Magnetic beads and method for producing magnetic beads

Abstract

Magnetic beads including a polymer and magnetic particles that have been modified with a silane coupling agent, wherein the polymer includes a structural unit derived from a monomer (a) having at least one type of group selected from the group consisting of a vinyl group, a vinylidene group, and a (meth)acryloyl group, and the silane coupling agent includes at least one type of group selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group, and a styryl group.

Description

Magnetic beads and method for producing magnetic beads

[0001] The present invention relates to magnetic beads and a method for producing magnetic beads.

[0002] As a technique relating to magnetic beads containing a polymer and magnetic particles, for example, the technique described in Patent Document 1 is known.

[0003] Patent Document 1 describes magnetic particles characterized by containing magnetic powder with polymer chains bonded to the surface via a coupling agent. The magnetic particles described in Patent Document 1 are described as being suitable for use as carriers and the like because they have good dispersibility, dispersion stability, and affinity with binder resins, small particle size with a narrow particle size distribution, excellent heat resistance, abrasion resistance, and the like, and are hard and difficult to crack.

[0004] Japanese Unexamined Patent Publication No. 6-102708

[0005] The present invention provides magnetic beads that can suppress variations in light scattering in light scattering measurements.

[0006] According to the present invention, the following magnetic beads and a method for producing magnetic beads are provided.

[0007] [1] Magnetic beads comprising a polymer and magnetic particles modified with a silane coupling agent, wherein the polymer comprises a structural unit 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, and the silane coupling agent comprises at least one selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group, and a styryl group. [2] The magnetic beads according to [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 beads according to [1] or [2], wherein the magnetic particles comprise at least one selected from the group consisting of magnetite and maghemite. [4] The magnetic beads according to any one of [1] to [3], wherein the particle diameter of the magnetic particles is 1 nm or more and 5,000 nm or less. [5] The magnetic beads according to any one of [1] to [4], wherein the monomer (a) comprises at least one selected from the group consisting of a styrene-based monomer and an alkyl(meth)acrylate. [6] The magnetic beads according to any one of [1] to [5], wherein the polymer further comprises a structural unit derived from a monomer (b) having a carboxy group. [7] The magnetic beads according to [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 beads according to any one of [1] to [7], which contain at least one group selected from the group consisting of a carboxy group, an ethynyl group, a hydroxy group, an amino group, and an epoxy group on the surface of the magnetic beads.[9] The magnetic beads according to any one of [1] to [8], wherein the average circularity of the magnetic beads is 0.80 to 1.00.

[10] The magnetic beads according to any one of [1] to [9], wherein the particle diameter of the magnetic beads is 0.1 μm to 300 μm.

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

[10] , wherein the shape of the magnetic beads is spherical.

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

[11] , wherein the magnetic particles are contained inside the polymer.

[13] The magnetic beads according to any one of [1] to

[12] , wherein the content of the magnetic particles in the magnetic beads is 1% by mass to 40% by mass, when the total mass of the magnetic beads is taken as 100% by mass.

[14] The magnetic beads according to any one of [1] to

[13] , wherein the content of the polymer in the magnetic beads is 50% by mass to 98% by mass, when the total mass of the magnetic beads is taken as 100% by mass.

[15] The magnetic beads according to any one of [1] to

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

[16] A method for producing magnetic beads, comprising: a step (A) of polymerizing a monomer (a) having at least one selected from the group consisting of a vinyl group, a vinylidene group, and a (meth)acryloyl group in a suspension containing the monomer and magnetic particles modified with a silane coupling agent, wherein the silane coupling agent contains at least one selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group, and a styryl group.

[17] The method for producing magnetic beads according to

[16] , further comprising, before the step (A), a step (B) of preparing a monomer mixture containing the monomer (a) and the magnetic particles modified with the silane coupling agent, and a step (C) of dispersing the monomer mixture in an aqueous medium to prepare the suspension.

[18] The method for producing magnetic beads according to

[16] or

[17] , wherein the suspension further contains a monomer (b) having a carboxy group.

[19] The method for producing magnetic beads according to any one of

[16] to

[18] , 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.

[20] The method for producing magnetic beads 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.

[21] The method for producing magnetic beads according to any one of

[16] to

[20] , wherein the magnetic particles have a particle diameter of 1 nm or more and 5000 nm or less.

[0008] According to the present invention, magnetic beads can be provided that can suppress variations in light scattering in light scattering measurements.

[0009] 1 is an example of an SEM image of magnetic beads of Example 1. FIG. 2 is an example of an SEM image of magnetic beads of Example 1. FIG. 3 is an example of an SEM image of magnetic beads of Comparative Example 1. FIG. 4 is an example of an SEM image of magnetic beads of Comparative Example 2.

[0010] Hereinafter, embodiments of the present invention will be described. Unless otherwise specified, the numerical range "A to B" represents A or more and B or less. In this embodiment, the expression "(meth)acryloyl group" represents a concept that includes both methacryloyl groups and acryloyl groups. The same applies to similar expressions such as "(meth)acrylate."

[0011] Magnetic beads containing a polymer and magnetic particles are known. Magnetic beads are used, for example, in diagnostic agents, bacterial isolation, cell culture, drug delivery, magnetic toner, magnetic ink, and magnetic paint. Furthermore, in medical and biomedical applications such as diagnostic agents, light scattering measurements such as flow cytometry may be performed on dispersions containing magnetic beads. Such magnetic beads are required to suppress variations in light scattering during light scattering measurements. The present invention provides magnetic beads capable of suppressing variations in light scattering during light scattering measurements.

[0012] [Magnetic beads] The magnetic beads of this embodiment are magnetic beads comprising a polymer and magnetic particles modified with a silane coupling agent, wherein the polymer comprises a structural unit 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, and the silane coupling agent comprises at least one selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group, and a styryl group.

[0013] The present inventors have discovered for the first time that magnetic beads comprising a polymer and magnetic particles can be provided that are capable of suppressing variations in light scattering in light scattering measurements by including magnetic particles modified with a specific silane coupling agent as the magnetic particles.

[0014] The magnetic beads of this embodiment preferably contain magnetic particles inside a polymer.

[0015] From the viewpoint of further suppressing variations in light scattering in light scattering measurements, the average circularity of the magnetic beads of this embodiment is preferably 0.80 to 1.00, more preferably 0.85 to 1.00, and even more preferably 0.88 to 1.00. Here, the average circularity of the magnetic beads refers to the average circularity calculated by performing image analysis on SEM images of the magnetic beads using the method described in the Examples.

[0016] The particle diameter of the magnetic beads of this embodiment is preferably 0.1 μm to 300 μm, more preferably 1 μm to 200 μm, and even more preferably 5 μm to 100 μm. The particle diameter of the magnetic beads refers to the particle diameter obtained when a particle size distribution of a 1% by mass magnetic bead dispersion is measured using a laser diffraction particle size distribution analyzer. Here, a 1% by mass magnetic bead dispersion can be, for example, a 1% by mass aqueous magnetic bead solution using water as the solvent. The above preferred range of magnetic bead particle diameter means that at least a portion of the individual particle diameters of the magnetic beads obtained by the above measurement method are within the above range.

[0017] The volume average particle diameter of the magnetic beads of this embodiment is preferably 0.5 μm to 110 μm, more preferably 1 μm to 50 μm, even more preferably 5 μm to 25 μm, and even more preferably 7 μm to 18 μm. The volume average particle diameter of the magnetic beads refers to the volume average particle diameter (MV) obtained when measuring the particle size distribution of a 1% by mass magnetic bead dispersion using a laser diffraction particle size distribution analyzer. Here, the 1% by mass magnetic bead dispersion can be, for example, a 1% by mass aqueous magnetic bead solution using water as the solvent.

[0018] The magnetic beads of this embodiment are preferably spherical in shape, and preferably solid in shape.

[0019] The surface of the magnetic beads of this embodiment preferably contains at least one selected from the group consisting of a carboxy group, an ethynyl group, a hydroxy group, an amino group, and an epoxy group, more preferably at least one selected from the group consisting of a carboxy group and an ethynyl group, and even more preferably a carboxy group. When the surface of the magnetic beads of this embodiment contains such functional groups, it becomes possible to immobilize a target substance by reacting the functional groups with a substance capable of binding to the functional group (hereinafter, the target substance). Magnetic beads containing such functional groups are preferred from the viewpoint of enabling applications in the medical and biomedical fields, such as diagnostic agents.

[0020] Each component contained in the magnetic beads of this embodiment will be specifically described below.

[0021] <Polymer> The magnetic beads of this embodiment contain a polymer. The polymer of this embodiment contains a structural unit derived from a monomer (a) having at least one group selected from the group consisting of a vinyl group, a vinylidene group, and a (meth)acryloyl group.

[0022] (Monomer (a)) The monomer (a) is a monomer having at least one group selected from the group consisting of a vinyl group, a vinylidene group, and a (meth)acryloyl group.

[0023] The monomer having a vinyl group includes, for example, at least one selected from the group consisting of a styrene-based monomer, vinyl chloride, vinyl acetate, etc. The monomer having a (meth)acryloyl group includes, for example, at least one selected from the group consisting of an alkyl (meth)acrylate, a hydroxyalkyl (meth)acrylate, an aminoalkyl (meth)acrylate, etc.

[0024] The monomer (a) of this embodiment preferably includes at least one selected from the group consisting of a styrene-based monomer and an alkyl(meth)acrylate.

[0025] The styrene-based monomer refers to styrene and styrene derivatives. Examples of the styrene-based monomer include 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, crotylbenzene, trivinylbenzene, and vinylnaphthalene, and preferably includes at least one selected from the group consisting of styrene, divinylbenzene, and α-methylstyrene, and more preferably includes styrene and divinylbenzene.

[0026] The alkyl (meth)acrylate includes, for example, at least one selected from the group consisting of methyl (meth)acrylate, ethyl (meth)acrylate, n-butyl (meth)acrylate, t-butyl (meth)acrylate, cyclohexyl (meth)acrylate, and isobornyl (meth)acrylate, and preferably includes at least one selected from the group consisting of methyl (meth)acrylate, n-butyl (meth)acrylate, t-butyl (meth)acrylate, cyclohexyl (meth)acrylate, and isobornyl (meth)acrylate, and more preferably includes at least one selected from the group consisting of methyl methacrylate, n-butyl methacrylate, t-butyl methacrylate, cyclohexyl methacrylate, and isobornyl methacrylate.

[0027] (Monomer (b)) The polymer of this embodiment preferably further contains a structural unit derived from monomer (b) having a carboxy group. By including a structural unit derived from monomer (b) having a carboxy group in the polymer of this embodiment, magnetic beads having carboxy groups on the surface thereof can be obtained.

[0028] Monomer (b) is not particularly limited as long as it is a monomer having a carboxy group, but is preferably a monomer further having a polymerizable double bond. Monomer (b) preferably includes 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 includes at least one selected from the group consisting of methacrylic acid and acrylic acid, and even more preferably includes methacrylic acid.

[0029] The polymer content in the magnetic beads of this embodiment, when the total mass of the magnetic beads is taken as 100% by mass, 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, and even more preferably 85% by mass or more, from the viewpoint of further increasing the functional groups on the surface of the magnetic beads, and is preferably 98% by mass or less, more preferably 95% by mass or less, and even more preferably 93% by mass or less, from the viewpoint of further improving the magnetic properties of the magnetic beads. The polymer content in the magnetic beads of this embodiment, when the total mass of the magnetic beads is taken as 100% by mass, is preferably 50% by mass or more and 98% by mass or less, more preferably 60% by mass or more and 95% by mass or less, even more preferably 70% by mass or more and 93% by mass or less, and even more preferably 80% by mass or more and 93% by mass or less, from the viewpoint of further increasing the functional groups on the surface of the magnetic beads and further improving the magnetic properties of the magnetic beads.

[0030] The method for synthesizing the polymer of this embodiment is not particularly limited, but suspension polymerization is preferred. Detailed synthesis conditions may be, for example, the conditions described in the method for producing magnetic beads described below.

[0031] <Magnetic Particles Modified with a Silane Coupling Agent> The magnetic beads of this embodiment contain magnetic particles modified with a silane coupling agent.

[0032] (Silane Coupling Agent) The silane coupling agent of the present embodiment contains at least one selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group, and a styryl group, and preferably contains a (meth)acryloyl group.

[0033] Examples of silane coupling agents containing a vinyl group include at least one selected from the group consisting of vinyltrimethoxysilane, vinyltriethoxysilane, and dimethoxymethylvinylsilane. Examples of silane coupling agents containing a (meth)acryloyl group include at least one selected from the group consisting of 3-methacryloxypropyltrimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, and 3-methacryloxypropyltriethoxysilane. Examples of silane coupling agents containing a styryl group include p-styryltrimethoxysilane.

[0034] The silane coupling agent of the present embodiment preferably contains 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 contains at least one selected from the group consisting of 3-methacryloxypropyltrimethoxysilane, 3-acryloxypropyltrimethoxysilane, and 3-methacryloxypropyltriethoxysilane.

[0035] (Magnetic Particles) The magnetic particles of the present embodiment are not particularly limited as long as they are particles having magnetism. For example, magnetite (Fe ３ O ４ ), Maghemite (γ-Fe ２ O ３ ), hematite (α-Fe ２ O ３ ), manganese ferrite (MnFe ２ O ４ ), cobalt ferrite (CoFe ２ O ４ ), nickel ferrite (NiFe ２ O ４ ), copper ferrite (CuFe ２ O４ ), Mn-Zn ferrite, Ni-Zn ferrite, Mn-Mg ferrite, Li ferrite, Cu-Zn ferrite, and goethite (FeO(OH)), and preferably includes at least one selected from the group consisting of magnetite and maghemite, and more preferably includes magnetite.

[0036] The particle diameter of the magnetic particles of this embodiment is preferably 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. Here, the particle diameter of the magnetic particles refers to a value measured by a transmission electron microscope (TEM), specifically, a value obtained by performing image analysis on a TEM image and calculating the arithmetic average of the particle diameters of any 10 magnetic particles.

[0037] The content of magnetic particles in the magnetic beads of this embodiment, when the total mass of the magnetic beads is taken as 100% by mass, is preferably 1% by mass or more, more preferably 3% by mass or more, even more preferably 5% by mass or more, and even more preferably 8% by mass or more, from the viewpoint of further improving the magnetic properties of the magnetic beads, and is preferably 40% by mass or less, more preferably 30% by mass or less, even more preferably 20% by mass or less, and even more preferably 15% by mass or less, from the viewpoint of further increasing the number of functional groups on the surface of the magnetic beads. The content of magnetic particles in the magnetic beads of this embodiment, when the total mass of the magnetic beads is taken as 100% by mass, 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, even more preferably 5% by mass or more and 20% by mass or less, and even more preferably 8% by mass or more and 15% by mass or less, from the viewpoint of further improving the magnetic properties of the magnetic beads and further increasing the number of functional groups on the surface of the magnetic beads.

[0038] The content of the silane coupling agent in the magnetic beads 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, from the viewpoint of further suppressing the variation in light scattering in light scattering measurements, when the content of the magnetic particles in the magnetic beads is 100 parts by mass.

[0039] The method for producing the magnetic particles modified with the silane coupling agent of this embodiment is not particularly limited, but examples thereof include the methods described in the examples.

[0040] <Other Components> The magnetic beads of this embodiment may further contain components other than the polymer and the magnetic particles modified with a silane coupling agent.

[0041] [Uses of Magnetic Beads] The uses of the magnetic beads of this embodiment are not particularly limited, and can be applied to, for example, diagnostic agents, bacterial separation, cell culture, drug delivery, magnetic toner, magnetic ink, magnetic paint, etc. The magnetic beads of this embodiment are preferably magnetic beads that can be used in diagnostic agents, from the viewpoint of further suppressing variations in light scattering in light scattering measurements. The uses of the magnetic beads of this embodiment preferably do not include at least one use selected from the group consisting of magnetic toner, developer, and electrophotographic carrier.

[0042] [Dispersion] The dispersion of this embodiment contains the magnetic beads of this embodiment and a solvent. The solvent contains at least one solvent selected from the group consisting of, for example, water, methanol, ethanol, isopropyl alcohol, propylene glycol monomethyl ether, and propylene glycol monomethyl ether acetate, and preferably contains water.

[0043] The concentration of the dispersion of this embodiment is, for example, 0.01% by mass to 20% by mass, preferably 0.1% by mass to 15% by mass, and more preferably 0.5% by mass to 10% by mass.

[0044] [Method for manufacturing magnetic beads] The method for manufacturing magnetic beads of this embodiment includes a step (A) of polymerizing a monomer in a suspension containing a monomer (a) having at least one selected from the group consisting of a vinyl group, a vinylidene group, and a (meth)acryloyl group, and magnetic particles modified with a silane coupling agent, wherein the silane coupling agent includes at least one selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group, and a styryl group.

[0045] The method for producing magnetic beads of this embodiment preferably further includes, before step (A), step (B) of preparing a monomer mixture containing monomer (a) and magnetic particles modified with a silane coupling agent, and step (C) of dispersing the monomer mixture in an aqueous medium to prepare a suspension.

[0046] Hereinafter, each step in the method for producing magnetic beads of this embodiment will be specifically described in the order in which the steps are performed.

[0047] <Step (B)> The method for producing magnetic beads of this embodiment preferably includes step (B) of preparing a monomer mixture containing monomer (a) and magnetic particles modified with a silane coupling agent.

[0048] The content of monomer (a) in the monomer mixture of the present 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, when the entire monomer mixture is taken as 100% by mass.

[0049] The content of magnetic particles modified with a 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, when the entire monomer mixture is taken as 100% by mass.

[0050] The monomer mixture of this embodiment preferably further contains a monomer (b) having a carboxy group.

[0051] The content of the monomer (b) in the monomer mixture of the present 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, from the viewpoint of further suppressing aggregation of the beads during polymerization, when the content of the monomer (a) in the monomer mixture is taken as 100 parts by mass.

[0052] The monomer mixture of this embodiment preferably further contains a polymerization initiator. The polymerization initiator preferably contains a thermal polymerization initiator, and more preferably contains a thermal radical polymerization initiator. The thermal radical polymerization initiator includes, for example, at least one selected from the group consisting of an azo polymerization initiator, a peroxide, and the like, and more preferably contains an azo polymerization initiator. 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-carbonitrile), and dimethyl azobis(isobutyrate), and preferably contains 2,2'-azobis(isobutyronitrile).

[0053] The content of the polymerization initiator in the monomer mixture of the present 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, when the total content of the monomer components in the monomer mixture is 100 parts by mass.

[0054] In step (B), the method for preparing the monomer mixture is not particularly limited, but is preferably a method in which the following steps (i) to (iii) are carried out in order: (i) mixing the monomer components; (ii) dissolving a polymerization initiator in the mixed monomer components; (iii) adding magnetic particles modified with a silane coupling agent to the monomer components, and dispersing the magnetic particles modified with the silane coupling agent to obtain a monomer mixture.

[0055] <Step (C)> The method for producing magnetic beads of this embodiment preferably further includes step (C) of dispersing the monomer mixture in an aqueous medium to prepare a suspension. Step (C) is performed after step (B). An optional step may be included between step (B) and step (C).

[0056] The aqueous medium of the present embodiment is not particularly limited as long as it is an aqueous medium that can be used in a suspension polymerization method. The aqueous medium of the present embodiment contains water, and preferably contains ion-exchanged water.

[0057] The aqueous medium of the present embodiment preferably contains a dispersion stabilizer. The dispersion stabilizer is not particularly limited, but preferably contains a polyvinyl alcohol-based dispersion stabilizer, and more preferably contains a partially saponified polyvinyl alcohol-based dispersion stabilizer.

[0058] The aqueous medium of the present embodiment may or may not contain a surfactant. The surfactant is not particularly limited, but preferably contains an anionic surfactant, and more preferably contains sodium dodecyl sulfate.

[0059] The aqueous medium of this embodiment may or may not contain a polymerization inhibitor. When the aqueous medium of this embodiment contains a polymerization inhibitor, emulsion polymerization occurring simultaneously with suspension polymerization can be suppressed. The polymerization inhibitor is not particularly limited, but preferably contains an inorganic salt, more preferably contains a nitrite, and even more preferably contains sodium nitrite.

[0060] The content of each component in the aqueous medium of this embodiment is not particularly limited, and may be adjusted appropriately taking into consideration the content of each component in the suspension of this embodiment.

[0061] In step (C), the method for dispersing the monomer mixture in the aqueous medium is not particularly limited, but examples thereof include a method in which the monomer mixture is added to an aqueous medium and stirred using a homogenizer to obtain a suspension.

[0062] The mixing ratio of the monomer mixture to the aqueous medium is, for example, monomer mixture:aqueous medium=1:99 to 25:75 by mass.

[0063] <Step (A)> The method for producing magnetic beads of this embodiment includes step (A) of polymerizing a monomer in a suspension containing a monomer (a) and magnetic particles modified with a silane coupling agent.

[0064] The content of the monomer (a) in the suspension of the present 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, when the entire suspension is taken as 100% by mass.

[0065] The content of magnetic particles modified with a 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, when the entire suspension is taken as 100% by mass.

[0066] The suspension of this embodiment preferably further contains a monomer (b) having a carboxy group. The content of the 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, based on 100 parts by mass of the monomer (a) in the suspension, from the viewpoint of further suppressing aggregation of the beads during polymerization.

[0067] The content of the polymerization initiator in the suspension of the present 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, when the total content of the monomer components in the suspension is 100 parts by mass.

[0068] The content of the dispersion stabilizer in the suspension of this embodiment is preferably 0.1% by mass or more and 10% by mass or less, more preferably 0.5% by mass or more and 5% by mass or less, and even more preferably 1% by mass or more and 3% by mass or less, when the entire suspension is taken as 100% by mass.

[0069] The suspension of this embodiment may or may not contain a surfactant. When the suspension of this embodiment contains a surfactant, the content of the surfactant in the suspension of 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, when the total mass of the suspension is 100% by mass.

[0070] The suspension of this embodiment may or may not contain a polymerization inhibitor. When the suspension of this embodiment contains a polymerization inhibitor, the content of the polymerization inhibitor in the suspension of 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, when the entire suspension is taken as 100% by mass.

[0071] Specific aspects of the polymerization initiator, dispersion stabilizer, surfactant, and polymerization inhibitor contained in the suspension of this embodiment are the same as those described in steps (B) and (C).

[0072] In step (A), the polymerization conditions are not particularly limited, but may be, for example, 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.

[0073] <Other Steps> The method for producing magnetic beads of this embodiment may further include other steps in addition to steps (A) to (C). Examples of other steps include a step of separating the magnetic beads from the suspension and a step of washing the magnetic beads with acid. Examples of methods for separating the magnetic beads from the suspension include centrifugation and magnetic separation.

[0074] The preferred aspects of the magnetic beads obtained by the method for producing magnetic beads of this embodiment are the same as the preferred aspects of the magnetic beads of this embodiment. Furthermore, the specific aspects of the raw materials, monomer (a), monomer (b), and magnetic particles modified with a silane coupling agent, in the method for producing magnetic beads of this embodiment are the same as the aspects of the magnetic particles modified with monomer (a), monomer (b), and silane coupling agent described in the description of the magnetic beads of this embodiment.

[0075] Although the embodiments of the present invention have been described above, these are merely examples of the present invention, and various other configurations may be adopted. Furthermore, the present invention is not limited to the above-described embodiments, and modifications and improvements within the scope of achieving the object of the present invention are included in the present invention.

[0076] The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples as long as the gist of the invention is not changed.

[0077] Example 1 Production of Magnetic Particles Modified with Silane Coupling Agent A separable flask was charged with FeCl ２ ・4H ２ O (Fujifilm Wako Pure Chemical Industries, Ltd.) 60 g, FeCl ３ ・6H ２ 135 g of FeCl 0 (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added, followed by the addition of 1500 mL of pure water that had been previously purged with nitrogen by nitrogen bubbling. ２ ・4H ２ O and FeCl ３ ・6H ２ O was dissolved in the mixture. 400 mL of 28 wt % aqueous ammonia was poured into the mixture, and the mixture was stirred at 200 rpm for 30 minutes in an oil bath at 30°C to obtain magnetic particles. The obtained magnetic particles were magnetically recovered, and the supernatant was removed and water was added. This procedure was repeated five times to wash the magnetic particles.

[0078] The magnetic particles obtained above were magnetically recovered, and water was added to prepare a magnetic particle aqueous slurry such that the magnetic particles in the magnetic particle aqueous slurry were 20 parts by mass when the magnetic particle aqueous slurry was 100 parts by mass. 320 g of diethylamine and 64 g of the magnetic particle aqueous slurry were added to a reaction vessel, and the mixture was treated in an ultrasonic bath for 15 minutes. 9.1 g of distilled water and 31.4 g of 3-methacryloxypropyltrimethoxysilane (Tokyo Chemical Industry Co., Ltd.) as a silane coupling agent were added, and the mixture was treated in an ultrasonic bath for 30 minutes. The reaction vessel was then placed on a shaker and stirred at 100 rpm for 24 hours. The magnetic particles were then recovered by centrifugation. Acetone was added to the recovered magnetic particles, and the centrifugation procedure was repeated three times to wash the magnetic particles. Magnetic particles modified with a silane coupling agent were obtained by air-drying.

[0079] <Production of Magnetic Beads> 2.4 parts by mass of styrene monomer (manufactured by Denka Co., Ltd.), 2.4 parts by mass of divinylbenzene (manufactured by Nippon Steel Chemical & Material Co., Ltd., product name: DVB-810), and 0.24 parts by mass of methacrylic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) were mixed, and 0.19 parts by mass of 2,2'-azobis(isobutyronitrile) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added as a polymerization initiator. The mixture was then treated in an ultrasonic bath (manufactured by Yamato Scientific Co., Ltd., tabletop ultrasonic cleaner, product name: CPX5800H-J) to completely dissolve the polymerization initiator. 0.27 parts by mass of the magnetic particles (median diameter 146 nm) modified with a silane coupling agent obtained above were added thereto, and the mixture was treated in the ultrasonic bath for 15 minutes to completely disperse the magnetic particles modified with the silane coupling agent, yielding a monomer mixture.

[0080] Separately, 92.27 parts by mass of ion-exchanged water was charged into a four-neck separable flask, and 0.03 parts by mass of sodium nitrite (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.), 0.2 parts by mass of sodium dodecyl sulfate (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.), and 2.0 parts by mass of partially saponified polyvinyl alcohol (manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd., saponification degree: 88 mol%, polymerization degree: 1500) as a dispersion stabilizer were dissolved therein to obtain an aqueous medium. 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 Co., Ltd., product name: T18 digital ULTRA-TURRAX, shaft generator: S18N-19G), to obtain a suspension in which the monomer mixture was dispersed as droplets in the aqueous medium.

[0081] Next, a four-neck separable flask was equipped with a stirring blade, a reflux condenser, a nitrogen purge tube, and a thermometer. The flask was immersed in a water bath, and nitrogen gas was blown in for 30 minutes while rotating the stirring blade at 150 rpm to perform nitrogen substitution. The temperature of the water bath was then raised to 70°C, and suspension polymerization was carried out for 5 hours to obtain magnetic beads.

[0082] After polymerization, the suspension was passed through a filter (manufactured by Yotoriyama Co., Ltd., 200 mesh) to remove aggregates. Next, the suspension was centrifuged and then water was added three times, ethanol was added once, and water was added once to wash the magnetic beads. Furthermore, magnetic separation was performed using a magnet, and the dried material transferred to a 50 mL glass bottle was placed in a vacuum device (manufactured by AS ONE Corporation, product name: AVO-250NS-D) and evacuated under reduced pressure using a vacuum pump (manufactured by Sato Vacuum Co., Ltd., product name: P135D, 0.67 Pa or less). The dried material was then dried overnight at 50°C under reduced pressure to obtain a dry powder. 10 parts by mass of 6N hydrochloric acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to 0.5 parts by mass of the obtained dry powder, and the mixture was exposed to the acid for 2 minutes. The treated magnetic beads were then washed and purified by magnetic separation, and finally water was added and ultrasonically irradiated to obtain a purified suspension.

[0083] [Example 2] Magnetic beads of Example 2 were produced in the same manner as in Example 1, except that 34.9 g of 3-methacryloxypropyltriethoxysilane (manufactured by Tokyo Chemical Industry Co., Ltd.) was used as the silane coupling agent instead of 31.4 g of 3-methacryloxypropyltrimethoxysilane.

[0084] [Example 3] Magnetic beads of Example 3 were produced in the same manner as in Example 1, except that 28.1 g of 3-acryloxypropyltrimethoxysilane (manufactured by Tokyo Chemical Industry Co., Ltd.) was used as the silane coupling agent instead of 31.4 g of 3-methacryloxypropyltrimethoxysilane.

[0085] [Comparative Example 1] The magnetic beads of Comparative Example 1 were produced in the same manner as in Example 1, except that magnetic particles modified with a fatty acid (manufactured by Ferrotec Corporation, product name: EMG1200) were used instead of the magnetic particles modified with a silane coupling agent in Example 1, and the amounts of each material in the monomer mixture and aqueous medium were set to the amounts listed in Table 1.

[0086] Comparative Example 2 Magnetic beads of Comparative Example 2 were produced in the same manner as in Comparative Example 1, except that the amounts of the monomer mixture and the aqueous medium were changed to the amounts shown in Table 1.

[0087] Comparative Example 3 Magnetic beads of Comparative Example 3 were produced in the same manner as in Example 1, except that 34.9 g of dodecyltrimethoxysilane (manufactured by Shin-Etsu Chemical Co., Ltd.) was used as the silane coupling agent instead of 31.4 g of 3-methacryloxypropyltrimethoxysilane, and the amounts of each material in the monomer mixture and aqueous medium were set to the amounts shown in Table 1.

[0088] [Measurement and Evaluation] Measurement and evaluation were carried out on the magnetic beads obtained in each Example and Comparative Example. The results are shown in Table 1.

[0089] <Shape of magnetic beads, etc.> The purified suspension obtained was placed on a sample stage, air-dried for 30 minutes or more, and then coated with osmium. The resultant was observed under a scanning electron microscope (SEM, manufactured by JEOL Ltd., product name: JCM-6000Plus) to evaluate the shape of the magnetic beads, their interior, and the presence or absence of particles inside.

[0090] Figures 1 and 2 are example SEM images of magnetic beads of Example 1. Figure 3 is an example SEM image of magnetic beads of Comparative Example 1. Figure 4 is an example SEM image of magnetic beads of Comparative Example 2. Here, magnetic beads having shell particles with hollow portions as shown in Figures 3 and 4 were evaluated as "capsule-type." Furthermore, the capsule-type magnetic beads were evaluated for the presence or absence of particles inside the hollow portions. Furthermore, particles with crater-like irregularities observed on the surface as shown in Figure 3 were evaluated as "angular."

[0091] <Average circularity of magnetic beads> Images were obtained by SEM in the same manner as in <Shape of magnetic beads, etc.> above. The circularity was determined by binarizing the images taken by SEM using image analysis software (Image J) to make the particle portion white and the background black, determining the area and perimeter of the particles, and applying this to the following formula: The average value of the circularities of 10 particles was taken as the average circularity. Circularity = perimeter of a circle with the same projected area / perimeter of a particle Circumference of a circle with the same projected area: When a particle is observed from directly above, the area of ​​the shadow of the particle projected on a flat surface below is determined, and a circle equivalent to this area is calculated, and the length of the outline of this circle is calculated. Particle perimeter: When a particle is observed from directly above, the length of the outline of the shadow of the particle projected on a flat surface below is calculated

[0092] <Volume average particle diameter of magnetic beads> After polymerization, the suspension was passed through a filter to remove aggregates, and a portion of the filtrate was collected with a pipette to prepare a measurement sample. The particle size distribution of the measurement sample was measured using a laser diffraction particle size distribution analyzer (manufactured by Beckman Coulter, Inc., product name: LS 13 320), and the volume average particle diameter (MV) was obtained.

[0093] <Content of magnetic particles in magnetic beads> A portion of the obtained purified suspension was sampled with a pipette and vacuum-dried to obtain a purified suspension dry powder. The purified suspension dry powder was subjected to thermogravimetric thermal analysis (TG-DTA). The content of magnetic particles in the magnetic beads was determined under the following conditions. Measuring device: 2000SR (manufactured by NETZSCH) Atmosphere: Nitrogen Heating rate: 10°C / min Sample measurement container: Platinum 5 mg of purified suspension dry powder was placed in a platinum cell and set in the measurement unit. The measurement unit was then heated to 800°C while injecting nitrogen. The temperature of the measurement unit was held at 800°C for 2 minutes, after which the weight of the residue was taken as the weight of the magnetic particles, and the content of magnetic particles in the magnetic beads was determined.

[0094] <Evaluation by Flow Cytometry> A portion of the obtained purified suspension was collected with a pipette, water was added to make the concentration 50,000 particles / μL, and the suspension was subjected to a flow cytometer (manufactured by Becton Dickinson, product name: BD LSRFortessa X-20). A scatter plot of side scattered light (SSC) versus forward scattered light (FSC) detected when the suspension was run through the flow cytometer was created and evaluated according to the following evaluation criteria. A (good): The intensity distribution in the scatter plot is narrow. B (poor): The intensity distribution in the scatter plot is wide. First, Example 1 was evaluated as "A (good)." Then, a sample with an intensity distribution in the scatter plot that was equal to or narrower than Example 1 was evaluated as "A (good)," and a sample with an intensity distribution that was wider than Example 1 was evaluated as "B (poor)."

[0095]

[0096] The magnetic beads of the examples were all evaluated favorably by flow cytometry. That is, it can be seen that the magnetic beads of this embodiment can provide magnetic beads that can suppress variations in light scattering in light scattering measurements.

[0097] This application claims priority based on Japanese Patent Application No. 2024-046395, filed March 22, 2024, the disclosure of which is incorporated herein by reference in its entirety.

Claims

1. Magnetic beads comprising a polymer and magnetic particles modified with a silane coupling agent, wherein the polymer comprises a structural unit 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, and the silane coupling agent comprises at least one selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group, and a styryl group.

2. The magnetic beads 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 beads according to claim 1 or 2, wherein the magnetic particles include at least one selected from the group consisting of magnetite and maghemite.

4. Magnetic beads according to claim 1 or 2, wherein the particle diameter of the magnetic particles is 1 nm or more and 5000 nm or less.

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

6. Magnetic beads according to claim 1 or 2, wherein the polymer further comprises a structural unit derived from a monomer (b) having a carboxy group.

7. The magnetic beads 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 succinate, and 2-acryloyloxyethyl succinate.

8. The magnetic beads according to claim 1 or 2, which contain at least one group selected from the group consisting of a carboxy group, an ethynyl group, a hydroxy group, an amino group, and an epoxy group on the surface of the magnetic beads.

9. The magnetic beads according to claim 1 or 2, wherein the average circularity of the magnetic beads is 0.80 or more and 1.00 or less.

10. Magnetic beads according to claim 1 or 2, wherein the particle diameter of the magnetic beads is 0.1 μm or more and 300 μm or less.

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

12. The magnetic beads according to claim 1 or 2, which contain the magnetic particles inside the polymer.

13. Magnetic beads according to claim 1 or 2, wherein the content of the magnetic particles in the magnetic beads is 1% by mass or more and 40% by mass or less, when the total mass of the magnetic beads is 100% by mass.

14. Magnetic beads according to claim 1 or 2, wherein the content of the polymer in the magnetic beads is 50% by mass or more and 98% by mass or less, when the total mass of the magnetic beads is 100% by mass.

15. Magnetic beads described in claim 1 or 2, wherein the content of the silane coupling agent in the magnetic beads is 0.01 parts by mass or more and 30 parts by mass or less when the content of the magnetic particles in the magnetic beads is 100 parts by mass.

16. A method for producing magnetic beads, comprising: a step (A) of polymerizing a monomer (a) having at least one selected from the group consisting of a vinyl group, a vinylidene group, and a (meth)acryloyl group in a suspension containing magnetic particles modified with a silane coupling agent, wherein the silane coupling agent contains at least one selected from the group consisting of a vinyl group, a vinylidene group, a (meth)acryloyl group, and a styryl group.

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