JPS62244438A - Preparation of magnetic microsphere - Google Patents

Abstract

PURPOSE:To prepare a chemically stable magnetic microsphere, by uniformly dispersing a solid composite prepared by adsorbing a polymer by ferromagnetic fine articles in a monomer, and dispersing and suspending the obtained dispersion in an aqueous medium to perform polymerization. CONSTITUTION:Ferromagnetic fine particles are subjected to hydrophobic treatment by a method for adsorbing unsaturated fatty acid such as oleic acid by the surfaces of said particles or a method for further adsorbing a surfactant by the adsorbing layer of unsaturated fatty acid. The ferromagnetic fine particles subjected to hydrophobic treatment are uniformly dispersed in a non- polar solvent and a coating grade polymer is dissolved therein under heating to be adsorbed by fine particles and the solvent is distilled off to obtain a solid composite. This solid composite is uniformly dispersed in a second layer forming monomer and the resulting dispersion is dispersed and suspended in an aqueous medium and polymerized to form the second layer to obtain a desired magnetic microsphere.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing magnetic microspheres in which fine ferromagnetic particles are included inside polymeric microspheres. More specifically, it has excellent dispersibility in various aqueous solutions and is suitable as a column packing material for magnetic separation and purification of M-extracted substances in solutions, or as a test reagent carrier for magnetic diagnosis of diagnostic reagents. The present invention relates to a method for efficiently producing magnetic microspheres that have excellent chemical stability, particularly resistance to elution of metal ions in acidic aqueous solutions, and good magnetic responsiveness.

Conventional technology Conventionally, polymer microspheres manufactured from various natural polymers and synthetic polymers are filled with various fillers.

It is widely used as colorants, spacers, toners, medical carriers, photochromic agents for substance separation, etc.

In particular, various synthetic high-resolution microspheres, including polystyrene, have excellent chemical stability and dimensional stability, so they can be used, for example, as liquid chromatography reagents, separation and purification agents for enzymes and proteins, and carriers for diagnostic reagents. As usual,
Demand for it is growing rapidly.

Unfortunately, recently, 0aO0 is inside these microspheres.
3. Composite microspheres that have been functionalized by blending inorganic powders such as Fe3O4 and TiO2, dyes, or various chemicals have been attracting attention, such as conductive paints.

Attempts are being made to apply it to electromagnetic wave-resistant paints, medical magnetic materials, and magnetic photoresists with improved separation functions.

By the way, magnetic microspheres used as fillers for various columns and medical carriers are generally produced by emulsion polymerization or suspended polymerization. For example, in emulsion polymerization, a surfactant-containing aqueous solution and a monomer are mixed, heated at a constant temperature while stirring, and then polymerized by adding an aqueous solution of a polymerization initiator. This method is being used. By changing the polymerization conditions of the Miku Sphere Jin J21 produced in this way, it is possible to make it suitable as a filler or a carrier for diagnostic reagents. When producing magnetic microspheres by blending all the ferromagnetic powders, there are drawbacks such as difficulty in getting the ferromagnetic powder inside the microspheres during the polymerization process.

On the other hand, in suspension polymerization, a monomer ffi in which a polymerization initiator is dissolved is mixed in an aqueous or non-aqueous m liquid in which a dispersant is dissolved, and heated at a constant temperature while stirring to form microspheres. There are known methods to do this. In this case, magnetic microspheres can be produced by making the ferromagnetic powder hydrophobic, dispersing it in a non-aqueous solution, adsorbing the monomer, and then polymerizing it.

Since the ferromagnetic powder is exposed on the surface of the microsphere, there are problems such as poor properties in the chemical chamber 'A1. Furthermore, the size of microspheres obtained by aqueous suspension polymerization is 0.3 to 3.5 mm, which is too large to be used as a carrier for diagnostic reagents.

Methods other than suspension polymerization to produce magnetic microspheres include, for example, dispersing magnetite colloids in a gelatin bath solution.
A method of adjusting c to form microspheres and further insolubilizing them with an altehyde crosslinking agent (Japanese Patent Application Laid-open No. 59-195161
After mixing magnetite colloid with water-soluble polymer or protein such as serum albumin,
There is no known method of forming microspheres by emulsification and making them insolubilized by heat treatment, but if the coating polymer is hydrophilic, the microspheres will swell in an aqueous solution and become saturated inside. Chemical stability is a problem because magnetite comes into contact with the dispersion medium solution. Furthermore, when magnetite colloid is directly coated with a polymer, there is a drawback that it is difficult to completely cover the magnetite particles.

Therefore, it has been desired to develop magnetic microspheres that have excellent chemical stability and dispersibility in various water bath liquids and have excellent magnetic responsiveness by completely enclosing them inside ferromagnetic powder lamicrospheres.

The inventors of the present invention have conducted extensive research into pegs to meet these demands, and first disperse ferromagnetic fine particles that have been hydrophobized with a surfactant in a monomer, then add a polymerization initiator. We have found a method in which magnetic microspheres are produced by dispersing and suspending and f'L in an aqueous solution containing a dispersion stabilizer and polymerizing with heating.

However, although the magnetic microspheres obtained by this method have excellent dispersibility and magnetic responsiveness, their chemical stability is not necessarily satisfactory; for example, in an acidic water bath, It has been found that there is a problem in that metal ions may be eluted from the magnetite inside the microspheres depending on the acid pressure angle and pH.

Therefore, this magnetic microsphere enzymatically.

When used as a protein separation and purification agent or as a medical carrier in various acidic water baths, the eluted metal ions can be used as enzymes,
Since it is thought that the magnetic microspheres act as a reaction inhibitor for proteins, etc., the magnetic microspheres have not always been satisfactory as agents for separating and purifying enzymes and proteins or as a medical phase.

Problems to be Solved by the Invention Under these circumstances, the purpose of the present invention is to provide not only good dispersibility and magnetic response, but also chemical stability, in particular, metal ion resistance even in various acidic water bath solutions. It is an object of the present invention to provide magnetic microspheres which have excellent acid resistance such as extremely little elution, and whose particle size can be arbitrarily adjusted within the range of 0.1 μm to several micrometers, and which have a narrow particle size distribution.

Means for Solving the Problems As a result of various research into the production of magnetic microspheres, the present inventor Hiiragi has previously discovered a method for producing magnetic microspheres that uses hydrophobically treated ferromagnetic materials. The inventors have discovered that the above object can be achieved by forming a complete polymer coating layer on the surface of the fine particles before dispersing them in a monomer, and have completed the present invention based on this finding.

That is, in the present invention, a polymer is adsorbed onto ferromagnetic fine particles subjected to hydrophobization treatment in a non-polar solvent, and then the solvent is distilled off (1 to 2), and then this solid composite is uniformly mixed into a monomer. After being dispersed, the magnetic material 1 is dispersed in an aqueous medium and polymerized by turbidity.
The present invention provides a method for producing Il'miku rJ spheres.

The ferromagnetic fine particles commonly used in the uninvented method are preferably those with a particle size of about 150 mm prepared by a coprecipitation method.

The fine particles are dispersed uniformly in various non-polar solvents.
Hydrophobization treatment is performed by adsorbing an unsaturated fatty acid such as oleic acid on the surface of the fine particles, or by forming an adsorption layer of this unsaturated fatty acid.
It is applied by adsorbing a surfactant on the surface of the water.

In the method of the present invention, it is necessary to form a solid layer in which a polymer coating layer is provided on the surface of ferromagnetic fine particles which have been subjected to hydrophobization treatment in a similar manner.

This solid composite is produced by uniformly dispersing the hydrophobically treated ferromagnetic fine particles in a non-polar solvent, thoroughly dissolving the coating polymer, heating it, and adsorbing it onto the particles. When the solvent is distilled off, the result is obtained.

The non-polar solvent used at this time is 0% of the ferromagnetic fine particles.
．． The solvent is appropriately selected depending on the polarity of the hydrophobicized fine particles so that they can be uniformly dispersed as fine particles of 1 μrn or less, and such solvents are usually toluene, cyclohexane, or Chlorobea Cef.

Methyl ethyl ketone and the like are preferably used.

In addition, from the viewpoint of adsorption effect on the surface of the hydrophobized ferromagnetic fine particles, the coating polymer is one that has a functional group tW that is more polar than the dispersion solvent and has a high affinity with the monomer for forming the second layer. It's disgusting.

Therefore, as the coating polymer, a copolymer having a polar group, such as a carbogyl group-containing copolymer, and containing the same monomer units as the monomer for forming the second layer is particularly preferred. For example, when the monomer for forming the second layer is styrene, the coating polymer is preferably a styrene-maleic anhydride copolymer, a styrene-methacrylate copolymer, or the like.

1. The hydrophobized ferromagnetic fine particles are uniformly dispersed in the non-polar solvent. A solution prepared by dissolving 1'J'l' of the coating polymer in the same solvent is added to the mixture and heated and mixed, so that the polymer is adsorbed onto the surface of the fine particles. At this time, the heating temperature is preferably selected within the range from 50 DEG C. to the boiling point of the dispersion medium, and the kneading treatment time is usually about 30 minutes to 10 hours. The dispersibility of the ferromagnetic fine particles after this adsorption treatment is mainly determined by the polarity 1 dispersion medium on the surface of the fine particles,
Although it is controlled by the type of polymer, it is also influenced by the ratio of the fine particles to the polymer, the polymer concentration, the degree of stirring, the heating temperature, etc.

After the polymer is adsorbed onto the ferromagnetic fine particles in this manner, the solvent is completely distilled off, thereby leaving a solid composite with a polymer coating layer on the surface of the fine particles. Ru. There are no particular restrictions on the method of distilling off the solvent, but a method of completely distilling off the solvent using a volator is usually carried out.

Next, the solid composite thus obtained was uniformly dispersed in the monomer for forming the second layer, and then the following steps were performed. The desired magnetic microspheres are obtained by suspending the microspheres in a completely aqueous medium for 11 minutes and polymerizing them, and further forming a second layer consisting of a polymer of the monomers on top of the polymer coating layer. Ru.

Polymerization of the monomer is carried out by adding a polymerization initiator to the monomer and a dispersant to an aqueous medium, and heating the mixture at a temperature of usually 60 to 80° C. for 4 hours or more.

The polymerization initiator is not particularly limited as long as it is an oil-soluble radical polymerization initiator, such as an organic peroxide such as benzoyl peroxide or an azo initiator such as azobisisobutyronitrile. .

Preferred examples of the dispersant include water bath polymers such as polyvinyl alcohol, carboquine methyl cellulose, and gelatin, which are used in ordinary suspension polymerization.

The particle size of the magnetic microspheres produced in Method 1 varies from 0.1 μm depending on the amount of dispersant added, the ratio of the monomer liquid to the dispersion medium water bath, and the method of dispersing the monomer during the suspension and polymerization processes. It can be changed by several mm.

When adding 11 d of monomer into a water bath solution using a regular machine, the stirring speed is 200 to 60 tons.
) Microspheres with a particle size of 0.3 to 1', 5+ nm are obtained by changing the above conditions in the rpm range. On the other hand, if the dispersion effect is enhanced by emitting low-frequency ultrasonic waves at the same time as stirring during the suspension or polymerization process, 1
Microspheres with a particle size of 0.1 to several +07 zm can be produced. Size C of microspheres generated under ultrasound radiation
2 Varies depending on the frequency of the ultrasonic wave, generally in the case of ultrasonic waves in the low frequency range, for example 100K, Hz or less'' ff1
i! Microspheres of varying size can be obtained.

In this way, the magnetic microspheres prepared by I (I) are free of polymers forming the microspheres and dissolve the monomers. After removing the initiator and excess dispersant, it may be dispersed in water to form a suspension, or it may be dried and taken out as a powder.In order to obtain microspheres with a uniform particle size For this purpose, normal classification operations such as centrifugation or mesh filtration may be performed.

Furthermore, in order to completely prevent the elution of metal ions from the magnetic microspheres in an acidic aqueous solution, it is necessary to -
After allowing the dispersion to stand for about a week, incompletely coated ferromagnetic particles may be eluted and removed as metal ions in advance, and then washed with water.

Effects of the Invention According to the method of the present invention, a solid composite is formed in which a polymer coating layer is provided on the surface of ferromagnetic fine particles that have been made completely hydrophobic, and then this composite is uniformly dispersed in a monomer. Thereafter, by dispersing and suspending this L in an aqueous medium and polymerizing it, a second layer made of a polymer of the monomer is further formed on the second side of the coating layer, so that it is strong. The percentage of magnetic fine particles that are completely encapsulated inside the microspheres is high, resulting in extremely stable magnetic microspheres that hardly elute metal ions even in various acidic aqueous solutions. can be manufactured.

In addition, by suspending the monomer in an aqueous medium or by emitting low-frequency ultrasonic waves during the polymerization process, we are able to produce microspheres with a size of 0, 1 to several tens of micrometers, which could not be obtained by conventional suspension polymerization. You can get fair.

The magnetic microspheres obtained by the method of the present invention are stable in various acidic water dispersions, have excellent dispersibility in solutions and magnetic responsiveness, and have particle sizes ranging from 0.1 μm to several The magnetic properties of various columns and diagnostic reagents can be adjusted arbitrarily to the desired range.

It is particularly suitable for use as a carrier.

Example Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Hydrophobized magnetite fine particles [ferricolloid Ha-
so (trade name, manufactured by Taihohe Corporation) washed with acetone and dried into a powder] 3'?
was added to toluene 702, and dispersed by ultrasonic waves for 1 hour.

On the other hand, styrene-maleic anhydride copolymer [trade name: DILARK, manufactured by Tanesui Kaseihin Kogyo ■] 1ii' was mixed with Toluev 3.
07 and heated to 100 mm to prepare a total polymer solution.

Next, i)? The polymer solution was added to a dispersion bath containing 9 particles (magnetite) and stirred at 80° C. for 4 hours.

At this point, the magnetite fine particles are dispersed as fine particles with a diameter of 1 μm or less. Next, this solution was applied to an evaporator to almost completely distill off toluene, and then styrene monomer 302 purified by vacuum distillation was added to the evaporator to uniformly disperse the fine particles. Even at this point, the magnetite fine particles were dispersed as fine particles of 0.1 μm or less.

Next, add 909% of distilled water and add 1.7
[Product name, ■Made by Kuraray] 0.649 and Poval PVA
-2], 7 [Product name, ■Made by Kuraray], 0.03ff
Dissolve the dispersion medium to prepare a water bath solution, put this aqueous solution in a three-neck flask for reaction, and stir at 10 Orpm while emitting ultrasonic waves of 715KH2. As a polymerization initiator, a solution containing VO2 [trade name, manufactured by Wako Tsumugi Kogyo ■] 0.1', / was added for 11 hours and heated for 4 hours at room temperature while blowing argon gas. . The reaction vessel was then maintained at 65° C. and the ultrasonic radiation was continued at 11 (l Orpm; 3.
Stirred for 5 hours.

Furthermore, the reaction tank temperature was kept at 70° C. and the reaction was carried out at 300 rpm for 10 hours. The suspension of microspheres thus obtained totaled 600 mj! After pouring it into methanol and leaving it for a day and night while stirring slowly, this m solution was filtered through filter paper, the collected microspheres were dispersed in distilled water, and then classified using a stainless mesh and a centrifuge to determine the particle size. Magnetic microspheres of 1 to 37 zm were obtained.

Comparative Example: Hydrophobized magnetite h, +! / 'f styrene monomer]O'? In addition, dispersion treatment was carried out for 1 hour using ultra-711 waves, and PVA was added to -10,000 distilled water 002 - ], ], 70.6
49], 'VA-2170,039 was dissolved to prepare an aqueous dispersion medium solution.

Next, this dispersion medium water bath solution was placed in a three-neck flask for reaction.
1. ．． 40Orp while emitting 45KHz ultrasonic waves
Stir with m and add ■-650 to the above monomer solution.]
? ', (The added solution was added, and dispersion was carried out at room temperature for 2 hours while blowing argon gas. Then, the reaction tank was heated to 65°C.
℃ and stirred at 40 rpm for 5 hours while continuing to radiate ultrasonic waves, and then slowly cooled to room temperature.

The suspension of microspheres thus obtained was
After pouring into 0.001 nl of methanol and leaving it for a day and night while stirring slowly, this solution was filtered through filter paper, the collected microspheres were dispersed in distilled water, and then classified using a stainless steel mesh and a centrifuge. Microspheres of 1-3 μm were obtained.

Examples 2 to 8 In the same manner as in Example 1, magnetite fine particles were adsorbed in toluene using three types of copolymers. Examples of adsorption polymers include styrene/maleic anhydride copolymer (trade name: DILARK, manufactured by Sekisui Plastics Co., Ltd.), styrene/butyl methacrylate copolymer (contains 50 styrene units by weight, manufactured by Zyentei Fikku Polymer Products Co., Ltd.). ), and ethylene-vinyl acetate copolymer (vinyl acetate unit 33 fijl
I-containing M1 (manufactured by Scieno Eye Fikku Polymer Products) was used.

Tables 1 to 3 show the dispersion state of magnetite in toluene solutions prepared by varying the concentrations of magnetite and copolymer to be mixed. The concentrations of magnetite and copolymer in the table are expressed in 11 parts by weight per 100 parts by weight.

○ means magnetite is uniformly dispersed to a size of 0.1 μm or less, △ means magnetite aggregates to form droplets of about J,ltm, × means magnetite aggregates It shows that the taste is present.

Next, based on the results of the dispersion state of magnetite in the prepared solution, the weight ratio of magnetite]./copolymer was determined to be 3/1. The solvent was removed from the solutions of filtration/3, 2/6, and 1/3 using an evaporator, and the resulting solid composite was uniformly dispersed in 30 parts by weight of styrene monomer.

Table 4 shows the state of dispersion of magnetite in the styrene monomer of each prepared sample.

Here, ○ indicates that the magnetite is uniformly dispersed to a size of 1 μm or less, MU indicates that aggregates of several It m of magnetite exist, and ※ indicates that the entire styrene monomer has gelled. [7teil.

Each shows that.

Next, based on the results shown in Table 4, dispersion polymerization was carried out using eight types of monomer liquids in which fine magnetite particles adsorbed with styrene/maleic anhydride copolymer and styrene/butyl methacrylate 1/-tocopolymer were dispersed. That is, the top layer of the monomer solution was weighed and collected, v-650,11/ was added to this solution, and dispersion polymerization was carried out under the same conditions as in Example 1. Magnetic microspheres were obtained.

Table 1 Table 3 Table 3 Table 4 Test Examples Examples 1 to 8 and Comparative Example (4) Total weight of magnetic microsphere powder death,
After performing a dispersion treatment for one week in an aqueous solution of oxalic acid, hydrochloric acid, acetic acid, and phosphoric acid 309 adjusted to pI, 5, it was washed with ion-exchanged water, and iron analysis by atomic absorption was performed.

Table 5 shows the magnetite loading ratio of the -4 magnetic microspheres and the magnetite content in the microspheres before and after acid treatment.

Next, the degree of elution of iron ions from magnetic microspheres in water distribution mtj at pH 1.5 was investigated. That is, four types of magnetic microsphere powder adsorbed with styrene-maleic anhydride copolymer were prepared.
(2) Weigh it out, disperse it in 5 ml of aqueous 7-euric acid solution at pH 1.5 for one week, and collect the liquid after centrifugation. Next, the precipitated microspheres are washed with water and dispersed again in 5 ml of an oxalic acid bath solution of pH 1.5 for 5 days, and after centrifugation, the supernatant is collected. Furthermore, the precipitated microspheres were washed with water and pI
(The supernatant was collected by centrifugation after dispersing in 1,50 oxalic acid aqueous solution for 50 minutes.The three kinds of two clear liquids collected by Kohan et al. and 5 ml of ion-exchanged water as a blank.
After dispersing the two magnetic microspheres in 25mf' (r17B), the eluted iron ion concentration in the clear solution obtained by centrifugation was measured by atomic absorption. The results are shown in Table 6.

Here the treated AO is dispersed in replacement water as a blank/supernatant treated horse in this case! 2 shows the supernatant treated with an oxalic acid aqueous solution for the first time; JIFL3 shows the supernatant treated with the oxalic acid aqueous solution for the third time;

Chapter 6 Table

Claims (1)

[Claims] 1. After adsorbing a polymer to ferromagnetic particles that have been subjected to hydrophobization treatment in a non-polar solvent, the solvent is distilled off, and then this solid composite is uniformly dispersed in a monomer. A method for producing magnetic microspheres, which comprises dispersing and suspending the microspheres in an aqueous medium and polymerizing them. 2. A patent claim that adjusts the particle size of magnetic microspheres obtained by using mechanical stirring and low-frequency ultrasonic radiation in combination when dispersing and suspending a monomer in which a solid composite is dispersed in an aqueous medium. The method described in item 1. 3. The method according to claim 1 or 2, wherein the polymer is a copolymer having a polar group. 4. The method according to claim 3, wherein the copolymer having a polar group contains the same monomer units as the monomer for forming the second layer.