Method for producing composite particles containing amorphous organic compounds

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] This specification relates to a method for producing composite particles containing amorphous organic compounds, etc. [Background technology]

[0002] Amorphizing crystalline organic compounds, which are the active ingredients of pharmaceuticals, is a promising method for improving their solubility and dissolution rate in aqueous media. Methods for amorphousizing crystalline organic compounds include dissolving crystalline powder in an organic solvent and spraying it onto core particles to amorphousize and granulate (Patent Document 1), granulating while amorphousizing the crystalline powder by thermally melting an amorphous stabilizer, and pulverizing the crystalline powder using a ball mill to amorphousize it. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2021-113183 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] However, these methods have drawbacks, including the problem of residual organic solvents, the complexity of the manufacturing process which involves heating and melting for amorphous formation, and the effects of heat on the compound.

[0005] This specification provides a method for producing composite particles comprising easily amorphous organic compounds, etc. [Means for solving the problem]

[0006] Through various studies on the amorphousization of crystalline powders, the present inventors have found that by mechanically stirring and mixing nucleation particles and crystalline organic compound particles smaller than the nucleation particles, the crystalline organic compound particles can be pulverized and amorphousized by the action of the nucleation particles accompanying the mechanical action of stirring and mixing, thereby generating amorphous organic compound particles from crystalline particles, and that the amorphous organic compound particles generated in situ can be attached and deposited on the nucleation particles. Based on this finding, the following means are provided in this specification.

[0007] [1] A method for producing composite particles, A manufacturing method comprising: a compounding step of mechanically stirring and mixing a core particle that does not have an amorphous stabilizing effect and a crystalline organic compound particle, thereby promoting the pulverization and amorphousization of the crystalline organic compound particle by the action of the core particle during stirring and mixing, and causing amorphous organic compound particles derived from the crystalline organic compound particle to adhere to the surface of the core particle, wherein the composite particle has amorphous organic compound particles on the surface of the core particle. [2] The manufacturing method according to [1], wherein the average particle diameter of the nucleus particles in the compounding step is 1.5 times or more and 30.0 times or less the average particle diameter of the crystalline organic compound particles. [3] The manufacturing method according to [1] or [2], wherein the mass of the core particles in the compounding 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 any one of [1] to [3], 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 composite step is performed such that the temperature inside the container in which the composite step is carried out is kept below the glass transition temperature of the organic compound of the amorphous organic compound particles, according to any one of [1] to [4]. [6] The nuclear particles are selected from pharmaceutically acceptable excipients, according to any one of the methods of [1] to [5]. [7] The method according to [6], wherein the nucleus particles are one or more selected from the group consisting of lactose, glucose, starch, corn starch, crystalline cellulose, and methylcellulose. [8] A composite particle, Nuclear particles that do not have amorphous stabilization properties, On the surface of the core particle, there is a layer derived from amorphous organic compound particles and amorphous stabilizer particles. A composite particle possessing the following characteristics. [Brief explanation of the drawing]

[0008] [Figure 1] This figure shows the action of the nucleus particles in the method for producing composite particles disclosed herein. [Figure 2] This figure shows an example of composite particles disclosed herein. [Figure 3] This figure shows another example of the composite particles disclosed herein. [Figure 4] This diagram schematically shows the configuration of a horizontally positioned composite device to explain the composite parameters. [Figure 5] This figure shows the relationship between various numerical elements in a composite device and the composite parameter, which is the compression efficiency. [Figure 6] This figure shows the X-ray diffraction spectrum (a), Raman spectrum (b), and DSC curve (c) in the example. [Figure 7] This figure shows scanning electron microscope images of crystalline cellulose core particles (a1)(a2) (a1 is 600x magnification, a2 is 5000x magnification, the same applies below), composite particles mixed for 30 minutes (b1)(b2), and composite particles mixed for 180 minutes (c1)(c2). [Figure 8] This figure shows the mixing time and the content of amorphous indomethacin in the composite particles (relative to the active ingredient). [Figure 9] This figure shows the results of the dissolution test of the composite particles. [Figure 10] This figure shows the results of a physical stability test of composite particles at 25°C in the presence of silica gel. [Figure 11]It is a diagram showing the X-ray diffraction spectrum and Raman spectrum of composite particles obtained by processing at different rotor rotation speeds in Example 4. [Figure 12] It is a diagram showing the X-ray diffraction spectrum and Raman spectrum of composite particles obtained by processing for different processing times in Example 4. [Figure 13] It is a diagram showing the X-ray diffraction spectrum and Raman spectrum of composite particles obtained by processing with different sample substantial volumes in Example 5.

Mode for Carrying Out the Invention

[0009] The disclosure of this specification relates to a method for producing composite particles containing an amorphous organic compound. The production method of the present disclosure mechanically stirs and mixes core particles having no amorphous stabilizing action and crystalline organic compound particles, and by the action of the core particles accompanying the mechanical action of the stirring and mixing, promotes the pulverization and amorphization of the crystalline organic compound particles, and attaches amorphous organic compound particles derived from the crystalline organic compound particles to the surface of the core particles, and includes a composite step of producing the composite particles having the amorphous organic compound particles on the surface of the core particles.

[0010] According to the above production 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 along with the mechanical action of the stirring and mixing. When the core particles collide with or compress the crystalline organic compound particles, the crystalline organic compound particles are pulverized and amorphized. Furthermore, the pulverized and amorphized amorphous organic compound particles have enhanced agglomeration adhesion properties. As a result, composite particles containing an organic compound with improved solubility and dissolution rate in water can be obtained more simply.

[0011] In addition, since no solvent is used and there is no heat melting, residual solvent is avoided, and the workability is excellent and the cost can be suppressed.

[0012] Furthermore, by mixing amorphous stabilizer particles in the compounding process, the recrystallization of amorphous organic compound particles can be suppressed, and composite particles can be obtained that stably maintain the amorphous nature of the amorphous particles.

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

[0014] The following is a detailed description of the method for producing composite particles (hereinafter also simply referred to as "this production method").

[0015] (Method for manufacturing composite particles) This manufacturing method comprises a compounding step in which core particles that do not have an amorphous stabilizing effect and crystalline organic compound particles (hereinafter also simply referred to as crystalline particles) are mechanically stirred and mixed, and the action of the core particles accompanying the mechanical action of stirring and mixing promotes the pulverization and amorphousization of the crystalline particles, thereby causing amorphous organic compound particles (hereinafter also simply referred to as amorphous particles) derived from the crystalline particles to adhere to the surface of the core particles. In carrying out this manufacturing method, the core particles and crystalline particles to be subjected to the compounding step are prepared separately.

[0016] (nuclear particle) The core particles constitute the nucleus of the composite particles and serve as carrier particles supported by the amorphous particles. While the core particles are not particularly limited, it is beneficial from the viewpoint of impact force against crystalline particles and their own fracture strength to have morphologies such as spheres, lumps, cubes, rectangular prisms, or other polyhedral shapes. In other words, it is beneficial that they are not plate-shaped, flake-shaped, rod-shaped, needle-shaped, columnar, or spongy. This is because plate-shaped, flake-shaped, needle-shaped, rod-shaped, columnar, or spongy shapes tend to have insufficient impact force and fracture strength. While not particularly limited, it is preferable from the viewpoint of impact force and fracture strength if the longest and minimum span dimensions of the core particles are, 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 for spherical, lumpy, or polyhedral shapes.

[0017] In the compounding process, the core particles are designed to suppress pulverization and maintain their particle shape. Using such core particles makes them more suitable as grinding media, such as balls or beads, in ball mill grinding compared to crystalline particles. Pulverization can be suppressed by considering the fracture strength based on the shape and size of the core particles.

[0018] These core particles are not particularly limited, but typically, pharmaceutically acceptable excipient particles can be used. Examples include 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 hydroxypropyl methylcellulose; and inorganic compounds known as excipients such as magnesium aluminometasilicate and anhydrous calcium phosphate. Monosaccharides, disaccharides, and polysaccharides can be naturally derived sugars, as well as their known derivatives (e.g., deoxy sugars, amino sugars, thio sugars, ester derivatives, etc.) as appropriate. Crystalline cellulose is sometimes preferred. Furthermore, it is preferable to use core particles that do not have amorphous stabilization properties. This is because the core particles also serve as carrier particles that support the crystalline particles, and it is more advantageous from a formulation standpoint to allow them to function as carrier particles alone.

[0019] The average particle diameter d1 of the nucleus particles is not particularly limited in relation to the average particle diameter d2 of the crystalline particles, but it is sometimes 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 exerted by the nucleus particles when they collide with the crystalline particles increases, which promotes the breakdown (amorphization) of the lattice structure of the crystalline organic compound particles. The average particle diameter d1 can be, for example, 1.1 times or more the average particle diameter d2, as well as 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, as well as, 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 so on.

[0020] On the other hand, if the average particle diameter d1 is too large compared to the average particle diameter d2, the collision frequency tends to decrease and the efficiency of amorphization decreases. Therefore, the average particle diameter d1 can 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 of the average particle diameter d2.

[0021] The range of the ratio between average particle diameter d1 and average particle diameter d2 is not particularly limited, but can be set by appropriately combining the upper and lower limits mentioned above. For example, it could 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 nucleus particles is not particularly limited, but may be, for example, 10 μm or larger, 15 μm or larger, 20 μm or larger, 25 μm or larger, 30 μm or larger, 35 μm or larger, 40 μm or larger, 45 μm or larger, 50 μm or larger, 60 μm or larger, 70 μm or larger, 80 μm or larger, 90 μm or larger, 100 μm or larger, 125 μm or larger, 150 μm or larger, 175 μm or larger, 200 μm or larger, 225 μm or larger, 250 μm or larger, 300 μm or larger, 350 μm or larger, 400 μm or larger, 450 μm or larger, or 500 μm or larger.

[0023] The average particle diameter d1 of the nuclear particles is not particularly limited, but from the viewpoint of ensuring that the fracture strength of the nuclear particles does not exceed the impact force of the nuclear particles, 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 nucleus particles is not particularly limited, but can be set by appropriately combining the upper and lower limits mentioned above. For example, it could be 10 μm to 500 μm, 15 μm to 500 μm, 20 μm to 500 μm, 20 μm to 400 μm, 20 μm to 350 μm, 20 μm to 300 μm, 10 μm to 200 μm, 20 μm to 200 μm, 20 μm to 150 μm, 20 μm to 100 μm, 10 μm to 30 μm, or 10 μm to 20 μm.

[0025] The average particle diameter d1 of the nucleus particles and the average particle diameter d2 of the crystalline particles can both be obtained as volume-based median diameters (central diameters) by laser diffraction and scattering methods.

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

[0027] The type of organic compound used in the crystalline organic compound particles is not particularly limited, but any organic compound that can be amorphous by grinding methods such as a ball mill can be amorphous using this manufacturing method. It is beneficial for the organic compound to be one that can be used as an active ingredient in pharmaceuticals, and even more beneficial for it to be an organic compound that is poorly soluble in water for crystallinity. Furthermore, it is possible to confirm in advance whether crystalline organic compounds that can be amorphous using this manufacturing method can be amorphous by grinding methods such as a ball mill, or whether they can be amorphous using this manufacturing method with crystalline cellulose as a core particle.

[0028] Crystalline particles are particles that are pulverized by collisions with core particles and compression actions resulting from mechanical action during stirring and mixing. These actions also destroy the lattice structure of the crystalline particles, causing them to become amorphous. The pulverized amorphous particles then adhere to and accumulate on the surface of the core particles. The average particle diameter d2 of the crystalline particles is made smaller than the average particle diameter d1 of the core particles, as previously explained. This makes them easier to pulverize through collisions with the core particles. It is preferable that the average particle diameter d2 of the crystalline particles has the relationship with the average particle diameter d1 of the core particles as previously described.

[0029] The average particle diameter d2 of crystalline particles is not particularly limited, but for example, it may be 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. Also, the average particle diameter d2 may be 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 can be set by appropriately selecting the upper and lower limits described above, but for example, it may be 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. Furthermore, in the particle size distribution measured by the method described above, it may be advantageous if, on a volume basis, for example, 80% or more, 85% or more, 90% or more, or 95% or more of particles are 100 μm or smaller within the range of 100 μm or smaller in particle size.

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

[0031] In the compounding process, the lattice structure of crystalline particles is destroyed and amorphous, but since the amorphous state is unstable, recrystallization may occur. In the compounding process, it is sometimes effective to pre-mix amorphous stabilizer particles (hereinafter also referred to as stabilizer particles) together with the amorphous particles and compound them into core particles. As such stabilizer particles, known amorphous stabilizers can be used as appropriate. Examples of amorphous stabilizers include polymer-based stabilizers, low-molecular-weight stabilizers, and inorganic stabilizers. Examples of polymer-based additives are not particularly limited, but include 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), which are cellulose derivatives. Low molecular weight stabilizers are not particularly limited, but examples include low molecular weight compounds having carbonyl or amino groups, and more specifically, amino acids such as arginine and tryptophan, and organic acids such as tartaric acid and citric acid. Inorganic additives are not particularly limited, but examples include porous materials of calcium carbonate and silicon dioxide.

[0032] The average particle size d3 of the stabilizer particles is not particularly limited, but it is preferable that they are directly attached to the surface of the core particles with an average particle size d1, or that they are pulverized in the compounding process and the pulverized 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 and deposited on the surface of the core particles, which is effective in stably maintaining the amorphous state of the amorphous particles. Such an average particle size 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 size d2 of the crystalline particles. In addition, the average particle size 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 size d2.

[0033] The average particle diameter d3 of the stabilizer particles is not particularly limited, but for example, it may be 5 μm or more, 10 μm or more, 20 μm or more, 25 μm or more, or 30 μm or more. Also, the average particle diameter d3 may be 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, for example, 5 μm or more and 50 μm or less, or 10 μm or more and 40 μm or less. 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 to be blended is not particularly limited and can be set appropriately depending on the type of stabilizer. For example, it can be set appropriately within the range of 0.01 times to 100 times the mass of the crystalline particles. For example, in the case of polymer-based stabilizers, it can be set to 0.05 times to 100 times, 0.1 times to 5 times, or 0.5 times to 2 times, while in the case of low-molecular-weight stabilizers and inorganic stabilizers, it can be set to 0.01 times to 10 times, etc.

[0035] In the compounding process, the core particles and crystalline particles are mechanically stirred and mixed. The impact and compressive forces of the core particles resulting from this mechanical action pulverize the crystalline particles, thereby reducing them to fine particles and making them amorphous. Furthermore, the amorphous particles obtained by pulverization have strong adhesive and cohesive properties, allowing them to adhere to the surface of the core particles and achieve compounding. According to this manufacturing method, the actions of the core particles resulting from the mechanical action allow for the pulverization of crystalline particles into amorphous particles without the use of an amorphous stabilizer, and simultaneously compounding them with the core particles, which act as excipients.

[0036] The mechanical action of stirring and mixing used in the compounding process is effectively generated by using a device equipped with a grinding mechanism that exhibits high shear force, for example. High shear stress can have a significant effect on the core particles. Such compounding devices can be known stirring granulators or compounding devices that have rotating stirring blades (rotating blades, rotors, etc.). Such devices are commercially available as appropriate. For example, high-speed stirring granulators from Glatt (TMG1 / 6, etc.), dry compounding devices such as the NOBMINI from Hosokawa Micron, and similar devices can be used.

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

[0038] Here, the stirring blades in the container of the compounding device that performs mixing and stirring may rotate around an axis aligned vertically, as in the high-speed stirring granulator described above; they may rotate around a horizontal axis, as in the dry compounding device described above; or they may rotate around an axis inclined at an angle. Furthermore, the shape of the stirring blades is not particularly limited, but examples include a plate-shaped blade extending perpendicularly from the axis of rotation. In the case of a plate-shaped blade, the blades may be mounted parallel to the axis of rotation, as in the dry compounding device described above; or they may be mounted obliquely to the axis of rotation, as in the high-speed stirring granulator described above.

[0039] (Combination parameters) Furthermore, in order to efficiently obtain composite particles using this manufacturing method, it is sometimes preferable to use a composite apparatus capable of exhibiting specific parameters as the composite apparatus for carrying out the composite process. Below, the composite parameters will be described using as an example a horizontal composite apparatus (for example, the dry composite apparatus described above) equipped with a rotating blade that rotates around an axis along a substantially horizontal direction, located in a cylindrical container extending along the horizontal direction.

[0040] Figure 4 schematically shows the configuration of a horizontally positioned composite apparatus to explain the composite parameters. As shown in Figure 4(a), since the container (cylinder) is oriented horizontally, the composite sample (nucleus particles and crystalline particles) accumulates on the lower inner wall of the container. The sample height (h0) at this time can be calculated from the actual volume of the sample (for example, the volume of a partially missing right circular cylinder - 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 and the mass of the sample, measured with a gas displacement pycnometer. The true density is determined as follows. The composite sample includes all of the nucleus particles, crystalline particles, stabilizing particles, and / or anti-adhesion agents used in composite formation. The true density of each component can be measured, and the true density of the composite sample can be obtained from 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 Figure 4(b), when the rotor rotates, the sample is forced to pass through the gap between the rotating blades and the inner wall of the container, so the sample is moved from the sample height (h0) to the clearance (h) between the inner wall of the container and the inner wall edge of the rotating blades. c It is compressed to 1.0 mm. At this time, the bulk of the sample is defined by the following formula.

[0042]

number

[0043] Next, as shown in Figure 4(c), since there are four sets of 18mm wide rotating blades mounted in the same straight line on a rotor with a total length of 56mm, the sample accumulated on the inner wall of the container is compressed an average of (18 × 2 ÷ 56) × 4 = 2.57 times when the rotor rotates once. At rotation speeds of 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, compression efficiency is defined as the product of bulkiness and the number of compression cycles. Figure 5 shows the numerical values ​​of various elements based on Figure 4 and the calculated compression efficiency derived from them. Compression efficiency (s -1 ) = Bulkiness × Number of compressions

[0045] In the above explanation, we described a horizontally mounted composite device that has a rotor rotating around an axis approximately aligned horizontally, housed in a cylindrical container extending horizontally. However, the explanation is not limited to this type of device. It can also be applied to a vertically mounted composite device that has a rotor rotating around an axis aligned vertically, housed in a cylindrical container extending vertically.

[0046] In this case, it can be assumed that the sample adheres uniformly to the inner wall of the container due to the centrifugal force caused by the rotor rotation. At this time, the sample height (h0) can be calculated from the actual volume of the sample using the volume calculation formula for 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] This compression efficiency increases with higher rotor speed and with greater bulk. It is believed that a higher compression efficiency in the compounding process leads to better compounding efficiency and enables compounding in a shorter time. According to the inventors, compound particles can be efficiently obtained by setting such a 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 upper limit of the compression efficiency is not particularly limited, as it depends on the rotor speed and container volume allowed in the compounding device, but for example, it could be 300 or less, 280 or less, 260 or less, 240 or less, 230 or less, or 220 or less.

[0048] To obtain a desirable compression efficiency, the actual volume of the sample to be compounded can be adjusted to increase the sample height (h0) or to reduce the clearance between the inner wall of the container and the stirring blades, thereby obtaining a desirable bulkiness. In addition, to obtain a desirable number of compression cycles, the rotational speed of the rotor can be increased or the number of rotor blades around the rotation axis can be increased.

[0049] Furthermore, a composite device capable of achieving the desired bulkiness and number of compression cycles for such effective compression efficiency can be considered a useful composite device for carrying out the composite process of this manufacturing method.

[0050] (compounding device) A composite apparatus suitable for this manufacturing method may include, for example, a cylindrical container with its long axis oriented horizontally or vertically for mixing and stirring, a rotor positioned within the cylindrical container along the long axis, and a rotor positioned perpendicular to the inner wall of the cylindrical container from the rotor. The rotor of such a composite apparatus can rotate at a speed of, for example, 5000 rpm or more, or 7000 rpm or more, in order to increase the number of compression cycles, and the rotor is equipped with, for example, three, four, five, or six or more blades around the rotor. Furthermore, in order to increase the bulkiness, the distance between the rotor and the inner wall of the cylindrical container can be, for example, 2 mm or less, 1 mm or less, etc.

[0051] Furthermore, to prevent the composite particles from adhering to the inner wall of the container used for mixing and stirring in the apparatus, lubricants and fluidizers 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 these, light anhydrous silicic acid and talc may be particularly useful. The average particle size of these anti-adhesion agents is not particularly limited, but may be, for example, 10 μm or less, 1 μm or less, or 100 nm or less. The amount of the anti-adhesion agent may be, for example, 0.1% to 10% by mass, or 0.5% to 2% by mass, relative to the total mass of crystalline particles and stabilizer particles.

[0052] In the compounding process, the mechanical stirring and mixing operation is effective when the temperature inside the container in which the core particles and crystalline particles are stirred and mixed is maintained 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), making the composite particles 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 temperature inside the stirring and mixing container can be set to, for example, 40°C or lower, 35°C or lower, 30°C or lower, 25°C or lower, 20°C or lower, 15°C or lower, or 10°C or lower. To set the temperature inside the stirring and mixing container to these temperatures, the jacket temperature for external temperature control of the stirring and mixing container can be set to, for example, 25°C or lower, 20°C or lower, 15°C or lower, 10°C or lower, 5°C or lower, or 0°C or lower.

[0053] In the compounding process, in addition to core particles and crystalline particles, stabilizer particles and anti-adhesion agents are supplied to the container of the compounding apparatus. These may be added to the container all at once, simultaneously, or individually, or they may be added individually, continuously or intermittently. Furthermore, there are no particular restrictions on the order of addition. Typically, the entire amount may be added all at once at the same time, or the core particles may be added all at once, followed by the addition of crystalline particles and other materials. For example, after adding all the core particles, a predetermined amount of crystalline particles may be supplied uniformly and continuously per hour for a predetermined time required to compound a predetermined amount of crystalline particles with the amount of core particles added. When other agents such as stabilizer particles and anti-adhesion agents are used in addition to crystalline particles, a mixture of crystalline particles and these other agents may be supplied to the container continuously from a single supply system in a predetermined ratio as described above. Alternatively, one or more types selected from the group consisting of crystalline particles and other agents may be appropriately combined and supplied to the container continuously from two or more supply systems in 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, they may be deposited on the surface of the core particles, forming an amorphous particle layer. Alternatively, the composite particles may have a mixed layer on the surface of the core particles where amorphous particles and stabilizer particles are attached and deposited, or a solid dispersion phase in which amorphous organic compounds are dispersed within or together with the stabilizer particles. This is because, when amorphous particles are stabilized by stabilizer particles, they may disperse at the molecular level together with or on the stabilizer particles, forming an amorphous solid dispersion. In this case, for example, it may be difficult to clearly distinguish between the two when observed with an electron microscope.

[0055] By providing amorphous particles or an amorphous particle layer, amorphous particles and stabilizer particles, or a mixed layer thereof (solid dispersion phase) on the surface, even a small amount of stabilizer particles can effectively contact the amorphous particles and stably maintain the amorphous state of the amorphous particles.

[0056] Furthermore, while there are no particular limitations on the degree of amorphousness in amorphous particles within composite particles, higher amorphousness is generally preferable. For example, it could be 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 99% or more, and so on.

[0057] Furthermore, if the composite particles obtained in the composite process are layers in which amorphous particles are attached to or deposited on the surface of core particles, stabilizing particles may be further attached to or deposited on these particles or layers.

[0058] As explained above, this manufacturing method is a practical method for producing composite particles that achieves amorphous formation and composite formation with core particles simultaneously through a compounding process, without the need for solvents, amorphous stabilizers, or thermal melting, and through the action of core particles resulting from mechanical action based on stirring and mixing. Such composite particles can be used as raw materials (components) for various formulations such as fine granules, granules, capsules, and tablets.

[0059] (composite particles) The composite particles disclosed herein may comprise a core particle that does not have an amorphous stabilizing effect, and a layer on the surface of the core particle derived from amorphous organic compound particles. As shown in Figure 2, these composite particles (composite particles of the first embodiment) are composited without the use of an amorphous stabilizer, as crystalline organic compound particles are amorphousized by mechanical action in the compounding process and the action of the core particle. Therefore, amorphous particles are provided on a core particle that does not contain an amorphous stabilizer. Various embodiments of the core particle and amorphous particle in these composite particles, as described above, can be applied.

[0060] Furthermore, this composite particle comprises a core particle that does not have an amorphous stabilizing effect, and a layer derived from amorphous organic compound particles and amorphous stabilizer particles. This layer may be a mixed layer or solid dispersion phase of amorphous particles and stabilizer particles attached to the surface of the core particle. As shown in Figure 3, this composite particle (composite particle of the second embodiment) can effectively suppress the recrystallization of amorphous particles. [Examples]

[0061] The following examples illustrate the disclosures of this specification in more detail. The following examples are for illustrative purposes only and do not limit the scope of the disclosures of this specification. In the following, the average particle diameter is the volume-based median diameter (center diameter) measured by laser diffraction-scattering. [Examples]

[0062] (Production of composite particles in dry layering granulation) In this example, we investigated the possibility of amorphization of drugs by layering granulation, a granulation method that involves attaching and layering smaller particles onto a core material with a larger particle size without the use of a solvent. As a crystalline substance, indomethacin (IND) (average particle size: 20.5 μm), which is easily amorphized mechanically and whose amorphous phase is relatively stable, was used as a model drug. Five types of MCC spherical particles with different particle sizes (CELLETS 127, 175, 200, 300, 500, Advanced Drug Delivery Technologies Ltd) were used as the core material (nucleus particles). 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 loaded into a high-speed stirring granulator (TMG1 / 6, Glatt), and mixed at an impeller rotation speed of 1000 rpm (peripheral speed 10.0 m / sec) for a maximum of 180 minutes. The physical properties of the resulting composite particles were evaluated to determine whether amorphous formation was possible. 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 composite particles obtained using MCCs-S, labeled (a) to (c). As shown in Figure 6(a), the XRPD pattern of the simple physical mixture (PM) showed sharp peaks (11.9°, 17.1°, 20.0°, 22.2°, 26.9°) originating from IND crystals (γ form) and broad peaks (14.7°, 22.5°, 34.6°) originating from MCC crystals of a few nanometers in size. As the mixing time increased, the peaks originating from IND crystals became smaller, suggesting amorphousization of IND crystals due to 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 reveal peaks specific to IND crystals and amorphous IND, respectively, at 1698 cm⁻¹.-1 and 1680cm -1 This was observed. As the mixing time increased, the peak of IND crystals became smaller, and the peak of amorphous IND became larger. From these results, it was found that IND crystals were amorphous without undergoing crystallization by high-speed stirring and mixing.

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

[0066] Furthermore, electron microscope images of the composite particles after mixing times of 30 minutes and 180 minutes are shown in Figure 7. As shown in Figure 7, IND particles with a particle size of approximately 1 μm were attached to 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. Similar to the case in which the inventors previously confirmed the use of acetaminophen (AAP) crystals, it was considered that the IND crystals were pulverized and layered granulated by the mixing process with the MCC particles.

[0067] The surface state and particle size of the composite particles processed for 180 minutes were equivalent to those processed for 30 minutes, indicating that the grinding and granulation of IND crystals were completed within 30 minutes of mixing. On the other hand, as shown in Figure 6, the amorphization of IND crystals continued even after 30 minutes of mixing. These results indicate that IND crystals are ground and amorphized simultaneously in the initial stages of the mixing process. Subsequently, the ground IND particles can no longer be further refined, but amorphization continues due to collisions between MCC spherical particles. In summary, the ball-mill effect of MCC spherical particles is shown to cause amorphization in addition to layering granulation of IND crystals. [Examples]

[0068] (Effects due to particle size of nuclear particles) Since the ball-milling effect of MCC spherical particles during the mixing process caused the amorphization of the drug crystals, the effect of the particle size of the MCC spherical particles was investigated. Raman spectra were measured of composite particles prepared using MCC spherical particles of various particle sizes, and the 1698 cm⁻¹ spectrum, which is characteristic of IND crystals, was observed. -1 The peak height and the amorphous IND characteristic of 1680 cm -1 The degree of amorphization of IND was calculated from the ratio of peak heights. The results are shown in Figure 8.

[0069] As shown in Figure 8, the amorphization rate of IND increased with increasing particle size of the MCC spherical particles, and 100% amorphization of IND crystals was achieved when using MCCs-L and MCCs-XL. This result suggests that larger particle sizes of MCC spherical particles promote amorphization. To examine the effect of particle size in detail, Table 1 shows the ratio 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 the MCCs were spheres).

[0070] [Table 1]

[0071] As already explained, the amorphous state of IND crystals occurs due to the ball-mill effect, i.e., collisions, of MCC spherical particles. The impact force due to collisions is determined by the mass and acceleration of the MCC spherical particles, and is therefore proportional to the volume (particle diameter cubed). Assuming equal acceleration, 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, with the collision force of MCCs-XL being approximately 90 times that of MCCs-XS. Therefore, MCC spherical particles with larger particle diameters generate strong collision forces during the mixing process, promoting the amorphous state 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 larger the particle diameter of the MCC spherical particles, the lower the amorphous state efficiency.

[0072] As shown in Figure 8, the amorphization rate was faster when using MCCs-XL than when using MCCs-L. However, the amorphization rate of MCCs-XL was slower than expected from the difference in volume (collision force) between MCCs-XL and MCCs-L. This is thought to be due to the decrease in collision frequency due to the increase in particle size. D of composite particles prepared using each MCC spherical particle 50 The values, drug content, and drug recovery rate (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 layered onto 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 during the mixing process, which released the IND particles that were held by the MCC spherical particles and caused them to adhere to the granulator wall. In conclusion, this study showed that when MCCs-L was used and mixed for 180 minutes, it was possible to produce composite particles in which completely amorphous IND particles were layered and granulated. [Examples]

[0075] A dissolution test was performed on composite particles obtained using MCCs-L under supersaturation conditions (10 times the solubility of IND crystals). The results are shown in Figure 9. As shown in Figure 9, the composite particles exhibited supersaturation, and the dissolution concentration reached 2.5 times the solubility of the crystals at a dissolution time of 10 minutes. On the other hand, as a comparative example, amorphous IND prepared by the quick quenching (QC) method showed a dissolution concentration equivalent to that of the composite particles, but required a dissolution time of 120 minutes. The particle size of the amorphous IND layered on the composite particles was about 1 μm, which was smaller than that of QCIND. In addition, while QC IND formed aggregates immediately after the dissolution test, aggregation was suppressed in the composite particles because the amorphous IND was retained on the surface of the MCC spherical particles. Therefore, it is thought that the dissolution rate was faster in amorphous IND layered on MCC spherical particles because it had a larger effective surface area than QCIND.

[0076] Furthermore, the composite particles underwent a physical stability test at 25°C in the presence of silica gel. 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 1 day of storage, and almost completely crystallized after 1 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, composite particles were prepared by adding polyvinylpyrrolidone (PVP) at 10% of the IND mass and mixing it with the MCC spherical particles.

[0077] This composite particle demonstrated that amorphous IND can maintain its amorphous state for at least four weeks, and that crystallization of layered amorphous particles can be suppressed by using additives that stabilize the amorphous material. Furthermore, by using the amino acid arginine as a coformer for IND, we succeeded in producing spherical particles with layered IND-ARG amorphous composites that possess high elution properties and physical stability.

[0078] Based on the above, we demonstrated the potential application of the dry layering granulation method using a high-speed stirring granulator to the design of amorphous formulations. [Examples]

[0079] (Examination of the Production of Composite Particles) In this example, corn starch (average particle diameter: 20.1 μm) was used as the core particles, and indomethacin (IND) (average particle diameter: 14.0 μm) was used. A total of 9 g with a mass ratio of core particles to IND of 10:1 was put into a dry compounding apparatus (NOBMINI, manufactured by Hosokawa Micron Corporation, vessel container 0.02 liter), and the rotor rotation speed was set to 3000 - 7000 rpm and mixed for 10 minutes. The jacket temperature of the vessel container was set to 20°C. The crystallinity of the processed product was evaluated by powder X-ray diffraction and Raman spectrum. The results are shown in Fig. 11.

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

[0081] Furthermore, a total of 9 g with a mass ratio of core particles to IND of 10:3 was put into the above dry compounding apparatus, and the rotor rotation speed was 7000 rpm and mixed for 10 minutes to 90 minutes. The jacket temperature of the vessel container 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 became longer, the powder X-ray diffraction peaks and the peaks of the Raman spectrum of IND crystals disappeared, and the peaks of amorphous IND appeared. At a mixing time of 90 minutes, the peaks derived from crystals disappeared. That is, it was found that even when crystalline particles are contained at a high concentration, complete amorphization can be realized in a short time.

[0082] The dry compounding apparatus used in this embodiment rotates along the inner wall of a cylindrical vessel container and the rotating blades provided on the rotor. When nucleus particles and crystalline particles are interposed between the end of the rotating blade facing the inner wall and the inner wall, a strong shear compressive force acts upon them. This action promotes the pulverization and amorphous formation of crystalline particles through collision and compression of the nucleus particles, and it is also thought that the mechanical action of the compounding apparatus itself contributes to the pulverization and amorphous formation of crystalline particles (IND). [Examples]

[0083] (Consideration of composite parameters) In this example, corn starch (average particle size: 20.1 μm) was used as the core particle, and indomethacin (IND) (average particle size: 14.0 μm) was used to mix the core particle and IND in a mass ratio of 10:1. Samples with substantial 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 apparatus used in Example 4, and compounded for 10 minutes at a rotor speed of 7000 rpm. The jacket temperature of the vessel was set to 20°C. The dry compounding apparatus used in this example had the element configuration shown in Figure 4, and the compression efficiency relative to the substantial volume of the sample was shown in Figure 5. The powder X-ray diffraction and Raman spectral crystallinity of the samples after compounding in this apparatus for 10 minutes were evaluated. The results are shown in Figure 13.

[0084] As shown in Figure 13, in the sample volume range of 4.0 to 6.0 mL, powder X-ray diffraction peaks of indomethacin crystals (11.9°, 17.1°, 20.0°, 22.2°, 26.9°) and Raman spectral peak (1698 cm⁻¹) were observed. -1 ) completely disappears, and the peak of amorphous indomethacin (1680 cm) -1The following was observed: When the rotor speed was 7000 rpm, complete amorphousization was achieved in 10 minutes of processing time even when the sample packing volume was reduced. When the rotor speed was 7000 rpm, the compression efficiency was 202 to 225 ( / s) even when the actual volume of the sample was 4.0 ml to 6.0 ml. It was considered that complete amorphousization of indomethacin was achieved when the compression efficiency was 200 / s or higher.

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

[0086] From this embodiment and Embodiment 4, it was found that compression efficiency can be an indicator of compounding. Furthermore, it was found that efficient compounding is possible when the compression efficiency is 200 or higher.

Claims

1. A method for producing composite particles, The composite step comprises: mechanically stirring and mixing amorphous organic compound particles, which have a polyhedral shape, an average particle diameter of 125 μm or more, and are one or more selected from the group consisting of crystalline cellulose, magnesium aluminometasilicate and anhydrous calcium phosphate, and do not have an amorphous stabilizing effect, with crystalline organic compound particles using a device equipped with a rotating stirring blade, thereby promoting the pulverization and amorphousization of the crystalline organic compound particles by the action of at least one of the impact force and compressive force of the core particles, which is generated by the mechanical action of the stirring and mixing causing the core particles to act as a pulverizing medium, and thereby causing amorphous organic compound particles derived from the crystalline organic compound particles to adhere to the surface of the core particles. The compounding step is carried out while maintaining the temperature inside the apparatus in which the compounding step is performed below the glass transition temperature of the organic compound of the amorphous organic compound particles. A method for producing the composite particle having a layer on the surface of the core particle containing at least the amorphous organic compound particles.

2. The manufacturing method according to claim 1, wherein the average particle diameter of the core particles in the composite step is 1.5 times or more and 30.0 times or less the average particle diameter of the crystalline organic compound particles.

3. The manufacturing 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 manufacturing method according to claim 1, wherein the average particle diameter of the core particles in the compounding step is 1.5 times or more and 30.0 times or less the average particle diameter of the crystalline organic compound particles, and the mass of the core particles is 3.0 times or more and 10.0 times or less the mass of the crystalline organic compound particles.

5. The manufacturing method according to claim 1, wherein the nuclear particles are selected from pharmaceutically acceptable excipients.

6. The manufacturing method according to claim 1, wherein the average particle diameter of the nucleus particles is 125 μm or more and 600 μm or less.

7. The manufacturing method according to claim 1, wherein the average particle diameter of the nucleus particles is 125 μm or more and 450 μm or less.

8. The impact force or the compressive force is generated by at least one of the collision and / or compression between the amorphous organic compound and the nuclear particles. The amorphous organic compound is pulverized by the impact force or compressive force. The manufacturing method according to claim 1.

9. The manufacturing method according to claim 1, wherein the stirring and mixing is performed by a stirring granulator.

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

11. A method for producing composite particles, A compounding step comprising: mechanically stirring and mixing nucleation particles having a polyhedral shape and an average particle diameter of 125 μm or more, and being one or more selected from the group consisting of crystalline cellulose, magnesium aluminometasilicate and anhydrous calcium phosphate, which do not have an amorphous stabilizing effect, with crystalline organic compound particles to promote the pulverization and amorphousization of the crystalline organic compound particles, thereby causing amorphous organic compound particles derived from the crystalline organic compound particles to adhere to the surface of the nucleation particles; Equipped with, The compounding step is carried out by performing the stirring and mixing using an apparatus including a cylindrical container equipped with rotating blades, while maintaining the temperature inside the apparatus below the glass transition temperature of the organic compound of the amorphous organic compound particles. A method for producing composite particles, wherein the gap between the rotating blade and the cylindrical container is such that the compression efficiency with respect to the substantial volume of the sample when the sample containing the core particles and the crystalline organic compound particles passes through it is 200 or more, and the core particles have a layer containing at least the amorphous organic compound particles on their surface. Compression efficiency (s-1) = Bulkiness × Number of compressions Bulkiness = h0 - hc / h0 However, h0 is the height within the container based on the actual volume of the sample, hc is the clearance between the inner wall of the container and the rotating blade, and the number of compressions indicates the number of times the sample is compressed by the rotating blade per second.

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