Method for producing composite particles including amorphized organic compound

Abstract

To provide a method for producing composite particles including an easily amorphized organic compound.SOLUTION: A method for producing composite particles comprises a compounding step in which nuclear particles having no amorphous stabilization effect and crystalline organic compound particles are mechanically stirred and mixed, pulverization and amorphization of the crystalline organic compound particles are promoted by an effect of the nuclear particles associated with mechanical action by stirring and mixing, and amorphous organic compound particles derived from the crystalline organic compound particles are attached on a surface of the nuclear particles. Thus, composite particles including amorphous organic compound particles on the surface of the nuclear particles are obtained.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present specification relates to a method for producing composite particles containing an amorphous organic compound, etc. [Background technology]

[0002] Amorphizing crystalline organic compounds, which are active ingredients of pharmaceuticals, is a promising method for improving the solubility and dissolution rate in aqueous media. Methods for amorphizing crystalline organic compounds include a method in which crystalline powder is dissolved in an organic solvent and sprayed onto core particles to amorphize and granulate (Patent Document 1), a method in which an amorphous stabilizer is thermally melted to amorphize and granulate the crystalline powder, and a method in which crystalline powder is pulverized by a ball mill to amorphize the powder. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2021-113183 A Summary of the Invention [Problem to be solved by the invention]

[0004] However, such methods have problems such as residual organic solvents, complicated manufacturing processes such as the need for heating and melting to make the compound amorphous, and the effect of heat on the compound.

[0005] The present specification provides a method for producing composite particles comprising an organic compound that is easily made amorphous, and the like. [Means for solving the problem]

[0006] The present inventors, while conducting various studies on amorphizing crystalline powder, have found that it is possible to generate amorphous organic compound particles from crystalline particles by mechanically stirring and mixing core particles and crystalline organic compound particles smaller than the core particles, and pulverizing and amorphizing the crystalline organic compound particles due to the action of the core particles accompanying the mechanical action of the stirring and mixing, and to cause the amorphous organic compound particles generated in situ to adhere and deposit on the core particles. Based on such findings, the present specification provides the following means.

[0007] [1] A method for producing composite particles, comprising the steps of: The present invention relates to a method for producing composite particles having amorphous organic compound particles on the surface of the core particles, the method comprising: a composite step of mechanically stirring and mixing core particles not having an amorphous stabilizing effect with crystalline organic compound particles, promoting the pulverization and amorphization of the crystalline organic compound particles by the action of the core particles accompanying the stirring and mixing, and attaching the amorphous organic compound particles derived from the crystalline organic compound particles to the surface of the core particles. [2] The method according to [1], wherein the average particle size of the core particles in the composite step is 1.5 to 30.0 times the average particle size of the crystalline organic compound particles. [3] The method for producing a crystalline organic compound particle according to [1] or [2], wherein the mass of the core particle in the composite step is 3.0 times or more and 10.0 times or less than the mass of the crystalline organic compound particle. [4] The method according to any one of [1] to [3], wherein the composite step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles. [5] The method according to any one of [1] to [4], wherein the compounding step is carried out so as to maintain a temperature inside a container in which the compounding step is carried out below a glass transition temperature of the organic compound of the amorphous organic compound particles. [6] The method according to any one of [1] to [5], wherein the core particles are selected from pharma-ceutically acceptable excipients. [7] The method according to [6], wherein the core particles are one or more selected from the group consisting of lactose, glucose, starch, corn starch, crystalline cellulose and methylcellulose. [8] A composite particle comprising: A core particle having no amorphous stabilizing effect; a layer derived from amorphous organic compound particles and amorphous stabilizer particles on a surface of the core particle; A composite particle comprising: [Brief description of the drawings]

[0008] [Figure 1] FIG. 2 is a diagram showing the function of a core particle in the method for producing a composite particle disclosed in the present specification. [Diagram 2] FIG. 1 illustrates an example of a composite particle disclosed herein. [Diagram 3] FIG. 2 is a diagram showing another example of a composite particle disclosed in the present specification. [Figure 4] FIG. 2 is a diagram showing a schematic configuration of a horizontally placed composite device for explaining composite parameters. [Diagram 5] FIG. 13 is a diagram showing the relationship between various numerical elements in a composite device and compression efficiency, which is a composite parameter. [Figure 6] FIG. 2 shows (a) an X-ray diffraction spectrum, (b) a Raman spectrum, and (c) a DSC curve in an example. [Figure 7] The figures show scanning electron microscope photographs (a1) and (a2) (a1 is 600x, a2 is 5000x, same below) of core particles which are crystalline cellulose particles, composite particles (b1) and (b2) with a mixing time of 30 minutes, and composite particles (c1) and (c2) with a mixing time of 180 minutes. [Figure 8] FIG. 1 is a graph showing mixing time and the content of amorphous indomethacin (relative to active ingredient) in composite particles. [Figure 9] FIG. 13 is a diagram showing the results of an elution test of composite particles. [Figure 10] FIG. 13 is a diagram showing the results of a physical stability test of composite particles in the presence of silica gel at 25° C. [Figure 11]FIG. 13 shows X-ray diffraction spectra and Raman spectra of composite particles obtained by processing at different rotor rotation speeds in Example 4. [Figure 12] FIG. 13 shows X-ray diffraction spectra and Raman spectra of composite particles obtained by treatment for different treatment times in Example 4. [Figure 13] FIG. 13 shows X-ray diffraction spectra and Raman spectra of composite particles obtained by treating different sample substantial volumes in Example 5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The disclosure of the present specification relates to a method for producing composite particles containing an amorphous organic compound. The production method of the present disclosure includes a composite step of mechanically stirring and mixing core particles that do not have an amorphous stabilizing effect with crystalline organic compound particles, promoting the pulverization and amorphization of the crystalline organic compound particles by the action of the core particles accompanying the mechanical action of the stirring and mixing, and attaching the amorphous organic compound particles derived from the crystalline organic compound particles to the surface of the core particles, thereby producing the composite particles having the amorphous organic compound particles on the surface of the core particles.

[0010] According to the above-mentioned manufacturing method, as shown in FIG. 1, the core particles function as a medium that promotes the pulverization and amorphization of the crystalline organic compound particles with the mechanical action of stirring and mixing. The core particles collide with and compress the crystalline organic compound particles, thereby pulverizing and amorphizing the crystalline organic compound particles. Furthermore, the amorphous organic compound particles that have been pulverized and amorphized have improved cohesive adhesion. As a result, composite particles containing an organic compound with improved solubility and dissolution rate in water can be obtained more easily.

[0011] Furthermore, since no solvent is used and no thermal melting is involved, residual solvent is avoided, workability is excellent, and costs can be reduced.

[0012] Furthermore, by mixing amorphous stabilizer particles together in the composite process, it is possible to obtain composite particles that can stably maintain the amorphous nature of the amorphous particles by suppressing recrystallization of the amorphous organic compound particles.

[0013] Furthermore, this manufacturing method can be widely applied to crystalline organic compound particles that can be made amorphous by mechanical treatment, for example, using a ball mill, and to organic compounds that can be made amorphous.

[0014] Hereinafter, the method for producing composite particles (hereinafter, also simply referred to as the present production method) will be described in detail in this specification.

[0015] (Method of manufacturing composite particles) This manufacturing method includes a composite step of mechanically stirring and mixing core particles that do not have an amorphous stabilizing effect with crystalline organic compound particles (hereinafter, also simply referred to as crystalline particles), promoting the pulverization and amorphization of the crystalline particles by the action of the core particles accompanying the mechanical action of stirring and mixing, and attaching the amorphous organic compound particles (hereinafter, also simply referred to as amorphous particles) derived from the crystalline particles to the surfaces of the core particles. In carrying out this manufacturing method, the core particles and the crystalline particles to be subjected to the composite step are each prepared.

[0016] (nuclear particle) The core particle is a particle that constitutes the core of the composite particle and becomes a carrier particle that supports the amorphous particle. The core particle is not particularly limited, but it is meaningful to have a shape such as a sphere, a block, a cube, a rectangular parallelepiped, or other polyhedron in terms of the impact force against the crystalline particle and its own breaking strength. That is, it is meaningful not to have a plate-like, flaky, rod-like, needle-like, columnar, spongy, or the like. If it is a plate-like, flaky, needle-like, rod-like, columnar, spongy, or the like, the impact force and breaking strength tend to be insufficient. Although not particularly limited, the maximum diameter and the minimum diameter of the core particle may be, for example, 0.7 to 1.3, 0.8 to 1.2, 0.85 to 1.15, 0.9 to 1.1, or, for example, 0.95 to 1.05, etc., and may be preferable in terms of impact force and breaking strength.

[0017] In the compounding step, the core particles are suppressed from being pulverized and the particle shape is maintained. By using such core particles, the core particles can easily act as a pulverizing medium such as balls or beads in ball mill pulverization for the crystalline particles. Pulverization can be suppressed by taking into account the breaking strength due to the shape and size of the core particles.

[0018] Although the core particles are not particularly limited, typically, pharma- ceutically acceptable excipient particles can be used. For example, monosaccharides and disaccharides known as excipients such as lactose, sucrose, mannitol, and glucose, polysaccharides known as excipients such as starch (including corn starch), crystalline cellulose, methylcellulose, and hydroxypropylmethylcellulose, and inorganic compounds known as excipients such as magnesium aluminometasilicate and anhydrous calcium phosphate can be mentioned. As monosaccharides, disaccharides, and polysaccharides, in addition to naturally occurring sugars, known derivatives thereof (e.g., deoxy sugars, amino sugars, thio sugars, ester derivatives, etc.) can also be used as appropriate. Crystalline cellulose may be preferred. In addition, it is preferable to use core particles that do not have an amorphous stabilizing effect. The core particles are also carrier particles that support crystalline particles, and it is more convenient in terms of formulation to have the carrier particles function alone.

[0019] The average particle diameter d1 of the core particles is not particularly limited in relation to the average particle diameter d2 of the crystalline particles, but it may be preferable that the average particle diameter d1 is larger than the average particle diameter d2. When the average particle diameter d1 is larger than d2, the impact force of the core particles when they collide with the crystalline particles is increased, and the destruction (amorphization) of the lattice structure of the crystalline organic compound particles is promoted. The average particle diameter d1 may be, for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.5 times or more, 1.8 times or more, 2.0 times or more, 2.5 times or more, and may be, for example, 3.0 times or more, 3.5 times or more, 4.0 times or more, 4.5 times or more, 5.0 times or more, 5.5 times or more, 6.0 times or more, 7.0 times or more, 8.0 times or more, 9.0 times or more, 10.0 times or more, 12.0 times or more, 14.0 times or more, and the like.

[0020] On the other hand, if the average particle diameter d1 is too large compared to the average particle diameter d2, the collision frequency decreases and the efficiency of amorphization tends to decrease, so the average particle diameter d1 may be, for example, 30.0 times or less, 25.0 times or less, 20.0 times or less, 18.0 times or less, 16.0 times or less, 14.0 times or less, 12.0 times or less, 10.0 times or less, 8.0 times or less, 7.0 times or less, 6.0 times or less, 5.0 times or less, 4.0 times or less, 3.5 times or less, or 3.0 times or less.

[0021] The range of the ratio between the average particle diameter d1 and the average particle diameter d2 is not particularly limited, but can be set by appropriately combining the upper and lower limits described above. For example, it can be 1.5 times or more and 30.0 times or less, 1.5 times or more and 25.0 times or less, 1.5 times or more and 20.0 times or less, 1.5 times or more and 15.0 times or less, 1.5 times or more and 10.0 times or less, 1.5 times or more and 5 times or less, 1.5 times or more and 3.0 times or less, etc.

[0022] The average particle diameter d1 of the core particles is not particularly limited, and can be, for example, 10 μm or more, 15 μm or more, 20 μm or more, 25 μm or more, 30 μm or more, 35 μm or more, 40 μm or more, 45 μm or more, 50 μm or more, 60 μm or more, 70 μm or more, 80 μm or more, 90 μm or more, 100 μm or more, 125 μm or more, 150 μm or more, 175 μm or more, 200 μm or more, 225 μm or more, 250 μm or more, 300 μm or more, 350 μm or more, 400 μm or more, 450 μm or more, or 500 μm or more.

[0023] The average particle diameter d1 of the core particle is not particularly limited, but from the viewpoint of ensuring that the breaking strength of the core particle does not exceed the impact force of the core particle, it may be, for example, 600 μm or less, 550 μm or less, 500 μm or less, 450 μm or less, 400 μm or less, 350 μm or less, 300 μm or less, 250 μm or less, 200 μm or less, 175 μm or less, 150 μm or less, 125 μm or less, 100 μm or less, 90 μm or less, 80 μm or less, 70 μm or less, 60 μm or less, 50 μm or less, 40 μm or less, 30 μm or less, or 20 μm or less.

[0024] The range of the average particle diameter d1 of the core particles is not particularly limited, but can be set by appropriately combining the upper and lower limits described above. For example, it can be 10 μm or more and 500 μm or less, 15 μm or more and 500 μm or less, 20 μm or more and 500 μm or less, 20 μm or more and 400 μm or less, 20 μm or more and 350 μm or less, 20 μm or more and 300 μm or less, 10 μm or more and 200 μm or less, 20 μm or more and 200 μm or less, 20 μm or more and 150 μm or less, 20 μm or more and 100 μm or less, 10 μm or more and 30 μm or less, or 10 μm or more and 20 μm or less.

[0025] Both the average particle diameter d1 of the core particles and the average particle diameter d2 of the crystalline particles can be obtained as a volume-based median diameter (central diameter) by a laser diffraction / scattering method.

[0026] (crystalline organic compound particles) The crystalline particles are typically crystalline powders of organic compounds. The crystalline particles may be single crystals or polycrystals. They may also be polymorphic. The shape of the crystalline particles is not particularly limited, but may take various forms such as spherical, cubic, blocky, plate-like, columnar, rod-like, needle-like, dendritic, spongy, and amorphous.

[0027] The type of organic compound in the crystalline organic compound particles is not particularly limited, but for example, any organic compound that can be amorphized by a grinding method using a ball mill or the like can be amorphized by this manufacturing method. As the organic compound, it is meaningful to have an organic compound that can be an active ingredient of a pharmaceutical, and it is even more meaningful to have an organic compound that is poorly soluble in water due to its crystallinity. In addition, it can be confirmed in advance whether the crystalline organic compound that can be amorphized by this manufacturing method can be amorphized by a grinding method using a ball mill or the like, or whether it can be amorphized by this manufacturing method using crystalline cellulose as a core particle.

[0028] The crystalline particles are particles that are crushed by collision with the core particles and compression action accompanying the mechanical action during stirring and mixing. The lattice structure of the crystalline particles is also destroyed by these actions, making them amorphous, and the crushed amorphous particles are attached to the surface of the core particles and deposited. As already explained, the average particle size d2 of the crystalline particles is made smaller than the average particle size d1 of the core particles. This makes it easier for the crystalline particles to be crushed by collision with the core particles. It is preferable that the average particle size d2 of the crystalline particles has the same relationship as that of the average particle size d1 of the core particles as already explained.

[0029] The average particle diameter d2 of the crystalline particles is not particularly limited, but may be, for example, 3 μm or more, 4 μm or more, 5 μm or more, 6 μm or more, 7 μm or more, 8 μm or more, 9 μm or more, 10 μm or more, 12 μm or more, 14 μm or more, 15 μm or more, 16 μm or more, 18 μm or more, or 20 μm or more. The average particle diameter d2 may be, for example, 50 μm or less, 40 μm or less, 30 μm or less, 28 μm or less, 25 μm or less, 22 μm or less, or 20 μm or less. The average particle diameter d2 may be set by appropriately selecting the upper and lower limits described above, but may be, for example, 3 μm or more and 50 μm or less, 5 μm or more and 30 μm or less, 5 μm or more and 20 μm or less, or 10 μm or more and 20 μm or less. In addition, in the particle size distribution measured by the above-mentioned method, it may be advantageous that, for example, 80% or more, 85% or more, 90% or more, or 95% or more of the particles have a particle size of 100 μm or less on a volume basis in the range of particle sizes of 100 μm or less.

[0030] The core particles and the crystalline particles can be subjected to the composite process at any ratio. Considering the size of the core particles and the composition of the composite particles, the core particles can be more than 1 times, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more, 8 times or more, 9 times or more, 10 times or more, 12 times or more, 14 times or more, 16 times or more, etc., in terms of mass ratio. The above mass ratio can also be set, for example, to 20 times or less, 18 times or less, 16 times or less, 14 times or less, 12 times or less, etc. For example, it can be set to 2 times or more and 20 times or less, 3 times or more and 16 times or less, or 3 times or more and 10 times or less, etc.

[0031] In the composite process, the lattice structure of the crystalline particles is destroyed and the particles are made amorphous, but the amorphous state is unstable, so the particles may recrystallize. In the composite process, it may be effective to mix amorphous stabilizer particles (hereinafter also referred to as stabilizer particles) together in advance and composite them with the amorphous particles into core particles. As such stabilizer particles, known amorphous stabilizers can be appropriately used. Examples of amorphous stabilizers include polymer stabilizers, low molecular stabilizers, and inorganic stabilizers. Examples of polymer additives include, but are not limited to, cellulose derivatives such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), methacrylic acid copolymer (MAEA), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), ceracephate (CAP), hypromellose phthalate (HPMCP), and hypromellose acetate succinate (HPMCAS). Examples of low molecular weight stabilizers include, but are not limited to, low molecular weight compounds having a carbonyl group or an amino group, more specifically, amino acids such as arginine and tryptophan, and organic acids such as tartaric acid and citric acid. Examples of inorganic additives include, but are not limited to, porous bodies such as calcium carbonate and silicon dioxide.

[0032] The average particle diameter d3 of the stabilizer particles is not particularly limited, but it is preferable that the stabilizer particles are directly attached to the surface of the core particles having the average particle diameter d1, or that the stabilizer particles are crushed in the compounding process and the crushed particles are attached to the surface of the core particles. This is because the amorphous particles and particles derived from the stabilizer particles are attached to the surface of the core particles, and are then deposited, which is effective in stably maintaining the amorphous state of the amorphous particles. The average particle diameter d3 may be, for example, 2.0 times or less, 1.5 times or less, 1.2 times or less, 1.0 times or less, 0.8 times or less, 0.9 times or less, 0.8 times or less, 0.7 times or less, 0.6 times or less, or 0.5 times or less, relative to the average particle diameter d2 of the crystalline particles. The average particle diameter d3 may be, for example, 0.2 times or more, 0.3 times or more, 0.4 times or more, 0.5 times or more, or 0.6 times or more relative to the average particle diameter d2.

[0033] The average particle diameter d3 of the stabilizer particles is not particularly limited, and may be, for example, 5 μm or more, 10 μm or more, 20 μm or more, 25 μm or more, or 30 μm or more. The average particle diameter d3 may be, for example, 50 μm or less, 40 μm or less, 30 μm or less, or 20 μm or less. The range of the average particle diameter d3 can be set by appropriately selecting the upper and lower limits described above, and may be, for example, 5 μm or more and 50 μm or less, 10 μm or more and 40 μm or less, etc. The average particle diameter d3 of the stabilizer particles can also be obtained by the same measurement method as the average particle diameters d1 and d2 described above.

[0034] The amount of stabilizer particles is not particularly limited, and is appropriately set according to the type, etc. For example, it can be appropriately set within a range of 0.01 times or more and 100 times or less of the mass of the crystalline particles. For example, in the case of a polymer stabilizer, it can be set to 0.05 times or more and 100 times or less, 0.1 times or more and 5 times or less, or 0.5 times or more and 2 times or less, and in the case of a low molecular stabilizer and an inorganic stabilizer, it can be set to 0.01 times or more and 10 times or less.

[0035] In the compounding process, the core particles and the crystalline particles are mechanically stirred and mixed, and the crystalline particles are pulverized by the action of the impact force and compression force of the core particles associated with this mechanical action, thereby making the crystalline particles finer and amorphous. Furthermore, the amorphous particles obtained by pulverization have strong adhesive and cohesive properties, so they can adhere to the surface of the core particles to achieve compounding. According to this manufacturing method, the action of the core particles associated with the mechanical action allows the crystalline particles to be pulverized into amorphous particles without using an amorphous stabilizer, and at the same time, they can be compounded with the core particles, which are excipients.

[0036] The mechanical action of the stirring and mixing used in the compounding step is effectively generated, for example, by using an apparatus equipped with a grinding mechanism that exerts a high shearing force. A large effect can be exerted on the core particles by the high shearing stress. As such a compounding apparatus, a known stirring granulation apparatus or compounding apparatus having a rotating stirring blade (rotating blade, rotor, etc.) can be used. Such an apparatus can be commercially obtained as appropriate. For example, a high-speed stirring granulator (TMG1 / 6, etc.) manufactured by Glatt, a dry compounding apparatus such as Nobilta NOBMINI manufactured by Hosokawa Micron Corporation, and similar apparatuses can be used.

[0037] In these composite devices, composite particles in which amorphous particles are composited with core particles can be obtained by adjusting the rotation speed and mixing (composite) time. For example, composite particles can be obtained by using the above-mentioned high-speed stirring granulator manufactured by Glatt at 1000 rpm for about 180 minutes, or by using the above-mentioned dry composite device manufactured by Hosokawa Micron Corporation at 7000 rpm for about 10 minutes.

[0038] Here, the impeller in the container of the compounding device that performs mixing and stirring may rotate around an axis along the vertical direction as in the above-mentioned high-speed stirring granulator, may rotate around a horizontal axis as in the above-mentioned dry compounding device, or may rotate around an axis inclined in an oblique direction. The shape of the impeller is not particularly limited, but examples include a plate-like blade shape extending vertically from the rotation axis. When the rotor is a plate-like blade, the blade may be attached parallel to the rotation axis as in the above-mentioned dry compounding device, or may be attached obliquely to the rotation axis as in the above-mentioned high-speed stirring granulator.

[0039] (composite parameters) In addition, in order to efficiently obtain composite particles by the present manufacturing method, it may be preferable to use, for example, a device capable of exerting specific parameters as a composite device for carrying out the composite step. The composite parameters will be described below using, as an example, a horizontal composite device (for example, the above-mentioned dry composite device) equipped with a rotor rotating around an axis along a substantially horizontal direction in a cylindrical container extending along the horizontal direction.

[0040] Figure 4 shows a schematic diagram of a horizontal-type composite device to explain the composite parameters. As shown in Figure 4(a), the container (cylinder) is turned sideways, so the composite sample (nucleus particles and crystalline particles) is deposited on the lower inner wall of the container. The height of the sample (h0) at this time can be calculated from the actual volume of the sample (for example, the volume of a right circular cylinder with a missing part - High-precision calculation site (casio.jp) (https: / / keisan.casio.jp / exec / system / 1440737868)). The actual volume of the sample can be determined from the true density of the sample measured with a gas displacement pycnometer and the mass of the sample. The true density is determined as follows. The composite sample contains all of the core particles, crystalline particles, stabilizer particles, and / or adhesion inhibitors used in the composite, and the true density of the composite sample can be obtained by measuring the true density of each component and calculating the weighted average of the true densities of each component, or the true density of the composite sample, which is a mixture, can be measured.

[0041] As shown in Fig. 4(b), when the rotor rotates, the sample is forced to pass through the gap between the rotating blade and the inner wall of the container. The sample height (h0) is reduced by the clearance (h c At this time, the bulk density of the sample is defined by the following formula:

[0042]

number

[0043] Next, as shown in Figure 4(c), four sets of 18 mm wide rotating blades are attached to a rotor with a total length of 56 mm, and two of them are aligned in the same line. As a result, when the rotor rotates once, the sample deposited on the inner wall of the container is compressed an average of (18 x 2 ÷ 56) x 4 = 2.57 times. When the rotation speeds are 7000 rpm (116.7 rps), 5000 rpm (83.3 rps), and 3000 rpm (50.0 rps), the number of times the sample is compressed per second is 300, 214, and 129, respectively.

[0044] Here, the compression efficiency is defined as the product of the degree of bulkiness and the number of compressions. Figure 5 shows the values ​​of various elements based on Figure 4 and the compression efficiency calculation results obtained from these values. Compression efficiency (s -1 ) = Bulkiness x Number of compressions

[0045] In the above description, the composite parameters are described for a horizontally-mounted composite device having rotors that rotate around an axis that is approximately horizontal and that is disposed within a cylindrical container that extends along the horizontal direction, but the present invention is not limited to such a device. The present invention can also be applied to a vertically-mounted composite device having rotors that rotate around an axis that is vertical and that is disposed within a cylindrical container that extends along the vertical direction.

[0046] In this case, it can be assumed that the sample sticks uniformly to the inner wall of the container due to the centrifugal force caused by the rotor rotation. In this case, the sample height (h0) can be calculated from the actual volume of the sample using the formula for calculating the volume of a hollow cylinder (https: / / keisan.casio.jp / exec / system / 1340326914). Using this sample height (h0), the bulkiness can be calculated in the same manner as above, and the compression efficiency can be calculated from the number of compressions.

[0047] The higher the rotor rotation speed, the higher the compression efficiency, and the higher the bulkiness. It is considered that the higher the compression efficiency in the compounding process, the better the compounding efficiency and the shorter the compounding time. According to the present inventors, by setting the compression efficiency to, for example, 150 or more, 155 or more, 160 or more, 165 or more, 170 or more, 175 or more, 180 or more, 190 or more, 195 or more, 200 or more, 205 or more, or 210 or more, the composite particles can be obtained efficiently. The upper limit of the compression efficiency is not particularly limited because it depends on the rotor rotation speed and the volume of the container allowed for the compounding device, but is, for example, 300 or less, 280 or less, 260 or less, 240 or less, 230 or less, or 220 or less.

[0048] In order to obtain a desired compression efficiency, the actual volume of the sample to be compounded can be adjusted to increase the sample height (h0) or the clearance between the inner wall of the container and the stirring blade can be reduced in order to obtain a desired degree of bulkiness. Also, in order to obtain a desired number of compressions, the rotation speed of the rotor can be increased or the number of rotor blades around the rotation shaft can be increased.

[0049] Furthermore, a compounding apparatus capable of realizing a degree of bulkiness and number of compressions that result in such effective compression efficiency can be said to be a compounding apparatus useful for carrying out the compounding step of the present manufacturing method.

[0050] (compounding device) A compounding device suitable for this manufacturing method may include, for example, a cylindrical container arranged with its long axis along the horizontal or vertical direction for mixing and stirring, a rotor arranged in the cylindrical container along the long axis direction, and a rotor blade arranged perpendicular to the rotor toward the inner wall of the cylindrical container. The rotor of such a compounding device can rotate at a rotation speed of, for example, 5000 rpm or more, 7000 rpm or more in order to increase the number of compressions, and the rotor blades are provided around the rotor in the number of, for example, 3, 4, 5, or 6 or more. In addition, the compounding device may have a distance between the rotor blade and the inner wall of the cylindrical container of, for example, 2 mm or less, 1 mm or less, in order to increase the degree of bulkiness.

[0051] In order to prevent the composite particles from adhering to the inner wall of the container for mixing and stirring the device, lubricants and flow agents such as light anhydrous silicic acid, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sucrose fatty acid esters can be used as appropriate. Among them, light anhydrous silicic acid and talc may be useful. The average particle size of these adhesion prevention agents is not particularly limited, but may be, for example, 10 μm or less, 1 μm or less, or 100 nm or less. The adhesion prevention agent may be, for example, 0.1% by mass or more and 10% by mass or less, and 0.5% by mass or more and 2% by mass or less, based on the total mass of the crystalline particles and the stabilizer particles.

[0052] In the composite step, it is effective to perform the mechanical stirring and mixing operation by maintaining the temperature in the container in which the core particles and the crystalline particles are stirred and mixed at a temperature that can suppress recrystallization. More specifically, it is effective to maintain the temperature so as not to exceed the glass transition temperature of the organic compound of the amorphous particles. If the temperature is higher than the glass transition temperature, the amorphous particles will soften (liquefy), the composite particles will be more likely to aggregate, and the recrystallization rate of the amorphous particles will increase. Depending on the type of organic compound of the crystalline particles, the inside of the stirring and mixing container can be set to, for example, 40°C or less, 35°C or less, 30°C or less, 25°C or less, 20°C or less, 15°C or less, or 10°C or less. To set the inside of the stirring and mixing container to such a temperature, the jacket temperature for controlling the temperature of the stirring and mixing container from the outside can be set to, for example, 25°C or less, 20°C or less, 15°C or less, 10°C or less, 5°C or less, 0°C or less.

[0053] In the compounding step, in addition to the core particles and crystalline particles, stabilizer particles and adhesion inhibitors are provided to the container of the compounding device. These may all be charged into the container at once, simultaneously, or individually, or may be charged continuously or intermittently. The order of charging is not particularly limited. Typically, the entire amount may be charged at once at the same time, or the entire amount of core particles may be charged, and then the crystalline particles and other particles may be charged. For example, after the entire amount of core particles is charged, a predetermined amount of crystalline particles may be uniformly and continuously supplied per hour for a required time previously acquired to compound a predetermined amount of crystalline particles with respect to the amount of core particles charged. When other agents such as stabilizer particles and adhesion inhibitors are used in addition to the crystalline particles, a mixture of the crystalline particles and these other agents may be continuously supplied to the container from one supply system at a predetermined ratio as described above. Also, one or more types selected from the group consisting of crystalline particles and other agents may be appropriately combined and continuously supplied to the container from two or more supply systems at a predetermined ratio.

[0054] The composite particles obtained in the composite process have amorphous particles attached to the surface of the core particles, and depending on the amount of amorphous particles, the amorphous particles are deposited on the surface of the core particles to form an amorphous particle layer. Also, the composite particles have a mixed layer of amorphous particles and stabilizer particles attached and deposited on the surface of the core particles, or a solid dispersion phase in which the amorphized organic compound is dispersed within or together with the stabilizer particles. When the amorphous particles are stabilized by the stabilizer particles, the amorphous particles may be dispersed together with or in the stabilizer particles at the molecular level to form an amorphous solid dispersion. In this case, for example, when observed with an electron microscope, it may be difficult to clearly distinguish between the two.

[0055] By providing the surface layer with amorphous particles or an amorphous particle layer, or with amorphous particles and stabilizer particles, or a mixed layer of these (solid dispersion phase), even a small amount of stabilizer particles can effectively come into contact with the amorphous particles, thereby stably maintaining the amorphous state of the amorphous particles.

[0056] The degree of amorphousness of the amorphous particles in the composite particles is not particularly limited, but it is useful to have a higher degree of amorphousness, for example, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 99% or more, etc.

[0057] In addition, when the composite particles obtained in the composite process are a layer in which amorphous particles are attached or deposited on the surface of a core particle, stabilizer particles may be further attached or deposited on these particles or layers.

[0058] As explained above, the present manufacturing method is a practical method for manufacturing composite particles that can achieve amorphization and composite with core particles in one go by the action of core particles accompanying mechanical action based on stirring and mixing without the need for solvents, amorphous stabilizers, or thermal melting in the composite step. Such composite particles can be used as raw materials (components) for various preparations such as fine granules, granules, capsules, and tablets.

[0059] (composite particles) The composite particle disclosed in the present specification can include a core particle that does not have an amorphous stabilizing effect, and a layer derived from an amorphous organic compound particle on the surface of the core particle. As shown in Fig. 2, this composite particle (composite particle of the first embodiment) is composed of crystalline organic compound particles that are amorphousized by the mechanical action in the composite step and the action of the core particle without using an amorphous stabilizer, and therefore includes amorphous particles on the core particle that does not contain an amorphous stabilizer. The core particle and the amorphous particle in this composite particle can be applied to various embodiments already described.

[0060] The composite particle includes a core particle having no amorphous stabilizing effect and a layer derived from amorphous organic compound particles and amorphous stabilizer particles. The layer may be a mixed layer of amorphous particles and stabilizer particles attached to the surface of the core particle or a solid dispersion phase. As shown in FIG. 3, the composite particle (composite particle of the second embodiment) can effectively suppress the recrystallization of the amorphous particles. EXAMPLES

[0061] In the following, examples are given as specific examples to more specifically explain the disclosure of this specification. The following examples are provided to explain the disclosure of this specification, but are not intended to limit the scope thereof. In the following, the average particle size is the volume-based median size (central size) measured by a laser diffraction / scattering method. EXAMPLES

[0062] (Production of composite particles using dry layering granulation method) In this example, we investigated the possibility of amorphizing drugs using layering granulation, a granulation method in which small particles are attached and layered on a core substance with a large particle size without using a solvent. As a crystalline substance, indomethacin (IND) (average particle size: 20.5 μm) was used as a model drug, as it is easy to mechanically amorphize and has a relatively stable amorphous phase. As core substances (core particles), five types of MCC spherical particles with different particle sizes (CELLETS 127, 175, 200, 300, 500, Advanced Drug Delivery Technologies Ltd) were used. The D of CELLETS 127, 175, 200, 300, 500 was 50 The values ​​were 140 μm, 195 μm, 275 μm, 414 μm, and 649 μm, respectively (hereinafter referred to as MCCs-XS, MCCs-S, MCCs-M, MCCs-L, and MCCs-XL). IND crystals (30 g) and MCC spherical particles (300 g) were charged into a high-speed mixing granulator (TMG1 / 6, manufactured by Glatt Co., Ltd.) and mixed for up to 180 minutes at an impeller rotation speed of 1000 rpm (circumferential speed of 10.0 m / sec). The physical properties of the obtained composite particles were evaluated to examine whether they could be made amorphous. The results are shown in Figures 6 and 7.

[0063] Figure 6 shows the powder X-ray diffraction (XRPD) patterns, Raman spectra, and differential scanning calorimetry (DSC) curves of the composite particles obtained using MCCs-S as (a) to (c). As shown in Figure 6(a), the XRPD pattern of the simple physical mixture (PM) had sharp peaks (11.9°, 17.1°, 20.0°, 22.2°, 26.9°) derived from IND crystals (γ-form) and broad peaks (14.7°, 22.5°, 34.6°) derived from MCC crystals of about several nanometers in size. As the mixing time increased, the peaks derived from IND crystals became smaller, suggesting that the IND crystals were made amorphous by the mixing process. On the other hand, no new peaks were observed due to the mixing process, and the appearance of crystalline polymorphism could not be confirmed.

[0064] As shown in Figure 6(b), the Raman spectra show that the peaks specific to crystalline and amorphous IND are at 1698 cm-1 and 1680cm -1 As the mixing time increased, the peak of IND crystals became smaller and the peak of amorphous IND became larger. These results indicate that high-speed mixing caused the IND crystals to become amorphous without undergoing a crystal transition.

[0065] As shown in Figure 6(c), the DSC measurement results showed that the composite particles exhibited a baseline shift due to the glass transition of amorphous IND and an exothermic peak due to crystallization, which supported the presence of amorphous IND, similar to the results of XRPD and Raman spectra.

[0066] Electron microscope images of the composite particles after mixing for 30 and 180 minutes are shown in Fig. 7. As shown in Fig. 7, IND particles with a particle size of about 1 µm were attached and layered on the surface of the composite particles after mixing for 30 minutes, and the particle size of the composite particles became larger than that of the MCC particles. As with the case of using acetaminophen (AAP) crystals confirmed by the present inventors in the past, it was considered that the IND crystals were pulverized by mixing with the MCC particles and layered granulation occurred.

[0067] The surface condition and particle size of the composite particles processed for 180 minutes were equivalent to those processed for 30 minutes, indicating that the pulverization and granulation of the IND crystals were completed by the 30-minute mixing time. On the other hand, as shown in Figure 6, the amorphization of the IND crystals continued even after the 30-minute mixing time. These results indicate that the IND crystals are amorphized as soon as they are pulverized in the early stages of the mixing process. After that, the pulverized IND particles are no longer pulverized any further, but amorphization proceeds due to collisions between the MCC spherical particles. These results indicate that the ball mill effect of the MCC spherical particles causes amorphization in addition to layering granulation of the IND crystals. EXAMPLES

[0068] (Effect of particle size of core particles) Since the ball mill effect of the MCC spherical particles during the mixing process caused the drug crystals to become amorphous, we investigated the effect of the particle size of the MCC spherical particles. Raman spectra of composite particles made using MCC spherical particles of various particle sizes were measured, and the 1698 cm -1 and the peak height of 1680 cm specific to amorphous IND. -1 The degree of amorphousness of IND was calculated from the ratio of the peak heights of the two peaks. The results are shown in Figure 8.

[0069] As shown in Figure 8, the amorphization rate of IND increases with increasing particle size of the MCC spherical particles, and 100% amorphization of IND crystals was achieved when MCCs-L and MCCs-XL were used. This result suggests that MCC spherical particles with a large particle size promote amorphization. To examine the effect of particle size in detail, the ratios of the average particle size, volume, and specific surface area of ​​each MCC spherical particle to the smallest MCCs-XS (volume and surface area were calculated assuming that MCCs are spheres) are shown in Table 1.

[0070] [Table 1]

[0071] As already explained, the amorphization of IND crystals occurs due to the ball mill effect, i.e., collision, of MCC spherical particles. The impact force due to the collision is determined by the mass and acceleration of the MCC spherical particles, and is therefore proportional to the volume (cubed particle diameter). Assuming that the acceleration is equal, the collision force of each MCC spherical particle increases by approximately three times in the order of MCCs-XS, MCCs-S, MCCs-M, MCCs-L, and MCCs-XL, and the collision force of MCCs-XL is approximately 90 times that of MCCs-XS. Therefore, MCC spherical particles with a large particle diameter generate a strong collision force during mixing, which promotes the amorphization of IND crystals. On the other hand, since the specific surface area is inversely proportional to the particle diameter, the collision frequency of MCC spherical particles decreases with increasing particle diameter. In other words, the amorphization efficiency decreases with increasing particle diameter of MCC spherical particles.

[0072] As shown in Figure 8, the amorphization rate was faster when MCCs-XL was used than when MCCs-L was used. However, the amorphization rate of MCCs-XL was slower than expected based on the difference in volume (collision force) between MCCs-XL and MCCs-L. This is considered to be due to the decrease in collision frequency caused by the increase in particle size. D of composite particles made using each MCC spherical particle 50 The values, drug contents and drug recovery rates (expressed as the ratio of measured drug content to theoretical drug content) are shown in Table 2.

[0073] [Table 2]

[0074] As shown in Table 2, the particle size of the composite particles was larger than that of the MCC spherical particles, except when MCCs-XL was used. Furthermore, the drug recovery rate exceeded 90%, suggesting that most of the IND particles were layered on the MCC spherical particles. On the other hand, when MCCs-XL was used, a decrease in particle size and drug content was observed. This is thought to be due to the destruction of the MCC spherical particles by the mixing process, which caused the IND particles held by the MCC spherical particles to be released and adhere to the wall of the granulator. From the above, in this study, when mixing was performed for 180 minutes using MCCs-L, it was possible to produce composite particles in which completely amorphous IND particles were layered and granulated. EXAMPLES

[0075] A dissolution test was carried out under supersaturated conditions (10 times the solubility of IND crystals) for the composite particles obtained using MCCs-L. The results are shown in FIG. 9. As shown in FIG. 9, the composite particles showed a supersaturated phenomenon, and the dissolution concentration reached 2.5 times the solubility of the crystals at 10 minutes of dissolution. On the other hand, as a comparative example, amorphous IND produced by the melt quenching method (QC) showed a dissolution concentration equivalent to that of the composite particles, but it took 120 minutes of dissolution time to achieve this. The particle diameter of the amorphous IND layered on the composite particles was about 1 μm, which was smaller than that of QCIND. In addition, QC IND formed aggregates immediately after the dissolution test, but in the composite particles, the aggregation was suppressed by the amorphous IND being held on the surface of the MCC spherical particles. Therefore, it is considered that the amorphous IND layered on the MCC spherical particles has a larger effective surface area than QCIND, which resulted in a faster dissolution rate.

[0076] In addition, a physical stability test was performed on the composite particles in the presence of silica gel at 25°C. The results are shown in Figure 10. As shown in Figure 10, more than 90% of the amorphous IND layered on the MCC spherical particles crystallized after one day of storage, and was almost completely crystallized after one week. This crystallization rate was faster than that of QC-IND, which is thought to be due to the small particle size and large surface area of ​​amorphous IND. Therefore, polyvinylpyrrolidone (PVP) was added at 10% of the IND mass and mixed with the MCC spherical particles to prepare composite particles.

[0077] The amorphous IND in this composite particle could maintain the amorphous state for at least 4 weeks, and it was shown that the crystallization of the layered amorphous particles could be suppressed by using an additive that stabilizes the amorphous form. Furthermore, by using the amino acid arginine as a coformer of IND, we succeeded in producing spherical particles layered with the IND-ARG amorphous complex, which has high dissolution and physical stability.

[0078] These results demonstrate the feasibility of applying the dry layering granulation method using a high-speed agitator granulator to the design of amorphous formulations. EXAMPLES

[0079] (Study on the production of composite particles) In this example, cornstarch (average particle size: 20.1 μm) was used as the core particles, and indomethacin (IND) (average particle size: 14.0 μm) was used. A total of 9 g of the core particles and IND with a mass ratio of 10:1 was placed in a dry composite device (NOBMINI, manufactured by Hosokawa Micron Corporation, vessel container 0.02 liters), and mixed for 10 minutes at a rotor rotation speed of 3000 to 7000 rpm. The jacket temperature of the vessel container was set to 20°C. The processed product was evaluated for powder X-ray diffraction and Raman spectrum crystallinity. The results are shown in FIG. 11.

[0080] As shown in FIG. 11, as the rotor speed increases, the powder X-ray diffraction peaks (11.9°, 17.1°, 20.0°, 22.2°, 26.9°) and the Raman spectrum peak (1698 cm -1 ) disappeared, and the peak of amorphous IND (1680 cm -1 At a rotor speed of 7000 rpm, the peaks derived from crystals disappeared, indicating that complete amorphization of IND could be achieved in a treatment time of 10 minutes.

[0081] Further, 9 g of the core particles and IND in a mass ratio of 10:3 was put into the dry compounding device and mixed for 10 to 90 minutes at a rotor speed of 7000 rpm. The jacket temperature of the vessel was set to 20°C. The results of evaluating the crystallinity of the mixture by powder X-ray diffraction and Raman spectrum are shown in FIG. 12. As shown in FIG. 12, as the mixing time increased, the powder X-ray diffraction peaks and Raman spectrum peaks of IND crystals disappeared, and the peaks of amorphous IND appeared. At a mixing time of 90 minutes, the peaks derived from crystals disappeared. In other words, it was found that complete amorphization can be achieved in a short time even if the mixture contains crystalline particles at a high concentration.

[0082] The dry-type composite device used in this embodiment rotates along the rotor blades and the inner wall of a cylindrical vessel. When the core particles and the crystalline particles are interposed between the inner wall and the end of the rotor blades facing the inner wall, a strong shear compression force acts on them. This action promotes the crushing and amorphization of the crystalline particles due to the collision and compression action of the core particles, and it is believed that the mechanical action of the composite device itself also contributed to the crushing and amorphization of the crystalline particles IND. EXAMPLES

[0083] (Consideration of composite parameters) In this example, cornstarch (average particle size: 20.1 μm) was used as the core particles, and indomethacin (IND) (average particle size: 14.0 μm) was used to mix the core particles and IND at a mass ratio of 10:1. Samples with actual volumes of 4.0 ml, 5.0 ml, and 6.0 ml (masses of 6.02 g, 7.53 g, and 9.04 g, respectively) were placed in the dry compounding device used in Example 4, and compounded for 10 minutes at a rotor rotation speed of 7000 rpm. The jacket temperature of the vessel container was set to 20° C. The dry compounding device used in this example had the element configuration shown in FIG. 4, and showed the compression efficiency relative to the actual volume of the sample shown in FIG. 5. The powder X-ray diffraction and Raman spectrum crystallinity of the sample after 10 minutes of compounding treatment with this device were evaluated. The results are shown in FIG. 13.

[0084] As shown in FIG. 13, in the range of the actual volume of the sample from 4.0 to 6.0 mL, the powder X-ray diffraction peaks (11.9°, 17.1°, 20.0°, 22.2°, 26.9°) of the indomethacin crystals and the peak of the Raman spectrum (1698 cm -1 ) completely disappeared, and the peak of amorphous indomethacin (1680 cm -1) appeared. When the rotor speed was 7000 rpm, complete amorphization could be achieved in a processing time of 10 minutes even with a reduced sample loading amount. When the rotor speed was 7000 rpm, the compression efficiency was 202-225 ( / s) even when the actual sample volume was 4.0 ml-6.0 ml. It was considered that complete amorphization of indomethacin could be achieved when the compression efficiency was 200 / s or more.

[0085] On the other hand, when the rotor speed was lowered, the efficiency of amorphization of indomethacin significantly decreased even though the actual volume of the sample was 6.0 mL, which was thought to be due to a decrease in compression efficiency.

[0086] From this embodiment and embodiment 4, it was found that the compression efficiency is an index of compounding. It was also found that efficient compounding is possible when the compression efficiency is 200 or more.

Claims

1. A method for producing composite particles, comprising: a composite step of mechanically stirring and mixing core particles having a polyhedral shape and an average particle diameter of 70 μm or more, which do not have an amorphous stabilizing effect, with crystalline organic compound particles, and promoting pulverization and amorphization of the crystalline organic compound particles by at least one of an impact force and a compressive force on the core particles due to the mechanical action of the stirring and mixing, thereby causing amorphous organic compound particles derived from the crystalline organic compound particles to adhere to the surfaces of the core particles, A method for producing the composite particles, which have the amorphous organic compound particles on the surface of the core particles.

2. The method according to claim 1 , wherein the average particle size of the core particles in the composite step is 1.5 to 30.0 times the average particle size of the crystalline organic compound particles.

3. The method according to claim 1 , wherein the mass of the core particles in the composite step is 3.0 times or more and 10.0 times or less the mass of the crystalline organic compound particles.

4. The method according to claim 1 , wherein the compounding step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles.

5. The method according to claim 1 , wherein the compounding step is carried out so that a temperature inside a container in which the compounding step is carried out is maintained below a glass transition temperature of the organic compound of the amorphous organic compound particles.

6. The manufacturing method described in claim 1, wherein the compounding step includes mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles, and is carried out so as to maintain the temperature inside a container in which the compounding step is carried out below the glass transition temperature of the organic compound of the amorphous organic compound particles.

7. The manufacturing method described in claim 3, wherein the compounding step further includes mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles.

8. The manufacturing method described in claim 3, wherein the compounding step is carried out so as to maintain the temperature inside the container in which the compounding step is carried out below the glass transition temperature of the organic compound of the amorphous organic compound particles.

9. The manufacturing method described in claim 3, wherein the compounding step further includes mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles, and the compounding step is carried out so as to maintain the temperature inside a container in which the compounding step is carried out below the glass transition temperature of the organic compound of the amorphous organic compound particles.

10. The method of claim 1 , wherein the core particles are selected from pharmaceutically acceptable excipients.

11. The method according to claim 10, wherein the core particles are one or more selected from the group consisting of lactose, glucose, starch, corn starch, crystalline cellulose, and methyl cellulose.

12. The manufacturing method described in claim 1, wherein the average particle diameter of the core particles is 100 μm or more and 600 μm or less.

13. The manufacturing method described in claim 1, wherein the average particle diameter of the core particles is 100 μm or more and 450 μm or less.

14. The impact force or the compression force is generated by at least one of a collision and a compression action between the amorphous organic compound and the core particle, The amorphous organic compound is pulverized by the impact force or compression force. The method of claim 1.

15. The manufacturing method described in claim 1, wherein the stirring and mixing is performed using a stirring granulator.

16. The manufacturing method described in Claim 15, wherein the core particles are one or more types selected from the group consisting of lactose, crystalline cellulose, and methylcellulose.

17. A manufacturing method as described in claim 1, wherein the stirring and mixing in the compounding process is performed by rotating a rotor.

18. The stirring and mixing in the compounding step is carried out in a cylindrical vessel equipped with a rotating blade, 2. The manufacturing method according to claim 1, wherein a compression efficiency relative to the actual volume of a sample containing the core particles and the crystalline organic compound particles when the sample passes through the gap between the rotating blade and the cylindrical container is 200 or more. Compression efficiency (s −1 )=bulk degree×number of compressions Bulkiness = h0 - hc / h0 where h0 is the height of the sample in the container based on the actual volume of the sample, hc is the clearance between the inner wall of the container and the rotating blades, and the number of compressions indicates the number of times the sample is compressed by the rotating blades per second.

19. A method for producing composite particles, comprising: a composite step of mechanically stirring and mixing core particles having a polyhedral shape and an average particle diameter of 70 μm or more, which do not have an amorphous stabilizing effect, with crystalline organic compound particles to promote pulverization and amorphization of the crystalline organic compound particles, and attaching amorphous organic compound particles derived from the crystalline organic compound particles to the surfaces of the core particles; Equipped with The stirring and mixing in the compounding step is carried out in a cylindrical container equipped with a rotary blade, A manufacturing method for manufacturing the composite particles having the amorphous organic compound particles on the surface of the core particles, wherein the compression efficiency with respect to the actual volume of the sample containing the core particles and the crystalline organic compound particles is set to 200 or more when the sample passes through the gap between the rotating blade and the cylindrical container. Compression efficiency (s −1 )=bulk degree×number of compressions Bulkiness = h0 - hc / h0 where h0 is the height of the sample in the container based on the actual volume of the sample, hc is the clearance between the inner wall of the container and the rotating blades, and the number of compressions indicates the number of times the sample is compressed by the rotating blades per second.

20. A core particle having a polyhedral shape and an average particle diameter of 70 μm or more, which does not have an amorphous stabilizing effect; a layer formed on the surface of the core particle by at least one of an impact force and a compression force of the core particle due to a mechanical action caused by stirring and mixing, the layer being derived from the amorphous organic compound particles and the amorphous stabilizer particles; A composite particle comprising:

21. A core particle having a polyhedral shape and an average particle diameter of 70 μm or more, which does not have an amorphous stabilizing effect; a mixed layer in which amorphous organic compound particles and amorphous stabilizer particles are laminated on the surface of the core particle, or a layer of a solid dispersion phase of the amorphous organic compound particles and the amorphous stabilizer particles; A composite particle comprising:

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