JP6795282B2 - Method for producing highly crystalline fine particles - Google Patents

Description

The present invention relates to a method for producing fine particles and the fine particles produced thereby.

Micronization of substances is required in various fields. For example, in the field of pharmaceuticals, it is required to atomize a compound in order to increase the specific surface area and improve the dissolution rate and bioavailability. Further, in the food field, fine particles are required for the purpose of improving solubility, suppressing precipitation, improving flavor, improving texture, improving safety, and the like.

The method of obtaining fine particles can be roughly divided into a build-up method in which particles are gradually enlarged from a raw material and a breakdown method in which the synthesized aggregated powder is mechanically pulverized into fine particles. Here, the breakdown method is considered to be suitable for industrialization because it is more suitable for mass production than the build-up method. The wet pulverization method is known as the main breakdown method. In the wet pulverization method, the powder is generally made into fine particles by stirring the beads in the dispersion medium. Patent Document 1 discloses a method for producing a dispersion of fine particles by stirring agglomerated powder in a dispersion medium in the presence of beads having an average particle diameter of 100 μm or less and a dispersant. In Non-Patent Document 1, a slurry of a substance is sent to a cylindrical container filled with beads, and in the presence of a dispersant, a stirring member is rotated at high speed to finely pulverize the substance to disperse fine particles. The method is disclosed.

JP 2010-23001

Toshihiro Ishii, "Powder and Industry", Vol. 37, No. 8 (2005), pp. 51-57

However, the prior art only refers to the production of a dispersion in which fine particles are dispersed in a medium in the presence of a dispersant by a wet pulverization method, and there is room for consideration in efficiently removing the medium. is there. There is a limit in the prior art to obtain solid fine particles in which the crystallinity is maintained without significantly changing the crystallinity of the compound by the wet pulverization method. An object of the present invention is to provide a method for producing solid fine particles in which the medium can be efficiently removed, the crystallinity of the particles is not significantly changed, and the crystallinity is maintained.

In view of the above circumstances, the present inventor has focused on the wet pulverization method and started to study its various conditions. As a result of investigating the micronization of the compound, the crystallinity was maintained without significantly changing the crystallites by sonication with the beads in the presence of the compound without using a dispersant in the medium. However, he found that the compound could be made into fine particles, and completed the present invention.

The present invention provides, but is not limited to,:
(1) A method for producing fine particles, which comprises pulverizing a compound by vibrating beads in a medium to make fine particles, and taking out the fine particles.
(2) The production method according to (1), wherein the beads are vibrated by ultrasonic treatment to pulverize the compound.
(3) The production method according to (1) or (2), wherein the fine particles are taken out by the flow of the medium.
(4) The production method according to any one of (1) to (3), wherein fine particles are taken out by passing a medium through a size sorting means.
(5) The production method according to any one of (1) to (4), wherein the medium is a gas medium or a liquid medium.
(6) The production method according to any one of (1) to (5), wherein the medium is used under pressure.
(7) The production method according to any one of (1) to (6), wherein the medium is an inert gas.
(8) The production method according to any one of (1) to (7), wherein the inert gas is selected from the group consisting of carbon dioxide, nitrogen, and a rare gas.
(9) The production method according to any one of (1) to (8), wherein the beads are ceramic beads.
(10) The production method according to any one of (4) to (9), wherein the size sorting means is a membrane filter or a mesh filter.
(11) Fine particles obtained by the production method according to any one of (1) to (10).
(12) A fine particle manufacturing apparatus including a container for accommodating beads, a means for vibrating the beads, a means for supplying a medium to the container, a fine particle taking-out means, and a fine particle collecting means.
(13) The manufacturing apparatus according to (12), which includes means for pressurizing the medium.
(14) The manufacturing apparatus according to (12) or (13), wherein the means for vibrating the beads is an ultrasonic generator .
(15) The manufacturing apparatus according to any one of (12) to (14), wherein the size sorting means is a membrane filter or a mesh filter.

According to the present invention, without requiring a dispersant, a compound becomes possible and the child micronization. Since the size of the fine particles is determined based on the gap of the closest packing of the beads, the diameter of the fine particles can be made more uniform. Further, by transporting the fine particles obtained in the compound pulverization step by the flow of the medium, a series of steps can be made continuous, so that high production efficiency can be achieved. Further, since the temperature rise during the pulverization process can be suppressed by the flow of the medium, even if the compound has low thermal stability, it is made into fine particles while maintaining the function of the compound even if no cooling means is particularly provided. be able to. Further, the fine particles from which the medium has been removed can be taken out without providing a step of actively removing the medium.

The fine particles obtained by the present invention have high stability because the diameter of the crystallites has not changed significantly from that before pulverization and the crystal structure is maintained, and the residual dispersant is not considered. Good. These lead to improved storage and safety, and maintenance of bioavailability.

On the other hand, in the wet pulverization method disclosed in the prior art combining beads and stirring, a dispersant is often used in the pulverization step, and it is difficult to improve the uniformity of the diameter of the fine particles by pulverization by stirring. is there. Since the crushing step and the drying step cannot be made continuous, a separate cooling means is required to suppress the temperature rise in the crushing step. In addition, it is difficult to achieve micronization while maintaining the crystal structure by the method disclosed in the prior art, and there is no description or suggestion regarding the matter.

The effect of the present invention is remarkable, and it is difficult or unpredictable to achieve by the prior art.

FIG. 1 shows an outline of the crystal structure. FIG. 2 shows an electron micrograph of sesamin. Sesamin powder (A) (B) before pulverization, sesamin fine particles (C) (D) after pulverization. FIG. 3 shows the X-ray diffraction (XRD) pattern of sesamin. A comparison of before (a) and after (b) when the sesamin powder is atomized is shown. FIG. 4 shows an electron micrograph of naproxen. Naproxen powder (A) (B) before crushing, naproxen powder (C) (D) after crushing. FIG. 5 shows an example of a manufacturing apparatus for carrying out the method for manufacturing fine particles of the present invention. 1: Medium storage container, 2-6: Valve, 7: Pump, 8: Ultrasonic generator, 9: Pressure-resistant container, 10: Filter, 11: Vacuum pump, 12: Nozzle, 13: Fine particle recovery container, 14: Regulator.

<Manufacturing method of fine particles>
The method for producing fine particles of the present invention includes pulverizing a compound with beads in a medium into fine particles, and taking out the fine particles. In this method, since a series of steps can be continuously performed by using the flow of the medium, the production efficiency of fine particles is higher than that of the batch method of the prior art. In addition, it becomes possible to make fine particles while maintaining crystallinity without significantly changing the crystallites.

Crushing Step In the method of the present invention, the crushing step is carried out by crushing the compound with beads in the medium. The pulverization step breaks down the compound into fine particles. Here, "micronization" means that the particle size of the compound is made smaller than that before the pulverization by pulverizing the compound. Grinding of the compound is carried out by vibrating the beads in the presence of the compound. The means for vibrating the beads is not particularly limited. For example, the beads can be vibrated by vibrating the container containing the beads. As another example, the beads can be vibrated by sonication. The beads are not limited to ultrasonic waves, and the beads can be vibrated by means such as magnetic force or turbulence. By vibrating the beads, the beads collide violently with each other, and the impact can cause the compound to become fine particles. The pulverization step can be performed by accommodating the compound and beads in a container, but the number and arrangement of the containers can be freely set according to the purpose. For example, a plurality of containers filled with beads of the same or different types and particle sizes may be connected in series, and the pulverization step may be composed of a plurality of stages. As another example, a plurality of containers filled with beads of the same or different types and particle sizes may be connected in parallel, and the crushing step may be performed in parallel for each container.

The "medium" referred to in the present specification has an action of dispersing a compound in a pulverization step. In the present invention, any medium can be used as a medium as long as it has the above-mentioned action. The medium that can be used in the present invention includes, for example, air, oxygen, hydrogen, inert gas (carbon dioxide, nitrogen, rare gas (for example, helium, neon, argon)), alcohols (for example, methanol, ethanol). , Propanol, butanol, pentanol, hexanol), ketones (eg, methyl ethyl ketone, methyl isobutyl ketone), ethers (eg, methyl cellosolve, ethyl cellosolve, propylene glycol monopropyl ether), esters (eg, methyl acetate, acetate) Ethyl, methyl lactate, ethyl lactate), ammonia, water, aqueous solutions (eg, aqueous ammonia, physiological saline, phosphate buffer, citrate buffer, carbon dioxide buffer, nitrate buffer, sulfate buffer), etc. Can be mentioned. These may be substantially purified, may contain impurities, may be used alone, or may be used in combination of two or more. The state of the medium is also not limited. For example, the medium may be a liquid or a gas. In addition, the medium may be used under pressure and / or temperature controlled conditions in order to bring the medium into a desired state. Here, the pressure may be reduced or pressurized, and this may be kept constant or varied. The temperature may be set to a low temperature or a high temperature state and may be maintained constant or varied. For example, it goes without saying that a medium that exists as a liquid under atmospheric conditions can be used as a liquid medium, but if it exists as a gas under specific conditions such as reduced pressure and / or high temperature, it can be used as a gas medium. It is possible.

For example, alcohols (eg methanol, ethanol, propanol, butanol, pentanol, hexanol), ketones (eg methyl ethyl ketone, methyl isobutyl ketone), ethers (eg methyl cellosolve, ethyl cellosolve, propylene glycol monopropyl ether). , Esters (eg, methyl acetate, ethyl acetate, methyl lactate, ethyl lactate), ammonia, water, aqueous solutions (eg, aqueous ammonia, physiological saline, phosphate buffer, citrate buffer, carbonate buffer, A medium that exists as a liquid under atmospheric conditions such as nitrate buffer and sulfate buffer) can be used as a liquid medium in the present invention, and can be used as a gas medium under reduced pressure and / or high temperature conditions. it can.

On the other hand, it goes without saying that a medium existing as a gas under atmospheric conditions can be used as a gas medium, but when it exists as a liquid under specific conditions such as pressurization and / or low temperature, it should be used as a liquid medium. Is possible. For example, a medium existing as a gas under atmospheric conditions such as air, oxygen, hydrogen, and an inert gas (carbon dioxide, nitrogen, rare gas (for example, helium, neon, argon)) is used as a gas medium in the present invention. It can be used as a liquid medium (eg, liquid oxygen, liquid hydrogen, liquid carbon dioxide, liquid nitrogen, liquid helium, liquid neon, liquid argon, etc.) under pressurization and / or low temperature conditions. Here, when liquid oxygen, liquid hydrogen, liquid carbon dioxide, liquid nitrogen, liquid helium, liquid neon, and liquid argon are used as the liquid medium in the method of the present invention, the medium is removed in order to maintain the liquid state. Until the step, it is necessary to carry out the method of the present invention under pressurized and / or low temperature conditions, but the medium can be easily removed only by returning to the atmospheric conditions, so that the production efficiency can be improved. That is, the medium can be removed, and the fine particles can be taken out and recovered without providing a step of actively removing the medium such as a drying step. Further, since the effect of suppressing the temperature rise during production due to the pulverization step or the like can be obtained, it is effective when the compound having low heat stability is made into fine particles.

With respect to the medium, an appropriate type and state can be selected depending on the compound to be micronized. For example, by selecting a medium in which the compound to be micronized is substantially insoluble, the compound can be micronized while maintaining the crystallites. Also, the medium can be selected in consideration of the means adopted for grinding the compound. For example, when the compound is pulverized by sonication, a liquid medium can be selected to transmit the vibration generated by the ultrasonic waves to the beads. Further, the medium can be selected in consideration of the step performed after the pulverization step. For example, when a medium removing step such as drying is performed after the crushing step, a medium that exists in a liquid state under atmospheric conditions can be selected, and a step of actively removing the medium after the crushing step is not performed. In some cases, it is possible to select a medium that is liquid under pressurized and / or low temperature conditions but is present as a gas under atmospheric conditions.

The term "compound" as used herein means a compound to be micronized. The compound may be either an organic compound or an inorganic compound, and may be a natural product or a synthetic product. Here, the compound may be in the form of solids such as agglomerates, powders, and particles. The compound may be either water-soluble or poorly water-soluble. For example, many pharmaceutical compounds and natural compounds are poorly water-soluble (40% of the pharmaceutical compounds are poorly water-soluble). (It is said), and it is required to improve the dissolution rate. That is, according to the method of the present invention, the poorly water-soluble compound can be made into fine particles and the surface area can be increased, so that the dissolution rate can be increased and the bioavailability can be improved. In addition, it is possible to suppress precipitation and improve flavor, texture, and stability. Therefore, it can be said that the method of the present invention is particularly useful when targeting a poorly water-soluble compound. The organic compound and the inorganic compound as the compound may be those extracted and isolated from nature, or those artificially synthesized. Specific examples of the organic compound include sesamin, polyphenols, vitamins and the like. More specific examples include sesamin, epigallocatechin, catechin, epicatechin, epigallocatechin, naproxen and the like. Specific examples of inorganic compounds include titanium oxide, silicon oxide, aluminum oxide, barium sulfate, zirconia, mulite, kaolinite, andalcite, carbon, talc, zinc white, zinc sulfide, antimony oxide, carbon black, barium chromate, and oxidation. Examples thereof include copper, iron oxide, zinc silicate, and barium sulfide.

As used herein, the term "beads" means a particulate matter that is present in a medium together with a compound and that is pulverized to make the compound finer. The beads may be made of any material as long as the particles of the compound can be atomized. For example, zircone, zirconia, alumina, tungsten carbide, silica, silicon nitride, nickel, copper and oxidation. It may be composed of silicon, iron, styrene steel, ceramic or the like. More specifically, ceramic beads made of zirconia, silica beads and the like can be mentioned. The beads may have any shape, for example, a spherical shape, an elliptical spherical shape, or the like. Here, when the shapes of the finely divided particles are made uniform, it is preferable to unify the shapes of the beads. Then, the size of the beads can be set according to the size of the target fine particles. For example, when spherical beads are used, the shape and particle size of the compound to be micronized are equal to or smaller than the gap of the closest packing of the beads. The particle size of the spherical beads can be 1 to 100,000 μm, 10 to 10000 μm, 20 to 5000 μm, and 30 to 3000 μm.

In the present invention, since the pulverization step can be performed without using a dispersant, it is not necessary to consider the residual dispersant. This matter is particularly useful when the dispersant inhibits the action of the active ingredient or affects the safety of the employee. In particular, it is difficult to achieve such an effect by the prior art in which a dispersant is often used to grind poorly water-soluble compounds.

On the other hand, in the present invention, it is also possible to use a dispersant as needed in the pulverization step. A surfactant can be used as the dispersant, for example, polyglycerin fatty acid esters such as glycerin monostearate, sorbitan fatty acid ester, decaglyceryl monomyristate, hexaglyceryl monolaurate and glyceryl monooleate, sucrose fatty acid esters. , Polyoxyethylene castor oil derivative, polyoxyethylene hydrogenated castor oil, monopalm oil fatty acid polyoxyethylene sorbitan, polysolvate 80, polysolvate 20, lauromacrogol, polyoxyethylene (20) cetyl ether, polyoxyethylene (15) oleyl ether Polyoxyethylene alkyl ether such as polyoxyethylene alkyl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether and other polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol monostearate, polyethylene glycol distearate and polyethylene glycol monooleate, etc. Fatty acid soap, acyl lactates such as stearoyl sodium lactate and calcium stearoyl lactate, sodium dodecyl sulfate, alkyl phosphates, benzalconium chloride, cetylpyridinium chloride, soy lecithin, hydrogenated soy phospholipids, egg yolk lecithin, lysolecithin, hydroxylated Alkylcarboxylic acids such as lecithin, sodium cholate, sodium deoxycholate, stearic acid, oleic acid, dodecanoic acid and their salts, phosphonic acid and amide and their salts, alkylsulfonic acid and its salts (sodium dialkylsuccinate sulfonate, Monoalkyl succinate sulfonic acid disodium salt, etc.), silane coupling agent (vinyltrimethoxysilane, vinyltriethoxysilane, 2- (3,4-epylcyclohexyl) ethyltrimethoxysilane, 3-glycidoxypropylmethyldimethoxy) Silane, 3-glycidoxypropyltrimethoxysilane, 3-glycidoxypropylmethyldiethoxysilane, 3-glycidoxypropyltriethoxysilane, p-styryltrimethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3 − Methacryloxypropyltrimethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, 3-acryloxypropyltrimethoxysilane, N-2- (aminoethyl) -3-aminopropylmethyl Dimethoxysilane, N-2- (aminoethyl) -3-Aminopropyltrimethoxysilane, 3-Aminopropyltrimethoxysilane, 3-Aminopropyltriethoxysilane, 3-Triethoxysilyl-N- (1,3-dimethyl-butylidene) propylamine, N-phenyl-3 -Aminopropyltrimethoxysilane, N- (vinylbenzyl) -2-aminoethyl-3-aminopropyltrimethoxysilane hydrochloride, tris- (trimethoxysilylpropyl) isocyanurate, 3-ureidopropyltrialkoxysilane, 3 − Mercaptopropylmethyldimethoxysilane, 3-mercaptopropyltrimethoxysilane, bis (triethoxysilylpropyl) tetrasulfide, 3-isocyandiapropyltriethoxysilane, etc.) and the like.

Step of taking out fine particles The fine particles produced by the crushing step are subjected to the step of taking out. In this step, the fine particles may be taken out by any means, but in the present invention, the fine particles are taken out by the flow of the medium. Here, the “media flow” means the flow of the medium from the inlet to the outlet of the container in which the crushing step is performed. The fine particles pass through the outlet of the container together with the medium by the flow of the medium, and are further subjected to a later step. The flow of the medium can be created by supplying the medium by pressurizing it toward the inlet of the container, by making the outlet side of the container negative pressure, or by a combination of both. Can be created.

In the step of taking out the fine particles, a size sorting means may be provided on the outlet side of the container. Here, the "size sorting means" means a means for passing only specific fine particles that satisfy the requirements regarding size among the fine particles generated by the pulverization step. Fine particles that do not meet the size requirements will remain in the container and be subjected to the grinding process until they meet the size requirements. That is, by providing the size sorting means, the compound can be sufficiently pulverized, and fine particles having a desired size can be efficiently taken out. As the size sorting means, any means may be used as long as only fine particles having a desired size can be passed through, but a sieve can be conveniently used. A membrane filter or a mesh filter can be used as the sieve. For example, by providing a membrane filter having a desired pore size at the outlet of the container, fine particles that pass through the membrane filter can be taken out. Examples of the membrane filter include those made of polypropylene, polyester, nylon, cellulose, metal, polytetrafluoroethylene (PTFE), polyvinylpyrrolidone (PVDF), polyether sulfone and the like. As another example, by providing a desired mesh filter at the outlet of the container, fine particles that pass through the mesh filter can be taken out. Examples of the mesh filter include those made of stainless steel, aluminum, copper, nickel, titanium, glass fiber, cellulose, polytetrafluoroethylene (PTFE), polyvinylpyrrolidone (PVDF), polyether sulfone and the like.

The pore size of the sieve can be set according to the type of the compound to be micronized and the degree of micronization required. For example, the pore size of the sieve can be 0.1 to 1000 μm, 0.2 to 100 μm, 0.3 to 50 μm, 0.5 to 20 μm. As one aspect, when a membrane filter or a mesh filter is used, the mesh size can be 0.1 to 1000 μm, 0.2 to 100 μm, 0.3 to 50 μm, 0.5 to 20 μm.

Media Removal Step The fine particles that have undergone the step of taking out the fine particles are subjected to the medium removal step by the flow of the medium. Here, the medium may be removed by any means. When removing a medium existing as a liquid under atmospheric conditions, for example, a method of actively removing the medium such as evaporation, lyophilization, centrifugation, spray drying, etc. can be applied. On the other hand, when a medium existing as a gas under atmospheric conditions is used as a liquid medium under pressurized and / or low temperature conditions, the medium is easily vaporized and removed from the fine particles by spraying the medium under atmospheric conditions. It is possible to do. That is, the medium can be removed without the need to actively remove the medium. Since this vaporization occurs instantaneously, the medium can be removed extremely efficiently.

The fine particles obtained through the step of removing the fine particle medium have a smaller particle size than that before pulverization, while the crystallinity of the particles does not change significantly and the crystallinity is maintained. Here, the general morphology of the particles will be described with reference to FIG. The particles attract each other by electrostatic force to form an agglomerate. This aggregate may be composed of smaller aggregates, may have a primary aggregate as the smallest unit, a secondary aggregate composed of a plurality of primary aggregates, and the like. The primary aggregate is composed of a plurality of smaller particles, which are called primary particles. The primary particle is composed of a plurality of crystallites (also referred to as primary crystallites). A crystallite is the largest group of crystals that can be called a single crystal, and the interface between the crystallites in the primary particle is called a grain boundary.

The fine particles obtained by the present invention can be specified by the diameter of the primary particles. The primary particles of the fine particles of the present invention have a smaller diameter than that of the particles before pulverization, while the diameter of the crystallites is not significantly different from that of the particles before pulverization. This suggests that in the present invention, micronization is achieved by breaking the grain boundaries without breaking the crystallites. Then, it means that the fine particles do not significantly change the diameter of the crystallite and maintain the crystal structure, and maintaining the crystal structure means that the stability is high. Such properties contribute to the improvement of storage stability. High storage stability is preferable, for example, in the case of pharmaceuticals and health foods, because it means that solubility and bioavailability are maintained throughout the storage period, and user safety is ensured. It can be said that. In this way, achieving fine particle formation of a compound while maintaining crystallinity without significantly changing the diameter of the crystallite is a matter that is difficult to achieve by conventional techniques, and a solution has long been required. This is an issue that has been done.

With respect to the fine particles of the present invention, the diameter of the primary particles can be adjusted by the shape and size of the beads used in the pulverization step, the pore size of the sieve as a size sorting means used in the step of taking out the fine particles, and the like. Here, as a method of observing the state of the fine particles and measuring the diameter of the primary particles, any method known to those skilled in the art can be adopted, and for example, the method is performed with the naked eye, a magnifying glass, an electron microscope, or the like. be able to. In the present specification, unless otherwise specified, the state of the fine particles is observed using an electron microscope, the diameter of the primary particles is measured, and the compound is compared with the compound before pulverization. Then, since the fine particles obtained by the method of the present invention are produced through the size selection means, it is suggested that the size is more uniform than that of the compound before pulverization. The diameter of the crystallite may be measured by any method known to those skilled in the art, but in the present invention, it can be confirmed by X-ray diffraction (XRD). For example, changes in crystallite diameter can be confirmed by subjecting the fine particles to XRD and directly comparing the full width at half maximum of the characteristic peak with the full width at half maximum of the corresponding peak for the compound before pulverization. When specified by the half-value width, the crystallites of the fine particles obtained by the present invention are, for example, 100 ± 50%, 100 ± 30%, 100 ± 20%, 100 ± 10% with respect to the half-value width of the compound before pulverization. can do. Alternatively, the crystallite diameter may be calculated from the obtained full width at half maximum using Scheller's equation and compared. When the fine particles of the present invention are specified by the crystallite diameter calculated from the half width, for example, 100 ± 50%, 100 ± 30%, 100 ± 20%, 100 ± with respect to the crystallite diameter of the compound before pulverization. It can be 10%.

In addition, the fine particles obtained by the method of the present invention can be used alone or in combination with other components as raw materials for pharmaceuticals, functional foods, foods for specified health uses, supplements, foods and drinks, and the like. Here, the other ingredients are pharmaceutically acceptable ingredients listed in the Japanese Pharmacopoeia, etc., ingredients permitted to be used in foods listed in the food additive list, etc., and old ingredients. Ingredients that have been used and have been confirmed to be safe can be mentioned.

<Particle manufacturing equipment>
From another aspect of the present invention, a fine particle production apparatus is provided. The device can be used to carry out the method for producing fine particles described herein. The fine particle manufacturing apparatus of the present invention includes a medium supply means, a compound crushing means, a means for taking out fine particles, and a fine particle recovery means, and each means can be connected by a pipe or the like.

The medium supply means include a container for storing the medium and a means for regulating the supply of the medium to the compound grinding means. The container for storing the medium may be any container as long as it can store the amount of the medium required for atomizing the compound, and an appropriate container can be selected according to the medium to be used. Further, when the fine particles are produced aseptically, the container for storing the medium is preferably a closed container. The container for storing the medium is preferably, for example, one having pressure resistance, acid resistance, alkali resistance, sterilization ability, and a combination thereof as characteristics. The means for adjusting the supply of the medium to the compound pulverizing means includes a means for supplying the medium and a means for adjusting the supply amount thereof. For example, a pump can be used as a means for supplying the medium, and a valve can be used as a means for adjusting the supply amount of the medium. In addition, when using a medium that exists as a gas under atmospheric conditions and exists as a liquid under pressurized and / or low temperature conditions as a liquid medium, the inside of the device is pressurized by adjusting the pump and valve. It is possible to maintain the liquid state of the medium.

The compound crushing means may be any one that crushes the compound to produce fine particles. The means includes a container and a vibration generating means. The container is a container that can contain compounds and beads and can be sealed, and has pressure resistance that can withstand the pressure generated by the flow of the medium and shock resistance that can withstand the impact caused by the beads vibrating by the vibration generating means. Anything that has sex may be used. Further, the container may have heat resistance that can withstand sterilization and the like. Here, if the container is filled with beads, the size of the fine particles can be adjusted to a size based on the gap of the closest packing. Here, the beads may be made of any material as long as the fine particles of the compound can be achieved. For example, zircone, zirconia, alumina, tungsten carbide, silica, silicon nitride, nickel, copper, etc. It may be composed of silicon oxide, iron, styrene steel, ceramic or the like. More specifically, ceramic beads made of zirconia, silica beads and the like can be mentioned. The beads may have any shape, for example, a spherical shape, an elliptical spherical shape, or the like. Here, when the shapes of the finely divided particles are made uniform, it is preferable to unify the shapes of the beads. Then, the size of the beads can be set according to the size of the target fine particles. For example, when spherical beads are used, the shape and particle size of the compound to be micronized are equal to or smaller than the gap of the closest packing of the beads. The particle size of the spherical beads can be 1 to 100,000 μm, 10 to 10000 μm, 20 to 5000 μm, and 30 to 3000 μm. The number and arrangement of the containers can be freely set according to the purpose. For example, a plurality of containers filled with beads of the same or different types and particle sizes may be connected in series, and the pulverization step may be composed of a plurality of stages. As another example, a plurality of containers filled with beads of the same or different types and particle sizes may be connected in parallel, and the crushing step may be performed in parallel for each container. By vibrating the beads housed in the container, the vibration generating means can violently collide with each other to give an impact to the compound, and the beads can be made into fine particles. For example, an ultrasonic generator and the like can be mentioned, but the present invention is not limited to this.

The fine particle taking-out means makes it possible to take out the fine particles generated by the compound pulverizing means. For example, a flow of the medium can be created in the direction of the outlet of the container, and the fine particles can be placed on the flow of the medium and taken out from the container. When the flow of the medium is used, it is possible to suppress the temperature rise in the container caused by the compound crushing means, which is effective when crushing a compound having low heat stability. Here, by providing the size sorting means on the outlet side of the container, fine particles of a desired size or smaller can be selectively taken out. On the other hand, fine particles that do not meet the size requirement will remain in the container and will continue to be ground until they meet the size requirement. It is convenient to use a sieve as the sorting means. As the sieve, for example, a membrane filter, a mesh filter, or the like can be used. Examples of the membrane filter include those made of polypropylene, polyester, nylon, cellulose, metal, polytetrafluoroethylene (PTFE), polyvinylpyrrolidone (PVDF), polyether sulfone and the like. Examples of the mesh filter include those made of stainless steel, aluminum, copper, nickel, titanium, glass fiber, cellulose, polytetrafluoroethylene (PTFE), polyvinylpyrrolidone (PVDF), polyether sulfone and the like. The pore size of the sieve can be set according to the type of the compound to be micronized and the degree of micronization required. For example, the pore size of the sieve can be 0.1 to 1000 μm, 0.2 to 100 μm, 0.3 to 50 μm, 0.5 to 20 μm. In one aspect, when a mesh filter is used, the mesh size can be 0.1 to 1000 μm, 0.2 to 100 μm, 0.3 to 50 μm, 0.5 to 20 μm.

The apparatus of the present invention may further have a medium removing means. The fine particles taken out from the container can be sent to the medium removing means through a pipe or the like. A flow rate adjusting means may be provided between the compound pulverizing means and the medium removing means to adjust the supply amount of the medium to the medium removing means. Here, any means capable of removing the medium can be used as the medium removing means. When the medium to be removed exists as a liquid under atmospheric conditions, means for positively removing the medium such as an evaporator, a freeze dryer, a centrifuge, a spray dryer, and distillation can be used. On the other hand, when the medium to be removed exists as a gas under atmospheric conditions but exists as a liquid under pressurized and / or low temperature conditions, the medium can be vaporized by exposing the medium to atmospheric conditions. , It is not necessary to take any means for positively removing the medium. That is, if such a medium is sprayed under atmospheric conditions, it can be easily and quickly removed from the fine particles.

The fine particle collecting means includes at least a container for collecting fine particles. Further, it may have a means for evacuating the inside of the fine particle recovery means and / or a means for replacing the inside of the fine particle recovery means with an inert gas.

The fine particle production apparatus of the present invention is illustrated in FIG. 5, but is not limited thereto. In order to understand the invention, the fine particle production apparatus will be described in more detail with reference to FIG. In the apparatus of the present invention, a medium such as liquid carbon dioxide is supplied from a storage container (1) such as a cylinder to a pressure-resistant container (9) under pressurized conditions. At that time, the medium is supplied by the pump (7), and the amount of the medium supplied is adjusted by the valves (2, 3). Further, since the pressure in the pressure-resistant container can be adjusted by the valves (2, 3, 4) and the pump (7), the liquid state of the medium such as liquid carbon dioxide can be maintained. The pressure-resistant container (9) contains a compound to be micronized and is filled with beads. The pressure-resistant container (9) to which the medium is supplied is exposed to ultrasonic waves derived from the ultrasonic generator (8). As a result, the beads in the pressure-resistant container (9) vibrate, and the beads collide violently with each other, so that the compound is crushed and fine particles are generated. The generated fine particles go to the outlet of the pressure-resistant container (9) by the flow of the medium. The fine particles are provided for size sorting means by a filter (10) provided at the outlet of the pressure-resistant container (9). The fine particles that have passed through the filter (10) are taken out from the pressure-resistant container (9) and sent to the spraying means. The amount of medium supplied to the spray means is regulated by the valve (4). In the fine particle collection container (13), the medium is sprayed from the nozzle (12). Since the sprayed medium is exposed to atmospheric conditions and instantly changes into a gas, it is not necessary to actively remove the medium. The gas medium is discharged by the vacuum pump (11). Further, if necessary, the inside of the fine particle recovery container (13) can be replaced with an inert gas such as nitrogen gas. On the other hand, the remaining fine particles are recovered by an appropriate container provided in the fine particle recovery container (13).

The details of the present invention will be described with reference to specific examples. The present embodiment is intended to facilitate the understanding of the invention, and is not intended to limit the scope of the invention to the aspects of the present embodiment.

[Test Example 1] Micronization of sesamin A compound of zirconia ceramic beads having a diameter of 50 μm and sesamin was placed in a container, and both ends of the container were sealed with a mesh filter. The diameter of the mesh filter on the outlet side of the container was 2 μm. The container was filled with liquid carbon dioxide. The zirconia ceramic beads in the container were vibrated by ultrasonic treatment and violently collided with each other to atomize sesamin. The fine particles of sesamin were moved to the outlet of the container by the flow of liquid carbon dioxide. Fine particles that could pass through the filter were selected by a mesh filter having a diameter of 2 μm. The selected fine particles were used as a medium removing means together with liquid carbon dioxide and sprayed from a nozzle. The sprayed liquid carbon dioxide was exposed to atmospheric conditions and vaporized, and the fine particles from which the medium had been removed were recovered.

The obtained fine particles were Pt coated by Pt sputtering, and the shape and size of the particles were confirmed with an electron microscope (scanning SEM) (FIG. 2). The long axis of the particles was measured, and the median value was taken as the particle diameter. The particle size (median value of the major axis) of the primary particles of the sesamine powder before being micronized is about 20 μm ((A) and (B) in FIG. 2), and the particle size (length) of the primary particles after being micronized. It was observed that the median axis) was about 300 nm ((C) and (D) in FIG. 2), and it was confirmed that nanoscale primary particles were obtained by micronization. Then, the powder before and after the micronization was subjected to XRD to confirm the crystal state (FIG. 3). When the half-value width of the large peak detected near 2θ = 15 degrees was measured, the half-value width before micronization was 0.0763 and the half-value width after micronization was 0.09062. When the crystallite diameter was calculated using the formula, the crystallite diameter after micronization was 84.3% (a decrease of 15.7%) of the crystallite diameter before micronization. This suggests that the method of the present invention achieves micronization by destroying grain boundaries rather than destroying crystallites.

[Test Example 2] Micronization of naproxen Fine particles of naproxen were prepared according to the method shown in Test Example 1 except that naproxen was used instead of sesamin. The obtained fine particles were Pt coated by Pt sputtering, and the shape and size of the particles were confirmed with an electron microscope (scanning SEM) (FIG. 4). The long axis of the particles was measured, and the median value was taken as the particle diameter. The particle size (median value of the major axis) of the primary particles of naproxene powder before micronization is about 12 μm ((A) and (B) in FIG. 4), and the particle size (length) of the primary particles after micronization. It was observed that the median axis) was about 400 nm ((C) and (D) in FIG. 4), and it was confirmed that the nanoscale primary particle size was obtained by micronization. Then, the particles before and after the micronization were subjected to XRD to confirm the crystal state, and as in Test Example 1, the micronization was achieved by breaking the grain boundaries without breaking the crystallites. It has been suggested.

1 Medium storage container 2-6 Valve 7 Pump 8 Ultrasonic generator 9 Pressure-resistant container 10 Filter 11 Vacuum pump 12 Nozzle 13 Fine particle recovery container 14 Regulator

Claims (12)

By vibrating the beads in the medium, the compound is crushed into fine particles.
A method for producing fine particles, which comprises taking out the fine particles by the flow of the medium.
The production method , wherein the medium comprises at least one selected from the group consisting of air, oxygen, hydrogen, and an inert gas . The production method according to claim 1, wherein the beads are vibrated by ultrasonic treatment to pulverize the compound. The production method according to claim 1 or 2, wherein the fine particles are taken out by passing the medium through a size sorting means. The production method according to any one of claims 1 to 3, wherein the medium is a gas medium or a liquid medium. The production method according to any one of claims 1 to 4, wherein the medium is used under pressure. The production method according to any one of claims 1 to 5, wherein the inert gas is selected from the group consisting of carbon dioxide, nitrogen, and a rare gas. The production method according to any one of claims 1 to 6, wherein the beads are ceramic beads. The manufacturing method according to any one of claims 3 to 7, wherein the size sorting means is a membrane filter or a mesh filter. Container for beads,
Means for vibrating the beads,
Means for supplying a medium to the container,
Means for extracting fine particles by the flow of a medium,
Particle recovery means,
It is a fine particle manufacturing device including
The manufacturing apparatus , wherein the medium comprises at least one selected from the group consisting of air, oxygen, hydrogen, and an inert gas . The manufacturing apparatus according to claim 9, further comprising means for pressurizing the medium. The manufacturing apparatus according to claim 9 or 10, wherein the means for vibrating the beads is an ultrasonic generator. The means for taking out the fine particles by the flow of the medium is to take out the fine particles by passing the medium through the size sorting means, wherein the size sorting means is a membrane filter or a mesh filter, according to any one of claims 9 to 11. The manufacturing equipment described.