JP2006111717A - Crosslinked (meth)acrylamide particle, method for producing the same and use thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve problems that an acrylamide particle has weak mechanical strength and difficulty in use as a particle having about 10 μm particle diameter for liquid chromatography and in production of an acrylamide having an arbitrary crosslinking degree of particle diameter monodispersion. <P>SOLUTION: The crosslinked (meth) acrylamide particle has a high crosslinking degree and high mechanical strength. The method which produces the crosslinked (meth) acrylamide particle as a particle having a particle diameter monodispersion is provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to crosslinked (meth) acrylamide particles.

  Polymerized particles containing a (meth) acrylamide monomer as a polymerization composition (hereinafter referred to as (meth) acrylamide particles) are highly hydrophilic, have excellent moisture retention, and have low biotoxicity. Therefore, ink binders, surface treatment agents, and cosmetics are used. It is widely used for. In particular, the substrate for liquid chromatography has excellent characteristics as a carrier for purification of proteins, nucleic acids, and the like because the hydrophobic interaction between the sample and the substrate is small when an aqueous eluent is used.

  Conventionally, as hydrophilic particles, particles obtained by crosslinking polysaccharides such as cellulose, dextran, or agarose are widely known. When preparing polysaccharide-based crosslinked particles, an aqueous solution of a polysaccharide and a crosslinking agent is suspended in an organic solvent in reverse phase, and the polysaccharide is crosslinked with an epoxy compound or dialdehyde as a crosslinking agent. .

  Further, (meth) acrylamide particles are prepared by polymerizing water-soluble (meth) acrylamide, and generally, a method of polymerizing by reverse phase suspension is employed (Patent Document 1, Patent Document 2, Patent Document). 3, Patent Document 4). As a production method other than the reverse phase suspension polymerization, a dispersion polymerization method in an organic solvent is known as a method for producing monodisperse particles having a uniform particle diameter of (meth) acrylamide particles (Patent Document 5). As other production methods, a polymerization method in critical carbon dioxide (Patent Document 6) and a spray method (Patent Document 7) are known.

  Further, N-alkoxymethyl (meth) acrylamide is a self-crosslinking monomer, and it is known that an alkoxy group can be eliminated by an acid catalyst and can easily bond to a self-crosslink or an amide group, an amino group or the like. For this reason, it is used for fiber processing (Patent Literature 8, Patent Literature 9), and used as a colloidal dispersant (Patent Literature 10, Patent Literature 11) or a coating film forming material (Patent Literature 12, Patent Literature 13). ing.

U.S. Pat. No. 4,070,348 (Claim 6) US Pat. No. 4,190,713 (abstract) U.S. Pat. No. 4,511,694 (Claim 1) JP 59-232101 (Claim 10) U.S. Pat. No. 4,988,568 (summary, claim 3) U.S. Pat. No. 4,748,220 (Abstract, Claim 4) JP 2003-211003 A (Claim 1) US Pat. No. 5,219,969 (abstract) US Pat. No. 5,149,943 (Background of the Invention) US Pat. No. 5,385,971 (Details of the Invention) US Pat. No. 6,316,568 (Claim 3) Japanese Patent Laid-Open No. 51-8343 (Section 3, Example 5) US Pat. No. 4,107,156 (Example 15)

  (Meth) acrylamide particles are used in various fields because of their properties as hydrophilic particles. However, there is a problem that the mechanical strength is weak. Since the mechanical strength is weak, it is difficult to make fine particles, and there remains a problem that particles of 50 μm or less, particularly about 10 μm, which are used in liquid chromatography cannot be used as a filler.

  Another problem is that it is difficult to control the particle diameter in the method for producing (meth) acrylamide particles. This is because it is difficult to control the particle size in the reverse phase suspension polymerization method, which is a general method for producing (meth) acrylamide particles, and the seed is a method for producing monodisperse particles in the normal phase suspension polymerization method. This is because the polymerization method cannot be performed. The dispersion polymerization method can produce (meth) acrylamide particles having a uniform particle diameter, but the range of particle diameters that can be produced is as narrow as 10 μm or less, and the ratio between the crosslinkable monomer and (meth) acrylamide. However, since the particle size also changes when the particle size is changed and the particle size decreases when the degree of crosslinking is increased, the degree of crosslinking cannot be arbitrarily changed.

  An object of the present invention is to provide crosslinked (meth) acrylamide particles having both high hydrophilicity and mechanical strength, and particularly to provide crosslinked (meth) acrylamide particles having excellent properties as a filler for liquid chromatography. There is to do. Another object of the present invention is to provide a production method capable of easily producing crosslinked (meth) acrylamide particles having a high degree of crosslinking by the production method of self-crosslinking polymer particles produced by normal phase suspension polymerization of the present invention. . Another object of the present invention is to provide a method for producing monodispersed crosslinked (meth) acrylamide particles by using a seed polymerization method.

  According to the present invention, substantially spherical fine particles comprising a polymer of (meth) acrylamide and a polyfunctional unsaturated monomer copolymerizable with (meth) acrylamide are derived from the (meth) acrylamide monomer. The structural unit is represented by Chemical Formula 1 (X in Chemical Formula 1 is hydrogen or methyl group, and R1 and R2 are bonded to the nitrogen atom of the structural unit derived from other (meth) acrylamide monomer via a methylene group. Cross-linked (meth) acrylamide particles having a particle diameter of 1 to 1000 μm, which are cross-linked by a cross-linked structure represented by the formula (1) indicate that (meth) acrylamide has high hydrophilicity and unprecedented high mechanical strength. In order to show, when using as a filler for liquid chromatography, since it becomes possible to reduce a particle diameter to about 10 micrometers, it is especially useful.

  In addition, the crosslinked (meth) acrylamide particles are produced by using an N-alkoxymethyl (meth) acrylamide monomer and a polyfunctional unsaturated monomer copolymerizable with the N-alkoxymethyl (meth) acrylamide monomer. After polymer particles produced by suspension polymerization (hereinafter referred to as the present polymer particles) are dispersed in an organic solvent, an acid catalyst represented by chemical formula 2 (A in chemical formula 2 represents polymer particles) is used. It can be easily produced by a self-crosslinking reaction. Normal phase suspension polymerization is possible by using an oil-soluble N-alkoxymethyl (meth) acrylamide monomer as a suspension polymerization method, and cross-linked acrylamide particles that are monodisperse particles by using a seed polymerization method It became possible to manufacture.

  The present invention is described in detail below.

  The crosslinked (meth) acrylamide particles having a particle diameter of 1 to 1000 μm according to the present invention are composed of a structural unit derived from a (meth) acrylamide monomer and a structural unit derived from a polyfunctional unsaturated monomer. As described above, the amide group nitrogen atom of the structural unit derived from the (meth) acrylamide monomer is cross-linked with another amide group nitrogen atom via the methylene group, and two cross-linked structures are owned per unit structure. be able to.

  As a method for producing the crosslinked (meth) acrylamide particles of the present invention, the (meth) acrylamide particles produced by the reverse phase suspension polymerization method can be formed into a crosslinked structure using formalin or the like, but by seed polymerization. Since it is possible to produce particles that are monodisperse in particle size, the polymer particles are produced by a normal phase suspension polymerization method from an oil-soluble N-alkoxymethyl (meth) acrylamide monomer and a polyfunctional unsaturated monomer, A production method in which this is self-crosslinked with an acid catalyst in an organic solvent is preferable because not only monodisperse particles with a particle size can be produced by a seed polymerization method, but also side reactions such as hydrolysis hardly occur.

  As the (meth) acrylamide monomer used for the production of the crosslinked (meth) acrylamide particles of the present invention, N-alkoxymethyl (meth) acrylamide is a precursor as the structure in the monomer in order to produce by normal phase suspension polymerization. It is preferable to use it as a body. Since the N-alkoxy (meth) acrylamide monomer is preferably oil-soluble, the N-alkoxy group needs to be hydrophobic, and is preferably a C4 or higher linear alkyl group, In particular, when the polymer particles are produced by a seed polymerization method, the alkoxy group carbon chain is preferably a linear alkyl group in the range of C4 to C8 in consideration of swelling properties.

  The polyfunctional unsaturated monomer used in the production of the crosslinked (meth) acrylamide particles of the present invention is a unit derived from an oil-soluble monomer and can be copolymerized with an N-alkoxymethyl (meth) acrylamide monomer. Need to be. Examples of these are (meth) acrylic acid esters such as ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, glycerin di (meth) acrylate, glycerin tri (meth) acrylate, Methylene bismaleimide, N, N ′-(4-methyl-1,3-phenylene) bismaleimide, N, N ′-(phenylene) bismaleimide, N, N ′-(sulfonyldi-m-phenylene) bismaleimide, etc. And bismaleimides, divinylbenzene, triallyl isocyanurate, and methylene bisacrylamide. The amount used can be within a range of 0.01% to 50% by weight with respect to N-alkoxymethyl (meth) acrylamide, but the hydrophobic effect of the polyfunctional vinyl monomer is reduced. Considering from the viewpoint of improving the strength of the obtained particles and the range of 0.05% by weight to 2% by weight, it is preferable.

  Other monomers can be copolymerized with the N-alkoxymethyl (meth) acrylamide monomer and the polyfunctional unsaturated monomer. However, since the other monomers need to be oil-soluble hydrophobic monomers, the hydrophobicity of the crosslinked (meth) acrylamide particles is increased. It is not preferable to add other monomers when preparing particles utilizing the hydrophilicity of (meth) acrylamide.

  In the method for producing crosslinked (meth) acrylamide particles of the present invention, an oil-soluble polymerization initiator generally used for radical polymerization of vinyl monomers can be used as a polymerization initiator used for normal phase suspension polymerization. However, since it is carried out by suspension polymerization, it is preferable to use a polymerization initiator having a 10-hour half-life of less than 100 degrees. The amount of the polymerization initiator used is in the range of 0.01 mol% to 1.0 mol%, particularly preferably in the range of 0.05 mol% to 0.5 mol%, based on the monomer. It is also possible to polymerize by ultraviolet rays or radiation without using a polymerization initiator.

  In the normal phase suspension polymerization in the present invention, it is possible to use a general polymer dispersion stabilizer used for stabilizing suspended oil droplets, such as polyvinyl alcohol and hydroxypropyl cellulose. , Polyvinyl pyrrolidone, polyethylene glycol, sodium polyacrylate, etc., but when using an organic acid polymer, it is necessary to adjust the pH to 4 or higher so that the aqueous phase does not become acidic. It is preferable to use nonionic polymers such as typical polyvinyl alcohol and hydroxypropyl cellulose. The amount used thereof can be 0.1 to 20% by weight as the concentration in the aqueous phase, and is preferably 0.5 to 10% by weight from the viewpoint of washing after polymerization. It is.

  Polymerization can be carried out by heating when using a thermally decomposable polymerization initiator, and by irradiation with radiation at room temperature when using radiation polymerization without using an initiator, and there is no particular limitation.

  In the case of normal phase suspension polymerization by seed polymerization, polystyrene and poly (styrene / acrylate ester) copolymer particles obtained by soap-free emulsion polymerization and dispersion polymerization methods used for the purpose of monodisperse particle size, For example, methacrylic acid ester particles can be used. In particular, it is preferable to use a seed particle polymer disclosed in JP-A-2001-2716 from the viewpoint of swelling property and the seed particle polymer hardly causing phase separation from the N-alkoxymethyl (meth) acrylamide polymer. There is no particular limitation on the swelling ratio expressed by the ratio of the seed particle polymer to the monomer when performing seed polymerization, and the swelling can be about 10,000 times the seed particle volume, and the target particle size can be achieved. Can be set together.

  As the emulsifier used when carrying out normal phase suspension polymerization by seed polymerization, a general sulfonate or nonionic emulsifier can be used. Examples include nonionic emulsifiers such as alkyl sulfonates such as sodium lauryl sulfonate and sodium dodecylbenzene sulfonate, polyoxyethylene sorbitan stearate, polyoxyethylene stearyl ether, and polyoxyethylene sorbitan monolaurate. It can be illustrated. In particular, from the viewpoint of oil droplet stability, an alkyl sulfonate and a nonionic emulsifier of HLB 8 to 20 can be used in combination. The ratio of the nonionic emulsifier used in combination is 10% to 90% by weight, preferably 20% to 80% by weight, based on the alkyl sulfonate.

  When only alkyl sulfonate is used as an emulsifier used in normal phase suspension polymerization by seed polymerization, a compound having a higher hydrophobicity than N-alkoxymethyl (meth) acrylamide is used to improve oil droplet stability. It is also possible to use it. Examples of such highly hydrophobic compounds are C4 or higher alcohols such as butanol, pentanol, hexanol, cyclohexanol, octanol, acetic acid butyl ester, acetic acid pentyl ester, acetic acid hexyl ester, acetic acid phenyl ester, acetic acid benzyl ester. And organic acid esters such as propionic acid ethyl ester, propionic acid butyl ester, benzoic acid methyl ester and benzoic acid ethyl ester, and C6 to C9 aromatic compounds such as benzene, toluene and xylene. From the viewpoint of swelling, it is preferable to use higher alcohols having 5 to 6 carbon atoms or organic acid esters having -4 to 7 carbon atoms, benzene, and toluene. The amount used is 1% by weight or more based on the whole monomer, but it is not necessary to add more than necessary, and it is preferable to use 1% to 50% by weight based on the whole monomer.

  The polymer particles obtained by polymerization are washed with an appropriate solvent, generally warm water, in order to remove the polymer dispersion stabilizer.

  In the production method of the present invention, the obtained polymer particles are dispersed in an organic solvent, alkoxy groups are eliminated by an acid catalyst, and crosslinked with other amide groups in the particles to form hydrophilic polymer particles. Hereinafter, this process is referred to as a second process.

  The organic solvent used in the second step in the production method of the present invention is preferably one that is stable to an acid catalyst and has no reactivity with an N-alkoxymethyl group, such as dioxane, tetrahydrofuran, benzene, toluene, xylene, dimethyl sulfoxide. , Higher alcohols such as dimethylformamide, butanol, pentanol, hexanol, acetic acid butyl ester, acetic acid pentyl ester, acetic acid hexyl ester, acetic acid phenyl ester, acetic acid benzyl ester, propionic acid ethyl ester, propionic acid butyl ester, benzoic acid methyl ester And organic acid esters such as ethyl benzoate. In addition, the organic solvent used in the second step can be a mixed solvent with water depending on the application. In particular, in order to make the polymer particles porous, it is preferable to carry out with a solvent in which the polymer particles swell. The amount used is 2 parts by weight, preferably 4 parts by weight or more, based on the polymer particles.

  The acid catalyst used in the second step in the production method of the present invention is not particularly limited, but strong acids are preferable, mineral acids such as hydrochloric acid, sulfuric acid and toluenesulfonic acid, and Lewis acids such as boron trifluoride are exemplified. it can. The amount used is not particularly limited, but is preferably 0.01% by weight or more, particularly preferably 0.1% by weight or more, based on the polymerized particles.

  In the second step in the production method of the present invention, the reaction temperature and reaction time are appropriately adjusted according to the type of acid used and the amount used, and the degree of progress is measured by measuring the amount of alcohol produced by the elimination of the alkoxy group. Can be determined.

  By washing the obtained crosslinked (meth) acrylamide particles with warm water or the like, it is possible to easily remove the acid catalyst, the organic solvent, and the like.

  According to the present invention, crosslinked (meth) acrylamide particles can be produced by normal phase suspension polymerization, and the particle diameter can be easily controlled. In particular, a seed polymerization method can be used, and it becomes possible to easily produce porous particles having a monodispersed particle size. Further, the particles obtained according to the present invention have a highly crosslinked structure, and it has become possible to produce particles having much higher mechanical strength than polysaccharide-based particles and acrylamide particles produced by conventional reverse phase suspension polymerization. By improving the mechanical strength, it is possible to set the particle size small, and it exhibits excellent performance as a packing material for liquid chromatography.

  Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1
<Manufacture of seed particles>
In a 500 mL three-necked flask, 30 g of benzyl methacrylate (manufactured by Tokyo Chemical Industry), 1.5 g of 2-ethylhexyl thioglycolic acid ester (manufactured by Tokyo Chemical Industry), 0.6 g of potassium persulfate (manufactured by Kishida Chemical) and Mill-Q water 250 g was added and a nitrogen purge was performed for 3 hours at room temperature with stirring. The flask was set in an oil bath set at 70 ° C., and polymerization was carried out for 6 hours. Aggregates were separated by filtration to obtain seed particles.
The particle size of the seed particles was 1.1 μm CV 6.8% by SEM observation. Further, the molecular weight was measured by the size exclusion chromatography method (hereinafter referred to as SEC) with the following measuring apparatus, and as a result, it was 7800 in terms of polystyrene. The solid content concentration in the seed particle solution was 8.8%.

SEC measurement condition column: TSKgel GMHXL 7.8 mm ID × 30 cm (manufactured by Tosoh Corporation)
Eluent: Tetrahydrofuran feed pump: DP-8020 (manufactured by Tosoh Corporation)
Detector: UV-8020 wavelength set to 254 nm (manufactured by Tosoh)
Standard sample: Standard polystyrene (manufactured by Tosoh)
Measurement flow rate: 1.0 mL / min
Sample concentration: 1 mg / mL (THF solution)

<Polymerization of N-alkoxymethylacrylamide particles>
N-butoxymethyl chloramide (manufactured by Wako Pure Chemical Industries) 298.5 g, ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry) 1.5 g, 1-pentanol (manufactured by Kishida Chemical) 60 g, V-65 (polymerization initiator Wako Pure) 0.46 g (manufactured by Yakuhin) and 1.8 g of sodium lauryl sulfonate (manufactured by Tokyo Chemical Industry) were weighed into a 1 L beaker and mixed well with stirring. To this, 600 mL of ion-exchanged water was added and emulsified using an ultrasonic homogenizer. To this, 0.182 g (solid content) of prepared seed particles, 600 mL of 4% polyvinyl alcohol aqueous solution (trade name POVAL 224, manufactured by Kuraray Industrial Co., Ltd.) was added and stirred well for 3 minutes.
The solution was transferred to a 3 L separable flask, a stirring blade was attached, and the mixture was slowly stirred at room temperature for 12 hours at a rotation speed of 100 rpm. Microscopic observation confirmed that the seed particles were swollen with the monomer mixture and swollen to about 13 μm.
The separable flask was placed in an oil bath set at 65 ° C., and polymerization was carried out for 3 hours while stirring. It was confirmed that the monomer had disappeared by gas chromatography analysis using an OV-17 (Gascro Industry) column. After completion of the polymerization, washing with warm water was performed to obtain polymer particles. The recovered weight was 477 g, and the water content was 41%.

<Second step>
The obtained polymer particles were vacuum-dried at 40 ° C. overnight. 50 g of dried polymer particles and 340 g of 1,4-dioxane (manufactured by Wako Pure Chemical Industries, Ltd.) were put into a 500 mL separable flask and stirred in an oil bath set at 40 ° C. Boron trifluoride ethyl ether complex (manufactured by Kishida Chemical Co., Ltd.) (0.5 mL) was added to the flask, and the mixture was stirred for 1 hour.

The obtained hydrophilized particles were washed with warm water to obtain hydrophilic porous particles.
The obtained hydrophilic porous particles were packed in a 6.0 mm ID × 15 cm column, and the pore characteristics were measured by size exclusion chromatography using polyethylene glycol (hereinafter referred to as PEG) as a standard sample. The hydrophilicity was compared with conventional hydrophilic particles using benzyl alcohol retention as an index. The mechanical strength was measured by a method in which pure water was passed in a state where the column was packed and the liquid feeding pressure was measured when the flow rate was changed linearly.

Pore property measurement condition column: 6.0 mm ID × 15 cm
Eluent: ion-exchanged water measurement flow rate: 0.5 mL / min
Liquid feed pump: DP-8020 (manufactured by Tosoh)
Detector: RI-8022 (manufactured by Tosoh)
Sample: ethylene glycol, polyethylene glycol (molecular weight 200, 300, 600, 1000, 3000, 6000, manufactured by Wako Pure Chemical Industries, Ltd.)
Exclusion limit molecular weight calculation method: PEG molecular weight PEG conversion molecular weight porosity calculation method at a linear molecular weight 6000 elution position passing through elution volumes of 200, 300 and 600: (ethylene glycol elution volume-PEG 6000 elution volume) / (column volume- PEG6000 elution volume) x100
Hydrophobicity measurement conditions Samples other than measurement samples Same as pore characteristic measurement conditions: ethylene glycol, benzyl alcohol Hydrophobicity value: benzyl alcohol elution capacity / ethylene glycol elution capacity Mechanical strength (liquid feeding resistance) measurement condition column: 4.6 mm ID × 10 cm
Liquid solvent: Ion-exchanged water flow rate gradient: 0.2 mL / min to 10.2 mL / min for 10 minutes Linear gradient liquid pump: CCPM-II
Detection: Converted intensity from liquid pump pressure gauge output: Liquid transfer pressure deviates from linear relationship with liquid feed speed (inflection point). Table 1 shows the results of exclusion limit molecular weight, pore volume, and hydrophobicity test in Table 1. Shows the mechanical strength measurement results. Although the hydrophobicity was slightly large, the mechanical strength was as high as about 6 MPa from which the effect of particle deformation was observed.

Example 2
Hydrophilic particles were produced in the same manner as in Example 1 except that 285.0 g of N-butoxymethyl chloramide (Wako Pure Chemical Industries, Ltd.) and 15 g of ethylene glycol dimethacrylate (Tokyo Chemical Industry) were used.

  The obtained hydrophilic porous particles were measured for pore characteristics, hydrophobicity and mechanical strength in the same manner as in Example 1. The hydrophobicity was large and the pore size was small. The mechanical strength was very high within the measurement range (10 MPa or less) and no effects such as particle deformation were observed.

Comparative Example 1
PIERCE polyacrylamide product name D-Salt Polyacrylamide 1800 was extracted from the column, and the same measurement as in Example 1 was performed. Although the pore volume is large and the hydrophobicity is small, the particle strength is large, so that the liquid feeding resistance is small, but the mechanical strength is weak and the material is crushed at about 1.7 MPa.

Comparative Example 2
Product name manufactured by Amersham Sephadex G25 Superfine The same measurement as in Example 1 was performed using crosslinked dextran particles. Although the pore volume is large and the hydrophobicity is small, the particle diameter is large, so that the liquid feeding resistance is small, but the mechanical strength is weak and it is crushed at about 0.95 MPa.

  Since the crosslinked (meth) acrylamide particles of the present invention have unprecedented mechanical strength, they can be used as various binders, coating materials, cosmetics, immunodiagnostic carriers, and liquid chromatography fillers. It is done. In particular, polymer particles having characteristics of having both low hydrophobicity and high mechanical strength have particularly excellent performance as a packing material for liquid chromatography.

Indicates the change in the liquid supply pressure when the flow rate of liquid sent to the column is changed.

Claims (10)

In a substantially spherical fine particle composed of a polymer of (meth) acrylamide and a polyfunctional unsaturated monomer copolymerizable with (meth) acrylamide, the structural unit derived from the (meth) acrylamide monomer is Chemical formula 1 (X in chemical formula 1 is hydrogen or a methyl group, and R1 and R2 are bonded to a nitrogen atom of a structural unit derived from another (meth) acrylamide monomer via a methylene group. Cross-linked (meth) acrylamide particles having a particle diameter of 1 to 1000 μm, which are cross-linked by a cross-linked structure represented by

The molar ratio of the unit derived from the (meth) acrylamide monomer and the unit derived from the polyfunctional unsaturated monomer is in the range of 99.99: 0.01 to 50:50. Cross-linked (meth) acrylamide particles. The crosslinked (meth) acrylamide particles according to claim 1 or 2, wherein the polymer particles have a pore diameter of 5000 or less with polyethylene glycol as a sample. A method for producing crosslinked (meth) acrylamide particles according to claims 1 to 3,
(1) An oil-soluble N-alkoxymethyl (meth) acrylamide, a polyfunctional unsaturated monomer copolymerizable with N-alkoxymethyl (meth) acrylamide, and a suspension stabilizer are suspended in an aqueous phase and polymerized. A step of obtaining polymer particles by
(2) a step of causing intra-particle cross-linking represented by Chemical Formula 2 by allowing an acid catalyst to act in the organic solvent in which the polymer particles in step (1) are dispersed;
A method for producing crosslinked (meth) acrylamide particles comprising:

5. The method for producing crosslinked (meth) acrylamide particles according to claim 4, wherein in the step (1), an oil-soluble N-alkoxymethyl (meth) acrylamide and a multi-polymerizable with N-alkoxymethyl (meth) acrylamide are copolymerized. A mixture containing a functional unsaturated monomer is emulsified in water using an emulsifier, and seed polymer particles are allowed to act on the mixture to absorb the monomer into the seed polymer particles, thereby creating monodisperse monomer oil droplets with a particle size. A method for producing crosslinked (meth) acrylamide particles characterized by polymerizing. In the method for producing crosslinked (meth) acrylamide particles, at least one or more selected from C4 or higher alcohols or organic acid esters and C6 to C9 aromatic compounds as stabilizers for the monodisperse monomer droplets having a particle size of The method for producing crosslinked (meth) acrylamide particles according to claim 5, wherein the organic solvent is allowed to act on the monomer in an amount of 1% by weight or more. The crosslinked (meth) acrylamide particles according to claim 5 or 6, wherein the emulsifier is an alkyl sulfonate, an alkyl benzene sulfonate, or an alkyl ether sulfate, and is used in an amount of 0.1 to 5% by weight based on the monomer. Manufacturing method. The method for producing crosslinked (meth) acrylamide particles according to claim 7, wherein a nonionic emulsifier which is 1 to 50% by weight of HLB 8 to 20% is used in combination with the emulsifier. The acid catalyst is selected from mineral acids such as hydrochloric acid, phosphoric acid and sulfuric acid, alkylsulfonic acid, benzenesulfonic acid, toluenesulfonic acid, organic acids such as oxalic acid, acetic acid and maleic acid, Lewis acid such as trifluoroboric acid, etc. 9. The method according to claim 4, wherein the acid is one or more acids. A packed column in which the crosslinked (meth) acrylamide particles according to claim 1 are packed in a liquid chromatography column.

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