Method for producing crystal

Abstract

An object of the present invention is to provide a method for preparing a crystal, which is advantageous for industrial-scale production and can control the particle size.SOLUTION: A step (A) of accommodating a stock solution in which raw materials are dissolved in a tank (1) having a volume of 2 to 30L and provided with an ultrasonic vibrator, and then precipitating crystals from the stock solution to prepare a seed crystal slurry, and then a step (B) of continuously discharging a slurry generated by precipitating crystals from the stock solution while continuously supplying the stock solution in which raw materials are dissolved to the tank (1) accommodating the prepared seed crystal slurry in a state where ultrasonic vibration is applied.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for producing crystals, and more specifically to a method for producing crystals by continuous crystallization under ultrasonic vibration. [Background technology]

[0002] Crystallization technology is widely used as a separation and purification technique in the fields of medicine, food, nanomaterials, biomaterials, electronic devices, environment-related fields, etc. 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 seen a shift 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, Non-Patent Document 1 discloses a cascade crystallization apparatus consisting of a Couette-Taylor apparatus and an MSMPR (mixed suspension mixed product removal) apparatus. In this continuous crystallization apparatus, a slurry containing crystal nuclei prepared in the Couette-Taylor apparatus is introduced into the MSMPR apparatus to carry out continuous crystallization. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Mana Koyama.et al,Development of novel cascade type crystallizer for continuous production of crystalline particles.Journal of Industrial and Engineering Chemistry,2020,89,pp.111-114 Summary of the Invention [Problem to be solved by the invention]

[0006] Although scaling up crystallization is required for industrial crystal production, the continuous crystallizer disclosed in Non-Patent Document 1 has a small capacity and is not suitable for industrial-scale production. Furthermore, the continuous crystallizer disclosed in Non-Patent Document 1 is characterized by spatially separating crystal nucleation and growth, and requires a Couette-Taylor apparatus for crystal nucleation in addition to the MSMPR apparatus for crystal growth. Therefore, if the scale of the continuous crystallizer disclosed in Non-Patent Document 1 itself is increased, the production equipment becomes complicated and a large space must be secured for installation, making it unsuitable for industrial-scale production. In the continuous crystallizer disclosed in Non-Patent Document 1, unless a Couette-Taylor apparatus is installed to simplify the production equipment, the quality of the crystal particles (particularly particle size) cannot be controlled.

[0007] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method for producing crystals that is advantageous for industrial-scale production and allows particle size control. [Means for solving the problem]

[0008] As a result of extensive research into solving the above problems, the present inventors have found that a method for producing crystals that is advantageous for industrial-scale production and allows particle size control can be provided by preparing a seed crystal slurry in a crystallization tank and then performing continuous crystallization while applying ultrasonic waves to the tank, and have thus completed the present invention.

[0009] The gist of the present invention is as follows. [1] A method for producing crystals, comprising the steps of: placing a stock solution containing raw materials in a tank (1) having a capacity of 2 to 30 L and equipped with an ultrasonic vibrator; then precipitating crystals from the stock solution to prepare a seed crystal slurry; and then continuously supplying the stock solution containing the raw materials to the tank (1) containing the prepared seed crystal slurry while applying ultrasonic vibrations, and continuously discharging the resulting slurry. [2] The manufacturing method according to [1], wherein the ultrasonic vibrator is provided on at least one of the side surface and the bottom surface of the tank (1). [3] The manufacturing method according to [1] or [2], wherein the tank (1) is made of metal. [4] The method according to any one of [1] to [3], wherein the raw material has a crystalline polymorphism, and the crystalline form obtained in step (A) is selected by selecting whether or not to irradiate with ultrasound in step (A). [5] The production method according to any one of [1] to [4], wherein the tank (1) is equipped with a stirring device, and stirring is performed in the tank (1) in at least one of the steps (A) and (B). [6] The method according to any one of [1] to [5], further comprising a step (C) of solid-liquid separation of the slurry discharged in the step (B). [7] The production method according to any one of [1] to [6], wherein in the step (B), a poor solvent is added to the tank (1) to precipitate crystals. [8] The method according to any one of [1] to [7], wherein the crystals precipitated in the step (B) have a Span value represented by the following formula of 0 or more and less than 6.4: Span=(D90-D10) / D50 (In the formula, D10, D50, and D90 respectively represent the particle sizes (μm) at which the cumulative frequency from the small particle size side is 10%, 50%, and 90% in the particle size distribution converted into volume by laser diffraction / scattering method.) [Effects of the Invention]

[0010] According to the present invention, a method for producing crystals that is advantageous for industrial-scale production and allows particle size control can be provided. Preferably, according to the present invention, a method for producing crystals that suppresses fouling can be provided. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic diagram showing an example of a part of the configuration of a manufacturing apparatus used in the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0012] The method for producing crystals of the present invention includes the steps of: placing a stock solution containing raw materials in a 2-30 L tank (hereinafter also referred to as tank (1)) equipped with an ultrasonic vibrator; then precipitating crystals from the stock solution to prepare a seed crystal slurry (hereinafter also referred to as step (A)); and continuously supplying the stock solution containing raw materials to tank (1) containing the prepared seed crystal slurry while applying ultrasonic vibrations, while precipitating crystals from the stock solution and continuously discharging the resulting slurry (hereinafter also referred to as step (B)). Step (B) is performed after step (A). According to the method for producing crystals of the present invention, the preparation of the seed crystal slurry in step (A) and the crystallization in step (B) are performed in the same tank, and continuous crystallization is performed while applying ultrasonic vibrations in step (B). This provides a method for producing crystals that is advantageous for industrial-scale production and allows particle size control. Preferably, the method for producing crystals of the present invention can provide a method for producing crystals that suppresses fouling.

[0013] <Manufacturing equipment> The production apparatus used in the method for producing crystals of the present invention will be described below with reference to Figure 1. The present invention is not limited to the illustrated example, and can be practiced with appropriate modifications within the scope of the above-mentioned and below-mentioned aims, all of which are included in the technical scope of the present invention.

[0014] Fig. 1 is a schematic diagram showing an example of a portion of the configuration of a production apparatus. The production apparatus includes a tank 1 having a capacity of 2 to 30 L and provided with an ultrasonic vibrator 2. The ultrasonic vibrator 2 is connected to an ultrasonic oscillator (not shown), and converts power supplied from the ultrasonic oscillator into ultrasonic vibrations. The ultrasonic vibrator 2 can apply ultrasonic vibrations to a raw liquid and / or a slurry (hereinafter also referred to as a contained fluid) contained in the tank 1 in order to perform a crystallization operation in the tank 1.

[0015] From the viewpoint of efficiently applying ultrasonic vibrations to the entire contained fluid 6, the ultrasonic vibrator 2 is preferably provided on at least one of the side surface and the bottom surface of the tank 1. By providing the ultrasonic vibrator 2 in the tank 1 so that ultrasonic vibrations can be efficiently applied to the entire contained fluid 6, the particle size and / or crystal shape of the crystals obtained in steps (A) and (B) described below can be well controlled. When the ultrasonic vibrator 2 is provided on the side surface of the tank 1, it is preferably provided at a position below the liquid level in the tank 1. The ultrasonic vibrator 2 is preferably provided so as to be in contact with the tank 1, and may be provided so as to be in contact with either the inside or the outside of the tank 1. By providing the ultrasonic vibrator 2 so as to be in contact with the tank 1 and applying ultrasonic vibrations directly to the tank 1, it is possible to efficiently apply ultrasonic vibrations to the entire contained fluid 6 even when an industrial-scale tank 1 (e.g., a capacity of 2 L or more) is used. From the viewpoint of ease of cleaning the device, the ultrasonic vibrator 2 is preferably provided so as to be in contact with the outside of the tank 1. When the ultrasonic vibrator 2 is provided inside the tank 1, a vibration plate may be bonded to the ultrasonic vibrator 2. In the example of FIG. 1, an ultrasonic vibrator 2 is provided so as to contact the outer bottom of the tank 1 .

[0016] The number of ultrasonic vibrators 2 is not particularly limited and may be set appropriately depending on the capacity of the tank 1 and the volume of the contained fluid 6, and is, for example, preferably 1 to 20, more preferably 1 to 16, and even more preferably 2 to 14. By setting the number of ultrasonic vibrators 2 to the above-mentioned lower limit or more, ultrasonic vibrations can be efficiently applied to the entire contained fluid 6, and by setting the number to the above-mentioned upper limit or less, power consumption can be reduced.

[0017] The capacity of tank 1 is 2 to 30 L, preferably 3 to 25 L, more preferably 4 to 20 L, and even more preferably 5 to 18 L. Setting the capacity of tank 1 to be equal to or greater than the lower limit enables efficient production on an industrial scale, while setting it to be equal to or less than the upper limit enables further space-saving of the production equipment.

[0018] The material of the tank 1 is not particularly limited as long as it can withstand ultrasonic vibrations, and examples thereof include synthetic resin, glass, metal, etc. Tank 1 is preferably made of glass or metal, more preferably metal, in order to efficiently apply ultrasonic vibrations to the entire contained fluid 6 and to prevent damage due to ultrasonic vibrations. As the metal used for tank 1, titanium alloys, nickel alloys, chromium alloys, and nickel-chromium alloys are preferred in terms of corrosion resistance (acid resistance, alkali resistance), and stainless steel, Hastelloy (registered trademark), Monel (registered trademark), and Inconel (registered trademark) are more preferred.

[0019] The manufacturing apparatus preferably further includes an agitator 3. The agitator 3 is configured to be able to agitate the contained fluid 6 in the tank 1, and although a blade-type agitator 3 is shown in the example of Fig. 1, any known agitator may be used as appropriate.

[0020] The production apparatus desirably further comprises a raw solution supply line 4 and / or a slurry discharge line 5. The raw solution supply line 4 is configured to be able to supply a raw solution in which raw materials are dissolved to the tank 1, and the slurry discharge line 5 is configured to be able to discharge the slurry from the tank 1. For example, the raw solution supply line 4 is a pipe connecting the tank 1 with a raw solution tank described below, and the slurry discharge line 5 is a pipe connecting the tank 1 with a slurry receiving tank described below. The raw solution supply line 4 and the slurry discharge line 5 may each be connected to a pump (not shown) independently, and the pumps can be used to facilitate liquid transfer.

[0021] When the production apparatus is equipped with the raw solution supply line 4, it is preferable that a raw solution tank (not shown) for storing the raw solution is connected upstream of the raw solution supply line 4.

[0022] When the production apparatus is equipped with a slurry discharge line 5, it may also be equipped with a slurry receiving tank (not shown) for receiving the slurry discharged from tank 1. The crystals can be separated from the slurry by filtering the slurry received in the slurry receiving tank through a filter or filter paper with a pore size smaller than the diameter of the crystals. Alternatively, a filter for separating the crystals from the slurry (specifically, a filter with a pore size smaller than the diameter of the desired crystals) can be connected to the slurry discharge line 5.

[0023] The production apparatus may further include a poor solvent supply line (not shown) for adding a poor solvent to the tank 1. A pump may be connected to the poor solvent supply line, and the pump can be used to facilitate liquid transfer. Furthermore, a poor solvent tank for storing the poor solvent is preferably connected upstream of the poor solvent supply line.

[0024] The production apparatus desirably further comprises a temperature regulator (not shown) for adjusting the temperature of the contained fluid 6 in the tank 1. 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 tank 1 may be used. By providing the temperature regulator, it is possible to maintain the temperature of the contained fluid 6 in the tank 1 at a predetermined value. When the production apparatus has at least one of a stock solution tank, a poor solvent tank, and a slurry receiving tank, each of the tanks may be provided with a temperature regulator that independently adjusts the temperature of the stock solution, poor solvent, and slurry in the tank.

[0025] The production apparatus may further include a temperature regulator (not shown) that regulates the temperature of at least one of the raw solution supply line 4, the slurry discharge line 5, and the poor solvent supply line. The temperature control method is not particularly limited, and for example, the line may have a double pipe structure with a heat transfer medium circulating around the periphery.

[0026] The production apparatus preferably further includes in-line measuring devices such as a thermometer, flow meter, and turbidity meter at appropriate locations such as tank 1, raw solution supply line 4, and slurry discharge line 5. In particular, it is preferable to measure the particle size distribution of the crystals in tank 1 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 to identify the polymorphs in tank 1 and measure the proportion of the polymorphs by Raman spectroscopy, powder X-ray analysis, infrared spectroscopy, differential scanning calorimetry, or the like. By monitoring the particle size distribution and polymorphism of the crystals in tank 1, crystals having the desired particle size and / or polymorphism can be suitably produced.

[0027] <Process (A)> Step (A) is a step of placing a stock solution in which raw materials are dissolved in a tank (1) having a capacity of 2 to 30 L and equipped with an ultrasonic vibrator, and then precipitating crystals from the stock solution to prepare a seed crystal slurry.

[0028] The raw material may be an inorganic or organic compound, preferably an organic compound, and may be a pharmacologically active compound, particularly a highly pharmacologically active compound. 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), daily acceptable exposure level (PDE), occupational exposure limit (OEL), etc. A highly pharmacologically active compound is a compound that exerts a strong pharmacological or toxic effect on the human body, such as an anticancer drug or cytotoxic agent. When handling highly pharmacologically active compounds, containment is required, for example, by creating a negative pressure space in the work space to protect the surrounding environment. Preparing the seed crystal slurry in tank (1) eliminates the need for a separate seed crystal preparation device. This eliminates the need for complex manufacturing equipment, reduces the space required for manufacturing facilities, and facilitates containment of the work space even on an industrial scale. The raw material may be a compound having crystalline polymorphism. Crystal polymorphism refers to a chemical substance in which molecules have the same chemical structure but the molecular arrangement within the crystal is different. In this specification, crystalline polymorphism also includes solvated crystals (pseudo-crystalline polymorphisms) in which a solvent such as water is incorporated into the crystal. Typically, crystalline polymorphs have different chemical potentials, such as stable crystals and metastable crystals with a higher chemical potential than the stable crystals. Generally, when various conditions such as temperature, solvent, and dissolution time are met, metastable crystals have characteristics such as a lower melting point, higher solubility, and faster dissolution rate than stable crystals. In one embodiment of the present invention, the raw material is preferably a compound having an anhydrous crystal and a hydrate crystal. Typically, the hydrate is the metastable crystal, and the anhydrous is the stable crystal. Crystal polymorphism can be confirmed by powder X-ray diffraction (XRD), thermal analysis (DSC, TG-DTA), IR spectroscopy, solid-state NMR, etc. Examples of raw materials include perampanel, riociguat, ruxolitinib phosphate, luseogliflozin hydrate, evocalcet, brexpiprazole, pemafibrate, baricitinib, etelcalcetide hydrochloride, rasagiline mesylate, esaxerenone, ponatinib hydrochloride, and venetoclax.

[0029] The stock solution containing the raw materials dissolved in the tank (1) may be prepared in the tank (1) or in a tank other than the tank (1). When the stock solution is prepared in a tank other than the tank (1), it is preferable from the viewpoint of production efficiency to prepare the stock solution in the stock solution tank and transfer it to the tank (1) through the stock solution supply line.

[0030] 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 solvents such as methanol, ethanol, isopropanol, etc.; ether solvents such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, etc.; ketone solvents such as acetone, methyl ethyl ketone, etc. These may be used alone or in combination of two or more.

[0031] 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 crystals obtained in step (B), it is preferable that the raw materials are completely dissolved in the raw material solution.

[0032] The method for precipitating crystals from the starting solution in tank (1) to prepare the seed crystal slurry is not particularly limited, and may be prepared by a known crystallization method, such as poor solvent crystallization, cooling crystallization, evaporation crystallization, neutralization crystallization, salt formation crystallization, etc., or a combination of these methods. From the viewpoint of production efficiency, it is preferable to carry out poor solvent crystallization in the preparation of the seed crystal slurry in step (A).

[0033] When preparing a seed crystal slurry by the poor solvent crystallization method, it is preferable from the viewpoint of production efficiency to store a poor solvent in the poor solvent tank and add the poor solvent to the tank (1) through the poor solvent supply line. A poor solvent is a solvent that hardly dissolves a solute (raw material) or does not dissolve it at all. In the poor solvent crystallization method, the addition of a poor solvent controls the supersaturation state of the solute, allowing the solute to crystallize.

[0034] The poor solvent used in the poor solvent crystallization method is not particularly limited as long as it is a solvent that can precipitate seed crystals from the raw solution, and may be appropriately selected depending on the types of raw materials and solvent that constitute the raw solution, and examples include water; hydrocarbon solvents such as benzene, toluene, hexane, etc. These may be used alone or in combination of two or more.

[0035] The preparation of seed crystal slurry by the anti-solvent crystallization method may be carried out under conditions that allow the precipitation of seed crystals from the stock solution, and the mixing ratio of the stock solution to the anti-solvent, the mixing temperature, the mixing time, and the like may be appropriately set depending on the types of stock solution and anti-solvent. For example, the mixing temperature of the stock solution and anti-solvent is preferably −20 to 100°C, more preferably −10 to 50°C, and even more preferably 0 to 30°C. By keeping the temperature within this range, sufficient crystallization efficiency can be ensured. The mixing time of the stock solution and anti-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. By keeping the temperature within this range, sufficient crystallization efficiency can be ensured.

[0036] When preparing the seed crystal slurry, the contained fluid may be stirred by the stirring device, and stirring is preferred from the viewpoints of promoting crystal nucleation and controlling particle size. When stirring is performed, the stirring power per unit volume of the contained fluid 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.

[0037] When the raw material has a crystalline polymorph, if crystal precipitation is performed without applying ultrasonic vibrations to the tank (1) during the preparation of the seed crystal slurry in the tank (1), crystals in a kinetically advantageous metastable state can be obtained. On the other hand, if crystal precipitation is performed while applying ultrasonic vibrations to the tank (1), the crystal form transitions due to the cavitation effect specific to ultrasound, and thermodynamically stable crystals in a stable state with a lower chemical potential than the metastable state can be obtained. In the preparation of the seed crystal slurry in step (A), the crystalline form of the seed crystals obtained in step (A) can be selected by selecting whether or not to apply ultrasonic vibrations from the ultrasonic vibrator installed in the tank (1). By selecting the crystalline form of the seed crystals used in the continuous crystallization in step (B), it is possible to create different crystalline forms obtained in step (B). In other words, by selecting whether or not to apply ultrasonic vibrations in step (A), the desired crystalline form can be easily selected for the crystals obtained by production.

[0038] When ultrasonic vibrations are applied in step (A), the ultrasonic irradiation time 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 keeping the irradiation time within this range, sufficient crystallization efficiency can be ensured. The ultrasonic frequency in step (A) is preferably 20 to 100 kHz, more preferably 22 to 80 kHz, even more preferably 25 to 60 kHz, and even more preferably 25 to 55 kHz. By keeping the frequency within this range, sufficient crystallization efficiency can be ensured, and in particular, by setting the frequency below the upper limit, fouling in the tank (1) can be effectively suppressed. Furthermore, when the tank (1) is made of metal, by setting the frequency above the lower limit, the outflow of metals from the tank (1) can be suppressed. The ultrasonic output in step (A) is preferably 10 to 500 W, more preferably 30 to 450 W, even more preferably 40 to 400 W, and even more preferably 50 to 380 W. By setting the output within the above range, sufficient crystallization efficiency can be ensured, and in particular, by setting the output to be equal to or higher than the above lower limit, fouling in the tank (1) can be effectively suppressed. Furthermore, when the tank (1) is made of metal, by setting the output to be equal to or lower than the above upper limit, outflow of metals originating from the tank (1) can be suppressed.

[0039] When ultrasonic vibrations are applied in step (A), the ultrasonic vibrations may be applied continuously or intermittently, but are preferably applied continuously from the viewpoint of production efficiency.

[0040] When the raw material has crystalline polymorphism, the proportion of the desired crystalline form in the crystals contained in the seed crystal slurry obtained in step (A) 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 there is no particular upper limit, it is preferably 100% (specifically, crystalline forms other than the desired one are below the detection limit).

[0041] <Process (B)> Step (B) is a continuous crystallization process under ultrasonic vibration. While continuously supplying a stock solution containing the raw materials to a tank (1) containing the seed crystal slurry prepared in step (A), crystals are precipitated from the stock solution, and the resulting slurry is continuously discharged from the tank (1). By applying ultrasonic vibration to the tank (1) where crystallization is performed during continuous crystallization using seed crystals, crystals with controlled particle size can be produced with a high precipitation rate and / or high recovery rate. Furthermore, performing seed crystal preparation and continuous crystallization in the same tank reduces the overall space required for the production facility and reduces the maintenance burden, such as tank cleaning, which is advantageous for industrial-scale production. Ideally, continuous crystallization should be in a steady state where the total mass of material supplied to the tank (1) is equal to the total mass of material withdrawn from the tank (1).

[0042] When a raw material is a substance with crystalline polymorphism, the solubility, bioavailability, stability, etc. usually differ between the crystalline polymorphs. Therefore, when a substance with crystalline polymorphism is used as a drug substance or pharmaceutical intermediate, high uniformity of the crystalline form is required to ensure uniform quality and consistent efficacy. To increase the uniformity of the crystalline form of the crystals obtained by crystallization, crystallization can be performed in the presence of seed crystals with the desired crystalline form. Since seed crystals can be easily produced by selecting whether or not to irradiate with ultrasound in step (A), it is easy to control the crystalline form of the crystals obtained in step (B).

[0043] The stock solution supplied to the tank (1) may have the same composition as the stock solution used in step (A) or may have a different composition, and from the viewpoint of production efficiency, it is preferable that the stock solution used in step (A) has the same composition. When the stock solution used in step (B) has a different composition from the stock solution used in step (A), at least the types of raw materials are the same, and the mixing ratio of the raw materials to the solvent and the solvent composition may be changed.

[0044] From the viewpoint of production efficiency, it is preferable that the stock solution to be supplied to the tank (1) is prepared in the stock solution tank and supplied to the tank (1) through the stock solution supply line. When a stock solution having the same composition as the stock solution used in the step (A) is used in the step (B), the stock solution to be used in the step (B) may be prepared in the stock solution tank together with the stock solution to be used in the step (A).

[0045] 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 solvents such as methanol, ethanol, isopropanol, etc.; ether solvents such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, etc.; ketone solvents such as acetone, methyl ethyl ketone, etc. These may be used alone or in combination of two or more.

[0046] The raw material solution can be prepared by mixing the raw material and the solvent under conditions in which the raw material dissolves in the solvent, and the mixing ratio of the raw material to the solvent, the mixing temperature, the mixing time, etc. can be appropriately set depending on the types of raw material and solvent. In order to obtain crystals of uniform quality, it is preferable that the raw material is completely dissolved in the raw material solution.

[0047] In step (B), continuous crystallization is carried out while applying ultrasonic vibrations to the crystallization tank (1). The application of ultrasonic vibrations promotes the formation of crystal nuclei while controlling the timing of crystal nucleation due to the cavitation effect unique to ultrasound. This allows crystallization to be carried out with a high precipitation rate even in a short time, and the particle size of the resulting crystals can be controlled to be small. Furthermore, applying ultrasonic vibrations can suppress fouling. Suppressing fouling reduces the amount of crystals remaining in tank (1), improving the crystal recovery rate. Furthermore, the reduction in management burdens such as tank cleaning makes this method advantageous for industrial-scale production.

[0048] The average residence time in tank (1) in the continuous crystallization of step (B) is not particularly limited, but is, for example, preferably 5 minutes to 2 hours, more preferably 10 minutes to 1.8 hours, even more preferably 15 minutes to 1.5 hours, and even more preferably 20 minutes to 1.0 hour. By setting the average residence time at or above the lower limit, particle size can be well controlled and sufficient crystallization efficiency can be ensured, while by setting it at or below the upper limit, production efficiency can be further improved.

[0049] In this specification, the mean residence time τ is the value obtained by dividing the volume of the fluid contained in the tank (1) by the discharge flow rate from the tank (1), and ideally refers to the time required for the volume V of the slurry contained in the tank (1) to be replaced by a substance newly flowing into the tank (1) at a flow rate Qi when the slurry of volume V contained in the tank (1) is discharged from the tank (1) at a flow rate Qo. Usually, when continuous crystallization is in a steady state, the flow rate Qi of the substance flowing into the tank (1) and the flow rate Qo of the substance discharged from the tank (1) are the same. In this case, if the volume of the seed crystal slurry contained in the tank (1) is V, the mean residence time τ can be calculated by V / Qi or V / Qo.

[0050] If the raw material has a crystalline polymorphism and a seed crystal slurry containing metastable crystals is prepared in step (A), the cavitation effect of ultrasound in step (B) promotes the transition of the crystal form from the metastable state to the stable state. Therefore, if the desired crystals are metastable crystals, it is desirable to control the average residence time in tank (1) and discharge the slurry from tank (1) before the crystal form transitions. That is, it is desirable to set the average residence time for crystallization in step (B) shorter than the time required for crystals precipitated under ultrasonic vibration to transition to a stable state with a lower chemical potential than the metastable state. The "time shorter than the time required for transition to the stable state" is determined by factors such as the stability of the metastable state of the crystals and the height of the energy barrier that must be overcome when transitioning from the metastable state to the stable state. Therefore, it is impossible to set it uniformly and it can be set appropriately depending on the type of raw material. For example, by shortening the average residence time to 2 hours or less, preferably 1.8 hours or less, more preferably 1.5 hours or less, and even more preferably 1.0 hour or less, the transition of the crystals to the stable state can be suppressed. For example, when the present invention is carried out industrially, it is preferable to carry out continuous crystallization tests under conditions with different mean residence times before carrying out industrial continuous crystallization, determine in advance the mean residence time at which metastable crystals are obtained, and then determine the conditions for continuous crystallization in industrial practice so as to obtain the predetermined mean residence time.

[0051] The flow rate of the raw solution supplied to the tank (1) and the flow rate of the slurry discharged from the tank (1) may be appropriately set so that the average residence time in the tank (1) is a desired value (for example, within the range of the average residence time described above).

[0052] The ultrasonic frequency in step (B) is preferably 20 to 100 kHz, more preferably 22 to 80 kHz, even more preferably 25 to 60 kHz, and even more preferably 25 to 55 kHz. By controlling the frequency within this range, sufficient crystallization efficiency can be ensured. In particular, by controlling the frequency below the upper limit, fouling in the tank (1) can be effectively suppressed and the particle size of the resulting crystals can be more effectively controlled. Furthermore, when the tank (1) is made of metal, controlling the frequency above the lower limit can prevent metals from leaking from the tank (1). The ultrasonic power output in step (B) is preferably 10 to 500 W, more preferably 30 to 450 W, even more preferably 40 to 400 W, and even more preferably 50 to 380 W. By controlling the power output within this range, sufficient crystallization efficiency can be ensured. In particular, by controlling the power output above the lower limit, fouling in the tank (1) can be effectively suppressed and the particle size of the resulting crystals can be more effectively controlled. Furthermore, when the tank (1) is made of metal, the output can be set to the upper limit or less to prevent metals from leaking out from the tank (1).

[0053] The internal temperature of tank (1) (i.e., the temperature of the contained fluid) 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 internal temperature of tank (1) within this range, sufficient crystallization efficiency can be ensured. Furthermore, when the production apparatus has a stock solution tank, the internal temperature of the stock solution tank (i.e., the temperature of the stock solution) is preferably adjusted to -20 to 100°C, more preferably -10 to 50°C, and even more preferably 0 to 30°C, and is preferably adjusted to within ±15°C of the internal temperature of tank (1), and more preferably ±10°C of the internal temperature of tank (1). By adjusting the internal temperature of the stock solution tank within this range, it is possible to prevent temperature distribution in the contained fluid when the stock solution is supplied to tank (1), and to more narrowly control the particle size distribution of the obtained crystals.

[0054] The volume of the fluid contained in the tank (1) may be appropriately set so that the average residence time in the tank (1) is a desired value (for example, within the range of the average residence time described above). For example, the volume is preferably 10 to 100%, more preferably 15 to 90%, and even more preferably 20 to 80% of the capacity (volume) of the tank (1). By setting the volume of the fluid contained in the tank (1) within the above range, ultrasonic waves can be efficiently applied to the entire fluid contained in the tank (1), and sufficient crystallization efficiency can be ensured.

[0055] In step (B), the method for precipitating (growing) crystals from the starting solution is not particularly limited, and may be crystallization by ultrasonic irradiation or a known crystallization method. Known crystallization methods include, for example, anti-solvent crystallization, cooling crystallization, evaporation crystallization, neutralization crystallization, and salt-forming crystallization, and these methods may be combined. From the viewpoints of operational simplicity and production efficiency, it is preferable to carry out anti-solvent crystallization in the continuous crystallization of step (B).

[0056] When crystals are precipitated from a stock solution by anti-solvent crystallization, it is preferable from the viewpoint of production efficiency to store the anti-solvent in the anti-solvent tank and add the anti-solvent to tank (1) through the anti-solvent supply line. When the production apparatus has an anti-solvent tank, the internal temperature of the anti-solvent tank (i.e., the temperature of the anti-solvent) is preferably -20 to 100°C, more preferably -10 to 50°C, and even more preferably 0 to 30°C, and is preferably adjusted to within ±15°C of the internal temperature of tank (1), more preferably ±10°C of the internal temperature of tank (1). By keeping the internal temperature of the anti-solvent tank within the above range, it is possible to prevent temperature distribution from occurring in the contained fluid when the anti-solvent is supplied to tank (1), and it is possible to more narrowly control the particle size distribution of the obtained crystals.

[0057] The poor solvent used in the poor solvent crystallization method is not particularly limited as long as it is a solvent that can precipitate crystals from the stock solution, and may be appropriately selected depending on the types of raw materials and solvent that constitute the stock solution, and examples thereof include water; hydrocarbon solvents such as benzene, toluene, and hexane; etc. These may be used alone or in combination of two or more. When the poor solvent crystallization method is used in preparing the seed crystal slurry in step (A), it is preferable from the viewpoint of production efficiency to use a solvent having the same composition as the poor solvent used in step (A) as the poor solvent used in step (B).

[0058] The amount of the poor solvent added in the poor solvent crystallization method may be appropriately determined depending on the types of the starting solution and poor solvent, the crystallization temperature (that is, the internal temperature of the tank (1)), and the like.

[0059] During continuous crystallization, the contained fluid may be stirred by the stirring device, and stirring is preferred from the viewpoints of promoting crystal nucleation and controlling particle size. By keeping the mother liquor and crystals in the tank (1) in a completely mixed state, it becomes easier to control the crystallization conditions. When stirring is performed, the stirring power per unit volume of the contained fluid 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 obtained crystals can be controlled more effectively.

[0060] The crystals contained in the slurry discharged in step (B) have a particle size D90, which corresponds to a cumulative frequency of 90% from the small particle size side in a particle size distribution measured by volume conversion using a laser diffraction / scattering method, of, for example, 1 to 100 μm, preferably 1 to 85 μm, more preferably 5 to 70 μm, and even more preferably 10 to 50 μm. The crystals contained in the slurry also have a particle size D50, which corresponds to a cumulative frequency of 50% from the small particle size side in a particle size distribution measured by volume conversion using a laser diffraction / scattering method, of, for example, 0.5 to 60 μm, more preferably 1 to 45 μm, and even more preferably 2 to 30 μm. The crystals contained in the slurry also have a particle size D10, which corresponds to a cumulative frequency of 10% from the small particle size side in a particle size distribution measured by volume conversion using a laser diffraction / scattering method, of, for example, 0.1 to 50 μm, more preferably 0.2 to 30 μm, and even more preferably 0.3 to 10 μm. Because the crystals obtained in step (B) are controlled to have a small particle size, they have excellent solubility and can be suitably used as active pharmaceutical ingredients or pharmaceutical intermediates.

[0061] The crystals contained in the slurry discharged in step (B) have a value (Span = (D90 - D10) / D50) obtained by dividing the difference between D10 (volume basis) and D90 (volume basis) (D90 - D10) by D50 (volume basis) of preferably 0 or more and less than 6.4, more preferably 3.0 or more and 6.0 or less, even more preferably 3.5 or more and 5.5 or less, and even more preferably 3.9 or more and 5.3 or less. The value obtained by dividing the difference between D10 and D90 by D50 is an index representing the width of the particle size distribution; the smaller this value, the narrower the particle size distribution and the more uniform the particle size. The crystals obtained in step (B) have a narrow particle size distribution and good uniformity of crystal properties, making them suitable for use as pharmaceutical active ingredients or pharmaceutical intermediates.

[0062] When the raw material has crystalline polymorphism and the crystal form is differentiated by controlling the presence or absence of ultrasonic irradiation in step (A) and the average residence time in step (B), the proportion of the desired crystal form in the crystals contained in the slurry discharged in step (B) 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 crystal forms other than the desired one is below the detection limit). Since the slurry discharged from tank (1) contains a high proportion of the desired crystal form, the desired crystal form can be easily obtained by purifying the slurry. In other words, according to a preferred embodiment of the method for producing crystals of the present invention, it is possible to efficiently produce crystals on an industrial scale while controlling the crystal form. The aforementioned "time shorter than the transition to the stable state" can also be defined in terms of the proportion of metastable crystals in the slurry withdrawn from tank 1. For example, the "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 the extent that the proportion of metastable crystals in the slurry withdrawn from tank 1 satisfies the range of the proportion of the desired crystal form.

[0063] The slurry discharged in step (B) may be supplied to a crystallization tank other than tank (1) depending on the intended use, but it is preferable not to supply it to a crystallization tank. Eliminating the need for multiple industrial-scale (e.g., 2 L or larger) crystallization tanks allows for space savings throughout the production facility and reduces the burden of tank cleaning and other management, making this method advantageous for industrial-scale production. In the crystal production method of the present invention, continuous crystallization is carried out under ultrasonic vibration, which promotes the generation of crystal nuclei, and high precipitation and / or recovery rates can be achieved even in single-stage continuous tank crystallization (i.e., when no additional crystallization tank is used).

[0064] <Process (C)> The production method of the present invention may further include a step (also referred to as step (C)) of solid-liquid separation of the slurry discharged in step (B). By including step (C), crystals can be easily obtained from the slurry, improving production efficiency. The crystals obtained in step (B) have a small particle size but a narrow particle size distribution, so solid-liquid separation can be performed efficiently using a filter without causing deterioration in filterability, such as clogging.

[0065] The method for solid-liquid separation of the slurry is not particularly limited, and for example, a filtration device such as a filter with a pore size smaller than the particle size of the crystals may be used, or a centrifuge may be used. From the viewpoint of simplifying the production equipment, it is preferable to use a filter. Examples of filtration methods include natural filtration, reduced pressure filtration, and pressure filtration. The crystals obtained by solid-liquid separation may be further treated, as necessary, by washing, drying, etc. The drying method is not particularly limited, and examples thereof include natural drying and reduced pressure drying (vacuum drying).

[0066] The mother liquor after solid-liquid separation may be returned to the tank (1). That is, the mother liquor contained in the slurry discharged from the tank (1) may be circulated by being returned to the tank (1) after solid-liquid separation. [Example]

[0067] 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-mentioned and below-mentioned 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".

[0068] (1) Raw materials Perampanel (manufactured by Yibin Hongguang Pharmaceutical Co., Ltd.) was used as a raw material. The solubilities of perampanel anhydrate form V and perampanel hydrate were measured by the following procedure. 0.03 g of perampanel (anhydrous Form V or hydrate) was added to 3.00 g of acetone / HO (55 / 45) 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 solubility of anhydrous Form V was 0.142%, and that of the hydrate was 0.189%, indicating that anhydrous Form V is less soluble than the hydrate. This indicates that anhydrous Form V is stable, while the hydrate is metastable. The conditions for HPLC analysis were as follows, and the perampanel content was measured in the same manner hereinafter. Equipment: LC-2050C (Shimadzu Corporation) Column: YMC-Pack Pro C18 150 mm x 4.6 mm i.d. (YMC) Column temperature: 35℃ 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: 1.0mL / min Detector: UV 290nm Injection volume: 5μL

[0069] (2) Average residence time In order to adjust the average residence time, the flow rates of pumps i to iii were determined based on the following formula (1): The flow rate ratio of the liquids sent from pumps i to ii was set to be the same as the volume ratio of the stock solution to the poor solvent used to form the seed crystal slurry contained in tank 1. Qi=Qo=V / τ (1) (In formula (1), τ: Average residence time (minutes) Qi: Sum of the flow rate of pump i and pump ii (mL / min) Qo: Flow rate of pump iii (mL / min) V: Volume of seed crystal slurry contained in tank 1 (mL) For example, in the case of Example 1 below, the flow rates of pumps i to iii are determined as follows from equations (1) and (2): Flow rate of pump i: Flow rate of pump ii = 42.0:26.9 (2) Flow rate of pump i = (2067 mL / 30 min) x 42.0 / (42.0 + 26.9) =42.0(mL / min) Flow rate of pump ii = (2067 mL / 30 min) x 26.9 / (42.0 + 26.9) =26.9(mL / min) Pump iii flow rate = 2067 mL / 30 min =68.9(mL / min)

[0070] (3) Crystal grain size The particle size of the crystals was measured by sampling the slurry in tank 1 after carrying out continuous crystallization for 2 hours or more and using a laser diffraction particle size distribution measuring device (Malvern Panalytical's "Mastersizer 3000").

[0071] (4) Crystal polymorphism The crystal polymorphism was measured using an X-ray diffractometer (MiniFlex II, manufactured by Rigaku Corporation) for the crystals obtained by filtering the slurry collected in the slurry receiving tank after carrying out continuous crystallization for 2 hours or more using a Kiriyama funnel and filter paper 5B (particle retention capacity 4 μm).

[0072] (5) Precipitation rate The crystal precipitation rate was determined by the following procedure. After continuous crystallization for 2 hours or more, the slurry in tank 1 was filtered through a membrane filter (pore size: 0.45 μm), and the perampanel content in the mother liquor was measured by HPLC analysis. From the perampanel content, the actual amount of perampanel precipitated by continuous crystallization (A) was calculated. The solubility of perampanel in the raw solution was also measured by HPLC analysis. From the perampanel solubility, the theoretically obtainable maximum amount of perampanel precipitated (B) was calculated. The precipitation rate was then calculated using the following formula: Precipitation rate (%) = precipitation amount (A) (g) / maximum precipitation amount (B) (g) × 100

[0073] (6) Recovery rate The crystal recovery rate was determined by the following procedure. The amount of precipitate (A) was calculated in the same manner as described in (5), and the recovery rate was calculated using the following formula. Recovery rate (%) = Amount of precipitate (A) (g) / Amount of crystals used for crystallization (g) × 100

[0074] (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"). A smaller Span value indicates a smaller spread of the particle size distribution. Span=(D90-D10) / D50

[0075] Example 1 A continuous crystallization system was constructed, including tank 1 (10 L, SUS316L, jacketed, direct-irradiation ultrasonic tank; Sonic Technology Corporation, "GSC300-10AG") equipped with ultrasonic transducer 2 and agitator 3 (stirring blade), a stock solution tank (5 L, glass bottle), a poor solvent tank (5 L), a slurry receiving tank (3 L), a diaphragm pump i (KNF Corporation, "SIMDOS® 10") for pumping liquid from the stock solution tank, a diaphragm pump ii (KNF Corporation, "SIMDOS® 10") for pumping liquid from the poor solvent tank, a peristaltic pump iii (Cole-Parmer Corporation, "Masterflex® L / S") for pumping liquid from tank 1, a flow sensor (KEYENCE Corporation, "FD-XS1"), and an FT-Raman spectrometer (Mettler-Toledo, "ReactRaman785"). Ultrasonic transducer 2 was installed so as to contact the outer bottom of tank 1. Perampanel (39.8 g, 114 mmol) and acetone (3938.2 g, 99 wt / wt) were added to a stock solution 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. Pumps i to iii, the ultrasonic device, and the agitator were stopped, and pumps i to ii were operated to send the stock solution from the stock solution tank at a flow rate of 42.0 mL / min and water from the antisolvent tank at a flow rate of 26.9 mL / min to Tank 1 for 30 minutes. Next, the ultrasonic device and the agitator were operated, and the mixture was stirred (agitation power: 0.04 kW / m) while irradiating with ultrasound (frequency: 40 kHz, output: 260 to 330 W) at 25 ± 2 °C for 30 minutes. 3 In vessel 1, the stock solution and water as a poor solvent were mixed at a volume ratio of 42.0:26.9 to form 2067 mL of seed crystal slurry, which contained perampanel crystals (anhydrous Form V) in a stable state (XRD analysis revealed that metastable perampanel (hydrate) was below the detection limit). Next, pumps i to iii were operated to supply the stock solution from the stock solution tank at a flow rate of 42.0 mL / min and water from the antisolvent tank at a flow rate of 26.9 mL / min to tank 1, and the slurry was discharged from tank 1 at a flow rate of 68.9 mL / min. At the same time, the ultrasonic device and the agitator were operated to directly apply ultrasonic vibrations to tank 1 at a frequency of 40 kHz and an output of 260 to 330 W, while the agitation power was 0.04 kW / m 3 The slurry was stirred at 25±2°C for an average residence time of 30 minutes in Tank 1, after which it was discharged from Tank 1 and supplied to the slurry receiving 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 using the methods described above, and the results are shown in Table 1. The slurry accumulated in the slurry receiving tank contained only stable perampanel crystals (anhydrous Form V) (the metastable perampanel (hydrate) was below the detection limit in XRD analysis).

[0076] (Examples 2 to 3, Comparative Example 1) Crystals were produced in the same manner as in Example 1, except that the ultrasonic output or stirring power in the continuous crystallization (step (B)) was changed as shown in Table 1. The crystal particle size, crystal polymorphism, precipitation rate, recovery rate, and Span value were measured by the above-mentioned methods, and the results are shown in Table 1.

[0077] [Table 1]

[0078] In the continuous crystallization of Examples 1 to 3, no fouling was observed in the vessel 1. [Explanation of symbols]

[0079] 1 tank 2 ultrasonic transducers 3. Stirring device 4. Concentrate supply line 5. Slurry discharge line 6. Contained fluid

Claims

1. A method for producing crystals, comprising the steps of: placing a stock solution containing raw materials in a tank (1) having a capacity of 2 to 30 L and equipped with an ultrasonic vibrator; precipitating crystals from the stock solution to prepare a seed crystal slurry; and then performing a step (A) of continuously supplying the stock solution containing the raw materials to the tank (1) containing the prepared seed crystal slurry while applying ultrasonic vibrations to the tank; and continuously discharging the resulting slurry.

2. The manufacturing method according to claim 1, wherein the ultrasonic vibrator is provided on at least one of the side and bottom of the tank (1).

3. 3. The method according to claim 1 or 2, wherein the vessel (1) is made of metal.

4. The method according to claim 1 or 2, wherein the raw material has a crystalline polymorphism, and the crystalline form obtained in step (A) is selected by selecting whether or not to irradiate with ultrasound in step (A).

5. The method according to claim 1 or 2, wherein the tank (1) is equipped with a stirring device, and stirring is performed in the tank (1) in at least one of the steps (A) and (B).

6. The method according to claim 1 or 2, further comprising a step (C) of solid-liquid separation of the slurry discharged in the step (B).

7. 3. The method according to claim 1, wherein in the step (B), a poor solvent is added to the tank (1) to precipitate crystals.

8. The method according to claim 1 or 2, wherein the crystals precipitated in step (B) have a Span value represented by the following formula of 0 or more and less than 6.4: Span=(D90-D10) / D50 (In the formula, D10, D50, and D90 respectively represent particle sizes (μm) at which the cumulative frequency from the small particle size side is 10%, 50%, and 90% in the particle size distribution converted into volume by a laser diffraction / scattering method.)

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