Method for producing solid object by continuous precipitation

Abstract

The present invention provides a production method by which a metastable-state solid object of a raw material is obtained with the particle diameter thereof being small.　The method for producing a metastable-state solid object of a raw material is characterized by including a continuous precipitation step in which a raw liquid containing the raw material dissolved therein is supplied to a precipitation tank of a tank-type continuous precipitation device and, simultaneously therewith, a slurry containing a solid object precipitated from the raw liquid is withdrawn, and is further characterized in that: in the continuous precipitation step, before the supply of the raw liquid and the withdrawal of the slurry are initiated, a slurry containing a metastable-state solid object of the raw material is accommodated in the precipitation tank, and while ultrasonic vibrations are applied to the precipitation tank, the raw liquid is supplied and a slurry containing a precipitated, metastable-state solid object of the raw material is withdrawn; and the average residence time is made shorter than a time period required for the solid object precipitated under the application of the ultrasonic vibrations to transition to a stable state that has a lower chemical potential than the metastable state.

Description

Method for producing solid objects by continuous precipitation

[0001] The present invention relates to a method for producing a solid object, and more particularly to a method for producing a solid object by continuous precipitation under ultrasonic vibration.

[0002] Technologies related to the precipitation of solids, such as crystallization, are widely used as separation and purification techniques in fields such as pharmaceuticals, food, nanomaterials, biomaterials, electronic devices, and the environment. For example, the crystallization process in the manufacture of active pharmaceutical ingredients is an important process that determines the physical and chemical properties of the final crystals, such as purity, crystalline polymorphism, particle size (particle size distribution), and shape (morphology).

[0003] In recent years, the field of reaction synthesis has been shifting from the traditionally mainstream batch synthesis to continuous flow synthesis, due to the benefits it offers in reaction efficiency, temperature control, safety, and the miniaturization of equipment and facilities. Continuous synthesis is also attracting attention in the field of crystallization technology, with an increasing number of reports from academia, industry, and regulatory authorities.

[0004] Regarding such continuous crystallization, for example, Patent Document 1 describes an invention relating to a crystallization apparatus including a raw material liquid supply unit that continuously supplies a raw material liquid containing a raw material substance, a treatment liquid supply unit that continuously supplies a treatment liquid, and a withdrawal unit that continuously withdraws a mixture of the raw material liquid and the treatment liquid (Claim 1). Patent Document 1 shows an example of the configuration of a treatment vessel 2 that includes an ultrasonic supply unit 242 that supplies ultrasonic vibrations via a rod-shaped ultrasonic vibrator 241 inserted into a first flow space 201, and explains that ultrasonic vibrations can be used to promote mixing of the raw material liquid 101 and the poor solvent 102 (Figure 7).

[0005] Patent No. 6761560

[0006] Depending on the raw material compound, substances that precipitate to form solids, such as crystals, may be in both a metastable state and a stable state with a lower chemical potential than the metastable state. For example, from the viewpoint of the manufacturing process, a stable solid (e.g., crystal) that is easy to handle is preferred, and a solid (e.g., crystal) with a large particle size is desirable because of its excellent filterability and drying efficiency. On the other hand, from the viewpoint of formulation, etc., a metastable solid (e.g., crystal) with a small particle size that has excellent solubility is desirable.

[0007] It is known that ultrasonic vibrations not only promote mixing of the liquid in the precipitation tank, but also enable control of the crystal polymorphism and particle size of the precipitated solid. Typically, when solids are precipitated while applying ultrasonic vibrations to the precipitation tank, the resulting solids are finer and thermodynamically stable. On the other hand, when solids are precipitated without applying ultrasonic vibrations, a kinetically favorable metastable solid is obtained, but the resulting solids tend to be larger. Applying ultrasonic vibrations to this coarse metastable solid results in a finer solid, but it also transitions to a stable solid. Thus, obtaining a metastable solid with small particle size is not an easy task.

[0008] The present invention has been made in view of the above-mentioned problems in the prior art. That is, an object of the present invention is to provide a production method for obtaining a metastable solid material of a raw material in a state of small particle size.

[0009] As a result of extensive research to solve the problems, the inventors have found that the above problems can be solved by carrying out continuous precipitation in a continuous precipitation step while applying ultrasonic vibrations to a precipitation tank containing a slurry containing solid matter in a metastable state, and by setting the average residence time in the continuous precipitation step to a time shorter than the time it takes for the precipitated solid matter to transition from a metastable state to a stable state under ultrasonic vibrations, thereby completing the present invention.

[0010] The gist of the present invention is as follows: [1] A method for producing a metastable solid material, comprising a continuous precipitation step of supplying a stock solution containing a raw material dissolved therein to a precipitation tank in a tank-type continuous precipitation apparatus while withdrawing a slurry containing solid material precipitated from the stock solution, wherein in the continuous precipitation step, a slurry containing metastable solid material is placed in the precipitation tank before starting to supply the stock solution and withdraw the slurry, and while applying ultrasonic vibration to the precipitation tank, the stock solution is supplied and the slurry containing the precipitated metastable solid material is withdrawn, and the mean residence time is set to be shorter than the time required for the precipitated solid material to transition to a stable state having a lower chemical potential than the metastable state under the ultrasonic vibration. [2] A method for producing a metastable solid material, comprising a continuous precipitation step of supplying a stock solution containing a raw material dissolved therein to a precipitation tank of a tank-type continuous precipitation apparatus while withdrawing a slurry containing solid material precipitated from the stock solution, wherein in the continuous precipitation step, a slurry containing metastable solid material is placed in the precipitation tank before starting the supply of the stock solution and the withdrawal of the slurry, the stock solution is supplied to the precipitation tank while applying ultrasonic vibrations to precipitate metastable solid material having a D90 (volume basis) of 100 μm or less in a particle size distribution determined by laser diffraction / scattering method, and the slurry containing the precipitated metastable solid material is withdrawn. [3] The method according to [1] or [2], wherein the average residence time in the continuous precipitation step is less than 2 hours. [4] The method according to any one of [1] to [3], wherein the proportion of metastable solid material in the slurry withdrawn from the precipitation tank is 50% or more. [5] The manufacturing method according to any one of [1] to [4], wherein the tank-type continuous precipitation apparatus is a complete mixing continuous precipitation apparatus. [6] The manufacturing method according to any one of [1] to [5], wherein the volume of the precipitation tank is 0.1 to 30 L. [7] The manufacturing method according to any one of [1] to [6], wherein a poor solvent capable of precipitating the solid material from the raw solution is added in the continuous precipitation step. [8] The manufacturing method according to any one of [1] to [7], wherein the metastable solid material precipitated in the continuous precipitation step has a Span value represented by the following formula of 0 or more and less than 5.0:Span = (D90 - D10) / D50 (wherein D10, D50, and D90 respectively represent D10, D50, and D90 on a volume basis in a particle size distribution determined by a laser diffraction / scattering method.) [9] The manufacturing method according to any one of [1] to [8], further comprising a solid-liquid separation step after the continuous precipitation step, wherein the slurry is supplied to the solid-liquid separation step without being subjected to any further precipitation device.

[10] The manufacturing method according to any one of [1] to [9], further comprising a raw material preparation step before the continuous precipitation step, capable of selectively preparing a first slurry containing solid matter in a metastable state and a second slurry containing solid matter in a stable state having a lower chemical potential than the metastable state, wherein the morphology of the solid matter obtained in the raw material preparation step is selected to be either a metastable state or a stable state by selecting whether or not to irradiate with ultrasound in the raw material preparation step.

[11] The manufacturing method according to

[10] , wherein the raw material preparation step is a step of storing a stock solution in which raw materials are dissolved in a raw material preparation tank capable of applying ultrasonic vibrations, and producing the first slurry or the second slurry by switching between the following i) and ii): i) obtaining a first slurry by adding a poor solvent without applying ultrasonic vibrations to the raw material preparation tank; ii) obtaining a second slurry by adding a poor solvent while applying ultrasonic vibrations to the raw material preparation tank;

[12] The manufacturing method according to

[10] or

[11] , wherein the slurry containing a metastable solid matter stored in the precipitation tank is the first slurry;

[13] The manufacturing method according to any one of

[10] to

[12] , wherein the raw material preparation tank in the raw material preparation step and the precipitation tank in the continuous precipitation step are the same tank.

[14] A method for producing a solid material, comprising: a raw material preparation step capable of selectively preparing a first slurry containing solid materials in a metastable state and a second slurry containing solid materials in a stable state having a chemical potential smaller than that of the metastable state; and a continuous precipitation step of supplying a stock solution in which a raw material is dissolved to a precipitation tank of a tank-type continuous precipitation device, and extracting a slurry containing the precipitated solid materials from the stock solution, wherein the raw material preparation step selects whether the state of the solid material obtained in the raw material preparation step is the metastable state or the stable state by selecting whether to irradiate with ultrasound in the raw material preparation step.

[15] The manufacturing method according to

[14] , wherein the raw material preparation step is a step of storing a stock solution in which a raw material is dissolved in a raw material preparation tank capable of applying ultrasonic vibrations, and producing the first slurry or the second slurry by switching between the following i) and ii): i) obtaining a first slurry by adding a poor solvent without applying ultrasonic vibrations to the raw material preparation tank; or ii) obtaining a second slurry by adding a poor solvent while applying ultrasonic vibrations to the raw material preparation tank.

[16] The manufacturing method according to

[14] or

[15] , wherein in the continuous precipitation step, before starting to supply the stock solution and withdraw the slurry, the first slurry is stored in the precipitation tank, the stock solution is supplied to the precipitation tank while applying ultrasonic vibrations, and a slurry containing the precipitated solid matter in a metastable state is withdrawn, and the average residence time is set to be shorter than the time required for the precipitated solid matter to transition under ultrasonic vibrations to a stable state having a lower chemical potential than the metastable state.

[17] The production method according to

[14] or

[15] , wherein in the continuous precipitation step, before starting the supply of the stock solution and the withdrawal of the slurry, the second slurry is placed in the precipitation tank, the stock solution is supplied, and a slurry containing the precipitated solid in a stable state is withdrawn.

[18] The production method according to any one of

[14] to

[17] , wherein the tank-type continuous precipitation apparatus is a complete mixing continuous precipitation apparatus.

[19] The production method according to any one of

[14] to

[18] , wherein the capacity of the precipitation tank is 0.1 to 30 L.

[0011] According to the present invention, a production method is provided that can obtain a metastable solid material of a raw material in a small particle size state.

[0012] FIG. 1 is a schematic diagram showing an example of a continuous deposition system used in the present invention.

[0013] <Continuous Precipitation Step> The continuous precipitation step in the present invention is a step of supplying a stock solution containing a raw material dissolved therein to a precipitation tank in a tank-type continuous precipitation apparatus while withdrawing a slurry containing solids precipitated from the stock solution, preferably a step of performing a precipitation operation in which a solid is precipitated from a liquid phase by continuous operation. Since precipitation is performed by continuous operation, the stock solution is continuously supplied to the precipitation tank at a constant flow rate, and the slurry containing the precipitated solids is continuously withdrawn from the precipitation tank at a constant flow rate. Ideally, the continuous precipitation step is in a steady state in which the total mass of materials supplied to the precipitation tank is equal to the total mass of materials withdrawn from the precipitation tank.

[0014] A first aspect of the present invention provides a method for producing a metastable solid material from a raw material (hereinafter simply referred to as a "metastable solid material"), comprising a continuous precipitation step of supplying a stock solution containing a raw material to a precipitation tank in a tank-type continuous precipitation apparatus while withdrawing a slurry containing the precipitated solid material from the stock solution, wherein in the continuous precipitation step, a slurry containing the metastable solid material is placed in the precipitation tank before starting to supply the stock solution and withdraw the slurry, supplying the stock solution to the precipitation tank while applying ultrasonic vibrations, and withdrawing the slurry containing the precipitated metastable solid material, and setting the average residence time to be shorter than the time required for the precipitated solid material to transition to a stable state having a lower chemical potential than the metastable state under the ultrasonic vibrations. In the present invention, in the continuous precipitation process, continuous precipitation is carried out while applying ultrasonic vibrations to a precipitation tank containing a slurry containing solid matter in a metastable state, and by setting the average residence time in the continuous precipitation process to a time shorter than the time it takes for the precipitated solid matter to transition from a metastable state to a stable state under ultrasonic vibration, metastable solid matter with small particle size is obtained.

[0015] A second invention relates to a method for producing a metastable solid material, which includes a continuous precipitation step of supplying a stock solution containing a raw material dissolved therein to a precipitation tank in a tank-type continuous precipitation apparatus while withdrawing a slurry containing the precipitated solid material from the stock solution. In the continuous precipitation step, before the start of supplying the stock solution and withdrawing the slurry, a slurry containing the metastable solid material is placed in the precipitation tank, and the stock solution is supplied to the precipitation tank while applying ultrasonic vibrations to precipitate a metastable solid material having a D90 (volume basis) of 100 μm or less in a particle size distribution measured by laser diffraction / scattering. The method also includes withdrawing a slurry containing the precipitated metastable solid material. According to the present invention, nucleation is promoted by applying ultrasonic waves, resulting in the production of a small-particle-size solid material. By controlling the average residence time, it is possible to produce a metastable solid material having a D90 (volume basis) of 100 μm or less in a particle size distribution measured by laser diffraction / scattering, which has been difficult to produce in the past. The D90 (volume basis) of the precipitated metastable solid is preferably 1 to 90 μm, more preferably 5 to 70 μm, even more preferably 10 to 50 μm, and even more preferably 12 to 40 μm. The D50 (volume basis) of the precipitated metastable solid is preferably 0.5 to 60 μm, more preferably 1 to 45 μm, and even more preferably 2 to 30 μm. The D10 (volume basis) of the precipitated metastable solid is preferably 0.1 to 50 μm, more preferably 0.2 to 30 μm, and even more preferably 0.3 to 10 μm.

[0016] The value (Span = (D90 - D10) / D50) obtained by dividing the difference between D10 (volume basis) and D90 (volume basis) of the metastable solid precipitated in the continuous precipitation process by D50 is preferably 0 or more and less than 5.0, more preferably 1.0 or more and 4.7 or less, even more preferably 2.0 or more and 4.3 or less, and even more preferably 2.5 or more and 4.0 or less. The value calculated by (D90 - D10) / D50 is an index representing the width of the particle size distribution, and it can be said that the smaller this value, the narrower the particle size distribution and the more uniform the particle size. The solid obtained in the continuous precipitation process has a narrow particle size distribution and uniform and good properties as a solid, and therefore can be suitably used as a pharmaceutical active ingredient or pharmaceutical intermediate.

[0017] In the continuous precipitation process, a slurry containing metastable solids is first placed in a precipitation tank before the start of supplying the raw solution and withdrawing the slurry. This configuration promotes nuclei formation even after the start of continuous precipitation. The proportion of metastable solids in the slurry placed in the precipitation tank is preferably 50% or more, more preferably 70% or more, even more preferably 80% or more, even more preferably 90% or more, and particularly preferably 95% or more. The upper limit is not particularly limited, but is preferably 100% (specifically, the stable-state solids of the raw material (hereinafter simply referred to as "stable-state solids") are below the detection limit).

[0018] Next, the raw solution is supplied to a precipitation tank containing a slurry containing metastable solids while applying ultrasonic vibrations, and the slurry containing the precipitated metastable solids is withdrawn, thereby carrying out continuous precipitation. By applying ultrasonic vibrations, the cavitation effect unique to ultrasound promotes nucleation while controlling the timing of nucleation, enabling precipitation with a high precipitation rate or high recovery rate even in a short period of time. Furthermore, applying ultrasonic vibrations can suppress fouling, making it possible to build a robust manufacturing process.

[0019] On the other hand, the cavitation effect may promote the transition from a metastable state to a stable state. Therefore, the present invention addresses this issue by controlling the average residence time. Specifically, in the present invention, the average residence time in the continuous deposition process is set to a time shorter than the time required for the deposited solid matter to transition to a stable state, which has a lower chemical potential than the metastable state, under ultrasonic vibration. The "time shorter than the time required for transition to a stable state" here depends on the stability of the metastable state of the solid matter and cannot be set uniformly. However, the average residence time is generally, for example, less than 2 hours, preferably 1.8 hours or less, more preferably 1.5 hours or less, and even more preferably 1.0 hour or less. Since a longer average residence time causes the solid matter to transition to a stable state, shortening the average residence time can prevent the solid matter from transitioning to a stable state. Furthermore, the average residence time is preferably 5 minutes or more, more preferably 10 minutes or more, and even more preferably 20 minutes or more. By setting the average residence time within the above range, sufficient deposition efficiency can be ensured. For example, when the present invention is carried out industrially, before carrying out industrial continuous precipitation, continuous precipitation tests are carried out under conditions with different average residence times, and the average residence time at which a metastable solid having a small particle size is obtained is determined in advance. In industrial implementation, the continuous precipitation conditions are then determined so as to achieve the predetermined average residence time.

[0020] In the present disclosure, the mean residence time τ refers to the time that a volume V of slurry contained in a precipitation tank remains in the precipitation tank. Ideally, when a volume V of slurry contained in the precipitation tank is discharged from the precipitation tank at a flow rate Qo, the mean residence time τ refers to the time required for the volume V in the precipitation tank to be replaced by a new substance flowing into the precipitation tank at a flow rate Qi. Typically, when a continuous precipitation process is in a steady state, the flow rate Qi of the substance flowing into the precipitation tank and the flow rate Qo of the substance discharged from the precipitation tank are the same. In this case, if the volume of the slurry contained in the precipitation tank is V, the mean residence time τ can be calculated by V / Qi or V / Qo.

[0021] The frequency of the ultrasonic waves in the continuous deposition step is preferably 20 to 60 kHz, more preferably 22 to 55 kHz, and even more preferably 25 to 60 kHz. By setting the frequency within this range, sufficient deposition efficiency can be ensured.

[0022] The method of applying ultrasonic vibration to the precipitation tank may be either direct irradiation or indirect irradiation. Examples of direct irradiation include a method in which an ultrasonic vibrator is provided on at least one of the side and bottom of the precipitation tank and ultrasonic waves are irradiated using a vibrating plate connected to the ultrasonic vibrator, and a method in which ultrasonic waves are irradiated using a horn-type device directly placed in the precipitation tank. Examples of indirect irradiation include a method in which the precipitation tank is placed in a standing wave device and ultrasonic waves are irradiated from the outside (preferably the bottom) of the precipitation tank. When scaling up the precipitation tank, direct irradiation, in which ultrasonic energy is transmitted to the precipitation tank, is desirable from the standpoint of production efficiency.

[0023] In the present disclosure, a "metastable solid" refers to a solid that is in phase B, and although phase A exists, which is thermodynamically more stable than phase B, it does not undergo a phase transition to phase A for a certain period of time and remains in phase B. In other words, a metastable state refers to a state in which, even when external conditions such as temperature and pressure are changed, the phase transition point is not crossed and a transition from phase B to phase A does not occur immediately, and the solid can temporarily remain stable in phase B. Although such a state is not a true equilibrium state, it can be considered a long-lived pseudo-equilibrium state, and can also be said to be a state in the process of transition toward equilibrium.

[0024] The metastable solid material obtained by the present invention is a solid material formed by precipitation of the material from a solution, which can transition to a thermodynamically more stable crystalline state under processing conditions such as ultrasonic irradiation. The term "solid material" encompasses both crystalline and amorphous materials. For example, a crystalline solid material obtained by the present invention is a metastable crystal that can transition to a stable crystal state with a lower chemical potential than the metastable state as needed. Furthermore, an amorphous solid material obtained by the present invention is a metastable amorphous solid that can transition to a more stable crystalline state as needed. Generally, when various conditions such as temperature, solvent, and dissolution time are met, metastable solid materials have characteristics such as a lower melting point, higher solubility, and faster dissolution rate than stable solid materials. Examples of such solids include crystalline polymorphs that can form metastable and stable forms with the same chemical composition but different arrangements of atoms, molecules, etc.; pseudo-crystalline polymorphs that can form hydrates and anhydrous forms; and solids that can take both amorphous and crystalline forms. Pseudo-crystalline polymorphs or solids that can take both amorphous and crystalline forms are preferred. When a crystal is a pseudo-crystalline polymorph, the metastable crystal is typically a hydrate, and the stable crystal is typically an anhydrous form. Crystal polymorphs can be confirmed by powder X-ray diffraction (XRD), thermal analysis (DSC, TG-DTA), IR spectroscopy, solid-state NMR, and the like. In this disclosure, "crystalline polymorph" broadly includes not only crystalline polymorphs that can form metastable and stable forms with the same chemical composition but different arrangements of atoms, molecules, etc., but also pseudo-crystalline polymorphs that can form hydrates and anhydrous forms.

[0025] The stable solid state of the raw material obtained by the present invention is a solid state in which the raw material is in a structural state with the lowest chemical potential, specifically, a solid state in a thermodynamic equilibrium phase in which structural changes are unlikely to occur over the long term.

[0026] The proportion of metastable solids in the slurry discharged from the precipitation tank is preferably 50% or more, more preferably 70% or more, even more preferably 80% or more, even more preferably 90% or more, and particularly preferably 95% or more. The upper limit is not particularly limited, but is preferably 100% (specifically, the amount of stable solids is below the detection limit). Because the slurry discharged from the precipitation tank contains a high concentration of metastable solids, purifying the slurry facilitates the production of small-particle metastable solids. The aforementioned "time shorter than the transition to the stable state" can also be defined as the proportion of metastable solids in the slurry discharged from the precipitation tank. For example, "time shorter than the transition to the stable state" can be defined as the time during which the transition to the stable state has not progressed to such an extent that the proportion of metastable solids in the slurry discharged from the precipitation tank satisfies the aforementioned range.

[0027] As the raw material, either an organic compound or an inorganic compound can be used, preferably an organic compound, and more preferably a compound with high pharmacological activity. Pharmacological activity can be evaluated, for example, by the no observed adverse effect level (NOAEL), no observed adverse effect level (NOEL), lowest observed adverse effect level (LOAEL), lowest observed adverse effect level (LOEL), permissible daily exposure (PDE), occupational exposure limit (OEL), etc. Examples of the raw material include perampanel, riociguat, ruxolitinib phosphate, luseogliflozin hydrate, evocalcet, brexpiprazole, pemafibrate, baricitinib, etelcalcetide hydrochloride, rasagiline mesylate, esaxerenone, ponatinib hydrochloride, and venetoclax.

[0028] The solvent used in preparing the stock solution is not particularly limited as long as it can dissolve the raw materials, and various solvents commonly used in crystallization can be used, including, for example, alcohol-based solvents such as methanol, ethanol, isopropanol, etc.; ether-based solvents such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, etc.; ketone-based solvents such as acetone, methyl ethyl ketone, etc. These may be used alone or in combination of two or more.

[0029] The raw material solution may be prepared by mixing the raw materials under conditions in which the raw materials are dissolved in the solvent, and the mixing ratio of the raw materials to the solvent, the mixing temperature, the mixing time, etc. may be appropriately set depending on the types of raw materials and solvent. In order to ensure uniform quality of the solid material obtained in the continuous precipitation step, it is preferable that the raw materials are completely dissolved in the raw material solution.

[0030] In the continuous precipitation step, known precipitation methods such as poor solvent precipitation, neutralization precipitation, and salt formation precipitation can be used as a method for precipitating (growing) a solid. Specifically, poor solvent precipitation can be used, and a poor solvent capable of precipitating a solid from the raw solution can be added. By adding a poor solvent, the supersaturation state of the solute can be controlled and the solute can be solidified. A poor solvent is a solvent that barely dissolves the solute or does not dissolve it at all. It is preferable that the poor solvent is mutually soluble with the raw solution. As the poor solvent, water; hydrocarbon solvents such as benzene, toluene, hexane, and heptane; etc. are generally used. In order to promote solidification, the continuous precipitation step may be performed in combination with supersaturation generation methods such as evaporation and cooling in addition to the addition of a poor solvent.

[0031] The internal temperature of the precipitation tank (i.e., the fluid temperature in the precipitation tank) is preferably adjusted to −20 to 100° C., more preferably −10 to 50° C., and even more preferably 0 to 30° C. By adjusting the temperature within the above range, sufficient precipitation efficiency can be ensured.

[0032] As the tank-type continuous precipitation apparatus, a complete mixing continuous precipitation apparatus, such as a mixed suspension mixed product removal (MSMPR), is preferably used. Compared to a tubular continuous precipitation apparatus, a tank-type continuous precipitation apparatus has advantages such as less clogging and easier temperature control in the precipitation tank, making it suitable for industrial production. Among them, a complete mixing tank-type continuous precipitation apparatus is preferable because it is easy to scale up the apparatus. In a complete mixing tank-type continuous precipitation apparatus, the mother liquor and solid matter in the precipitation tank are in a completely mixed state, making it easy to control the precipitation conditions even when the operation is scaled up.

[0033] The capacity of the precipitation tank provided in the tank-type continuous precipitation apparatus is, for example, 0.1 to 30 L, preferably 2 to 30 L, more preferably 3 to 25 L, and even more preferably 4 to 20 L. The precipitation tank can be appropriately selected from sizes suitable for laboratory equipment to sizes suitable for industrial production.

[0034] The material of the precipitation tank is not particularly limited as long as it can withstand ultrasonic vibrations, and examples thereof include synthetic resin, glass, metal, etc. The precipitation tank is preferably made of glass or metal because it is less likely to be damaged by ultrasonic vibrations. As the metal used for the precipitation tank, titanium alloys, nickel alloys, chromium alloys, and nickel-chromium alloys are preferred from the viewpoint of corrosion resistance (acid resistance, alkali resistance), and stainless steel, Hastelloy (registered trademark), Monel (registered trademark), and Inconel (registered trademark) are more preferred.

[0035] The tank-type continuous precipitation apparatus is preferably further equipped with an agitator capable of stirring the inside of the precipitation tank. By providing an agitator, the mixed state in the precipitation tank can be made uniform. Any known agitator can be used as appropriate. When agitation is performed, the agitation power per unit volume of the fluid in the precipitation tank is preferably 0.001 to 1.0 kW / m. 3 , more preferably 0.005 to 0.8 kW / m 3 , and more preferably 0.01 to 0.6 kW / m 3 , and even more preferably 0.02 to 0.6 kW / m 3 By setting the stirring power within the above range, the particle size of the resulting solid can be controlled more effectively.

[0036] The tank-type continuous precipitation apparatus preferably further includes a temperature regulator that regulates the temperature of the slurry in the precipitation tank. The temperature control method is not particularly limited, and for example, a jacket-type temperature regulator in which a heat medium is circulated through a jacket surrounding the precipitation tank may be used. By including the temperature regulator, the temperature in the precipitation tank can be maintained at a predetermined value.

[0037] The tank-type continuous precipitation apparatus desirably further comprises a raw material supply line and / or a slurry discharge line. The raw material supply line is configured to be able to supply the raw material dissolved in the raw material to the precipitation tank, and the slurry discharge line is configured to be able to discharge the slurry from the precipitation tank. Specifically, the raw material supply line is a pipe connecting the raw material tank containing the raw material to the precipitation tank, and the slurry discharge line is a pipe connecting the precipitation tank to the receiver tank. The raw material supply line and the slurry discharge line may each be independently connected to a pump, and the pump can be used to facilitate liquid transfer. When the tank-type continuous precipitation apparatus comprises a raw material supply line, it is preferable that a raw material tank for containing the raw material is connected upstream of the raw material supply line.

[0038] It is desirable that the tank-type continuous precipitation apparatus further includes in-line measuring devices such as a thermometer, a flow meter, and a turbidity meter at appropriate locations such as the precipitation tank, the raw solution supply line, and the slurry discharge line. In particular, it is preferable that the particle size distribution of the solids in the precipitation tank is measured using a focused beam reflectance measurement (FBRM) in-line particle size analyzer, an imaging in-line particle size analyzer, a microscope, or the like, and that the crystalline polymorphism in the precipitation tank is identified and the proportion of the solids (e.g., crystalline polymorphism) is measured using Raman spectroscopy, powder X-ray analysis, infrared spectroscopy, differential scanning calorimetry, or the like. By monitoring the particle size distribution and crystalline polymorphism of the solids in the precipitation tank, a solid having a desired particle size and crystalline polymorphism can be suitably produced.

[0039] <Raw Material Preparation Step> Next, the raw material preparation step will be described. The raw material preparation step is a step that can selectively prepare a first slurry containing a solid material in a metastable state and a second slurry containing a solid material in a stable state with a chemical potential lower than that of the metastable state. By selecting the crystalline polymorph of the slurry in advance before performing the continuous precipitation step, it is possible to selectively produce a solid material in a metastable state and a solid material in a stable state in the continuous precipitation step.

[0040] In the present invention, by selecting whether or not to irradiate with ultrasound in the raw material preparation step, the morphology of the solid obtained in the raw material preparation step can be selected to be either metastable or stable. By selecting whether or not to irradiate with ultrasound, the crystalline polymorph of the slurry can be easily selected.

[0041] The ultrasonic irradiation time in the raw material preparation step is preferably 5 minutes to 4 hours, more preferably 10 minutes to 1.5 hours, and even more preferably 20 minutes to 1 hour. By setting the time within this range, sufficient precipitation efficiency can be ensured. For the same reason, the ultrasonic frequency in the raw material preparation step is preferably 20 to 60 kHz, more preferably 22 to 55 kHz, and even more preferably 25 to 60 kHz.

[0042] In the raw material preparation step, examples of the method for preparing the first slurry or the second slurry include known precipitation methods such as poor solvent precipitation, cooling precipitation, evaporation precipitation, neutralization precipitation, and salt formation precipitation, and these methods may be combined.

[0043] Preferably, the raw material preparation step is a step of producing a first slurry or a second slurry by storing a stock solution in which raw materials are dissolved in a raw material preparation tank capable of applying ultrasonic vibrations and switching between the following i) and ii). i) A first slurry is obtained by adding a poor solvent without applying ultrasonic vibrations to the raw material preparation tank. By performing precipitation without applying ultrasonic vibrations, a kinetically advantageous metastable solid is obtained. ii) A second slurry is obtained by adding a poor solvent while applying ultrasonic vibrations to the raw material preparation tank. By applying ultrasonic vibrations, a thermodynamically stable solid is obtained. In this case, ultrasonic vibrations can be applied to the raw material preparation tank continuously or intermittently, but from the viewpoint of productivity, it is preferable to apply ultrasonic vibrations to the raw material preparation tank continuously.

[0044] The stock solution in the raw material preparation step may be the same as or different from the stock solution used in the continuous precipitation step, but it is preferable that at least the types of raw materials contained in the stock solution are the same in the raw material preparation step and the continuous precipitation step. As the solvent used to prepare the stock solution, various solvents detailed in the section on the continuous precipitation step may be appropriately adopted.

[0045] In both i) and ii), a poor solvent capable of precipitating a solid from the stock solution is added. By adding a poor solvent, the supersaturation state of the solute can be controlled and the solute can be solidified. A poor solvent is a solvent that hardly dissolves the solute or does not dissolve it at all. It is preferable that the poor solvent is mutually soluble with the stock solution. As the poor solvent, generally used are water; hydrocarbon solvents such as benzene, toluene, hexane, and heptane; etc. In both i) and ii), in addition to the addition of a poor solvent, a supersaturation generation method represented by evaporation, cooling, etc. may be used in combination to promote solidification.

[0046] The preparation of the first slurry or the second slurry may be carried out under conditions that allow precipitation of a solid from the stock solution, and the mixing ratio of the stock solution to the poor solvent, the mixing temperature, the mixing time, and the like may be appropriately set depending on the types of stock solution and poor solvent. For example, the mixing temperature of the stock solution and the poor solvent is preferably −20 to 100° C., more preferably −10 to 50° C., and even more preferably 0 to 30° C., and by keeping it within this range, sufficient precipitation efficiency can be ensured. The mixing time of the stock solution and the poor solvent is preferably 5 minutes to 4 hours, more preferably 10 minutes to 1.5 hours, and even more preferably 20 minutes to 1 hour, and by keeping it within this range, sufficient precipitation efficiency can be ensured.

[0047] In the raw material preparation step, the fluid in the raw material preparation tank may be stirred. When stirring is performed, the stirring power per unit volume of the fluid in the raw material preparation tank is preferably 0.001 to 1.0 kW / m 3 , more preferably 0.005 to 0.8 kW / m 3 , and more preferably 0.01 to 0.6 kW / m 3 , and even more preferably 0.02 to 0.6 kW / m 3 is.

[0048] As the raw material preparation tank, a batch precipitation apparatus, a continuous precipitation apparatus, etc. are appropriately used, and from the viewpoint of productivity, a continuous precipitation apparatus is preferable. A continuous precipitation apparatus makes it possible to save space in the manufacturing equipment required for the raw material preparation step. Furthermore, the raw material preparation tank in the raw material preparation step and the precipitation tank in the continuous precipitation step may be the same or different, but it is preferable that they are the same tank. By performing the raw material preparation step and the continuous precipitation step in the same tank, it is possible to save space in the entire manufacturing equipment and the management burden of tank cleaning, etc. is reduced, which is advantageous for industrial-scale production. Since this simplifies the manufacturing equipment, if the raw material preparation tank in the raw material preparation step and the precipitation tank in the continuous precipitation step are the same, it is preferable to use a common stock solution in the raw material preparation step and the continuous precipitation step.

[0049] The proportion of metastable solid matter in the obtained first slurry is preferably 50% or more, more preferably 70% or more, even more preferably 80% or more, even more preferably 90% or more, and particularly preferably 95% or more, and although the upper limit is not particularly limited, it is preferably 100% (specifically, the proportion of metastable solid matter is below the detection limit).

[0050] The proportion of stable solid matter in the resulting second slurry is preferably 50% or more, more preferably 70% or more, even more preferably 80% or more, even more preferably 90% or more, and particularly preferably 95% or more, and although the upper limit is not particularly limited, it is preferably 100% (specifically, the proportion of metastable solid matter is below the detection limit).

[0051] The first and second slurries produced in the raw material preparation step can be subjected to a continuous precipitation step as raw materials having nuclei. That is, the present disclosure provides, as a third invention, a method for producing a solid material, comprising: a raw material preparation step capable of selectively preparing a first slurry containing a metastable solid material and a second slurry containing a stable solid material having a chemical potential lower than that of the metastable solid material; and a continuous precipitation step in which a stock solution containing the raw material is supplied to a precipitation tank of a tank-type continuous precipitation device while extracting a slurry containing the precipitated solid material from the stock solution. By selecting whether or not to irradiate with ultrasound in the raw material preparation step, the morphology of the solid material obtained in the raw material preparation step can be selected to be the metastable state or the stable state. By selecting the crystalline polymorph of the slurry before the continuous precipitation step, it is possible to produce a metastable solid material or a stable solid material in the continuous precipitation step.

[0052] When a first slurry containing metastable solids is subjected to the continuous precipitation process (hereinafter sometimes referred to as "Case 1"), it can be subjected to the continuous precipitation process described above. Specifically, it is convenient to use the first slurry produced in the raw material preparation process as the slurry containing metastable solids contained in the precipitation tank. In this case, in the continuous precipitation process, before starting the supply of the raw material solution and the withdrawal of the slurry, the first slurry containing metastable solids is placed in the precipitation tank, and the raw material solution is supplied to the precipitation tank while applying ultrasonic vibrations, and the slurry containing the precipitated metastable solids is withdrawn, with the average residence time being set to be shorter than the time required for the precipitated solids to transition from the metastable state to a stable state with a lower chemical potential under ultrasonic vibration. By setting the average residence time in the continuous precipitation process to be shorter than the time required for the precipitated solids to transition from the metastable state to a stable state under ultrasonic vibration, metastable solids with small particle size can be obtained.

[0053] The average residence time in Case 1 is, for example, less than 2 hours, preferably 1.8 hours or less, more preferably 1.5 hours or less, and even more preferably 1.0 hour or less. If the average residence time is long, there is a risk that the solid matter will transition to a stable state. Therefore, by shortening the average residence time, the transition of the solid matter to a stable state can be suppressed. Furthermore, the average residence time is preferably 5 minutes or more, more preferably 10 minutes or more, and even more preferably 20 minutes or more. By setting the average residence time within the above range, sufficient precipitation efficiency can be ensured. Regarding other conditions, the matters described above for the continuous precipitation process may be applied as appropriate.

[0054] When the second slurry containing the stable solid matter is subjected to the continuous precipitation process (hereinafter, sometimes referred to as "Case 2"), the second slurry may be placed in a precipitation tank, the raw solution may be supplied, and the precipitated slurry containing the stable solid matter may be withdrawn before the supply of the raw solution and the withdrawal of the slurry are started in the continuous precipitation process.

[0055] In Case 2, since the deposited solid matter in a stable state is unlikely to be transferred, the average residence time is not particularly limited, but from the viewpoint of productivity, it is, for example, 2 hours or less, preferably 1.8 hours or less, more preferably 1.5 hours or less, even more preferably 1.0 hour or less, preferably 5 minutes or more, more preferably 10 minutes or more, and even more preferably 20 minutes or more. By setting it within this range, sufficient deposition efficiency can be ensured.

[0056] In addition, in Case 2, ultrasonic irradiation in the continuous precipitation step is optional, and the continuous precipitation step may be performed while applying ultrasonic vibrations to the precipitation tank, or may be performed without applying ultrasonic vibrations to the precipitation tank. In Case 2, when the continuous precipitation step is performed while applying ultrasonic vibrations to the precipitation tank, it becomes easier to obtain stable solid matter with small particle sizes, and when the continuous precipitation step is performed without applying ultrasonic vibrations to the precipitation tank, it becomes easier to obtain stable solid matter with large particle sizes. Furthermore, when the second slurry contains solid matter in a metastable state as a part of it, ultrasonic irradiation effectively promotes the transition to the stable state, making it easier to obtain a slurry containing solid matter in a high concentration in a stable state.

[0057] In Case 2, when the continuous precipitation step is performed while applying ultrasonic vibrations to the precipitation tank, the D90 (volume basis) of the precipitated stable-state solid is, for example, 1 to 100 μm, preferably 1 to 90 μm, more preferably 5 to 70 μm, and even more preferably 10 to 50 μm. The D50 (volume basis) of the precipitated stable-state solid is preferably 0.5 to 60 μm, more preferably 1 to 45 μm, and even more preferably 2 to 30 μm. The D10 (volume basis) of the precipitated stable-state solid is preferably 0.1 to 50 μm, more preferably 0.2 to 30 μm, and even more preferably 0.3 to 10 μm.

[0058] In Case 2, when the continuous precipitation step is performed without applying ultrasonic vibration to the precipitation tank, the D90 (volume basis) of the precipitated solid in a stable state is preferably 100 to 300 μm, more preferably 120 to 220 μm, and even more preferably 150 to 200 μm. The D50 (volume basis) of the precipitated solid in a stable state is preferably 10 to 150 μm, more preferably 30 to 120 μm, and even more preferably 50 to 100 μm. The D10 (volume basis) of the precipitated solid in a stable state is preferably 1 to 50 μm, more preferably 3 to 40 μm, and even more preferably 5 to 30 μm.

[0059] <Solid-Liquid Separation Step> The present invention may further include a solid-liquid separation step after the continuous precipitation step in order to isolate the solid matter precipitated in the continuous precipitation step.

[0060] The slurry containing the precipitated metastable solid material extracted from the precipitation tank may be supplied to a further precipitation device depending on the application, or may be supplied to a solid-liquid separation step without being subjected to a further precipitation device. In the present invention, the continuous precipitation step is performed under ultrasonic vibration, which promotes nucleation, and a high precipitation rate or high recovery rate can be achieved even with a single-stage continuous tank-type precipitation device (i.e., without being subjected to a further precipitation device). Examples of solid-liquid separation include filtration separation such as natural filtration, reduced pressure filtration, and pressure filtration, sedimentation separation, and centrifugation. The solid material obtained by solid-liquid separation may be further treated, for example, by washing or drying. The drying method is not particularly limited, and examples include natural drying and reduced pressure drying (vacuum drying).

[0061] The mother liquor after the solid-liquid separation step may be returned to the continuous precipitation step (precipitation tank). That is, the mother liquor contained in the slurry discharged from the precipitation tank may be circulated by being returned to the continuous precipitation step (precipitation tank) via the solid-liquid separation step.

[0062] This application claims the benefit of priority based on Japanese Patent Application No. 2024-102209, filed on June 25, 2024. The entire contents of the specification of Japanese Patent Application No. 2024-102209, filed on June 25, 2024, are incorporated herein by reference.

[0063] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples, and can of course be practiced with appropriate modifications within the scope of the above and below-described aims, all of which are included within the technical scope of the present invention. In the following, unless otherwise specified, "parts" means "parts by mass" and "%" means "% by mass."

[0064] (1) Raw Materials (1-1) Perampanel Perampanel (manufactured by Yibin Hongguang Pharmaceutical Co., Ltd.) was used as a raw material. The solubilities of perampanel anhydrous form V and perampanel hydrate were measured by the following procedure. 0.03 g of perampanel (anhydrous form V or hydrate) was dissolved in acetone / H2SO4. ２3.00 g of 55 / 45 ethanol was added and stirred at 25°C for 1 hour. The slurry was then filtered through a membrane filter (pore size: 0.45 µm), and the perampanel content (solubility) in the mother liquor was measured by high-performance liquid chromatography (HPLC). The measurement results showed that the solubility of Anhydrous Form V was 0.142%, and the solubility of the hydrate was 0.189%, indicating that Anhydrous Form V is less soluble than the hydrate. This indicates that of Anhydrous Form V and the hydrate of perampanel, Anhydrous Form V is in a stable state, and the hydrate is in a metastable state. The HPLC analysis was performed under the following conditions, and the perampanel content was measured in the same manner hereinafter. Apparatus: LC-2050C (Shimadzu Corporation) Column: YMC-Pack Pro C18 150 mm x 4.6 mm i.d. (YMC) Column temperature: 35°C Mobile phase A: Water / acetonitrile / ammonium acetate = 900:100:1 (v / v / w) Mobile phase B: Water / acetonitrile / ammonium acetate = 100:900:1 (v / v / w) (Isocratic conditions: B concentration = 40%) Measurement time: 20 minutes Flow rate: 1.0 mL / min Detector: UV 290 nm Injection volume: 5 μL

[0065] (1-2) Evocalcet The solubility of amorphous and crystalline evocalcet was measured by the following procedure. THF / hexane (9 / 91) was added to 0.10 g of evocalcet (crystalline or amorphous) and stirred at 5°C for 2 hours. The slurry was then filtered through a membrane filter (pore size: 0.45 μm), and the evocalcet content (solubility) in the mother liquor was measured by high-performance liquid chromatography (HPLC). The results showed that the solubility of type A crystals was 0.0015%, that of type B crystals was 0.0016%, and that of the amorphous form was 0.0065%, indicating that the crystalline form was less soluble than the amorphous form. This indicates that the crystalline form is stable and the amorphous form is metastable for evocalcet crystals and amorphous form. The HPLC analysis was performed under the following conditions, and the evocalcet content was measured in the same manner hereafter. Apparatus: LC-2050C (Shimadzu Corporation) Column: L-column2 (CERI) 150 mm x 4.6 mm i.d. Column temperature: 40°C Mobile phase A: water / acetonitrile / trifluoroacetic acid = 1900:100:1 (v / v / v) Mobile phase B: water / acetonitrile / trifluoroacetic acid = 200:1800:1 (v / v / v) Mobile phase delivery method: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient and deliver the mobile phase. [Mobile phase concentration gradient] Flow rate: 1.0 mL / min Detector: UV 220 nm Injection volume: 5 μL

[0066] (2) Average Residence Time To adjust the average residence time, the flow rates of pumps 1 to 3 were determined based on the following formula (1). The flow rate ratio of the liquids sent from pumps 1 and 2 was set to be the same as the volume ratio of the stock solution to the poor solvent used to form the slurry contained in the precipitation tank. Qi = Qo = V / τ (1) (In formula (1), τ: average residence time (minutes), Qi: total flow rate of pump 1 and pump 2 (mL / min), Qo: flow rate of pump 3 (mL / min), V: volume of the slurry contained in the precipitation tank (mL)) In Example 1, the flow rates of pumps 1 to 3 were determined from formulas (1) and (2) as follows: Flow rate of pump 1: Flow rate of pump 2 = 3.67:2.33 (2) Flow rate of pump 1 = (180 mL / 30 min) x 3.67 / (3.67 + 2.33) = 3.67 (mL / min) Flow rate of pump 2 = (180 mL / 30 min) x 2.33 / (3.67 + 2.33) = 2.33 (mL / min) Flow rate of pump 3 = 180 mL / 30 min = 6.00 (mL / min)

[0067] (3) Particle size of solid matter The particle size of solid matter was measured by sampling the slurry in the precipitation tank after continuous precipitation had been carried out for 2 hours or more, and using a laser diffraction particle size distribution measuring device (Mastersizer 3000 manufactured by Malvern Panalytical).

[0068] (4) Crystal Polymorphism The crystal polymorphism was measured using an X-ray diffractometer ("MiniFlex II" manufactured by Rigaku Corporation) for crystals obtained by filtering the slurry accumulated in the receiver tank after carrying out continuous precipitation for 2 hours or more using a Kiriyama funnel and filter paper 5B (particle retention capacity 4 μm).

[0069] (5) Deposition Rate The deposition rate of solid matter was determined by the following procedure. After continuous precipitation for 2 hours or more, the slurry in the precipitation tank was filtered through a membrane filter (pore size: 0.45 μm), and the content of perampanel or evocalcet in the mother liquor was measured by HPLC analysis. From this content, the actual deposition amount (A) of perampanel or evocalcet due to continuous precipitation was calculated. In addition, the solubility of perampanel or evocalcet in the raw solution was measured by HPLC analysis. From this solubility, the theoretically obtainable maximum deposition amount (B) of perampanel or evocalcet was calculated. The deposition rate was then determined by the following formula: Deposition rate (%) = Deposition amount (A) (g) / Maximum deposition amount (B) (g) × 100

[0070] (6) Recovery Rate The recovery rate of solid matter was determined by the following procedure. The amount of precipitation (A) was calculated in the same manner as described in (5). The recovery rate was then determined by the following formula. The total amount of raw materials used for precipitation means the total amount of perampanel or evocalcet used for precipitation. Recovery rate (%) = Amount of precipitation (A) (g) / Total amount of solid raw materials used for precipitation (g) × 100

[0071] (7) Span Value The Span value, expressed by the following formula, was calculated from D10, D50, and D90 measured using a laser diffraction particle size distribution analyzer (Malvern Panalytical's "Mastersizer 3000"). The smaller the Span value, the smaller the spread of the particle size distribution. Span = (D90 - D10) / D50

[0072] Example 1 As shown in FIG. 1 , a feed tank 1 (1 L flask), a poor solvent tank 2 (1 L), a precipitation device (precipitation tank) 4 (300 mL, glass separable flask) equipped with a stirring blade 3, a diaphragm pump 1 (11, "SIMDOS (registered trademark) 02" manufactured by KNF) for transferring liquid from the feed tank 1, a diaphragm pump 2 (12, "SIMDOS (registered trademark) 02" manufactured by KNF) for transferring liquid from the poor solvent tank 2, and a diaphragm pump 3 (13, "SIMDOS (registered trademark) 02" manufactured by KNF) for transferring liquid from the precipitation device 4. A continuous precipitation system 10 was constructed, including a peristaltic pump 3 (13, Cole-Parmer "Masterflex® L / S"), a flow sensor (KEYENCE "FD-XS1"), an FT-Raman spectrometer 5 (Mettler-Toledo "ReactRaman 785"), an indirect irradiation ultrasonicator 6 (AS ONE Corporation "USK-4R") to which ice was added for temperature control, and a receiver tank 7. Perampanel (6.89 g, 19.7 mmol) and acetone (682.1 g, 99 wt / wt) were added to a feed tank and stirred at 25±5°C to prepare a stock solution in which perampanel was dissolved. Meanwhile, the antisolvent tank was filled with water. With pumps 1 to 3, the ultrasonic device, and the rotating motor of the stirring blade turned off, pump 1 was first operated to pump the stock solution from the feed tank at a flow rate of 3.67 mL / min for 30 minutes. Next, the rotating motor of the stirring blade was turned on (0.04 kW / m) while the ultrasonic device was left off. 3Pump 2 was operated to pump water from the anti-solvent tank at a flow rate of 2.33 mL / min for 30 minutes. A 180 mL slurry was formed in the precipitator, consisting of a mixture of the stock solution and anti-solvent water at a volume ratio of 3.67:2.33. This slurry contained metastable perampanel crystals (hydrate). (XRD analysis revealed stable perampanel (anhydrous Form V) below the detection limit.) Pumps 1 to 3 were then operated to supply the stock solution (3.67 mL / min) and anti-solvent (2.33 mL / min) to the precipitator, and the slurry (6.00 mL / min) was extracted from the precipitator. The ultrasonicator was also operated to indirectly irradiate the slurry in the precipitator with ultrasound (40 kHz). The slurry remained in the precipitator at 25±2°C for an average residence time of 30 minutes, after which it was extracted from the precipitator and supplied to a receiver tank. After operation for 2 hours or more to stabilize the slurry, the crystal particle size, crystal polymorphism, precipitation rate, recovery rate, and Span value were measured by the methods described above, and the results are shown in Table 2. The slurry accumulated in the receiver tank contained only perampanel crystals (hydrate) in a metastable state (perampanel (anhydrous Form V) in a stable state was below the detection limit in XRD analysis).

[0073] Example 2 A continuous precipitation system 10 was constructed in the same manner as in Example 1, except that Feed Tank 1 (1 L flask) was replaced with Feed Tank 1 (100 mL flask). Evocalcet (2.82 g, 7.53 mmol) and tetrahydrofuran (125.6 g, 45 wt / wt) were added to the feed tank and stirred at 25±5°C to prepare a stock solution in which evocalcet was dissolved. Meanwhile, the anti-solvent tank was filled with heptane. With Pumps 1 to 3, the ultrasonic device, and the rotating motor of the stirring blade turned off, Pump 2 was first operated to pump heptane from the anti-solvent tank at a flow rate of 6.50 mL / min for 30 minutes. Next, the rotating motor of the stirring blade was turned on (0.04 kW / m) while the ultrasonic device was turned off. ３Pump 1 was operated to deliver the stock solution from the feed tank at a flow rate of 0.52 mL / min for 30 minutes. A 211 mL slurry was formed in the precipitator, consisting of a mixture of the stock solution and the antisolvent heptane at a volume ratio of 0.52:6.50. This slurry contained metastable evocalcet (amorphous). (XRD analysis revealed that stable evocalcet (crystalline) was below the detection limit.) Pumps 1 to 3 were then operated to supply the stock solution (0.52 mL / min) and antisolvent (6.50 mL / min) to the precipitator, and the slurry (7.02 mL / min) was extracted from the precipitator. The ultrasonicator was also operated to indirectly irradiate the slurry in the precipitator with ultrasound (40 kHz). The slurry remained in the precipitator at 5±2°C for an average residence time of 30 minutes, after which it was extracted from the precipitator and supplied to a receiver tank. After operation for 2 hours or more to stabilize the slurry, the amorphous particle size, precipitation rate, recovery rate, and Span value were measured by the above-mentioned methods, and the results are shown in Table 2. The slurry accumulated in the receiver tank contained only metastable evocalcet (amorphous) (evocalcet (crystalline) in a stable state was below the detection limit in XRD analysis).

[0074] Comparative Example 1 The process up to forming a slurry containing metastable perampanel crystals (hydrate) in the continuous precipitation system and precipitation apparatus (perampanel (anhydrous form V) in a stable state was below the detection limit by XRD analysis) was the same as in Example 1. Thereafter, pumps 1 to 3 were operated to supply the stock solution (3.67 mL / min) and poor solvent (2.33 mL / min) to the precipitation apparatus. The rotating motor of the stirring blade was turned on (0.04 kW / m) without driving the ultrasonic device. 3 The slurry was retained in the precipitator at 25±2°C for an average retention time of 30 minutes, after which it was withdrawn from the precipitator, and the withdrawn slurry (6.00 mL / min) was fed to a receiver tank. The results after operation for more than 2 hours are shown in Table 2.

[0075] Comparative Example 2 The continuous precipitation system and the process up to forming a slurry containing metastable perampanel crystals (hydrate) in the precipitation device (perampanel (anhydrous Form V) in a stable state was below the detection limit by XRD analysis) were the same as in Example 1. Pumps 1 to 3 were then operated to supply the stock solution (0.92 mL / min) and antisolvent (0.58 mL / min) to the precipitation device, and the slurry (1.5 mL / min) was extracted from the precipitation device. The ultrasonic device was also driven to indirectly irradiate the slurry in the precipitation device with ultrasound (40 kHz). The slurry remained in the precipitation device at 25±2°C for an average residence time of 2 hours, after which it was extracted from the precipitation device and supplied to a receiver tank. The results after operation for more than 2 hours are shown in Table 2.

[0076] Comparative Example 3 The process up to forming a slurry containing metastable evocalcet (amorphous) in the continuous precipitation system and the precipitation device (stable evocalcet (crystalline) was below the detection limit by XRD analysis) was the same as in Example 2. Then, pumps 1 to 3 were operated to supply the stock solution (0.52 mL / min) and poor solvent (6.50 mL / min) to the precipitation device. The rotating motor of the stirring blade was turned on (0.04 kW / m) without driving the ultrasonic device. 3 The slurry was retained in the precipitator at 5±2°C for an average retention time of 30 minutes, after which it was withdrawn from the precipitator, and the withdrawn slurry (7.02 mL / min) was fed to a receiver tank. The results after more than two hours of operation are shown in Table 2.

[0077] Reference Example 1 The continuous precipitation system was the same as in Example 1. Perampanel (6.89 g, 19.7 mmol) and acetone (682.1 g, 99 wt / wt) were added to a feed tank and stirred at 25±5°C to prepare a stock solution in which perampanel was dissolved. Meanwhile, the anti-solvent tank was filled with water. With pumps 1 to 3, the ultrasonic device, and the rotary motor of the stirring blade turned off, pumps 1 and 2 were operated to pump the stock solution from the feed tank at a flow rate of 3.67 mL / min and water from the anti-solvent tank at a flow rate of 2.33 mL / min for 30 minutes. Next, the ultrasonic device and the rotary motor of the stirring blade were turned on, and stirring was performed while applying ultrasonic vibrations at 25±2°C for 30 minutes. A slurry was formed in the precipitation device, and the slurry contained stable perampanel crystals (anhydrous Form V) (perampanel (hydrate) in a stable state was below the detection limit by XRD analysis). Pumps 1 to 3 were operated to supply the stock solution (3.67 mL / min) and poor solvent (2.33 mL / min) to the precipitator, and a slurry (6.00 mL / min) was extracted from the precipitator. The ultrasonic device was also operated to indirectly irradiate the slurry in the precipitator with ultrasound (40 kHz). The slurry was retained in the precipitator at 25±2°C for an average retention time of 30 minutes, after which it was extracted from the precipitator and supplied to a receiver tank. The results after operation for more than two hours are shown in Table 2.

[0078]

[0079] In the continuous deposition in Example 1 and Reference Example 1, no fouling was observed in the deposition tank.

[0080] REFERENCE SIGNS LIST 1 Feed tank 2 Antisolvent tank 3 Stirring blade 4 Precipitation device (precipitation tank) 5 FT-Raman spectrometer 6 Indirect irradiation ultrasonic device 7 Receiver tank 10 Continuous precipitation system 11 Diaphragm pump 1 12 Diaphragm pump 2 13 Peristaltic pump 3

Claims

1. A method for producing a metastable solid material of a raw material, comprising a continuous precipitation step of supplying a stock solution containing a raw material dissolved therein to a precipitation tank in a tank-type continuous precipitation device while withdrawing a slurry containing solid material precipitated from the stock solution, wherein in the continuous precipitation step, a slurry containing a metastable solid material of the raw material is placed in the precipitation tank before starting to supply the stock solution and withdraw the slurry, and while applying ultrasonic vibration to the precipitation tank, the stock solution is supplied and the slurry containing the precipitated metastable solid material of the raw material is withdrawn, and the average residence time is set to be shorter than the time required for the precipitated solid material to transition to a stable state having a lower chemical potential than the metastable state under the ultrasonic vibration.

2. A method for producing a metastable solid material of a raw material, comprising a continuous precipitation step of supplying a stock solution containing a raw material dissolved therein to a precipitation tank in a tank-type continuous precipitation device while withdrawing a slurry containing solid material precipitated from the stock solution, wherein in the continuous precipitation step, before starting to supply the stock solution and withdraw the slurry, a slurry containing metastable solid material of the raw material is placed in the precipitation tank, the stock solution is supplied to the precipitation tank while applying ultrasonic vibrations, thereby precipitating metastable solid material of the raw material having a D90 (volume basis) of 100 μm or less in a particle size distribution determined by laser diffraction / scattering method, and the slurry containing the precipitated metastable solid material of the raw material is withdrawn.

3. The method of claim 1 or 2, wherein the average residence time in the continuous precipitation step is less than 2 hours.

4. The method according to claim 1 or 2, wherein the proportion of metastable solid matter in the raw material in the slurry discharged from the precipitation tank is 50% or more.

5. The method according to claim 1 or 2, wherein the tank-type continuous precipitation apparatus is a complete mixing continuous precipitation apparatus.

6. The method according to claim 1 or 2, wherein the volume of the precipitation tank is 0.1 to 30 L.

7. The manufacturing method according to claim 1 or 2, wherein a poor solvent capable of precipitating the solid matter from the raw solution is added in the continuous precipitation step.

8. The production method according to claim 1 or 2, wherein the metastable solid material of the raw material precipitated in the continuous precipitation step has a Span value, represented by the following formula, of 0 or more and less than 5.0: Span = (D90 - D10) / D50 (where D10, D50, and D90 respectively represent D10, D50, and D90 on a volume basis in the particle size distribution determined by a laser diffraction / scattering method).

9. The method according to claim 1 or 2, further comprising a solid-liquid separation step after the continuous precipitation step, wherein the slurry is supplied to the solid-liquid separation step without being subjected to any further precipitation device.

10. The manufacturing method according to claim 1 or 2, further comprising a raw material preparation step, prior to the continuous precipitation step, capable of selectively preparing a first slurry containing a solid material of the raw material in a metastable state and a second slurry containing a solid material of the raw material in a stable state having a smaller chemical potential than the metastable state, wherein the form of the solid material obtained in the raw material preparation step is selected to be either a metastable state or a stable state by selecting whether or not to irradiate with ultrasound in the raw material preparation step.

11. The manufacturing method according to claim 10, wherein the raw material preparation step is a step of producing the first slurry or the second slurry by storing a stock solution in which raw materials are dissolved in a raw material preparation tank capable of applying ultrasonic vibrations, and switching between the following i) and ii): i) obtaining a first slurry by adding a poor solvent without applying ultrasonic vibrations to the raw material preparation tank, and ii) obtaining a second slurry by adding a poor solvent while applying ultrasonic vibrations to the raw material preparation tank.

12. The manufacturing method according to claim 11, wherein the slurry containing the metastable solid material of the raw material contained in the precipitation tank is the first slurry.

13. The manufacturing method according to claim 11, wherein the raw material preparation tank in the raw material preparation step and the precipitation tank in the continuous precipitation step are the same tank.

14. A method for producing a solid material, comprising: a raw material preparation step capable of selectively preparing a first slurry containing solid material in a metastable state of the raw material and a second slurry containing solid material in a stable state having a chemical potential lower than that of the metastable state; and a continuous precipitation step in which a stock solution in which the raw material is dissolved is supplied to a precipitation tank of a tank-type continuous precipitation device, and a slurry containing the solid material precipitated from the stock solution is extracted, characterized in that by selecting whether or not to irradiate with ultrasound in the raw material preparation step, the form of the solid material obtained in the raw material preparation step can be selected to be in the metastable state or the stable state.

15. The manufacturing method according to claim 14, wherein the raw material preparation step is a step of producing the first slurry or the second slurry by storing a stock solution in which raw materials are dissolved in a raw material preparation tank capable of applying ultrasonic vibrations and switching between the following i) and ii): i) obtaining a first slurry by adding a poor solvent without applying ultrasonic vibrations to the raw material preparation tank, and ii) obtaining a second slurry by adding a poor solvent while applying ultrasonic vibrations to the raw material preparation tank.

16. A manufacturing method according to claim 14, wherein in the continuous precipitation step, before starting the supply of the raw material solution and the withdrawal of the slurry, the first slurry is placed in the precipitation tank, the raw material solution is supplied to the precipitation tank while ultrasonic vibrations are applied, and a slurry containing the precipitated solid material in a metastable state is withdrawn, and the average residence time is set to be shorter than the time required for the precipitated solid material to transition under ultrasonic vibration to a stable state having a smaller chemical potential than the metastable state.

17. The manufacturing method according to claim 14, wherein in the continuous precipitation step, before starting the supply of the raw material solution and the withdrawal of the slurry, the second slurry is placed in the precipitation tank, the raw material solution is supplied, and a slurry containing a stable solid matter of the precipitated raw material is withdrawn.

18. The method of claim 14, wherein the tank-type continuous precipitation apparatus is a complete mixing continuous precipitation apparatus.

19. The method of claim 14, wherein the volume of the precipitation tank is 0.1 to 30 L.

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