Magnetic microbeads and method for manufacturing magnetic microbeads

Abstract

A magnetic microbead comprising a polymer and a magnetic particle modified with a silane coupling agent, the polymer comprising structural units derived from a monomer (a) having at least one selected from the group consisting of a vinyl group, a vinylidene group and a (meth)acryloyl group, the silane coupling agent comprising at least one selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group and a styryl group.

Description

Technical Field

[0001] This invention relates to a magnetic microsphere and a method for manufacturing the magnetic microsphere. Background Technology

[0002] As for technologies related to magnetic microbeads containing polymers and magnetic particles, the technology described in Patent Document 1 is known, for example.

[0003] Patent document 1 describes a magnetic particle characterized by containing magnetic powder on the surface with polymer chains bonded by a coupling agent.

[0004] Patent document 1 describes the following: the magnetic powder of the magnetic particles has good dispersibility, dispersion stability, and affinity with the binding resin. It has small particle size and narrow particle size distribution. It also has excellent heat resistance, wear resistance, hardness and is not easy to break. Therefore, it can be preferably used as a carrier, etc.

[0005] Previous technical documents Patent documents Patent Document 1: Japanese Patent Application Publication No. 6-102708 Summary of the Invention

[0006] The technical problem to be solved by the invention This invention provides a magnetic microbead that can suppress light scattering deviations in light scattering measurements.

[0007] means for solving technical problems According to the present invention, a magnetic microsphere and a method for manufacturing the magnetic microsphere are provided. [1] A type of magnetic microbead comprising a polymer and magnetic particles modified with a silane coupling agent. The polymer comprises structural units derived from monomer (a), which has at least one group selected from the group consisting of vinyl, vinylidene, and (meth)acryloyl groups. The silane coupling agent comprises at least one selected from the group consisting of vinyl, vinylidene, (meth)acryloyl, and styrene. [2] According to the magnetic microspheres of [1], wherein the silane coupling agent comprises at least one selected from the group consisting of 3-methacryloxypropyltrimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, p-styryltrimethoxysilane, vinyltrimethoxysilane and vinyltriethoxysilane. [3] According to the magnetic microspheres described in [1] or [2], wherein the magnetic particles comprise at least one selected from the group consisting of magnetite and maghematite. [4] The magnetic microspheres according to any one of [1] to [3], wherein the particle size of the magnetic particles is 1 nm or more and 5000 nm or less. [5] The magnetic microspheres according to any one of [1] to [4], wherein the monomer (a) comprises at least one selected from the group consisting of styrene monomers and alkyl (meth)acrylates. [6] The magnetic microbeads according to any one of [1] to [5], wherein the polymer further comprises structural units derived from a monomer (b) having a carboxyl group. [7] According to the magnetic microspheres of [6], wherein the monomer (b) comprises at least one selected from the group consisting of methacrylic acid, acrylic acid, 2-(methacryloyloxy)ethyl phthalate, 2-(acryloyloxy)ethyl phthalate, 2-methacryloyloxyethyl succinic acid and 2-acryloyloxyethyl succinic acid. [8] The magnetic microspheres according to any one of [1] to [7], wherein the surface of the magnetic microspheres comprises at least one selected from the group consisting of carboxyl, ethynyl, hydroxyl, amino and epoxy groups. [9] The magnetic microspheres according to any one of [1] to [8], wherein the average roundness of the magnetic microspheres is 0.80 or more and 1.00 or less.

[10] The magnetic microspheres according to any one of [1] to [9], wherein the particle size of the magnetic microspheres is 0.1 μm or more and 300 μm or less.

[11] The magnetic microbeads according to any one of [1] to

[10] are spherical in shape.

[12] The magnetic microbeads according to any one of [1] to

[11] , wherein the interior of the polymer contains the magnetic particles.

[13] According to any one of [1] to

[12] , the magnetic microspheres wherein, when the total mass of the magnetic microspheres is set to 100% by mass, the content of the magnetic particles in the magnetic microspheres is 1% by mass or more and 40% by mass or less.

[14] According to any one of [1] to

[13] , the magnetic microspheres wherein, when the total mass of the magnetic microspheres is set to 100% by mass, the content of the polymer in the magnetic microspheres is 50% by mass or more and 98% by mass or less.

[15] According to any one of [1] to

[14] , when the content of the magnetic particles in the magnetic microsphere is set to 100 parts by mass, the content of the silane coupling agent in the magnetic microsphere is 0.01 parts by mass or more and 30 parts by mass or less.

[16] A method for manufacturing magnetic microspheres includes: step (A), polymerizing the monomer in a suspension comprising a monomer (a) having at least one group selected from the group consisting of vinyl, vinylidene, and (meth)acryloyl groups, and magnetic particles modified with a silane coupling agent. The silane coupling agent comprises at least one selected from the group consisting of vinyl, vinylidene, (meth)acryloyl, and styrene.

[17] According to the method for manufacturing magnetic microspheres described in

[16] , it further includes the following steps prior to step (A): Step (B) is to prepare a monomer mixture comprising the monomer (a) and magnetic particles modified by the silane coupling agent; and step (C) is to disperse the monomer mixture in an aqueous medium to prepare the suspension.

[18] According to the method for manufacturing magnetic microspheres as described in

[16] or

[17] , the suspension further comprises a monomer (b) having a carboxyl group.

[19] The method for manufacturing magnetic microspheres according to any one of

[16] to

[18] , wherein the silane coupling agent comprises at least one selected from the group consisting of 3-methacryloyloxypropyltrimethoxysilane, 3-acryloyloxypropyltrimethoxysilane, 3-methacryloyloxypropylmethyldimethoxysilane, 3-methacryloyloxypropylmethyldiethoxysilane, 3-methacryloyloxypropyltriethoxysilane, p-styryltrimethoxysilane, vinyltrimethoxysilane and vinyltriethoxysilane.

[20] The method for manufacturing magnetic microspheres according to any one of

[16] to

[19] , wherein the magnetic particles comprise at least one selected from the group consisting of magnetite and maghemite. [twenty one] The method for manufacturing magnetic microspheres according to any one of

[16] to

[20] , wherein the particle size of the magnetic particles is 1 nm or more and 5000 nm or less.

[0029] Invention Effects According to the present invention, it is possible to provide a magnetic microsphere that can suppress the deviation of light scattering in light scattering measurement. Attached Figure Description

[0030] Figure 1 This is an example of a SEM image of the magnetic microbeads in Example 1.

[0031] Figure 2 This is an example of a SEM image of the magnetic microbeads in Example 1.

[0032] Figure 3 This is an example of a SEM image of the magnetic microbeads in Comparative Example 1.

[0033] Figure 4 This is an example of a SEM image of the magnetic microspheres in Comparative Example 2. Detailed Implementation

[0034] The embodiments of the present invention will now be described. Unless otherwise specified, the numerical range "A to B" means A or more and B or less. In this embodiment, the term "(meth)acryloyl" indicates that it includes both methacryloyl and acryloyl groups. The same applies to similar terms such as "(meth)acrylate".

[0035] Magnetic microbeads, which contain polymers and magnetic particles, are known. Magnetic microbeads are used, for example, in diagnostic drugs, bacterial isolation, cell culture, drug delivery, magnetic toners, magnetic inks, and magnetic coatings.

[0036] Furthermore, in medical and biological applications such as diagnostic drugs, light scattering measurements, such as flow cytometry, are sometimes performed on dispersions containing magnetic microbeads. These magnetic microbeads require the suppression of light scattering bias during the light scattering measurement.

[0037] This invention provides a magnetic microbead that can suppress light scattering deviations in light scattering measurements.

[0038] [Magnetic microbeads] The magnetic microspheres of this embodiment are magnetic microspheres comprising a polymer and magnetic particles modified by a silane coupling agent. The polymer comprises structural units derived from monomer (a), which has at least one selected from the group consisting of vinyl, vinylidene, and (meth)acryloyl groups. The silane coupling agent comprises at least one selected from the group consisting of vinyl, vinylidene, (meth)acryloyl, and styrene groups.

[0039] The inventors have discovered for the first time that, by including magnetic particles modified with a specific silane coupling agent as magnetic particles in magnetic microspheres comprising polymers and magnetic particles, it is possible to provide magnetic microspheres that can suppress deviations in light scattering measurements.

[0040] The magnetic microspheres in this embodiment preferably contain magnetic particles inside the polymer.

[0041] From the viewpoint of further suppressing the deviation of light scattering in light scattering measurement, the average roundness of the magnetic microspheres in this embodiment is preferably 0.80 or more and 1.00 or less, more preferably 0.85 or more and 1.00 or less, and even more preferably 0.88 or more and 1.00 or less.

[0042] Here, the average roundness of the magnetic microspheres refers to the average roundness calculated by image analysis of the SEM images of the magnetic microspheres using the method described in the embodiments.

[0043] The magnetic microspheres of this embodiment preferably have a particle size of 0.1 μm or more and 300 μm or less, more preferably 1 μm or more and 200 μm or less, and even more preferably 5 μm or more and 100 μm or less.

[0044] The particle size of magnetic microspheres refers to the particle size obtained when measuring the particle size distribution of a 1% by mass magnetic microsphere dispersion using a laser diffraction particle size distribution measuring device. Here, a 1% by mass magnetic microsphere dispersion can be, for example, a 1% by mass aqueous solution of magnetic microspheres with water as the solvent.

[0045] The preferred range of particle size for the aforementioned magnetic microspheres means that at least a portion of the particle sizes of the magnetic microspheres obtained by the aforementioned measurement method are within the aforementioned range.

[0046] The volume average particle size of the magnetic microspheres in this embodiment is preferably 0.5 μm or more and 110 μm or less, more preferably 1 μm or more and 50 μm or less, even more preferably 5 μm or more and 25 μm or less, and even more preferably 7 μm or more and 18 μm or less.

[0047] The volume average particle size of magnetic microspheres refers to the volume average particle size (MV) obtained when measuring the particle size distribution of a 1% by mass magnetic microsphere dispersion using a laser diffraction particle size distribution measuring device. Here, a 1% by mass magnetic microsphere dispersion can be, for example, a 1% by mass aqueous solution of magnetic microspheres with water as the solvent.

[0048] The magnetic microspheres in this embodiment are preferably spherical in shape.

[0049] The magnetic microspheres in this embodiment are preferably solid in shape.

[0050] The surface of the magnetic microspheres in this embodiment preferably contains at least one selected from the group consisting of carboxyl, ethynyl, hydroxyl, amino and epoxy groups, more preferably at least one selected from the group consisting of carboxyl and ethynyl groups, and even more preferably contains carboxyl groups.

[0051] If the surface of the magnetic microspheres in this embodiment contains the functional groups described above, the target substance can be immobilized by reacting with a substance capable of bonding with the functional groups (hereinafter, the target substance). From the viewpoint of being applicable to medical and biological fields such as diagnostic drugs, magnetic microspheres containing such functional groups are preferred.

[0052] The components contained in the magnetic microspheres of this embodiment will be described in detail below.

[0053] <Polymer> The magnetic microspheres in this embodiment comprise a polymer.

[0054] The polymer of this embodiment comprises a structural unit derived from monomer (a), which has at least one selected from the group consisting of vinyl, vinylidene, and (meth)acryloyl groups.

[0055] (Single (a)) The monomer (a) is a monomer having at least one group selected from the group consisting of vinyl, vinylidene and (meth)acryloyl groups.

[0056] Monomers having vinyl groups include, for example, at least one selected from the group consisting of styrene monomers, vinyl chloride, vinyl acetate, etc.

[0057] Monomers containing (meth)acryloyl groups include, for example, at least one selected from the group consisting of alkyl (meth)acrylates, hydroxyalkyl (meth)acrylates, aminoalkyl (meth)acrylates, etc.

[0058] The monomer (a) in this embodiment preferably comprises at least one selected from the group consisting of styrene monomers and alkyl (meth)acrylates.

[0059] Styrene monomers refer to styrene and styrene derivatives.

[0060] Styrene monomers include, for example, at least one selected from the group consisting of styrene, divinylbenzene, 2-methylstyrene, 3-methylstyrene, 4-methylstyrene, 2,4,6-trimethylstyrene, 4-tert-butoxystyrene, 4-methoxystyrene, 3-chlorostyrene, 4-aminostyrene, α-methylstyrene, 2,4-dimethylstyrene, ethylstyrene, isopropylstyrene, butylstyrene, phenylstyrene, cyclohexylstyrene, 4-chloromethylstyrene, styrene-butadiene, trivinylbenzene, and vinylnaphthalene, preferably at least one selected from the group consisting of styrene, divinylbenzene, and α-methylstyrene, more preferably styrene and divinylbenzene.

[0061] Alkyl methacrylates include, for example, at least one selected from the group consisting of methyl methacrylate, ethyl methacrylate, n-butyl methacrylate, tert-butyl methacrylate, cyclohexyl methacrylate, and isobornyl methacrylate, preferably at least one selected from the group consisting of methyl methacrylate, n-butyl methacrylate, tert-butyl methacrylate, cyclohexyl methacrylate, and isobornyl methacrylate, more preferably at least one selected from the group consisting of methyl methacrylate, n-butyl methacrylate, tert-butyl methacrylate, cyclohexyl methacrylate, and isobornyl methacrylate.

[0062] (Single (b)) The polymer in this embodiment preferably also includes structural units derived from monomers (b) having carboxyl groups.

[0063] The polymer of this embodiment also includes structural units derived from monomers (b) having carboxyl groups, enabling the production of magnetic microspheres containing carboxyl groups on the surface of the magnetic microspheres.

[0064] There are no particular limitations on monomer (b) as long as it is a monomer with a carboxyl group, but it is preferred to be a monomer that also has a polymerizable double bond.

[0065] Monomer (b) preferably comprises at least one selected from the group consisting of methacrylic acid, acrylic acid, mono-2-(methacryloyloxy)ethyl phthalate, mono-2-(acryloyloxy)ethyl phthalate, 2-methacryloyloxyethyl succinic acid and 2-acryloyloxyethyl succinic acid, more preferably at least one selected from the group consisting of methacrylic acid and acrylic acid, and even more preferably methacrylic acid.

[0066] When the total mass percentage of the magnetic microspheres is set to 100%, from the viewpoint of further increasing the functional groups on the surface of the magnetic microspheres, the polymer content in the magnetic microspheres of this embodiment is preferably 50% by mass or more, more preferably 60% by mass or more, even more preferably 70% by mass or more, even more preferably 80% by mass or more, even more preferably 85% by mass or more. Moreover, from the viewpoint of further improving the magnetic properties of the magnetic microspheres, it is preferably 98% by mass or less, more preferably 95% by mass or less, and even more preferably 93% by mass or less.

[0067] When the total mass percentage of the magnetic microspheres is set to 100%, from the viewpoint of further increasing the functional groups on the surface of the magnetic microspheres and further improving the magnetic properties of the magnetic microspheres, the polymer content in the magnetic microspheres of this embodiment is preferably 50% or more and 98% or less by mass, more preferably 60% or more and 95% or less by mass, more preferably 70% or more and 93% or less by mass, and even more preferably 80% or more and 93% or less by mass.

[0068] The synthesis method of the polymer in this embodiment is not particularly limited, but suspension polymerization is preferred. Detailed synthesis conditions can be set as described in the method for manufacturing magnetic microspheres, which will be explained later.

[0069] <Magnetic particles modified with silane coupling agents> The magnetic microspheres of this embodiment comprise magnetic particles modified with a silane coupling agent.

[0070] (Silane coupling agent) The silane coupling agent of this embodiment contains at least one selected from the group consisting of vinyl, vinylidene, (meth)acryloyl, and styrene, preferably containing (meth)acryloyl.

[0071] Silane coupling agents containing vinyl groups include, for example, at least one selected from the group consisting of vinyltrimethoxysilane, vinyltriethoxysilane, and dimethoxymethylvinylsilane.

[0072] Silane coupling agents containing (meth)acryloyl groups include, for example, at least one selected from the group consisting of 3-methacryloyloxypropyltrimethoxysilane, 3-acryloyloxypropyltrimethoxysilane, 3-methacryloyloxypropylmethyldimethoxysilane, 3-methacryloyloxypropylmethyldiethoxysilane, and 3-methacryloyloxypropyltriethoxysilane.

[0073] Silane coupling agents containing styrene groups, such as those containing p-styrenetrimethoxysilane, etc.

[0074] The silane coupling agent of this embodiment is preferably at least one selected from the group consisting of 3-methacryloxypropyltrimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, p-styryltrimethoxysilane, vinyltrimethoxysilane, and vinyltriethoxysilane, and more preferably at least one selected from the group consisting of 3-methacryloxypropyltrimethoxysilane, 3-acryloxypropyltrimethoxysilane, and 3-methacryloxypropyltriethoxysilane.

[0075] (Magnetic particles) The magnetic particles in this embodiment are not particularly limited as long as they are magnetic particles. For example, they may include at least one of the following: magnetite (Fe3O4), maghematite (γ-Fe2O3), hematite (α-Fe2O3), manganese ferrite (MnFe2O4), cobalt ferrite (CoFe2O4), nickel ferrite (NiFe2O4), copper ferrite (CuFe2O4), Mn-Zn ferrite, Ni-Zn ferrite, Mn-Mg ferrite, Li ferrite, Cu-Zn ferrite, and goethite (FeO(OH)). Preferably, they include at least one of the following: magnetite and maghematite. More preferably, they include magnetite.

[0076] The magnetic particles in this embodiment preferably have a particle size of 1 nm or more and 5000 nm or less, more preferably 3 nm or more and 1000 nm or less, and even more preferably 10 nm or more and 300 nm or less.

[0077] Here, the particle size of magnetic particles refers to the value measured by transmission electron microscopy (TEM), specifically, the value obtained by performing image analysis on TEM images and calculating the arithmetic mean of the particle sizes of any 10 magnetic particles.

[0078] When the total mass percentage of the magnetic microspheres is set to 100%, from the viewpoint of further improving the magnetic properties of the magnetic microspheres, the content of magnetic particles in the magnetic microspheres of this embodiment is preferably 1% by mass or more, more preferably 3% by mass or more, even more preferably 5% by mass or more, even more preferably 8% by mass or more. Furthermore, from the viewpoint of further increasing the functional groups on the surface of the magnetic microspheres, it is preferably 40% by mass or less, more preferably 30% by mass or less, even more preferably 20% by mass or less, even more preferably 15% by mass or less.

[0079] When the total amount of magnetic microspheres is set to 100% by mass, from the viewpoint of further improving the magnetic properties of magnetic microspheres and further increasing the functional groups on the surface of magnetic microspheres, the content of magnetic particles in the magnetic microspheres of this embodiment is preferably 1% by mass or more and 40% by mass or less, more preferably 3% by mass or more and 30% by mass or less, more preferably 5% by mass or more and 20% by mass or less, and more preferably 8% by mass or more and 15% by mass or less.

[0080] When the content of magnetic particles in the magnetic microspheres is set to 100 parts by mass, from the viewpoint of further suppressing the deviation of light scattering in the light scattering measurement, the content of silane coupling agent in the magnetic microspheres of this embodiment is preferably 0.01 parts by mass or more and 30 parts by mass or less, more preferably 0.05 parts by mass or more and 20 parts by mass or less, and even more preferably 0.1 parts by mass or more and 10 parts by mass or less.

[0081] The method for manufacturing the magnetic particles modified with silane coupling agent in this embodiment is not particularly limited; for example, the method described in the embodiments can be cited.

[0082] <Other Ingredients> The magnetic microspheres of this embodiment may also contain components other than polymers and magnetic particles modified with silane coupling agents.

[0083] Applications of magnetic microbeads The magnetic microbeads of this embodiment have no particular limitations in their application. For example, they can be used in diagnostic drugs, bacterial isolation, cell culture, drug delivery, magnetic toners, magnetic inks, magnetic coatings, etc.

[0084] From the viewpoint that the deviation of light scattering can be further suppressed in light scattering measurement, the magnetic microbeads of this embodiment are preferably magnetic microbeads that can be used in diagnostic drugs.

[0085] The use of the magnetic microspheres in this embodiment preferably does not include at least one use selected from the group consisting of magnetic toners, developers, and electrophotographic carriers.

[0086] [Dispersion] The dispersion of this embodiment includes the magnetic microspheres and solvent of this embodiment.

[0087] The solvent may include at least one selected from the group consisting of water, methanol, ethanol, isopropanol, propylene glycol monomethyl ether and propylene glycol monomethyl ether acetate, preferably water.

[0088] The concentration of the dispersion in this embodiment is, for example, 0.01% by mass or more and 20% by mass or less, preferably 0.1% by mass or more and 15% by mass or less, and more preferably 0.5% by mass or more and 10% by mass or less.

[0089] [Manufacturing Method of Magnetic Microspheres] The method for manufacturing magnetic microspheres according to this embodiment includes: step (A), in which the monomer is polymerized in a suspension containing a monomer (a) having at least one selected from the group consisting of vinyl, vinylidene and (meth)acryloyl groups and magnetic particles modified by a silane coupling agent, wherein the silane coupling agent contains at least one selected from the group consisting of vinyl, vinylidene, (meth)acryloyl and styrene groups.

[0090] The method for manufacturing magnetic microspheres in this embodiment preferably includes, before step (A): step (B), preparing a monomer mixture comprising monomer (a) and magnetic particles modified by a silane coupling agent; and step (C), dispersing the monomer mixture in an aqueous medium to prepare a suspension.

[0091] The following describes each step in the manufacturing method of magnetic microbeads according to the order of implementation.

[0092] <Process (B)> The method for manufacturing magnetic microspheres in this embodiment preferably includes a step (B) of preparing a monomer mixture comprising a monomer (a) and magnetic particles modified by a silane coupling agent.

[0093] When the total content of the monomer mixture is set to 100% by mass, the content of monomer (a) in the monomer mixture of this embodiment is preferably 50% by mass or more and 98% by mass or less, more preferably 70% by mass or more and 95% by mass or less, and even more preferably 80% by mass or more and 90% by mass or less.

[0094] When the total amount of the monomer mixture is set to 100% by mass, the content of magnetic particles modified by silane coupling agent in the monomer mixture of this embodiment is preferably 0.1% by mass or more and 30% by mass or less, more preferably 0.5% by mass or more and 20% by mass or less, and even more preferably 1% by mass or more and 10% by mass or less.

[0095] The monomer mixture of this embodiment preferably further comprises a monomer (b) having a carboxyl group.

[0096] When the content of monomer (a) in the monomer mixture is set to 100 parts by mass, from the viewpoint of further suppressing the aggregation between beads in the polymerization, the content of monomer (b) in the monomer mixture of this embodiment is preferably 0.1 parts by mass or more and 15 parts by mass or less, more preferably 1 part by mass or more and 10 parts by mass or less, and even more preferably 3 parts by mass or more and 8 parts by mass or less.

[0097] The monomer mixture in this embodiment preferably also contains a polymerization initiator.

[0098] The polymerization initiator preferably includes a thermal polymerization initiator, and more preferably a thermal free radical polymerization initiator.

[0099] The thermal free radical polymerization initiator includes, for example, at least one selected from the group consisting of azo polymerization initiators, peroxides, etc., and more preferably includes an azo polymerization initiator.

[0100] The azo polymerization initiator includes, for example, at least one selected from the group consisting of 2,2′-azobis(isobutyronitrile), 2,2′-azobis(2-methylbutyronitrile), 2,2′-azobis(2,4-dimethylvaleronitrile), 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile), 1,1′-azobis(cyclohexane-1-carboxylonitrile) and dimethyl azobis(isobutyrate), preferably 2,2′-azobis(isobutyronitrile).

[0101] When the total content of monomer components in the monomer mixture is set to 100 parts by mass, the content of polymerization initiator in the monomer mixture of this embodiment is preferably 0.1 parts by mass or more and 10 parts by mass or less, more preferably 1 part by mass or more and 8 parts by mass or less, and even more preferably 2 parts by mass or more and 6 parts by mass or less.

[0102] In step (B), there is no particular limitation on the method for preparing the monomer mixture, but it is preferable to carry out the methods described in (i) to (iii) in sequence.

[0103] (i) Mixed monomer components.

[0104] (ii) Dissolve the polymerization initiator in the mixed monomer components.

[0105] (iii) Add magnetic particles modified with silane coupling agent to the monomer component to disperse the magnetic particles modified with silane coupling agent to obtain a monomer mixture.

[0106] <Process (C)> The method for manufacturing magnetic microspheres in this embodiment preferably further includes a step (C) of dispersing a monomer mixture in an aqueous medium to prepare a suspension.

[0107] Operation (C) is performed after operation (B). Any operation can be performed between operation (B) and operation (C).

[0108] The aqueous medium in this embodiment is not particularly limited as long as it is an aqueous medium that can be used in suspension polymerization.

[0109] The aqueous medium in this embodiment contains water, preferably ion-exchanged water.

[0110] The aqueous medium in this embodiment preferably contains a dispersant stabilizer.

[0111] The dispersant is not particularly limited, but it is preferred to include a polyvinyl alcohol-based dispersant, and more preferably a partially saponified polyvinyl alcohol-based dispersant.

[0112] The aqueous medium in this embodiment may or may not contain surfactants.

[0113] The surfactant is not particularly limited, but it is preferred to include anionic surfactants, and more preferably sodium dodecyl sulfate.

[0114] The aqueous medium in this embodiment may or may not contain a polymerization inhibitor.

[0115] If the aqueous medium of this embodiment contains a polymerization inhibitor, emulsion polymerization that occurs simultaneously during suspension polymerization can be suppressed.

[0116] The polymerization inhibitor is not particularly limited, but it is preferred to contain an inorganic salt, more preferably a nitrite, and even more preferably sodium nitrite.

[0117] The content of each component in the aqueous medium of this embodiment is not particularly limited, and can be adjusted appropriately taking into account the content of each component in the suspension of this embodiment.

[0118] In step (C), there is no particular limitation on the method of dispersing the monomer mixture in an aqueous medium. For example, a method can be given by adding the monomer mixture to an aqueous medium and stirring it with a homogenizer to obtain a suspension.

[0119] The mixing ratio of monomer mixture to aqueous medium is expressed by mass, for example, monomer mixture: aqueous medium = 1:99 to 25:75.

[0120] <Process (A)> The method for manufacturing magnetic microspheres according to this embodiment includes: step (A), in which the monomer is polymerized in a suspension containing monomer (a) and magnetic particles modified by a silane coupling agent.

[0121] When the total content of the suspension is set to 100% by mass, the content of monomer (a) in the suspension of this embodiment is preferably 0.1% by mass or more and 20% by mass or less, more preferably 0.5% by mass or more and 15% by mass or less, and even more preferably 1% by mass or more and 10% by mass or less.

[0122] When the total weight of the suspension is set to 100%, the content of magnetic particles modified by silane coupling agent in the suspension of this embodiment is preferably 0.01% by mass or more and 3.00% by mass or less, more preferably 0.05% by mass or more and 1.00% by mass or less, and even more preferably 0.10% by mass or more and 0.50% by mass or less.

[0123] The suspension in this embodiment preferably further comprises a monomer (b) having a carboxyl group.

[0124] When the content of monomer (a) in the suspension is set to 100 parts by mass, from the viewpoint of further suppressing the aggregation between beads in the polymerization, the content of monomer (b) in the suspension of this embodiment is preferably 0.1 parts by mass or more and 15 parts by mass or less, more preferably 1 part by mass or more and 10 parts by mass or less, and even more preferably 3 parts by mass or more and 8 parts by mass or less.

[0125] When the total content of monomer components in the suspension is set to 100 parts by mass, the content of polymerization initiator in the suspension of this embodiment is preferably 0.1 parts by mass or more and 10 parts by mass or less, more preferably 1 part by mass or more and 8 parts by mass or less, and even more preferably 2 parts by mass or more and 6 parts by mass or less.

[0126] When the total weight of the suspension is set to 100%, the content of the dispersant stabilizer in the suspension of this embodiment is preferably 0.1% or more and 10% or less by weight, more preferably 0.5% or more and 5% or less by weight, and even more preferably 1% or more and 3% or less by weight.

[0127] The suspension in this embodiment may or may not contain surfactants.

[0128] When the suspension in this embodiment contains a surfactant, when the total amount of the suspension is set to 100% by mass, the surfactant content in the suspension in this embodiment is preferably 0.01% by mass or more and 3.0% by mass or less, more preferably 0.05% by mass or more and 1.0% by mass or less, and even more preferably 0.1% by mass or more and 0.5% by mass or less.

[0129] The suspension in this embodiment may or may not contain a polymerization inhibitor.

[0130] When the suspension in this embodiment contains a polymerization inhibitor, when the total amount of the suspension is set to 100% by mass, the content of the polymerization inhibitor in the suspension in this embodiment is preferably 0.001% by mass or more and 1.0% by mass or less, more preferably 0.005% by mass or more and 0.5% by mass or less, and even more preferably 0.01% by mass or more and 0.1% by mass or less.

[0131] Furthermore, the specific manner in which the polymerization initiator, dispersion stabilizer, surfactant, and polymerization inhibitor are included in the suspension of this embodiment is the same as that described in steps (B) and (C).

[0132] In process (A), the polymerization conditions are not particularly limited. For example, they can be set to a temperature of 50°C or higher and 90°C or lower, and a time of 1 hour or higher and 30 hours or lower.

[0133] <Other Processes> The method for manufacturing magnetic microspheres in this embodiment may also include other steps besides steps (A) to (C).

[0134] Other processes include, for example, separating magnetic microspheres from a suspension, and acid washing of the magnetic microspheres.

[0135] Methods for separating magnetic microspheres from suspension include, for example, centrifugal separation and magnetic separation.

[0136] The preferred method for manufacturing magnetic microspheres using the method described in this embodiment is the same as the preferred method for manufacturing magnetic microspheres in this embodiment.

[0137] Furthermore, the specific manner in which the monomer (a), monomer (b), and magnetic particles modified with silane coupling agent are raw materials in the manufacturing method of the magnetic microspheres of this embodiment are the same as the manner in which the monomer (a), monomer (b), and magnetic particles modified with silane coupling agent are described in the magnetic microspheres of this embodiment.

[0138] The embodiments of the present invention have been described above, but these are examples of the present invention, and various structures other than those described above can also be adopted.

[0139] Furthermore, the present invention is not limited to the aforementioned embodiments, and variations and improvements within the scope of achieving the objectives of the present invention are also included in the present invention.

[0140] Example The present invention will now be specifically described through embodiments. However, the present invention is not limited to these embodiments as long as its spirit remains unchanged.

[0141] [Example 1] <Manufacturing of Magnetic Particles Modified with Silane Coupling Agents> 60 g of FeCl₂·4H₂O (manufactured by FUJIFILM Wako Pure Chemical Corporation) and 135 g of FeCl₃·6H₂O (manufactured by FUJIFILM Wako Pure Chemical Corporation) were added to a separable flask. Then, 1500 mL of pure water, pre-purged with nitrogen by bubbling, was added to dissolve the FeCl₂·4H₂O and FeCl₃·6H₂O. 400 mL of 28% (w / w) ammonia solution was then added, and the mixture was stirred at 200 rpm for 30 minutes in an oil bath at 30°C to obtain magnetic particles. The process of magnetic recovery, removal of the supernatant, and addition of water was repeated five times to clean the magnetic particles.

[0142] The magnetic particles obtained above were magnetically recovered, and water was added to prepare a magnetic particle slurry, such that when the magnetic particle slurry was set at 100 parts by mass, the magnetic particles in the slurry were 20 parts by mass. 320 g of diethylamine and 64 g of the above magnetic particle slurry were added to a reaction vessel and treated in an ultrasonic bath for 15 minutes. 9.1 g of distilled water and 31.4 g of 3-methacryloyloxypropyltrimethoxysilane (manufactured by Tokyo Chemical Industry Co., Ltd.) as a silane coupling agent were added, and the reaction vessel was treated in an ultrasonic bath for 30 minutes. Then, the reaction vessel was placed on a shaker and stirred at 100 rpm for 24 hours. The magnetic particles were then recovered by centrifugation. The process of adding acetone to the recovered magnetic particles and centrifuging was repeated three times to clean the magnetic particles. After air drying, magnetic particles modified with the silane coupling agent were obtained.

[0143] <Manufacturing of Magnetic Microbeads> 2.4 parts by weight of styrene monomer (manufactured by Denka Company Limited), 2.4 parts by weight of divinylbenzene (manufactured by NIPPONSTEEL Chemical & Material Co., Ltd., product name: DVB-810), and 0.24 parts by weight of methacrylic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) were mixed together, and 0.19 parts by weight of 2,2′-azobis(isobutyronitrile) (manufactured by FUJIFILM Wako Pure Chemical Corporation) as a polymerization initiator were added. The mixture was then treated in an ultrasonic bath (manufactured by Yamato Scientific Co., Ltd., benchtop ultrasonic cleaner, product name: CPX5800H-J) to completely dissolve the polymerization initiator. Then, 0.27 parts by weight of the magnetic particles (median particle size 146 nm) modified with the silane coupling agent obtained above were added, and the mixture was treated in an ultrasonic bath for 15 minutes to completely disperse the magnetic particles modified with the silane coupling agent, thus obtaining the monomer mixture.

[0144] In addition, 92.27 parts by mass of ion-exchanged water were placed in a four-necked separable flask, and 0.03 parts by mass of sodium nitrite (manufactured by FUJIFILM Wako Pure Chemical Corporation), 0.2 parts by mass of sodium dodecyl sulfate (manufactured by FUJIFILM Wako Pure Chemical Corporation), and 2.0 parts by mass of partially saponified polyvinyl alcohol (manufactured by FUJIFILM Wako Pure Chemical Corporation, degree of saponification: 88 mol%, degree of polymerization: 1500) as a dispersant and stabilizer were dissolved in it to obtain an aqueous medium.

[0145] The monomer mixture obtained above was added to the obtained aqueous medium, and the mixture was stirred at 3000 rpm for 10 minutes in an ice bath using a rotor / stator homogenizer (manufactured by IKA Japan KK, product name: T18 digital ULTRA-TURRAX, dispersing head: S18N-19G) to obtain a suspension in which the monomer mixture was dispersed in droplets in the aqueous medium.

[0146] Next, a stirring blade, a reflux condenser, a nitrogen purging tube, and a thermometer were installed in a four-necked separable flask. The flask was immersed in a water bath, and nitrogen was purged for 30 minutes while the stirring blade rotated at 150 rpm to perform nitrogen replacement. Then, the water bath temperature was raised to 70°C, and suspension polymerization was carried out for 5 hours to obtain magnetic microspheres.

[0147] After polymerization, the suspension is passed through a filter (manufactured by YOTORIYAMA Co., Ltd., 200 mesh) to remove the aggregates.

[0148] Next, the magnetic microspheres were cleaned by the following steps: centrifuging the suspension and adding water three times, centrifuging and adding ethanol once, and centrifuging and adding water once. Furthermore, magnetic separation using a magnet was performed. The dried object, transferred to a 50 mL glass bottle, was placed in a vacuum apparatus (manufactured by AS ONE Corporation, product name: AVO-250NS-D) and vacuum-dried overnight at 50°C using a vacuum pump (manufactured by SATO VAC INC., product name: P135D, 0.67 Pa or less) under reduced pressure, to obtain a dried powder. 10 parts by weight of 6N hydrochloric acid (manufactured by FUJIFILM Wako PureChemical Corporation) were added to 0.5 parts by weight of the obtained dried powder, exposing it to the acid for 2 minutes. The treated magnetic microspheres were then cleaned and purified by magnetic separation, and finally, water was added and the mixture was subjected to ultrasonic irradiation to obtain a purified suspension.

[0149] [Example 2] In Example 1, 31.4 g of 3-methacryloxypropyltrimethoxysilane was replaced with 34.9 g of 3-methacryloxypropyltriethoxysilane (manufactured by Tokyo Chemical Industry Co., Ltd.) as a silane coupling agent. Otherwise, the magnetic microbeads of Example 2 were manufactured in the same manner as in Example 1.

[0150] [Example 3] In Example 1, 31.4 g of 3-methacryloxypropyltrimethoxysilane was replaced with 28.1 g of 3-acryloxypropyltrimethoxysilane (manufactured by Tokyo Chemical Industry Co., Ltd.) as a silane coupling agent. Otherwise, the magnetic microbeads of Example 3 were manufactured in the same manner as in Example 1.

[0151] [Comparative Example 1] In Example 1, magnetic particles modified with fatty acids (manufactured by FerroTec Corporation, product name: EMG1200) were used instead of magnetic particles modified with silane coupling agents. The amounts of each material in the monomer mixture and aqueous medium were set as described in Table 1. Otherwise, magnetic microspheres of Comparative Example 1 were manufactured in the same manner as in Example 1.

[0152] [Comparative Example 2] In Comparative Example 1, the amounts of each material, including the monomer mixture and the aqueous medium, were set as recorded in Table 1. Otherwise, the magnetic microspheres of Comparative Example 2 were manufactured using the same method as in Comparative Example 1.

[0153] [Comparative Example 3] In Example 1, 34.9 g of dodecyltrimethoxysilane (manufactured by Shin-Etsu Chemical Co., Ltd.) was used as the silane coupling agent to replace 31.4 g of 3-methacryloyloxypropyltrimethoxysilane. The amounts of each material in the monomer mixture and the aqueous medium were set as described in Table 1. Otherwise, the magnetic microbeads of Comparative Example 3 were manufactured in the same manner as in Example 1.

[0154] [Measurement / Evaluation] The magnetic microspheres obtained in each embodiment and comparative example were measured / evaluated. The results are shown in Table 1.

[0155] <Shape of magnetic microbeads, etc.> The obtained refined suspension was placed on the sample stage and air-dried for more than 30 minutes. After osmium coating, it was observed by scanning electron microscope (SEM, manufactured by JEOL Ltd., product name: JCM-6000Plus) to evaluate the shape, interior and presence of particles in the magnetic microspheres.

[0156] Figure 1 and Figure 2 This is an example of a SEM image of the magnetic microbeads in Example 1. Figure 3 This is an example of a SEM image of the magnetic microbeads in Comparative Example 1. Figure 4 This is an example of a SEM image of the magnetic microbeads in Comparative Example 2. Here, we will show an example of a magnetic microbead containing, for instance... Figure 3 and Figure 4 Magnetic microspheres with hollow outer shell particles are evaluated as "capsule-type." Furthermore, the presence of particles inside the hollow portion of the capsule-type magnetic microspheres was assessed. And, as... Figure 3 Microbeads with crater-like bumps and depressions visible on their surface are described as "angular".

[0157] <Average sphericity of magnetic microspheres> Images were obtained by SEM in the same manner as described above regarding the shape of the magnetic microspheres, etc.

[0158] Roundness was determined as follows: Image analysis software (Image J) was used to binarize the SEM image, setting the particle area to white and the background to black. The area and perimeter of the particles were calculated and substituted into the following formula. Furthermore, the average roundness of the 10 particles was taken as the average roundness.

[0159] Roundness = circumference of circles with equal projected area / circumference of the particle Circumference of circles with equal projected areas: When observing a particle from directly above, calculate the area of ​​the particle's shadow projected onto the lower plane, calculate the circle with the same area, and then calculate the length of the circle's outline. The perimeter of a particle: the length of the outline of the particle's shadow cast on the lower plane when viewed from directly above. <Volume average particle size of magnetic microspheres> After polymerization, the suspension is passed through a filter to remove the aggregates. A portion of the filtrate is collected using a pipette as the test sample.

[0160] The particle size distribution of the sample was determined using a laser diffraction particle size distribution measuring device (manufactured by Beckman Coulter, Inc., product name: LS 13320), and the volume average particle size (MV) was obtained.

[0161] <Content of magnetic particles in magnetic microspheres> A portion of the obtained purified suspension was collected using a pipette and vacuum dried to obtain a purified suspension powder. Thermogravimetric analysis (TG-DTA) was performed on the purified suspension powder.

[0162] The content of magnetic particles in the magnetic microspheres was determined under the following conditions.

[0163] Measuring apparatus: 2000SR (manufactured by NETZSCH) Environment: Nitrogen Heating rate: 10℃ / min Sample measuring container: Platinum 5 mg of the purified suspension powder was placed in a platinum sample cell and placed in the measuring section. Then, nitrogen gas was injected while the measuring section was heated to 800°C. After maintaining the temperature of the measuring section at 800°C for 2 minutes, the weight of the residue was used as the weight of the magnetic particles to determine the content of magnetic particles in the magnetic microspheres.

[0164] <Evaluation of Flow Cytometry> A portion of the purified suspension was collected using a pipette, water was added to make a concentration of 50,000 particles / μL, and the suspension was fed into a flow cytometer (Becton, Dickinson and Company, product name: BDLSLRFortessa X-20). A scatter plot of side-scattered light (SSC) versus forward-scattered light (FSC) detected during flow in the flow cytometer was constructed and evaluated according to the following evaluation criteria.

[0165] A (Good): Narrow distribution of intensity in the scatter plot. B (Poor): The intensity distribution in the scatter plot is wide. First, Example 1 is rated "A (Good)". Then, those with an intensity distribution that is the same or narrower than that of Example 1 in the scatter plot are rated "A (Good)" and those with a wider distribution than that of Example 1 are rated "B (Poor)".

[0166] [Table 1]

[0167] The flow cytometry evaluations of the magnetic microspheres in the embodiments were all satisfactory. Therefore, it can be seen that the magnetic microspheres according to this embodiment can provide a type of magnetic microsphere capable of suppressing light scattering deviations in light scattering measurements.

[0168] This application claims priority based on Japanese Patent Application No. 2024-046395, filed on March 22, 2024, the entire contents of which are incorporated herein by reference.

Claims

1. A type of magnetic microsphere comprising a polymer and magnetic particles modified with a silane coupling agent. The polymer comprises structural units derived from monomer (a), which has at least one group selected from the group consisting of vinyl, vinylidene, and (meth)acryloyl groups. The silane coupling agent comprises at least one selected from the group consisting of vinyl, vinylidene, (meth)acryloyl, and styrene.

2. The magnetic microspheres according to claim 1, wherein, The silane coupling agent comprises at least one selected from the group consisting of 3-methacryloxypropyltrimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, p-styryltrimethoxysilane, vinyltrimethoxysilane, and vinyltriethoxysilane.

3. The magnetic microspheres according to claim 1 or 2, wherein, The magnetic particles comprise at least one selected from the group consisting of magnetite and maghematite.

4. The magnetic microspheres according to claim 1 or 2, wherein, The magnetic particles have a particle size of 1 nm or more and 5000 nm or less.

5. The magnetic microspheres according to claim 1 or 2, wherein, The monomer (a) comprises at least one selected from the group consisting of styrene monomers and alkyl (meth)acrylates.

6. The magnetic microspheres according to claim 1 or 2, wherein, The polymer also contains structural units derived from monomers (b) having carboxyl groups.

7. The magnetic microspheres according to claim 6, wherein, The monomer (b) comprises at least one selected from the group consisting of methacrylic acid, acrylic acid, mono-2-(methacryloyloxy)ethyl phthalate, mono-2-(acryloyloxy)ethyl phthalate, 2-methacryloyloxyethyl succinic acid and 2-acryloyloxyethyl succinic acid.

8. The magnetic microspheres according to claim 1 or 2, wherein, The surface of the magnetic microspheres contains at least one group selected from the group consisting of carboxyl, ethynyl, hydroxyl, amino, and epoxy groups.

9. The magnetic microspheres according to claim 1 or 2, wherein, The average roundness of the magnetic microspheres is above 0.80 and below 1.

00.

10. The magnetic microspheres according to claim 1 or 2, wherein, The magnetic microspheres have a particle size of 0.1 μm or larger and 300 μm or smaller.

11. The magnetic microspheres according to claim 1 or 2, wherein, The magnetic microspheres are spherical in shape.

12. The magnetic microspheres according to claim 1 or 2, wherein, The polymer contains the magnetic particles inside.

13. The magnetic microspheres according to claim 1 or 2, wherein, When the total mass percentage of the magnetic microspheres is set to 100%, the content of the magnetic particles in the magnetic microspheres is more than 1% by mass and less than 40% by mass.

14. The magnetic microspheres according to claim 1 or 2, wherein, When the total mass percentage of the magnetic microspheres is set to 100%, the content of the polymer in the magnetic microspheres is more than 50% by mass and less than 98% by mass.

15. The magnetic microspheres according to claim 1 or 2, wherein, When the content of the magnetic particles in the magnetic microspheres is set to 100 parts by mass, the content of the silane coupling agent in the magnetic microspheres is more than 0.01 parts by mass and less than 30 parts by mass.

16. A method for manufacturing magnetic microspheres, comprising: Step (A) involves polymerizing the monomer in a suspension containing a monomer (a) having at least one group selected from the group consisting of vinyl, vinylidene, and (meth)acryloyl groups, and magnetic particles modified with a silane coupling agent. The silane coupling agent comprises at least one selected from the group consisting of vinyl, vinylidene, (meth)acryloyl, and styrene.

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