mass of the total mass of monomer.

[0064] Methods for dispersing the liquid composition include mixing with a stirrer equipped with stirring blades, passing it through the pores of a porous membrane, passing it through a microchannel, colliding droplets under high pressure, and irradiating it with ultrasound, and these can be appropriately selected depending on the desired particle size. Here, if a salt-containing aqueous medium is used in step (i), then in step (ii), it is preferable to disperse the liquid composition such that the ratio of the weight of the liquid composition to the weight of the water contained in the hydrocolloid-containing aqueous medium [(weight of liquid composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] is 5 to 50, in order to reduce the leakage of monomers into the aqueous medium (aqueous phase) during suspension polymerization and improve manufacturing efficiency. The ratio [(weight of liquid composition) / (weight of water contained in hydrocolloid-containing aqueous medium) × 100] is preferably 10 to 45, more preferably 10 to 40, and particularly preferably 15 to 40, in order to reduce monomer leakage into the aqueous medium (aqueous phase) during suspension polymerization and improve manufacturing efficiency. When this ratio is 10 or higher, manufacturing efficiency is particularly good.

[0065] (Step (iii)) Step (iii) is a step in which the monomer dispersed in step (ii) is suspended and polymerized in an aqueous medium containing hydrocolloid and salt. In this step, suspension polymerization is carried out in an aqueous medium containing the hydrocolloid prepared in step (i), and when the salt is dissolved in the aqueous medium at 23°C and 1 atm and a saturated solution is reached, the amount of salt dissolved per unit mass in the saturated solution is set to 100 parts by mass, and the amount of salt dissolved per unit mass is 10 parts by mass or more. This makes it less likely for monomers to leak into the aqueous medium (aqueous phase) during suspension polymerization. In particular, even when highly hydrophilic monomers are used, it is less likely for monomers to leak into the aqueous medium (aqueous phase) during suspension polymerization.

[0066] The total amount of monomer used is preferably 0.1 parts by mass or more, more preferably 0.5 parts by mass or more, and particularly preferably 1 part by mass or more, per 100 parts by mass of aqueous medium, in order to enhance stability during polymerization. Furthermore, to enhance the uniformity of porous particles, the monomer is preferably 100 parts by mass or less, more preferably 70 parts by mass or less, and particularly preferably 30 parts by mass or less, per 100 parts by mass of aqueous medium. Specifically, the range is preferably 0.1 parts by mass or more and 100 parts by mass or less, more preferably 0.5 parts by mass or more and 70 parts by mass or less, and particularly preferably 1 part by mass or more and 30 parts by mass or less, per 100 parts by mass of aqueous medium.

[0067] The amount of salt dissolved per unit mass of the aqueous medium in step (iii) is 10 parts by mass or more, when the mass of salt per unit mass in the saturated solution reached by dissolving the salt in the aqueous medium at 23°C and 1 atm is taken as 100 parts by mass. However, in order to reduce the leakage of monomer into the aqueous medium (aqueous phase) during suspension polymerization and improve production efficiency, the amount of salt in the aqueous medium is preferably 30 parts by mass or more, more preferably 50 parts by mass or more, and particularly preferably 60 parts by mass or more, with an upper limit of, for example, 100 parts by mass. Production efficiency is particularly good when the amount of salt dissolved per unit mass is 50 parts by mass or more or 60 parts by mass or more, when the mass of salt per unit mass in the saturated solution reached by dissolving the salt in the aqueous medium at 23°C and 1 atm is taken as 100 parts by mass.

[0068] The hydrocolloid concentration of the aqueous medium in step (iii) is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, even more preferably 0.5% by mass or more, and particularly preferably 1% by mass or more, relative to the total mass of the suspension polymerization reaction system, in order to reduce monomer leakage into the aqueous medium (aqueous phase) during suspension polymerization and improve production efficiency. Furthermore, in order to enhance stability during polymerization, it is preferably 10% by mass or less, more preferably 8% by mass or less, even more preferably 5% by mass or less, and particularly preferably 3% by mass or less, relative to the total mass of the suspension polymerization reaction system. Specifically, the range is preferably 0.01% by mass or more and 10% by mass or less, more preferably 0.1% by mass or more and 8% by mass or less, even more preferably 0.5% by mass or more and 5% by mass or less, and particularly preferably 1% by mass or more and 3% by mass or less, relative to the total mass of the suspension polymerization reaction system. Production efficiency is particularly good when the hydrocolloid concentration of the aqueous medium in step (iii) is 1% by mass or more.

[0069] Here, more specific methods for steps (ii) to (iii) include, for example, a method in which a liquid composition containing hydrophobe, a non-hydrophobe monomer, a suspension stabilizer, and a polymerization initiator is dispersed in a hydrocolloid-containing aqueous medium and heated to a predetermined temperature to polymerize, and a method in which a liquid composition containing hydrophobe, a non-hydrophobe monomer, a suspension stabilizer, and a polymerization initiator is added to a hydrocolloid-containing aqueous medium heated to a predetermined temperature and polymerized.

[0070] The polymerization temperature for suspension polymerization can be appropriately determined depending on the type of polymerization initiator, but it is usually around 2 to 100°C. The polymerization time is usually between 5 minutes and 48 hours.

[0071] The suspension polymerization in step (iii) is preferably carried out by stirring, emulsification and dispersion, or ultrasonic irradiation, and is particularly preferably carried out by stirring. The stirring speed is usually 100 rpm or more, and is preferably 200 to 1200 rpm.

[0072] (Step (iv)) In order to obtain high-purity porous particles, the porous particle manufacturing method of the present invention preferably further includes the following step (iv) in addition to steps (i) to (iii): (iv) A step of separating the particles obtained in step (iii) from the hydrocolloid.

[0073] Step (iv) may include, for example, washing with water if the hydrocolloid is highly water-soluble, such as hydroxyethylcellulose hydrocolloid. Alternatively, if the hydrocolloid is poorly water-soluble, such as magnesium hydroxide hydrocolloid, a method may be used to treat the hydrocolloid in the liquid phase containing the porous particles with an acid or alkali. This method can decompose the hydrocolloid in the liquid phase. The resulting porous particles may also be subjected to the introduction of a crosslinking structure or surface modification as described in WO2019 / 039545, JP 2011-252929 A, WO2017 / 155105, JP Sho 62-25102 A, etc.Examples of crosslinking agents that provide a crosslinked structure include oxalyl dihydrazide, malonic acid dihydrazide, succinic acid dihydrazide, 2,3-dihydroxysuccinate dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide, pimelic acid dihydrazide, octanedioic acid dihydrazide, nonanedioic acid dihydrazide, sebacate dihydrazide, dodecanedioic acid dihydrazide, phthalate dihydrazide, and isophthalate dihydrazide. Dicarboxylic acid dihydrazides such as radid, terephthalic acid dihydrazide, and quinolinic acid dihydrazide; tricarboxylic acid trihydrazides such as cyclohexanetricarboxylic acid trihydrazide; (alkylene bisimino)bis(oxoalkanoic acid) compounds such as N1,N1-(ethane-1,2-diyl)bis(succinic acid monoamide); halohydrins such as epichlorohydrin, epibromohydrin, and dichlorohydrin; Examples include bisoxiranes such as resorcinol diglycidyl ether, neopentyl glycol diglycidyl ether, 1,6-hexanediol diglycidyl ether, hydrogenate bisphenol A diglycidyl ether, glycerol polyglycidyl ether, trimethylolpropane diglycidyl ether, diglycidyl terephthalate, diglycidyl orthophthalate, ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, and propylene glycol diglycidyl ether; diamines such as 1,2-bis(2-aminoethoxy)ethane, m-xylylenediamine, 1,3-propanediamine, tetramethylenediamine, pentamethylenediamine, hexamethylenediamine, and 1,3-bis(aminomethyl)cyclohexane; and polyoxiranes with three or more functions. The crosslinking agent crosslinks the residues of functional groups derived from the functional group-containing monomers via substructures derived from the crosslinking agent. Alternatively, the crosslinking agent may be reacted via a linker. For example, if the porous particles contain a hydroxyl group within the molecule, a compound having two or more cyclic ether groups within the molecule (e.g., ethylene glycol diglycidyl ether) can be reacted with the cyclic ether groups derived from this compound, and then the crosslinking agent can be reacted with the cyclic ether groups derived from this compound.

[0074] Furthermore, the porous particle manufacturing method of the present invention enables the efficient production of porous particles having excellent antifouling properties or excellent carbon dioxide adsorption properties. In particular, even when highly hydrophilic monomers are used, the monomers are less likely to leak into the aqueous medium (aqueous phase) during suspension polymerization. Therefore, the porous particles obtained by this manufacturing method are useful as purification or adsorption carriers and their supports, such as affinity purification carriers, ion exchange purification carriers, and carbon dioxide adsorption carriers. The purification or adsorption carrier manufacturing method of the present invention, similar to the porous particle manufacturing method of the present invention, enables the efficient production of purification or adsorption carriers having excellent antifouling properties or excellent carbon dioxide adsorption properties, and even when highly hydrophilic monomers are used, the monomers are less likely to leak into the aqueous medium (aqueous phase) during suspension polymerization. In addition, the porous particles, affinity purification carriers, and ion exchange purification carriers obtained by the manufacturing method of the present invention are less likely to cause non-specific adsorption of impurities when used in affinity purification or ion exchange purification.

[0075] [Method for manufacturing affinity purification carriers] The affinity purification carrier manufacturing method of the present invention is characterized by obtaining porous particles using the porous particle manufacturing method of the present invention, and immobilizing affinity ligands on the obtained porous particles.

[0076] Preferably, the affinity ligand is one or more affinity ligands selected from protein A, protein G, protein L, and their related substances, with protein A and protein A related substances being more preferred. Protein A contains five domains, E, D, A, B, and C, which have the ability to bind to immunoglobulins. Among the protein A related substances, those having modified domains of the B and C domains are preferred, and those having a modified domain of the C domain are more preferred.

[0077] The amount of affinity ligand immobilized is preferably 10 mg to 300 mg, more preferably 25 mg to 150 mg, per gram of dry weight of porous particles, in order to increase the dynamic binding capacity.

[0078] The fixation of affinity ligands to porous particles can be carried out in the same manner as conventional methods. Chemical bonding is preferred as the ligand fixation method. For example, one method is to attach the ligand to a functional group capable of binding the ligand. This method can be carried out by referring to the descriptions in WO2024 / 029394, WO2015 / 119255, WO2015 / 041218, etc. Specifically, one method is to attach the amino group of the ligand to the cyclic ether group, carboxyl group, -C(=O)-O-C(=O)-, formyl group, etc. of the porous particle.

[0079] Furthermore, the ligand may be immobilized using methods to control the orientation of the ligand (U.S. Patent No. 6,399,750, Ljungquist C. et al., rEur. J. Biochem., 1989, Vol. 186, pp. 557-561), or by methods to immobilize the ligand onto porous particles via a linker (spacer) such as diglycidyl ethers of aliphatic polyhydroxy compounds (e.g., ethylene glycol diglycidyl ether) (WO2024 / 029394, U.S. Patent No. 5,260,373, JP 2010-133733, JP 2010-133734), or by methods to accumulate the ligand on porous particles using associative groups (JP 2011-256176). The linker introduction reaction is preferably carried out in a buffer with a pH of 7 to 14 to increase reaction efficiency. Furthermore, the reaction time for the linker introduction reaction is not particularly limited, but is usually around 0.5 to 72 hours. The reaction temperature can be appropriately selected below the boiling point of the solvent, but is usually around 2 to 100°C.

[0080] Furthermore, the affinity purification carrier obtained in the above process may be subjected to a blocking treatment. A blocking treatment method involves reacting the affinity purification carrier with a compound having a total of two or more hydrophilic groups selected from hydroxyl groups and mercapto groups within its molecule. As the compound having a total of two or more hydrophilic groups within its molecule, compounds having a total of two to four hydrophilic groups selected from hydroxyl groups and mercapto groups within its molecule are preferred. Examples include alcohols having mercapto groups within their molecule, such as mercaptoethanol and thioglycerol; and polyhydric alcohols, such as glycerol and diglycerol. Compounds having a total of two or more hydrophilic groups within their molecule can be used individually or in combination of two or more.

[0081] [Method for producing ion-exchange purification carriers, method for producing carbon dioxide adsorption carriers] Ion-exchange purification carriers can be produced by a method in which at least one monomer having an ion-exchange group and a polymerizable unsaturated group is used as one or more monomers different from the hydrophobe used in step (ii) of the porous particle production method of the present invention (hereinafter also referred to as the "first method for producing ion-exchange purification carriers"), or by a method in which porous particles are obtained using the porous particle production method of the present invention, and an ion-exchange group is introduced into the obtained porous particles (hereinafter also referred to as the "second method for producing ion-exchange purification carriers"). Carbon dioxide adsorption carriers can be produced by a method in which at least one monomer having an amino group and a polymerizable unsaturated group is used as one or more monomers different from the hydrophobe used in step (ii) of the porous particle production method of the present invention (hereinafter also referred to as the "first method for producing carbon dioxide adsorption carriers"), or by a method in which porous particles are obtained using the porous particle production method of the present invention, and an amino group is introduced into the obtained porous particles (hereinafter also referred to as the "second method for producing carbon dioxide adsorption carriers"). Among these, the first method for producing carbon dioxide adsorption carriers is preferred.

[0082] Examples of monomers having ion exchange groups and polymerizable unsaturated groups, amino groups and polymerizable unsaturated groups used in the first method for producing a carrier for ion exchange purification and the first method for producing a carrier for carbon dioxide adsorption include those similar to those listed as monomers having ion exchange groups and polymerizable unsaturated groups, amino groups and polymerizable unsaturated groups that can be used in the porous particle production method of the present invention.

[0083] The method for introducing ion exchange groups or amino groups into porous particles in the second method for producing a carrier for ion exchange purification and the second method for producing a carrier for carbon dioxide adsorption can be carried out according to known methods described in WO2023 / 058409, etc. For example, if the porous particles contain a cyclic ether group in the molecule, they can be reacted with mercapto alcohols such as thioglycerol to produce -SH, -S - M + and -S - An ion exchange group can be introduced from the above. Alternatively, mercapto alcohols may be reacted via a linker. For example, if the porous particles contain a hydroxyl group in the molecule, a compound having two or more cyclic ether groups in the molecule (e.g., ethylene glycol diglycidyl ether) can be reacted, and then the cyclic ether groups derived from this compound can be reacted with the mercapto alcohols.

[0084] The volume-average particle diameter of the porous particles, purified or adsorbent carrier is preferably 10 to 200 μm, more preferably 40 to 120 μm. The coefficient of variation of the volume-average particle diameter is preferably 40% or less, more preferably 30% or less. The specific surface area of ​​the porous particles, purified or adsorbent carrier is preferably 1 to 500 m². 2 / g, more preferably 10 to 300m 2 The value is / g. Furthermore, the volume-average pore diameter of the porous particles, purified or adsorbent carrier is preferably 10 to 300 nm. The volume-average particle diameter, coefficient of variation, specific surface area, and volume-average pore diameter can be measured by laser diffraction / scattering particle size distribution measurement, etc.

[0085] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0086] (Example 1) (1) To 217.8 g of pure water, 63.2 g of sodium chloride and 18.0 g of magnesium chloride hexahydrate were added and stirred to dissolve, thereby preparing aqueous solution S. Next, to a monomer consisting of 7.3 g of 2-hydroxyethyl methacrylate, 7.3 g of glycidyl methacrylate and 3.6 g of divinylbenzene, 35.8 g of 1-hexanol as a suspension stabilizer, 0.54 g of hexadecane as a hydrophobe, and 0.73 g of 2,2'-azobis(isobutyrate)dimethyl as an initiator were added to prepare a monomer composition. (2) The entire aqueous solution S was poured into a separable flask, a thermometer, a stirring blade and a condenser were attached, and the flask was set in a hot water bath and stirred under a nitrogen atmosphere. 45.9 g of 5 M aqueous sodium hydroxide solution was added to the separable flask to prepare an aqueous magnesium hydroxide hydrocolloid dispersion. Here, the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution was calculated from the weight of the pure water used to prepare aqueous solution S, the weight of the water introduced from the magnesium chloride hexahydrate, and the weight of the water introduced from the 5M sodium hydroxide aqueous solution. Then, the ratio of the weight of the monomer composition to the weight of water contained in this magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated. This value is shown in Table 1. Next, the stirring speed was set to 600 rpm, and the entire amount of the monomer composition was added to the separable flask and heated in a hot water bath until the internal temperature reached 86°C. (3) Next, suspension polymerization was carried out by stirring for 3 hours while maintaining the temperature at 86°C, and then it was cooled to room temperature. Next, 5M hydrochloric acid was added and stirred so that the pH of the supernatant was 5.0 or less. Next, the reaction solution was filtered and washed with pure water and ethanol. Next, a sieve classification operation was performed to obtain the particle sizes listed in Table 1, and the particles after sieve classification were recovered with pure water to obtain porous particle dispersion 1.(4) Next, an amount of porous particle dispersion 1 equivalent to 1.5 g by dry weight was replaced with 10 mL of 5% by mass ethylene glycol diglycidyl ether / 0.7 M sodium sulfate / 0.1 M sodium carbonate aqueous solution, and reacted for 16 hours to introduce epoxy groups. The resulting particles are referred to as epoxy group-introduced particles. Subsequently, 0.15 g of modified protein A (rSPA, manufactured by Repligen) was dissolved in 40 mL of 1.2 M sodium sulfate / 0.1 M sodium phosphate buffer (pH 6.6) to obtain a protein A solution. The epoxy group-introduced particles were added to this protein A solution. Protein A was immobilized into the particles by shaking the dispersion at 25°C for 10 hours. Next, the resulting protein A-immobilized particles were dispersed in 40 mL of 1.0 M α-thioglycerol / 0.1 M sodium sulfate (pH 8.3), and the unreacted epoxy groups were opened by shaking the mixture at 25°C for 17 hours. Furthermore, the unreacted epoxy groups that had been ring-opened, resulting in the immobilized protein A particles, were washed with 0.1 M sodium phosphate buffer (pH 6.6), 0.1 M aqueous sodium hydroxide solution, and 0.1 M sodium citrate buffer (pH 3.2) to obtain a packing material-containing solution for affinity chromatography. The packing material contained in this solution is referred to as "ligand immobilization support W1".

[0087] (Example 2) In the preparation of the monomer composition in step (1) of Example 1, the same steps as in steps (1) to (3) of Example 1 were carried out, except that the amount of 1-hexanol used was changed to 36.2 g and the amount of hexadecane used was changed to 0.05 g, to obtain a porous particle dispersion 2. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W2". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 1.

[0088] (Example 3) In the preparation of the monomer composition in step (1) of Example 1, the same steps as in steps (1) to (3) of Example 1 were carried out, except that the amount of 1-hexanol used was changed to 33.4 g and the amount of hexadecane used was changed to 2.90 g, to obtain a porous particle dispersion 3. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W3". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 1.

[0089] (Example 4) In the preparation of the monomer composition in step (1) of Example 1, the amount of 2-hydroxyethyl methacrylate used was changed to 6.7 g and the amount of 1-hexanol used to 36.3 g, and stearyl methacrylate was used instead of hexadecane as hydrophobe. Except for these changes, the same steps as in steps (1) to (3) of Example 1 were carried out to obtain porous particle dispersion 4. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W4". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 1.

[0090] (Example 5) In the preparation of the monomer composition in step (1) of Example 1, the same steps as in steps (1) to (3) of Example 1 were carried out, except that hexadecane was replaced with 1-hexadecanol, to obtain a porous particle dispersion 5. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W5". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 1.

[0091] (Example 6) In the preparation of the monomer composition in step (1) of Example 1, the same steps as in steps (1) to (3) of Example 1 were carried out, except that 1-hexanol was replaced with 1-butanol, to obtain a porous particle dispersion 6. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W6". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 1.

[0092] (Example 7) In the preparation of the monomer composition in step (1) of Example 1, the same steps as in steps (1) to (3) of Example 1 were performed, except that 2-hydroxyethyl methacrylate was replaced with glycerin monomethacrylate and 1-hexanol was replaced with 1-pentanol, to obtain a porous particle dispersion 7. Next, the same steps as in step (4) of Example 1 were performed to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W7". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 1.

[0093] (Example 8) In the preparation of the monomer composition in step (1) of Example 1, the same steps as in steps (1) to (3) of Example 1 were performed, except that 2-hydroxyethyl methacrylate was replaced with methyl methacrylate, to obtain a porous particle dispersion 8. Next, the same steps as in step (4) of Example 1 were performed to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W8". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 1.

[0094] (Example 9) In the preparation of aqueous solution S in step (1) of Example 1, the amount of pure water used was changed to 237.2 g, the amount of sodium chloride used to 68.8 g, and the amount of magnesium chloride hexahydrate used to 19.6 g. In the preparation of the monomer composition, the amount of 2-hydroxyethyl methacrylate used was changed to 3.2 g, the amount of glycidyl methacrylate used to 3.2 g, the amount of divinylbenzene used to 1.6 g, the amount of 1-hexanol used to 15.6 g, and the amount of hexadecane used to 0.24 g. The amount of 5M aqueous sodium hydroxide added in step (2) of Example 1 was changed to 50.0 g. Except for these changes, the same steps as in steps (1) to (3) of Example 1 were carried out to obtain a porous particle dispersion 9. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W9". Furthermore, the ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 2.

[0095] (Example 10) In the preparation of aqueous solution S in step (1) of Example 1, the amount of pure water used was changed to 201.3 g, the amount of sodium chloride used to 58.4 g, and the amount of magnesium chloride hexahydrate used to 16.7 g. In the preparation of the monomer composition, the amount of 2-hydroxyethyl methacrylate used was changed to 10.7 g, the amount of glycidyl methacrylate used to 10.7 g, the amount of divinylbenzene used to 5.4 g, the amount of 1-hexanol used to 52.9 g, and the amount of hexadecane used to 0.81 g. The amount of 5M aqueous sodium hydroxide added in step (2) of Example 1 was changed to 42.3 g. Except for these changes, the same steps as in steps (1) to (3) of Example 1 were carried out to obtain a porous particle dispersion 10. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W10". Furthermore, the ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 2.

[0096] (Example 11) In the preparation of aqueous solution S in step (1) of Example 1, the amount of pure water used was changed to 231.7 g, the amount of sodium chloride used to 46.3 g, and the amount of magnesium chloride hexahydrate used to 17.9 g. In the preparation of the monomer composition, the amount of 2-hydroxyethyl methacrylate used was changed to 7.7 g, the amount of glycidyl methacrylate used to 7.7 g, the amount of divinylbenzene used to 3.9 g, the amount of 1-hexanol used to 38.0 g, and the amount of hexadecane used to 0.58 g. The amount of 5M aqueous sodium hydroxide added in step (2) of Example 1 was changed to 45.4 g. Except for these changes, the same steps as in steps (1) to (3) of Example 1 were carried out to obtain a porous particle dispersion 11. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W11". Furthermore, the ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 2.

[0097] (Example 12) In the preparation of aqueous solution S in step (1) of Example 1, the amount of pure water used was changed to 249.4 g, the amount of sodium chloride used to 24.9 g, and the amount of magnesium chloride hexahydrate used to 17.6 g. In the preparation of the monomer composition, the amount of 2-hydroxyethyl methacrylate used was changed to 8.3 g, the amount of glycidyl methacrylate used to 8.3 g, the amount of divinylbenzene used to 4.2 g, the amount of 1-hexanol used to 41.0 g, and the amount of hexadecane used to 0.62 g. The amount of 5M aqueous sodium hydroxide added in step (2) of Example 1 was changed to 44.8 g. Except for these changes, the same steps as in steps (1) to (3) of Example 1 were carried out to obtain a porous particle dispersion 12. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W12". Furthermore, the ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 2.

[0098] (Example 13) (1) To 258.7 g of pure water, 75.0 g of sodium chloride and 0.78 g of hydroxyethylcellulose were added and stirred to dissolve, thereby preparing an aqueous hydroxyethylcellulose hydrocolloid dispersion. Next, to a monomer consisting of 8.6 g of 2-hydroxyethyl methacrylate, 8.6 g of glycidyl methacrylate, and 4.3 g of divinylbenzene, 42.5 g of 1-hexanol as a suspension stabilizer, 0.65 g of hexadecane as a hydrophobe, and 0.86 g of 2,2'-azobis(isobutyrate)dimethyl as an initiator were added to prepare a monomer composition. Here, the ratio of the weight of the monomer composition to the weight of water contained in the aqueous hydroxyethylcellulose hydrocolloid dispersion (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated. This value is shown in Table 2. (2) The entire volume of the hydrocolloid dispersion aqueous solution was poured into a separable flask, a thermometer, a stirring blade and a condenser were attached, and the flask was placed in a hot water bath and stirring was started under a nitrogen atmosphere. Next, the stirring speed was set to 600 rpm, the entire volume of the monomer composition was poured into the separable flask, and the flask was heated in the hot water bath until the internal temperature reached 86°C. (3) Next, suspension polymerization was carried out by stirring for 3 hours while maintaining the temperature at 86°C, and then it was cooled to room temperature. Next, the reaction solution was filtered and washed with pure water and ethanol. Next, a sieving classification operation was performed to obtain the particle size shown in Table 2, and the particles after sieving classification were recovered with pure water to obtain a porous particle dispersion 13. (4) Next, the same process as in step (4) of Example 1 was carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is called "ligand immobilization carrier W13".

[0099] (Example 14) In the preparation of aqueous solution S in step (1) of Example 1, the amount of pure water used was changed to 245.7 g, the amount of sodium chloride used to 71.2 g, and the amount of magnesium chloride hexahydrate used to 5.9 g. In the preparation of the monomer composition, the amount of 2-hydroxyethyl methacrylate used was changed to 8.2 g, the amount of glycidyl methacrylate used to 8.2 g, the amount of divinylbenzene used to 4.1 g, the amount of 1-hexanol used to 40.3 g, and the amount of hexadecane used to 0.61 g. The amount of 5M aqueous sodium hydroxide added in step (2) of Example 1 was changed to 15.0 g. Except for these changes, the same steps as in steps (1) to (3) of Example 1 were carried out to obtain a porous particle dispersion 14. Next, the same steps as in step (4) of Example 1 were carried out to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W14". Furthermore, the ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 2.

[0100] (Example 15) The process was the same as in Example 1, except that the stirring speed in step (2) was changed to 1000 rpm and a sieving classification operation was performed in step (3) to obtain the particle size shown in Table 1, to obtain a porous particle dispersion 15. Next, the same process as in Example 1, step (4), was performed to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W15". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 2.

[0101] (Example 16) The process was the same as in Example 1, except that the stirring speed in step (2) was changed to 200 rpm and a sieving classification operation was performed in step (3) to obtain the particle size shown in Table 1, to obtain a porous particle dispersion 16. Next, the same process as in Example 1, step (4), was performed to obtain a packing material containing affinity chromatography. The packing material contained in this liquid is referred to as "ligand immobilization carrier W16". The ratio of the weight of the monomer composition to the weight of water contained in the magnesium hydroxide hydrocolloid dispersion aqueous solution (weight of water contained in the hydrocolloid-containing aqueous medium) [(weight of monomer composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] was calculated in the same manner as in Example 1. This value is shown in Table 2.

[0102] (Comparative Example 1) The same steps as in steps (1) to (3) of Example 1 were performed, except that sodium chloride and magnesium chloride hexahydrate were not added in the preparation of aqueous solution S in step (1) of Example 1, hexadecane was not added in the preparation of the monomer composition, and the 5M aqueous sodium hydroxide solution in step (2) of Example 1 was not added. However, particle formation by suspension polymerization did not proceed, and the target particles could not be prepared.

[0103] (Comparative Example 2) The same steps as in steps (1) to (3) of Example 1 were performed, except that magnesium chloride hexahydrate was not added in the preparation of aqueous solution S in step (1) of Example 1, hexadecane was not added in the preparation of the monomer composition, and the 5M aqueous sodium hydroxide solution in step (2) of Example 1 was not added. However, particle formation by suspension polymerization did not proceed, and the target particles could not be prepared.

[0104] (Test Example 1) Particle Yield Approximately 1 g each of the porous particle dispersions 1 to 16 obtained in each example was weighed into an aluminum cup and heated on a hot plate to obtain dry particles. The drying conditions were as follows: heated at approximately 100°C for 5 minutes to remove most of the moisture, followed by drying at 180°C for 10 minutes. After that, the mixture was cooled in a desiccator for 2 minutes, and the weight of the dry particles was measured using a precision balance. The porous particle dispersion concentration was calculated based on the following formula: Porous particle dispersion concentration (%) = (Weight of dry particles (g) / Weight of porous particle dispersion weighed into aluminum cup (g)) × 100

[0105] Using the porous particle dispersion concentration, the total weight of the porous particle dispersion, and the sum of the amount of monomer and initiator used in the polymerization reaction, the particle yield was calculated according to the following formula. The results are shown in Tables 1 and 2. Particle yield (%) = (Porous particle dispersion concentration (%) ÷ 100 × Total weight of porous particle dispersion (g)) ÷ (Amount of monomer used in polymerization reaction (g) + Amount of initiator (g)) × 100

[0106] If the particle yield was 50% or higher, it was classified as "A"; if the particle yield was 20% or more but less than 50%, it was classified as "B"; and if the particle yield was less than 20% or no particles were formed, it was classified as "C".

[0107] (Test Example 2) Volume-Average Particle Size The volume-average particle size of ligand-immobilized carriers W1 to W16 in each example was measured using a laser diffraction scattering particle size distribution analyzer (MicrotracBEL MT3300) in accordance with JIS Z 8825 (2013). The refractive index of the solvent (water) was set to 1.333, and the refractive index of the particles (ligand-immobilized carriers) was set to 1.50. The results are shown in Tables 1 and 2. The values ​​in the tables are rounded to the nearest whole number.

[0108] (Test Example 3) For each example of the HCP test, ligand immobilization carriers W1 to W16 were packed into a 4 mL (5 mmφ × 200 mm long) column to a packing height of approximately 20 cm by passing a 20 mM sodium phosphate / 150 mM sodium chloride aqueous solution (pH 7.5) through the column at a flow rate of 1 to 3 mL / min using an AKTAprime plus manufactured by Cytiva. Next, CHO cell culture supernatant containing the monoclonal antibody Trastuzumab was passed through the column at a flow rate of 1 mL / min with a loading of approximately 23 mg antibody / mL carrier. Then, 20 mM sodium phosphate buffer (pH 7.5), 20 mM sodium phosphate / 1 M sodium chloride buffer (pH 7.5), and 20 mM sodium phosphate buffer (pH 7.5) were sequentially passed through the column at a flow rate of 1 mL / min for 20 mL each. Subsequently, 50 mM sodium citrate buffer (pH 3.2) was passed through the column at a flow rate of 1 mL / min to elute the monoclonal antibody trapped in the column, and fractions with an absorbance of 100 mAu or more at a wavelength of 280 nm were collected. The antibody concentration (mg / mL) contained in the collected fraction was then measured using a spectrophotometer. In addition, the concentration of Host Cell Protein (HCP) (ng / mL) contained in the collected fraction was measured using a CHO HCP ELISA kit, 3G from Cygnus Technologies. Furthermore, the amount of HCP per unit amount of antibody was calculated by dividing the HCP concentration by the antibody concentration and evaluated according to the following criteria. The results are shown in Tables 1 and 2. (HCP evaluation criteria) A: HCP is 10,000 ppm or less B: HCP is greater than 10,000 ppm

[0109]

[0110]

[0111]

[0112] The symbols and other terms in each table indicate the following: HEMA: 2-hydroxyethyl methacrylate (LogPOW: 0.60, solubility in water (25°C): ≥100 g / L), GLM: glycerin monomethacrylate (LogPOW: -0.12, solubility in water (25°C): 100 g / L), MMA: methyl methacrylate (LogPOW: 1.61, solubility in water (25°C): 15 g / L), GMA: glycidyl methacrylate (LogPOW: 0.81, solubility in water (25°C): 50 g / L), DVB: divinylbenzene (LogPOW: 3.59, solubility in water (25°C): 0.053 g / L), SMA: stearyl methacrylate (solubility in water (25°C): ≤1.0 × 10⁻¹⁰ －７ (g / L) HEC: Solubility of hydroxyethylcellulose hexadecane in water (25°C): 2.1 × 10 －８ Solubility of 1-hexadecanol in water (g / L) at 25°C: 4.1 × 10⁻⁶ －５ g / L *1: (Weight of hydrophobe / Weight of monomer composition) × 100 *2: When the salt is dissolved in an aqueous medium at 23°C and 1 atm and a saturated solution is reached, the amount of salt dissolved per unit mass of the aqueous medium is set to 100 parts by mass. *3: (Weight of dispersant / Weight of aqueous medium containing hydrocolloid and salt) × 100

[0113] (Example 17: Production of a carbon dioxide adsorption carrier) A carbon dioxide adsorption carrier was produced using a macromonomer of polyethyleneimine and glycidyl methacrylate. The specific procedure is as follows: (1) 63.2 g of sodium chloride and 18.0 g of magnesium chloride hexahydrate were added to 217.8 g of pure water and stirred to dissolve, thereby preparing aqueous solution S. Next, 9.2 g of glycidyl methacrylate was added dropwise to 44.9 g of acetophenone and 11.5 g of polyethyleneimine, and stirred overnight at room temperature to react glycidyl methacrylate with polyethyleneimine to obtain monomer solution 1. 2.3 g of divinylbenzene, 0.54 g of hexadecane as a hydrophor, and 0.73 g of 2,2'-azobis(isobutyrate)dimethyl as an initiator were added to monomer solution 1 to prepare a monomer composition. (2) The entire aqueous solution S was poured into a separable flask, a thermometer, a stirring blade and a condenser were attached, and the flask was placed in a hot water bath and stirring was started under a nitrogen atmosphere. 45.9 g of 5 M sodium hydroxide aqueous solution was added to the separable flask to prepare a magnesium hydroxide hydrocolloid dispersion aqueous solution. Next, the stirring speed was set to 600 rpm, the entire monomer composition was poured into the separable flask, and the flask was heated in a hot water bath until the internal temperature reached 86°C. (3) Next, suspension polymerization was carried out by stirring for 3 hours while maintaining the temperature at 86°C, and then it was cooled to room temperature. Next, 5 M hydrochloric acid was added so that the pH of the supernatant was 5.0 or less, and the mixture was stirred. Next, the reaction solution was filtered, washed with pure water and ethanol, and sieved to obtain the particle size shown in Table 4. Then, it was vacuum dried at 80°C to obtain carbon dioxide adsorption carrier powder 1. Using the obtained carbon dioxide adsorption carrier powder 1, the particle yield was calculated and determined in the same manner as in Test Example 1. Furthermore, the volume-average particle size was measured in the same manner as in Test Example 2. The results are shown in Table 4.

[0114] (Example 18: Production of Ion Exchange Purification Carrier) An ion exchange purification carrier was produced using a macromonomer of polyethyleneimine and glycidyl methacrylate. Specifically, the same steps as in steps (1) to (3) of Example 17 were performed, except that the particles were recovered with pure water after the sieving classification operation in (3) of Example 17, to obtain a dispersion of the ion exchange purification carrier. Using the obtained dispersion of the ion exchange purification carrier, the particle yield was calculated and determined in the same manner as in Test Example 1. The volume-average particle diameter was also measured in the same manner as in Test Example 2. The results are shown in Table 4.

[0115] (Example 19: Production of a carrier for ion exchange purification) A porous particle dispersion 1 was obtained by performing the same steps as in steps (1) to (3) of Example 1. Next, 10 g of the porous particle dispersion 1 (on a dry weight basis) was replaced with 70 mL of 5% by mass ethylene glycol diglycidyl ether / 0.7 M sodium sulfate / 0.1 M sodium carbonate aqueous solution and reacted for 16 hours. The resulting particles are referred to as epoxy group-introduced particles. Next, 0.837 g of 1,2-bis(aminoethoxy)ethane and 0.452 g of diisopropylethylamine were added to 100 g of a 10% by mass aqueous dispersion of epoxy group-introduced particles, and the mixture was heated to 70°C and stirred for 8 hours while maintaining the temperature at 70°C. After that, 12.215 g of α-thioglycerol was added and stirred for 3 hours. Next, after cooling the reaction solution, the reaction solution was filtered, washed with pure water and ethanol, and the resulting particles were recovered with pure water to obtain a carrier for ion exchange purification. Using the obtained ion-exchange purification carrier, the particle yield was calculated and determined in the same manner as in Test Example 1. The volume-average particle diameter was also measured in the same manner as in Test Example 2. The results are shown in Table 4.

[0116] (Comparative Example 3) The same steps as in steps (1) to (3) of Example 17 were performed, except that sodium chloride and magnesium chloride hexahydrate were not added in the preparation of aqueous solution S in step (1) of Example 17, hexadecane was not added in the preparation of the monomer composition, and the 5M aqueous sodium hydroxide solution in step (2) of Example 17 was not added. However, particle formation by suspension polymerization did not proceed, and the target particles could not be prepared.

[0117] (Test Example 4) Carbon Dioxide Adsorption Test The carbon dioxide adsorption performance of carbon dioxide adsorption carrier powder 1 obtained in Example 17 was evaluated using STA 2500 Regulus manufactured by NETZSCH. Specifically, carbon dioxide adsorbed carbon dioxide was removed from carbon dioxide adsorbed in the powder 1 obtained in Example 17 by decarbonizing it under nitrogen at 80°C for 5 hours. After that, it was returned to room temperature and brought into contact with dry air, and the amount of carbon dioxide adsorbed was determined from the weight increase when the weight increase stopped changing, and the carbon dioxide adsorption performance was evaluated according to the following criteria. The results are shown in Table 4.

[0118] (Evaluation criteria for carbon dioxide adsorption performance) A: Carbon dioxide adsorption amount is 1 mmol / g or more B: Carbon dioxide adsorption amount is less than 1 mmol / g

[0119]

[0120] In Table 4, GMA + PEI represents the macromonomer of polyethyleneimine and glycidyl methacrylate. Other symbols have the same meaning as those in Tables 1-3.

Claims

1. A method for producing porous particles, comprising the following steps (i) to (iii), wherein the aqueous medium in step (iii) is an aqueous medium in which, when the mass of salt per unit mass in a saturated solution reached by dissolving a salt in the aqueous medium at 23°C and 1 atm is set to 100 parts by mass, the amount of salt dissolved per unit mass is 10 parts by mass or more. (i) A step of producing a hydrocolloid in a salt-containing aqueous medium (ii) In the hydrocolloid-containing aqueous medium obtained in step (i), a salt having a solubility in water at 25°C of 1.0 × 10 －４ (iii) A step of dispersing a liquid composition containing a hydrophobe in a concentration of g / L or less and one or more monomers different from the hydrophobe; (iii) A step of suspension polymerization of the monomer dispersed in step (ii) in an aqueous medium containing a hydrocolloid and a salt.

2. The manufacturing method according to claim 1, further comprising the following step (iv). (iv) A step to separate the particles obtained in step (iii) from the hydrocolloid.

3. The manufacturing method according to claim 1 or 2, wherein the salt-containing aqueous medium used in step (i) is at least water as the aqueous medium, and step (ii) is a step of dispersing the liquid composition such that the ratio of the weight of the liquid composition to the weight of water contained in the hydrocolloid-containing aqueous medium [(weight of liquid composition) / (weight of water contained in the hydrocolloid-containing aqueous medium) × 100] is 10 to 40.

4. The manufacturing method according to any one of claims 1 to 3, wherein the content of hydrophobe is 0.05 to 20% by mass relative to the total mass of the liquid composition used in step (ii).

5. The hydrophobe used in step (ii) has a solubility in water of 1.0 × 10⁻¹⁶ at 25°C. －４ Hydrocarbons with a concentration of less than g / L and a solubility in water at 25°C of 1.0 × 10⁻⁶ －４ Higher alcohols with a solubility of 1.0 × 10⁻¹⁰ g / L or less in water at 25°C. －４ The method for producing a product according to any one of claims 1 to 4, wherein the product is at least one hydrophobe selected from the group consisting of monomers in a concentration of g / L or less.

6. The manufacturing method according to any one of claims 1 to 5, wherein the liquid composition used in step (ii) further comprises a suspension stabilizer.

7. The manufacturing method according to claim 6, wherein the suspension stabilizer is a suspension stabilizer having a solubility in water of 1 to 100 g / L at 25°C.

8. The manufacturing method according to claim 6, wherein the suspension stabilizer is an alcohol having 5 to 10 carbon atoms.

9. The manufacturing method according to any one of claims 1 to 8, wherein at least one monomer different from the hydrophobe used in step (ii) is used, wherein the monomer has a 1-octanol / water partition coefficient (log Pow) of 2 or less.

10. The manufacturing method according to any one of claims 1 to 9, wherein the average particle size of the porous particles is 20 to 500 μm.

11. A method for producing an affinity purification carrier, comprising obtaining porous particles by the manufacturing method described in any one of claims 1 to 10, and immobilizing affinity ligands on the obtained porous particles.

12. The manufacturing method according to any one of claims 1 to 10, wherein at least one or more monomers different from the hydrophobe used in step (ii) are monomers having an ion exchange group and a polymerizable unsaturated group, and the porous particles are carriers for ion exchange purification.

13. A method for producing a carrier for ion exchange purification, comprising obtaining porous particles by the manufacturing method described in any one of claims 1 to 10, and introducing ion exchange groups into the obtained porous particles.

14. The manufacturing method according to any one of claims 1 to 10, wherein at least one monomer having an amino group and a polymerizable unsaturated group is used as one or more monomers different from the hydrophobe used in step (ii), and the porous particles are carbon dioxide adsorption carriers.

15. A method for producing a carbon dioxide adsorption carrier, comprising obtaining porous particles by the manufacturing method described in any one of claims 1 to 10, and introducing amino groups into the obtained porous particles.

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