Method for producing organic nanoparticles and organic nanoparticles

Abstract

To provide a new method which maintains adequate processing speed and is capable of considerably suppressing a concentration of contaminants from beads or a bead mill apparatus member, in nano-pulverization of organic powder using a wet-type bead mill.SOLUTION: A manufacturing method of organic nanoparticles includes a step of agitating a mixture which contains slurry with organic particles, and beads with an average particle diameter of at least 0.15 mm but not more than a value (mm) calculated by 1.07-0.11*[the outer peripheral speed (m / sec) of an agitating rotor], in a container of a wet-type bead mill by using an agitating rotor rotating at an outer peripheral speed of 7 m / sec or less.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present disclosure relates to a method for producing organic nanoparticles using a wet bead mill. The present disclosure particularly relates to a method for producing nanoparticles of poorly soluble pharmaceutical compounds.

Background Art

[0002] In recent years, processes for improving functions such as enhancing the activity by pulverizing (nano-pulverizing) powders of health foods and pharmaceuticals to a nanometer size have been attempted. In particular, attempts to pulverize powders of pharmaceutical agents to a nano size in order to improve the activity of poorly soluble drugs have been actively made. Further, by miniaturizing drug particles to a nano size, there is also an effect of making the timing of drug efficacy constant. Thus, in recent years, research on drugs pulverized to a nano size (nano drugs) has progressed and has been put into practical use.

[0003] As a method for nano-pulverizing organic powders, a pulverization treatment using a jet mill or a bead mill is common. Among these, a pulverization treatment using a wet bead mill is often performed, and generally, it is performed as follows. A mixture (slurry) of a pharmaceutical raw material powder prepared to be several to several tens of micrometers and a dispersion medium is prepared and supplied to a bead mill in which spherical pulverization media (beads) are contained. By the high-speed rotation of the stirring rotor in the bead mill, the mixture of the slurry and the beads is stirred, and the pharmaceutical raw material powder is pulverized. As the material of the beads, inorganic substances such as zirconia, alumina, hard glass, and silicon carbide, and polymer materials such as polystyrene and polypropylene are used.

[0004] Regarding the size of the beads used for nanogrinding, Patent Document 1 states that it is preferably 3 mm or less, more preferably 1 mm or less. Patent Document 2 describes that by using beads of 10 to 1000 micrometers, it is possible to perform a grinding process to finer particles. Patent Document 3 mentions that in the grinding process, it is desirable to use beads of less than 500 micrometers. However, Patent Documents 1 to 3 only describe the appropriate bead diameter and do not provide specific descriptions regarding the grinding conditions.

[0005] Patent Document 4 describes that by using beads of 20 to 200 micrometers and driving a bead mill device equipped with a stirring rotor of a special shape so that the outer peripheral speed of the stirring rotor is 3 to 8 m / second, a grinding process is performed. However, Patent Document 4 does not describe the mixing of fragments generated from the beads and the stirring rotor into the slurry. In the grinding method of Patent Document 4, although the grinding efficiency can be improved by using a stirring rotor of a special shape, since the contact area between the beads and the stirring rotor member increases and a locally high-speed flow is formed, the mixing of fragments of the beads and the stirring rotor member into the slurry can increase.

[0006] In the field of pharmaceuticals, generally, an allowable concentration is set for the content of substances that may be harmful to health in drugs, and this also applies to nanopharmaceuticals. In nanopharmaceuticals, there is a problem that as the beads and the members of the mill wear during the grinding process, their components mix into the drug. In the grinding process using a wet bead mill, elements such as zirconium, yttrium, aluminum, silicon, etc., which are components of the beads, and elements such as iron, nickel, chromium, tungsten, etc., which are components of the metal parts of the mill, can mix into the drug.

[0007] The concentration of these elements in the active ingredient needs to comply with regulatory limits. However, since the contaminants are nanosized, it is preferable to keep the concentration as low as possible. Patent Document 5 states that in the production of pharmaceuticals, it is desirable that the amount of heavy metal contamination be less than about 10 ppm, but it is difficult to achieve this with a grinding process using beads.

[0008] Patent Document 5 describes using beads coated with a polymer resin as a grinding medium to reduce the presence of metal substances in nanosized organic ground materials. However, even if the presence of metal substances from the beads can be suppressed, there is a risk of polymer resin contamination. Furthermore, metal substance contamination from the parts of the bead mill device is conceivable, but no solution to this is described.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0010] Thus, in the conventional method for nanogrinding organic substances, there was only the idea that efficient grinding treatment was sufficient, and the processing speed was maintained by rotating the stirring rotor at high speed. Also, although a method for suppressing the mixing of metal substances was known as in Patent Document 5, it was necessary to use special beads, and general beads could not solve the problem. Moreover, in the method described in Patent Document 5, there was a risk of mixing of the polymer resin which was the coating component of the beads and heavy metals (such as chromium, nickel, iron, etc.) which were the components of the metal parts of the bead mill device.

[0011] Therefore, in the nanogrinding of organic substance powders using a wet bead mill, there has been a demand for a new method capable of maintaining a sufficient processing speed and significantly suppressing the concentration of contaminants from the beads and the members of the bead mill device.

Means for Solving the Problems

[0012] This specification discloses the following: (1) A method for producing organic nanoparticles, comprising a step of stirring, by a stirring rotor rotating at an outer peripheral speed of 7 m / s or less, a mixture containing a slurry containing organic particles and beads having an average particle diameter of 0.15 mm to 0.9 mm in a container of a wet bead mill. (2) A method for producing organic nanoparticles, comprising a step of stirring, by a stirring rotor rotating at an outer peripheral speed of 7 m / s or less, a mixture containing a slurry containing organic particles and beads having an average particle diameter of 0.15 mm or more and a value (mm) calculated by 1.07 - 0.11 × [outer peripheral speed (m / s) of the stirring rotor] or less in a container of a wet bead mill. (3) The production method according to (1) or (2) above, wherein the beads are made of partially stabilized zirconia. (4) The production method according to any one of (1) to (3) above, wherein the rotating shaft for rotating the stirring rotor is installed in the vertical direction in the container of the wet bead mill. (5) A method for producing organic nanoparticles, comprising a step of stirring a mixture containing a slurry containing organic particles and beads with a stirring rotor in a container of a wet bead mill, wherein the container of the wet bead mill is a vertical cylindrical container, the upper part of the cylindrical container is provided with an opening, a rotating shaft for rotating the stirring rotor is inserted into the cylindrical container from above the cylindrical container through the opening, and the stirring rotor is connected to the rotating shaft. (6) There is a slurry storage tank above the cylindrical container, the cylindrical container and the slurry storage tank are connected via a communication pipeline, a rotating shaft for rotating the stirring rotor is inserted into the cylindrical container from above the slurry storage tank through the slurry storage tank and the communication pipeline, the stirring rotor is connected to the rotating shaft, and the slurry after bead separation treatment is discharged from the lower part of the cylindrical container. The production method according to (5) above. (7) The production method according to (5) or (6) above, wherein the stirring rotor rotates at an outer peripheral speed of 7 m / s or less. (8) The production method according to any one of (5) to (7) above, wherein the average particle diameter of the beads is 0.15 mm to 0.9 mm. (9) The production method according to any one of (5) to (7) above, wherein the average particle diameter of the beads is 0.15 mm or more and 1.07 - 0.11 × [outer peripheral speed of the stirring rotor (m / s)] or less (mm). (10) The production method according to any one of (5) to (9) above, wherein the beads are made of partially stabilized zirconia, and (11) Organic nanoparticles obtained by the production method according to any one of (1) to (10) above.

Advantages of the Invention

[0013] By the method of the present disclosure, when using a wet bead mill to grind an organic powder such as a pharmaceutical compound into nanoparticles (for example, with an average particle diameter of 400 nanometers or less), contaminants from the beads and bead mill parts can be reduced, and drug contamination can be prevented. The method of the present disclosure can prevent contamination not only in the production of pharmaceuticals but also in the production of nanoparticles such as health foods and X-ray contrast agents.

Brief Description of the Drawings

[0014]

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Mode for Carrying Out the Invention

[0015] In this specification, the "average particle diameter" is obtained from the particle size distribution measured by a particle size distribution measuring instrument and is represented as the volume-based median diameter (D50). In this disclosure, the value obtained by measurement using LA-950 manufactured by Horiba, Ltd. is described as the average particle diameter. Note that if it is a particle size analyzer using the static laser diffraction / scattering method, substantially the same measurement results can be obtained. The terms "particle diameter" or "grain size" used in this specification have the same meaning as the above "average particle diameter" unless otherwise specified.

[0016] In this specification, a "slurry" is a suspension of solid particles of an organic substance of approximately 100 micrometers or less in a liquid dispersion medium. Generally, a slurry can be prepared using organic substance particles with an average particle diameter of 1 to 100 micrometers, but even those with a particle diameter of 100 micrometers or more can be used to implement the method of this disclosure. In the grinding method using the bead mill of this disclosure, the grinding treatment speed up to a particle diameter of 5 micrometers or more is extremely fast. For example, the grinding treatment time from 30 micrometers to 5 micrometers is about 3 minutes, which is extremely short compared to the total grinding treatment time of 45 to 400 minutes. Therefore, the influence of the particle diameter of the organic substance before the grinding treatment on the operating conditions of the bead mill is small. In this disclosure, the particle diameter of the organic substance particles in the raw material slurry before the grinding treatment is preferably 1 to 100 micrometers, but if it is 1 micrometer or more, there is no substantial influence on the setting of the operating conditions.

[0017] The dispersion medium used in the method of the present disclosure is not particularly limited as long as it is a liquid medium in which the organic particles to be pulverized are essentially insoluble, and those skilled in the art can appropriately select it according to the properties of the organic particles. For example, water or various organic solvents (such as alcohols such as methanol, ethanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone, methyl propyl ketone, and methyl isobutyl ketone; ethers such as isopropyl ether and methyl cellosolve; glycol esters such as ethylene glycol, propylene glycol monomethyl ether acetate, and ethylene glycol monoethyl ether acetate; esters such as ethyl acetate; halogenated hydrocarbons such as methylene chloride and trichloroethane; non-aromatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as toluene; linear hydrocarbons such as normal hexane, etc.) can be mentioned.

[0018] In this specification, the "organic particles" (sometimes referred to as "organic powder" in this specification) can be any solid particles containing organic compounds. For example, particles of any organic compounds used in various fields such as electronic component materials, phosphors, pigments, paints, pharmaceuticals, agricultural chemicals, and foods can be mentioned, but are not limited thereto. Examples of organic particles used in the pharmaceutical field include pharmaceutical compounds that are active ingredients of pharmaceuticals, additives used in pharmaceutical preparations, and those used in the production of X-ray contrast agents, etc., but are not limited thereto.

[0019] The pharmaceutical compound is not particularly limited, and any one can be used. For example, phenytoin, mefenamic acid, indomethacin, ibuprofen, itraconazole, sulfamethoxazole, probucol, griseofulvin, digoxin, perapamil, tacrolimus, dexamethasone, haloperidol, lamivudine, levamipide, aripiprazole, risperidone, ketoprofen, flurbiprofen, loxoprofen, felbinac, diflunac, acemetacin, alclofenac, fenbufen, lobenzarit, penicillamine, naproxen, pranoprofen, etodolac, cyclosporine, etc. can be mentioned, but are not limited thereto.

[0020] The concentration of organic particles in the slurry (also referred to as "slurry concentration" in this specification) is not particularly limited as long as it provides fluidity that allows for grinding treatment by a bead mill. In this specification, the slurry concentration is expressed as the weight percentage of the material to be ground (organic particles) with respect to the total weight of the slurry. Examples of the slurry concentration used in the method of the present disclosure include any concentration within the range of 1 to 70 wt%, 2 to 65 wt%, 3 to 60 wt%, 4 to 55 wt%, 5 to 50 wt%.

[0021] In this specification, "organic nanoparticles" means particles obtained by grinding the above-mentioned organic particles to a size of less than 1 micrometer in average particle diameter, for example, less than 500 nanometers, less than 400 nanometers, less than 300 nanometers, less than 200 nanometers, less than 100 nanometers, less than 50 nanometers, less than 20 nanometers (also referred to as "nano-grinding" in this specification).

[0022] In the method of the present disclosure, in the container of the wet bead mill, the stirring rotor fixed to the rotating shaft is rotated to stir the mixture of the slurry and the beads, thereby grinding the organic particles.

[0023] The vessel of the wet bead mill that can be used in the method of the present disclosure has an inner wall surface that forms a point-symmetric circle with respect to the central axis. In the direction parallel to the central axis, the diameter of the inner wall surface may be constant or may vary. Further, there may be a portion that is not point-symmetric for the slurry supply port or the like. The wet bead mill that can be used in the method of the present disclosure stirs a mixture of beads and slurry in a vessel made of reinforced alumina, silicon carbide, sialon (SiAlON), partially stabilized zirconia, stainless steel, or the like. When it is necessary to suppress the rise in the temperature of the slurry in the vessel due to friction during the grinding process, the outside of the vessel may be a jacket structure and water-cooled. The capacity of the wet bead mill that can be used in the method of the present disclosure is a capacity generally used in the art, for example, any capacity from 0.15 L to 10 L (0.15 L, 0.5 L, 1 L, 2 L, 5 L, 10 L, etc.).

[0024] For the stirring rotor, those made of hard ceramics such as reinforced alumina, silicon carbide, sialon, and partially stabilized zirconia can be used, but a stirring rotor made of partially stabilized zirconia is preferred.

[0025] By adding calcium oxide or yttrium oxide to zirconia, cubic zirconia crystals are formed and the strength becomes high. Further, by making the amount of the additive slightly less than the amount that completely stabilizes the crystal (partially stabilizing), the toughness is increased and it becomes a ceramic material that is resistant to wear and breakage. Generally, partially stabilized zirconia contains 4 to 6% by weight of yttrium oxide as an additive with respect to 94 to 96% by weight of zirconium oxide, and in addition, other oxides are added thereto. Thus, partially stabilized zirconia not only has high strength but also high toughness and is less likely to cause local defects. Therefore, a stirring rotor made of partially stabilized zirconia has an advantage of generating less debris.

[0026] The method of the present disclosure can be carried out using, for example, a wet bead mill apparatus as shown in FIGS. 1 to 4, but is not limited to these apparatuses and can be carried out using apparatuses generally used in the art.

[0027] In one embodiment, the bead mill used in the method of the present disclosure is a vertical bead mill (device 1) of the type that supplies slurry from above and discharges it from below, as shown in FIG. 1. The container of the bead mill is a vertical cylindrical container, having an opening at the upper part, and a rotating shaft 4 connected to a driving device such as a rotating shaft pulley 9 is vertically inserted into the cylindrical container from above through the opening. A stirring rotor 5 is connected to the rotating shaft 4. A mechanical seal 13 is installed at the connection part between the rotating shaft 4 and the cylindrical container. The slurry flows from above to below, and after the beads are separated by the slit-type bead separator 8, it is discharged from the lower part of the cylindrical container.

[0028] In one embodiment, the bead mill used in the method of the present disclosure is a vertical bead mill (device 2) of the type that supplies slurry from below and discharges it from above, as shown in FIG. 2. The container of the bead mill is a vertical cylindrical container, having an opening at the upper part of the cylindrical container, and a rotating shaft 4 connected to a driving device such as a rotating shaft pulley 9 is vertically inserted into the cylindrical container from above through the opening. A stirring rotor 5 and a centrifugal bead separation device 14 are connected to the rotating shaft 4. Two mechanical seals 13 are installed at the connection part of the cylindrical container. After the beads are separated by the centrifugal bead separation device 14, the slurry rises in the hollow flow path installed in the rotating shaft and is discharged from the discharge port 7.

[0029] As in the above devices 1 and 2, in a wet bead mill device, generally, a mechanical seal or a sealing device similar thereto is provided for the purpose of sealing between the rotating shaft and the cylindrical container. Examples of the material of the contact part between the rotating part and the fixed part of the mechanical seal include high-strength metals such as iron, nickel, molybdenum, tungsten, chromium, and silicon, and high-strength ceramics. These can be mixed into the slurry as the sealing device wears during the grinding process in the bead mill. Therefore, by grinding the organic powder using a bead mill without a sealing device, the concentration of contaminants can be further reduced.

[0030] As a wet bead mill without a sealing device, there is one that uses a vertical cylindrical container. A through-hole is provided on the upper surface of the cylindrical container, and a rotating shaft is inserted into the cylindrical container from above the cylindrical container via the through-hole. An example of the structure is one in which an agitation rotor is connected to the rotating shaft. In the case of a batch-type wet bead mill, it is the device described above. In the case of a circulating wet bead mill, a mechanism for supplying and discharging slurry into the cylindrical container without a mechanical seal for the rotating part is required. As an embodiment, an example of such a device is shown in FIG. 3.

[0031] The bead mill (device 3) in FIG. 3 has the same structure and capacity inside the mill as the above device 1, but the connection part between the rotating shaft and the cylindrical container is open, and it is an example of a circulating wet bead mill without a sealing device. There is a slurry storage tank 15 above the upper lid 2, and the upper lid 2 and the slurry storage tank 15 are connected by a communication pipeline 16. A rotating shaft 4 connected to a driving device such as a rotating shaft pulley 9 is inserted vertically into the cylindrical container via the slurry storage tank 15 and the communication pipeline 16. An agitation rotor 5 is connected to the rotating shaft 4. The slurry flows into the slurry storage tank 15 from the circulation tank 20 via the slurry communication pipe 22, and further flows into the cylindrical container via the communication pipeline 16. The slurry being pulverized while descending in the cylindrical container is discharged out of the cylindrical container from the slurry discharge port 7 after bead separation by the plug-type bead separator 8. The slurry is further returned to the circulation tank 20 by the pump 19 via the slurry pipe 18. In order to improve the slurry flow, a pumping device 17 may be installed on the rotating shaft 4 in the communication pipeline 16 to push the slurry downward.

[0032] Moreover, bead mills without other forms of sealing devices are also applicable to the method of the present disclosure. Examples of other forms of bead mills include those with the following structures. There is a slurry storage tank above a cylindrical container, and a through hole connecting the cylindrical container and the slurry storage tank is installed. Through this through hole, a rotating shaft extends into the cylindrical container and is connected to a stirring rotor there. There is a slurry supply port at the lower part of the cylindrical container. The slurry is pulverized while rising, and after the beads are separated by a centrifugal bead separation device installed at the upper part of the cylindrical container, it rises through a hollow flow path installed in the rotating shaft and is discharged into the slurry storage tank. On the rotating shaft in the through hole, similar to the device in FIG. 3, there is a structure for flowing the slurry from the slurry storage tank to the cylindrical container by a pumping mechanism for circulation, slurry swirling blades, etc. This flow can prevent bead leakage at the through hole. The slurry flowing downward through the through hole returns to the slurry storage tank via the centrifugal bead separation device and the hollow flow path.

[0033] In the bead mills of the above-described apparatuses 1 to 3, the stirring rotor has a plurality of rod-shaped pins installed. However, the stirring rotor may also be one with a plurality of horizontally arranged disks installed in the height direction, or a plurality of plate-shaped ones installed in the vertical direction, etc.

[0034] In the method of the present disclosure, since the rotational speed of the stirring rotor is relatively slow, a vertical bead mill is preferably used as the bead mill. In the case of a vertical bead mill, centrifugal force acts in a direction perpendicular to gravity, and the force applied to the beads is almost constant in the circumferential direction within the cylindrical container. Therefore, no excessive force acts locally, and the uniformity is high.

[0035] The flow direction of the slurry in the cylindrical container of the bead mill can be either upward flow or downward flow. However, by flowing the slurry downward, the beads can be filled downward, and the contact frequency between the beads at the bottom of the cylindrical container is improved. Therefore, it is more preferable to use a vertical bead mill such as Device 1 or Device 3 that flows the slurry from top to bottom. However, since the flow velocity of the slurry in the vertical direction is low, the difference is small, and the method of the present disclosure can also be implemented using a vertical bead mill that flows the slurry from bottom to top.

[0036] Also, even in the case of a horizontal bead mill, the method of the present disclosure can be implemented. An example of a horizontal bead mill is the bead mill (Device 4) shown in FIG. 4. In Device 4, the rotating shaft 4 is installed horizontally, and a plurality of petal-shaped and perforated stirring rotors 5 installed parallel to the rotation direction stir the slurry and the beads. The slurry after the treatment is discharged outside the cylindrical container after the beads are separated by the screen 23.

[0037] In the case of a horizontal bead mill, the directions of the centrifugal force and the gravitational force are different depending on the circumferential position inside the cylindrical container. At the upper part of the side surface of the cylindrical container, the gravitational force is subtracted from the centrifugal force, and the force pressing the beads becomes weak. On the other hand, at the lower part, since the centrifugal force and the gravitational force are combined, the force pressing the beads becomes strong. Since the method of the present disclosure is implemented under the condition that the outer peripheral speed of the stirring rotor (also referred to as "outer peripheral speed" in this specification) is relatively slow and the centrifugal force is small, the degree of the above-mentioned phenomenon is large, and it is difficult for the beads to rise to the uppermost part of the cylindrical container, resulting in a decrease in the processing speed. Therefore, in a horizontal bead mill, when the outer peripheral speed is particularly low, the concentration of contaminants increases slightly compared to a vertical bead mill, but it can be used in the method of the present disclosure.

[0038] In a circulating wet bead mill, the slurry treatment time per circulation is 3 to 10 minutes, and generally about 5 to 50 circulations are performed. The general treatment time is 30 to 400 minutes, but it may be shorter or longer depending on the capacity of the mill.

[0039] The beads used in the method of the present disclosure are not particularly limited as long as they are those commonly used in the grinding process using a wet bead mill. A person skilled in the art can appropriately select them in consideration of various factors such as the specifications of the bead mill, the characteristics of the material to be ground (e.g., particle hardness, density, and particle size), the target particle size of the ground fine particles, and the viscosity of the slurry.

[0040] Examples of the material of the beads used in the bead mill include, but are not limited to, glass, alumina, zircon (zirconia-silica ceramics), zirconia, steel, etc. Zirconia is preferred as the material of the beads because it has high hardness and tends to have less contamination of fragments due to bead deterioration. In particular, beads made of partially stabilized zirconia are particularly preferred because, as described above, they have not only high strength but also high toughness and are less likely to cause local defects.

[0041] In one embodiment, in the method of the present disclosure, beads made of partially stabilized zirconia are used. In this specification, beads made of partially stabilized zirconia may also be simply referred to as "beads".

[0042] In this specification, the "bead filling rate" refers to the apparent volume (volume %) of the beads with respect to the effective volume of the cylindrical container of the bead mill (the volume obtained by subtracting the volume of the stirring rotor from the internal volume of the cylindrical container).

[0043] A person skilled in the art can appropriately select the bead filling rate in consideration of various factors such as the specifications of the bead mill, the operating conditions, and the viscosity of the slurry. Generally, it can be appropriately set within the range of 10 to 95 volume %, for example, within the ranges of 15 to 95 volume %, 25 to 90 volume %, 35 to 90 volume %, 50 to 90 volume %, and 75 to 90 volume %.

[0044] The amount of the slurry charged into the bead mill can be appropriately selected by a person skilled in the art according to the specifications of the bead mill (e.g., the capacity of the grinding chamber of the bead mill to be used) and the operating conditions.

[0045] Generally, organic powder is relatively soft and can be pulverized even with a small collision energy of beads. Therefore, in the method of the present disclosure, the average particle size of the beads (also referred to as "bead diameter" in this specification) may be relatively small. Also, the smaller the particle size of the beads, the larger the specific surface area and the faster the pulverization rate. Generally, bead wear has two factors: the factor of increased wear due to the specific surface area of the beads and the factor of increased wear due to the single mass. The former has less wear as the particle size of the beads is larger, and the latter has less wear as the particle size of the beads is smaller. Considering both, it is considered that the intermediate-sized bead diameter has less wear. In the method of the present disclosure, beads having an arbitrary average particle size within the range of 0.15 mm to 0.9 mm can be used. For example, beads commercially available with particle size specifications of 0.15 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, or 0.9 mm can be used.

[0046] Generally, the surface area of the beads is overwhelmingly larger than the surface area of the members of the bead mill. For example, in a bead mill with an effective internal volume of 200 milliliters, the total area of the inner surface of the cylindrical container and the stirring rotor is about 10 5 mm 2 whereas the total surface area of the beads is on the order of 10 6 ~10 7 mm 2 and the wear due to the contact between the beads is overwhelmingly larger than the wear of the members of the bead mill. Therefore, the method of the present disclosure for suppressing bead wear can achieve different minimum values of the contaminant concentration depending on the shape of the stirring rotor, but in principle, it can be applied to all shapes of stirring rotors, and even for a stirring rotor with a complex shape, the effect of the method of the present disclosure can be expected.

[0047] Examples of the agitation rotor of the wet bead mill used in the method of the present disclosure include an agitation rotor in which rod-shaped pins are installed at point-symmetrical positions with respect to the rotation direction, an agitation rotor composed of a plurality of plates parallel to the rotation direction, and an agitation rotor composed of a plurality of plates parallel to the rotation axis direction. The agitation rotor having a pin shape does not necessarily have a cylindrical shape, may be plate-shaped, or may not have a simple plate shape.

[0048] In this specification, the "outer peripheral speed" or "outer peripheral velocity" means the outer peripheral speed during the rotation of the agitation rotor. Under the condition that the bead diameter is the same, generally, the higher the outer peripheral speed of the agitation rotor, the shorter the processing time. In the method of the present disclosure, an outer peripheral speed of 1 m / second or more is preferable, but even when the outer peripheral speed is 0.5 m / second, it is possible to grind organic substance particles to a particle size of about 200 nanometers. In addition, the outer peripheral speed of the agitation rotor also affects the wear of the beads and the agitation rotor members. In the method of the present disclosure, when the outer peripheral speed of the agitation rotor is 7 m / second or less, a sufficient processing speed can be maintained and the concentration of contaminants from the beads and the agitation rotor members can be significantly suppressed. Examples of the outer peripheral speed of the agitation rotor in the method of the present disclosure include any speed within the range of 0.5 m / second to 7 m / second (for example, 0.5 m / second, 1 m / second, 2 m / second, 3 m / second, 4 m / second, 5 m / second, 6 m / second, 7 m / second).

[0049] In one embodiment, the method of the present disclosure includes a step of performing a grinding process using partially stabilized zirconia beads having an average particle size of 0.15 mm or more and 1.07 - 0.11 × [outer peripheral speed of the agitation rotor (m / second)] (mm) or less and an outer peripheral speed of the agitation rotor of 7 m / second or less. Thereby, a sufficient grinding processing speed can be maintained and the concentration of contaminants from the beads and the agitation rotor members can be significantly suppressed.

[0050] In one embodiment, the amount of contaminants contained in the organic nanoparticles obtained by the method of the present disclosure is, for example, 0.0001 ppm or more and less than 50 ppm, 0.0001 ppm or more and less than 40 ppm, 0.0001 ppm or more and less than 30 ppm, 0.0001 ppm or more and less than 20 ppm, 0.0001 ppm or more and less than 10 ppm, based on the total weight of the obtained particles. In this specification, the concentration of contaminants is expressed as parts per million (ppm by mass) of the mass of the contaminant substance with respect to the mass of the entire slurry. Further, in this specification, the "ZY concentration" refers to the total mass of zirconium and yttrium with respect to the mass of the entire slurry, expressed as parts per million (ppm by mass). In one embodiment, the ZY concentration in the slurry pulverized by the method of the present disclosure is about 5 ppm or less. The concentration of contaminants in the slurry can be determined by a measurement method commonly used in the art, such as inductively coupled plasma mass spectrometry (ICP-MS).

[0051] In the field of pharmaceuticals, as described in Patent Document 5, since setting the heavy metal concentration in the active ingredient to 10 ppm or less is one of the indicators, for example, when the concentration of the slurry subjected to the pulverization treatment is 50% by weight, it is desirable that the concentration of heavy metals in the entire pulverized slurry is about 5 ppm or less. However, the present disclosure provides a method for rapidly pulverizing organic powder with a wet bead mill and reducing the concentration of contaminants, and it is not necessarily required to satisfy this condition.

[0052] When implementing the method of the present disclosure, an additive can be blended into the slurry as needed. For example, a dispersant can be blended into the slurry for the purpose of improving the dispersibility of the organic particles in the slurry, preventing aggregation, or stabilizing the dispersed state.

[0053] The dispersant can be appropriately selected in consideration of various factors such as the properties of organic particles and the dispersion medium, the specifications of the bead mill, and the operating conditions. Examples of the dispersant include surfactants such as carboxylates (fatty acid salts, etc.), sulfonates (sodium linear alkylbenzene sulfonate, etc.), phosphates (monoalkyl phosphates, etc.), sulfate esters (sodium lauryl sulfate, etc.), and polymer compounds such as hydroxypropyl cellulose (HPC), hypromellose (hydroxypropyl methylcellulose (HPMC)), methylcellulose (MC), polyvinylpyrrolidone (PVP), etc. The amount of the dispersant can be appropriately selected by those skilled in the art according to conventional procedures.

[0054] Other grinding conditions necessary for carrying out the method of the present disclosure can be appropriately set by those skilled in the art in consideration of various factors (properties of the organic substance, type of the dispersion medium, viscosity of the slurry, particle size of the nanoparticles obtained after grinding, grinding efficiency, etc.).

[0055] The slurry discharged from the bead mill may be dried according to conventional procedures in the art to distill off the dispersion medium, and may be a powder containing organic nanoparticles.

[0056] In a further aspect of the present disclosure, organic nanoparticles obtained by the method of the present disclosure are provided. In one embodiment, the organic nanoparticles of the present disclosure comprise a pharmaceutical compound.

[0057] The form of the organic nanoparticles obtained by the method of the present disclosure is not particularly limited, and may be the slurry obtained by the method of the present disclosure, or may be the powder obtained by drying the slurry.

[0058] In a further aspect of the present disclosure, a composition or material comprising the organic nanoparticles obtained by the method of the present disclosure is provided. Examples of such a composition or material include electronic component materials such as dielectrics, piezoelectric bodies, and magnetic bodies, phosphors, electrode materials for batteries, pigments, paints, raw materials for fine ceramics, abrasives, pharmaceuticals, agricultural chemicals, foods, etc.

[0059] In a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising organic nanoparticles obtained by the method of the present disclosure.

[0060] The pharmaceutical composition of the present disclosure uses the organic nanoparticles obtained by the method of the present disclosure, and after appropriately undergoing several steps commonly used in the field of pharmaceutical preparations (for example, granulation, sizing, tableting, coating, etc.) according to the target dosage form, it can be obtained as a final product.

[0061] As an embodiment, taking apparatus 1 as an example, the operation method of the bead mill used in the method of the present disclosure will be described. The slurry is supplied from the slurry supply port 6 into a container composed of a cylinder 1, an upper lid 2, and a lower lid 3. The mixture of the slurry and the beads is stirred by a stirring rotor 5 connected to a rotating shaft 4. The stirring rotor 5 is composed of a plurality of rod-shaped pins. The slurry descends in the cylindrical container from the slurry supply port 6, and generally, its speed is 10 to several tens of mm / second. By the stirring of the stirring rotor 5, the organic particles in the slurry are pulverized. The treated slurry is separated from the beads by a plug-type bead separator 8 and then discharged out of the cylindrical container from the slurry discharge port 7. In order to ensure the pressure inside the bead mill, a mechanical seal 13 is installed on the rotating shaft 4. Although not shown in FIG. 1, the discharged slurry flows through the pipe by the liquid delivery of a pump and returns to the circulation tank. Thus, it is common for the slurry to be circulated between the circulation tank and the bead mill for treatment.

[0062] The following test examples and examples further illustrate the present disclosure and should not be construed as limiting its scope in any way.

Example

[0063] Test Example 1: Influence of bead diameter on treatment time Using a wet bead mill (Apex Mill Model 015 manufactured by Hiroshima Metal & Machinery Co., Ltd. (corresponding to the above "Apparatus 1"; hereinafter referred to as "Apparatus 1" in the following test examples and examples)), a slurry (500 g) containing 5 wt% phenytoin (manufactured by Shizuoka Caffeine Industry Co., raw material particle size: 16 - 20 μm), polyvinylpyrrolidone (3 wt%) and sodium lauryl sulfate (0.25 wt%) as dispersants was stirred at an outer peripheral speed of 2 m / s of the stirring rotor together with partially stabilized zirconia beads (YTZ balls manufactured by Nikkato Co., hereinafter the same beads were used, bead filling rate: 75%) having various average particle sizes (particle size specifications) to perform a grinding process. Sampling was carried out at a predetermined time point during the grinding process, and the particle size of phenytoin particles and the contaminant concentration (total concentration of zirconium and yttrium; hereinafter referred to as "ZY concentration") in the sample were measured. The particle size of phenytoin particles was measured by LA-950 (manufactured by Horiba, Ltd.) (the same applies to the following test examples and examples). Measurement conditions: Particle refractive index: 1.610 (phenytoin) Set Zero: 60 seconds Measurement time: 60 seconds Number of measurements: 2 times Shape: non-spherical Solvent refractive index: 1.333 (water) Ultrasonic wave: none Particle size standard: volume The contaminant concentration in the slurry was measured according to the following procedure (the same applies to the following test examples and examples). 0.5 g of the sample after the grinding process was weighed into a metal-free container, and after adding an internal standard substance (Co), NMP / HCl / HNO 3 mixed solution (90:5:5) was added and dissolved by ultrasonic irradiation to obtain a sample solution. This sample was used to measure the concentration (weight ppm) of contaminants (zirconium and yttrium) in the sample using an inductively coupled plasma mass spectrometry (ICP-MS) apparatus (iCAPQ (trademark), Thermo Fisher Scientific). Measurement conditions: Measured elements: Zr (m / z = 90), Y (m / z = 89) Nebulizer: coaxial nebulizer Spray chamber: Cyclone type Spray chamber temperature: Constant temperature around 3°C Injector inner diameter: 1.0 mm Sample introduction method: Natural suction High-frequency power: 1550 W Cooling gas flow rate: 14 L / min Auxiliary gas flow rate: 0.8 L / min Measurement mode: KED Collision gas: Helium Added gas: Oxygen Peristaltic pump rotation speed: 20 rpm Integration time: 0.1 second Integration count: 3 times The results are shown in Figs. 5 and 6. The ZY concentration is shown in mass ppm with respect to the weight of the pulverized slurry (the same hereinafter). As shown in Fig. 5, for bead diameters of 0.2 mm or more, pulverization proceeds rapidly until the particle size of phenytoin reaches about 400 nanometers. When it becomes 400 nanometers or less, the processing speed decreases and the influence of the bead diameter becomes greater. The smaller the bead diameter, the faster the processing speed, and the time until it reaches 200 nanometers is the shortest for bead diameters of 0.2 mm (◇ in Fig. 5) and 0.3 mm (○ in Fig. 5). In the case of a bead diameter of 0.1 mm (△ in Fig. 5), the initial processing speed was slow and a very small amount of coarse particles of 1 micrometer or more remained, but it was possible to pulverize them until 200 nanometers. Thus, since the organic powder is relatively soft, it can be pulverized even with small-diameter beads with small collision energy of the beads. Also, with small-diameter beads, the specific surface area is large, so the processing speed is fast. In the case of a bead diameter of 0.1 mm, the impact force of the beads is small and it takes time to pulverize powder of several tens of micrometers or more, but when the particle size of the powder becomes 8 micrometers or less, pulverization proceeds rapidly. As shown in Fig. 6, in the data plotting the ZY concentration against the treatment time, good results were obtained when beads with a diameter of 0.2 to 0.8 mm were used, and the case of a bead diameter of 0.3 mm (○ in Fig. 6) gave the best results. When beads with a diameter of 0.1 mm (△ in Fig. 6) and 1 mm (◆ in Fig. 6) were used, the concentration of contaminants (ZY concentration) was high due to the wear of the beads. As described above, there are two factors contributing to the wear of the beads: the factor of increased wear due to the specific surface area of the beads and the factor of increased wear due to the single mass. For beads with a diameter of 0.1 mm, the influence of the specific surface area is large, so the wear of the beads is large. For beads with a diameter of 1 mm, the mass of each bead is large, and the collision energy between the beads is large, so the wear is large.

[0064] Test Example 2: Influence of the outer peripheral speed on the treatment time The relationship between the outer peripheral speed and the treatment time in the grinding process of the present disclosure was investigated. Using apparatus 1, a slurry (500 g) containing 5% by weight of phenytoin (raw material particle size: 16 to 20 μm), polyvinylpyrrolidone (3% by weight) and sodium lauryl sulfate (0.25% by weight) as a dispersant was ground using partially stabilized zirconia beads with a diameter of 0.2 mm to 0.8 mm (bead filling rate: 75%) until the average particle size reached around 200 nanometers. The results are shown in Fig. 7. Under the condition of the same bead diameter, the higher the outer peripheral speed, the shorter the treatment time. When beads with a diameter of 0.3 mm were used (○ in Fig. 7), even at an outer peripheral speed of 0.5 m / s, it was possible to grind to 200 nanometers in about 420 minutes.

[0065] Test Example 3: Influence of the outer peripheral speed on the contaminant concentration Using apparatus 1, a slurry (500 g) containing 5 wt% phenytoin (raw material particle size: 16 - 20 μm), 3 wt% polyvinylpyrrolidone and 0.25 wt% sodium lauryl sulfate as dispersants was ground using partially stabilized zirconia beads (bead filling rate: 75%) while changing the outer peripheral speed of the stirring rotor until the average particle size reached around 200 nanometers in the same manner as in Test Example 2, and the contaminant concentration (ZY concentration) when the average particle size of the phenytoin particles reached 200 nanometers was measured. The results are shown in Fig. 8.

[0066] Test Example 4: Influence of bead diameter on contaminant concentration Using apparatus 1, a slurry (500 g) containing 5 wt% phenytoin (raw material particle size: 16 - 20 μm), 3 wt% polyvinylpyrrolidone and 0.25 wt% sodium lauryl sulfate as dispersants was ground until the average particle size reached around 200 nanometers in the same manner as in Test Example 2 using partially stabilized zirconia beads with various bead diameters (bead filling rate: 75%). The slurry was ground at outer peripheral speeds of the stirring rotor of 2 m / s, 4 m / s, and 6 m / s, respectively, and the contaminant concentration (ZY concentration) in the slurry when the average particle size of the phenytoin particles reached 200 nanometers was measured. The results are shown in Fig. 9. The bead diameter used was 0.1 - 1 mm. The ZY concentration at each outer peripheral speed was the lowest at a bead diameter of 0.2 - 0.3 mm, and the ZY concentration was higher when the bead diameter was small or large. As shown in Fig. 9, when the outer peripheral speed was 2 m / s (△ in Fig. 9), between a bead diameter of 0.8 mm and 1.0 mm; when the outer peripheral speed was 4 m / s (◇), between a bead diameter of 0.5 mm and 0.8 mm; when the outer peripheral speed was 6 m / s (〇), between a bead diameter of 0.3 mm and 0.5 mm, the ZY concentration increased rapidly. As shown in Fig. 9, for each peripheral speed, from the intersection of the straight line connecting the data points of the above bead diameters and the horizontal straight line indicating a ZY concentration of 5 ppm, the value of the bead diameter at which the ZY concentration reaches 5 ppm was obtained and described. Even when the bead diameter was small, the ZY concentration increased. At a bead diameter of 0.1 mm, the ZY concentration was higher compared to the case of a bead diameter of 0.2 mm. Judging from the graph in Fig. 9, the lower limit of the bead diameter at which the ZY concentration exceeds 5 ppm is approximately 0.15 mm. Therefore, the upper limit of the bead diameter at which the ZY concentration increases rapidly is a value affected by the outer peripheral speed, while the lower limit is approximately 0.15 mm.

[0067] Test Example 5: Relationship between bead diameter and outer peripheral speed Using Apparatus 1, a slurry (500 g) containing 5 wt% of phenytoin (raw material particle size: 16 - 20 μm), polyvinylpyrrolidone (3 wt%) and sodium lauryl sulfate (0.25 wt%) as a dispersant was pulverized at the outer peripheral speeds shown in the following table together with partially stabilized zirconia beads of various bead diameters shown in the following table (bead filling rate: 75%), and the contaminant concentration (ZY concentration) in the slurry when the average particle diameter of the phenytoin particles reached around 200 nanometers was measured.

Table 1

[0068] Test Example 6: Influence of bead filling rate A slurry containing 5% by weight of phenytoin (raw material particle size: 16 - 20 μm), polyvinylpyrrolidone (3% by weight) and sodium lauryl sulfate (0.25% by weight) as a dispersant was used with 0.3 mm diameter partially stabilized zirconia beads, the bead filling rate was changed, and at an outer peripheral speed of 2 m / sec, it was pulverized to near an average particle size of 200 nanometers in the same manner as in Test Example 1, and the contaminant concentration (ZY concentration) when the average particle size of the phenytoin particles reached 200 nanometers was measured. The treatment time and the ZY concentration were 600 minutes at a filling rate of 25% and 0.50 ppm, 330 minutes at a filling rate of 35% and 0.70 ppm, 90 minutes at a filling rate of 75% and 0.99 ppm, and 90 minutes at a filling rate of 90% and 1.4 ppm, respectively. At a filling rate of 25%, the ZY concentration was low but the treatment time was long. Also, at a filling rate of 90%, the treatment time did not change compared to a filling rate of 75%, and the ZY concentration increased slightly.

[0069] Test Example 7: Influence of slurry concentration The concentration of phenytoin in the slurry (raw material particle size: 16 - 20 μm) was changed, and 0.3 mm diameter partially stabilized zirconia beads were used (bead filling rate: 75%). Grinding treatment was carried out with apparatus 1 at an outer peripheral speed of 2 m / sec in the same manner as in Test Example 1. The grinding treatment time until reaching 200 nanometers and the concentration of the contaminant (ZY) in the slurry when reaching 200 nm are shown in the table below.

Table 2

[0070] Examples 1 - 31 Using the bead mills (apparatus 1 - 4) shown in FIGS. 1 - 4, slurries of various organic particles (phenytoin, sulfamethoxazole, fenofibrate, mefenamic acid, itraconazole) were subjected to grinding treatment. The bead mill apparatuses used are as follows (all of the following zirconia contain yttrium as an additive). Apparatus 1: Apex Mill 015 type (manufactured by Hiroshima Metal & Machinery). The material of the chemical feeding part is tungsten carbide, nickel (mechanical seal), reinforced alumina with zirconia (stator), zirconia (rotor), perfluoro (O - ring). Apparatus 2: Ultra Apex Mill 015 type (manufactured by Hiroshima Metal & Machinery). The material of the chemical feeding part is tungsten carbide, nickel (mechanical seal UPPER side, LOWER side), reinforced alumina with zirconia (stator), zirconia (separator, rotor), perfluoro (O - ring). Apparatus 3: Experimental prototype. The material of the chemical feeding part is reinforced alumina with zirconia (stator), zirconia (rotor), SUS316L (pumping device), perfluoro (O - ring). Device 4: Dyno Mill Research Laboratory Type [Miniature Bead-Compatible Small Wet Dispersion and Grinding Machine] (manufactured by Shinmaru Enterprises). The materials of the dosing part are zirconia (including hafnium) (accelerator, wear bush), SSiC (silicon carbide) (grinding cylinder), nickel, hard chrome plating (screen), and Viton (registered trademark) (O-ring). The conditions and results of the grinding processes of the respective examples are shown in Table 3. Also, as comparative examples, Comparative Example 1 using beads made of reinforced alumina, and Comparative Examples 2 to 6 where the peripheral speed or bead diameter is outside the range of the conditions of the present disclosure are shown. The concentration of contaminants is described for zirconium and yttrium of the bead component, the component (aluminum) of the reinforced alumina which is the material of the container of the bead mill, and the concentrations of iron, nickel, chromium, and tungsten which are the main components of the metal members used in the bead mill, respectively (expressed in mass ppm with respect to the weight of the ground slurry).

Table 3

[0071] Examples 1 to 25 are the results of grinding 500 grams of slurry to a final particle size of around 200 nanometers using Device 1 with an effective internal volume of 150 milliliters. The ZY concentration in the slurry (in the column of "Total ZrY" in the table) was 5 ppm or less in all cases. The processing time was also within an industrially appropriate range. Also, even when the slurry concentration was as high as 50% by weight, it could be processed without extending the processing time, and the ZY concentration was also as low as 1.48 ppm (Example 17).

[0072] Examples 26 and 27 are the results of grinding phenytoin using Device 2 with an effective internal volume of 150 milliliters. In Example 26, the ZY concentration was extremely low at 0.48 ppm.

[0073] Examples 28 to 30 are the results of treating phenytoin with apparatus 3 having an internal volume of 150 milliliters, the apparatus configuration in the mill being substantially the same as that of apparatus 1. In any of the examples, the ZY concentration was low (maximum 1.07 ppm), and the processing time was also within an appropriate range at a maximum of 300 minutes. Since apparatus 3 is not equipped with a mechanical seal, the concentrations of nickel and tungsten were lower than when using apparatus 1 having a mechanical seal (Examples 1 to 25). Thus, it was also confirmed that in a bead mill not equipped with a mechanical seal, there is an effect of reducing the concentration of heavy metal contaminants in the slurry from the metal members.

[0074] Example 31 is the result of performing a grinding process using apparatus 4. Apparatus 4 is a horizontal bead mill, and a plurality of stirring rotors with holes in irregularly shaped plates are installed. In terms of the processing time, there was no problem with the grinding up to 210 nanometers in 70 minutes. In terms of the contaminant concentration, the ZY concentration was approximately 2.1 ppm, which was a higher concentration compared to the case of treating with apparatus 1 under the same operating conditions (approximately 1.4 ppm in Example 10), but the results were sufficiently good.

[0075] On the other hand, in Comparative Example 1 using reinforced alumina beads, the aluminum contamination in the slurry was nearly 100 ppm, and the contaminant concentration was extremely high. This is because although reinforced alumina has high strength, it has low ductility, so wear progresses rapidly. Comparative Examples 2 to 6 are processes using partially stabilized zirconia beads with apparatus 1, but the outer peripheral speed or bead diameter deviates from the conditions of the present disclosure (0.15 mm or more and 1.07 - 0.11 × [outer peripheral speed of the stirring rotor (m / s)] (mm) or less). In all of Comparative Examples 2 to 6, the ZY concentration exceeded 5 ppm, and the maximum value was approximately 54.5 ppm.

Industrial Applicability

[0076] The present disclosure can be applied to the production of organic nanoparticles such as pharmaceuticals, health foods, and X-ray contrast agents.

Explanation of Reference Numerals

[0077] 1‥‥Cylinder 2‥‥Upper lid 3‥‥Lower lid 4‥‥Rotating shaft 5‥‥Agitating rotor 6‥‥Slurry supply port 7‥‥Slurry discharge port 8‥‥Flag type bead separator 9‥‥Rotating shaft pulley 10‥‥Belt 11‥‥Motor pulley 12‥‥Motor 13‥‥Mechanical seal 14‥‥Centrifugal bead separator 15‥‥Slurry storage tank 16‥‥Connecting pipeline 17‥‥Pumping device 18‥‥Slurry pipe 19‥‥Slurry pump 20‥‥Slurry tank 21‥‥Agitating device 22‥‥Slurry connecting pipe 23‥‥Screen

Claims

1. A method for producing organic nanoparticles, comprising the step of stirring a mixture containing a slurry containing organic particles and beads having an average particle size of 0.2 to 0.8 mm in a container of a wet bead mill with a stirring rotor rotating at a peripheral speed of 2 to 6 m / sec, wherein a rotation shaft for rotating the stirring rotor is installed in the vertical direction in the container of the wet bead mill, the organic nanoparticles are organic nanoparticles used in the fields of medicines or health foods, the beads are made of partially stabilized zirconia, and the amount of impurities contained in the organic nanoparticles is 5 ppm or less.

2. A method for producing organic nanoparticles, comprising the step of stirring, in a container of a wet bead mill, a mixture containing a slurry containing organic particles and beads having an average particle size of 0.2 mm or more and a value (mm) or less calculated by 1.07-0.11 x [circumferential speed of the stirring rotor (m / sec)], with a stirring rotor rotating at a peripheral speed of 2 to 6 m / sec, wherein a rotation shaft for rotating the stirring rotor is installed in the vertical direction in the container of the wet bead mill, the organic nanoparticles are organic nanoparticles used in the fields of medicines or health foods, the beads are made of partially stabilized zirconia, and the amount of impurities contained in the organic nanoparticles is 5 ppm or less.

3. A method for reducing the contaminant concentration in the entire milled slurry, comprising the step of stirring a mixture containing a slurry containing organic particles and beads having an average particle size of 0.2 to 0.8 mm in a container of a wet bead mill with a stirring rotor rotating at a peripheral speed of 2 to 6 m / sec, wherein a rotating shaft for rotating the stirring rotor is installed in the vertical direction in the container of the wet bead mill, the organic nanoparticles are organic nanoparticles used in the fields of pharmaceuticals or health foods, the beads are made of partially stabilized zirconia, and the contaminant concentration is 5 ppm or less.

4. A method for reducing a contaminant concentration in the entire pulverized slurry, comprising the step of stirring, in a container of a wet bead mill, a mixture containing a slurry containing organic particles and beads having an average particle size of 0.2 mm or more and a value (mm) or less calculated by 1.07-0.11 x (circumferential speed of the stirring rotor (m / sec)), with a stirring rotor rotating at a peripheral speed of 2 to 6 m / sec or less, wherein a rotating shaft for rotating the stirring rotor is installed in the vertical direction in the container of the wet bead mill, the organic nanoparticles are organic nanoparticles used in the fields of pharmaceuticals or health foods, the beads are made of partially stabilized zirconia, and the contaminant concentration is 5 ppm or less.

5. A method or method for producing an organic nanoparticle according to any one of claims 1 to 4, wherein the organic nanoparticle comprises a pharmaceutical compound.

6. A manufacturing method or method described in any of claims 1 to 5, wherein the container of the wet bead mill is a vertical cylindrical container having an opening at the top of the cylindrical container, a rotating shaft that rotates the agitator rotor is inserted into the cylindrical container from above through the opening, and the agitator rotor is connected to the rotating shaft.

7. 7. The manufacturing method or method according to claim 6, wherein a slurry storage tank is provided above the cylindrical container, the cylindrical container and the slurry storage tank are connected via a connecting pipeline, a rotating shaft for rotating the stirring rotor is inserted into the cylindrical container from above the slurry storage tank via the slurry storage tank and the connecting pipeline, the stirring rotor is connected to the rotating shaft, and the slurry after the bead separation process is discharged from the bottom of the cylindrical container.

8. A manufacturing method or method described in any one of claims 1 to 7, wherein the impurities contained in the organic nanoparticles originate from components of the beads or components of metal parts of a bead mill apparatus.

9. The manufacturing method or method described in claim 8, wherein the contaminant is a heavy metal.

10. The method or process of claim 9, wherein the heavy metal is zirconium, yttrium, aluminum, iron, nickel, chromium, and / or tungsten.

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