Crystallization method

Abstract

Provided is a crystallization method with which a crystal form to be deposited over the entirety of a container can be uniformly controlled. A crystallization method according to an embodiment of the present invention includes: a step for placing a solution containing a crystallization target compound and a solvent in a temperature-controlled container; and a step for evaporating the solvent from the solution disposed in the container. In the step for evaporating the solvent, when a portion in which the peripheral edge of the solution in the container is in contact with the container is taken to be a peripheral portion at the start of the step for evaporating the solvent, the temperature of the peripheral portion to the temperature at the center portion of the container is adjusted to 0.85-1.30.

Description

Crystallization method

[0001] The present invention relates to a crystallization method.

[0002] It has been known that crystals of a specific compound can be precipitated by evaporating the solvent from a solution in which the specific compound is dissolved. For example, a crystallization method has been proposed in which a solution of the specific compound is placed in a container, heated to the boiling point of the solvent, and the solvent is evaporated while maintaining a constant temperature (see Patent Document 1).

[0003] Patent No. 5714228

[0004] In recent years, attention has been focused on compounds that exhibit crystalline polymorphism, which means that even crystals with the same chemical composition can take different crystalline forms depending on the crystallization conditions. Different crystalline forms can result in different properties even for crystals of the same compound. Therefore, it is anticipated that crystalline polymorphism can be controlled to produce crystals of compounds with properties appropriate for their intended use. However, when a compound with crystalline polymorphism is crystallized using the crystallization method described in Patent Document 1, the resulting crystalline form may differ depending on the location of crystal precipitation in the container. Therefore, there is a problem in that crystals with the desired crystalline form cannot be sufficiently produced. The main object of the present invention is to provide a crystallization method that can uniformly control the crystalline form precipitated throughout the entire container.

[0005] [1] A crystallization method according to an embodiment of the present invention includes the steps of placing a solution containing a compound to be crystallized and a solvent in a temperature-controlled container and evaporating the solvent from the solution placed in the container. When the portion of the container that is in contact with the periphery of the solution at the start of the solvent evaporation step is defined as the periphery, the temperature of the periphery relative to the temperature of the center of the container is adjusted to 0.85 to 1.30. [2] In the crystallization method described in [1] above, the container may be placed in contact with a jig placed on a temperature-adjustable heat source. [3] In the crystallization method described in [2] above, the jig may have a recess capable of accommodating the container. [4] In the crystallization method described in [2] or [3] above, the jig may be made of a metal material. [5] In the crystallization method described in any of [2] to [4] above, the jig may include a main body and a sidewall. The main body contacts the bottom surface of the container during the solvent evaporation step. The sidewall contacts the side of the container in the step of evaporating the solvent. The sidewall is detachable from the main body. [6] In the crystallization method according to any one of [1] to [5] above, the solution may be irradiated with infrared rays in the step of evaporating the solvent. [7] In the crystallization method according to [6] above, the infrared rays may include an absorption wavelength band of the solvent. [8] In the crystallization method according to any one of [1] to [7] above, the container may be a watch glass.

[0006] According to embodiments of the present invention, the crystal form precipitated can be controlled uniformly throughout the container.

[0007] Fig. 1 is a schematic cross-sectional view for explaining a crystallization method according to one embodiment of the present invention, and Fig. 2 is a schematic perspective view of a jig used in the crystallization method of Fig. 1.

[0008] Hereinafter, embodiments of the present invention will be described with reference to the drawings, but the present invention is not limited to these embodiments. In addition, in order to clarify the description, the drawings may show the width, thickness, shape, etc. of each part more schematically than in the embodiment, but these are merely examples and do not limit the interpretation of the present invention.

[0009] A. Crystallization Method of a Target Compound for Crystallization FIG. 1 is a schematic cross-sectional view illustrating a crystallization method according to one embodiment of the present invention; FIG. 2 is a schematic perspective view of a jig used in the crystallization method of FIG. 1. In one embodiment, the crystallization method includes a solution disposing step and an evaporation step. In the solution disposing step, a solution 1 containing a target compound for crystallization and a solvent is disposed in a temperature-controlled container 3. The target compound for crystallization typically has two or more crystalline forms, in other words, crystalline polymorphism. In the evaporation step, the solvent is evaporated from the solution 1 disposed in the container 3. At the start of the evaporation step, the portion of the container 3 where the periphery of the solution 1 contacts is defined as the peripheral portion 32. In the evaporation step, the temperature of the peripheral portion 32 relative to the temperature of the central portion 31 of the container 3 (hereinafter referred to as the peripheral temperature / central temperature) is adjusted to 0.85 or more and 1.30 or less. The peripheral temperature / central temperature ratio in the container 3 is preferably 0.95 or more, more preferably 0.98 or more. On the other hand, the peripheral temperature / center temperature ratio in the container 3 is preferably 1.20 or less, more preferably 1.05 or less. In this specification, the "center of the container" refers to the geometric center of the container's external shape as viewed vertically from above. The inventors have discovered that the crystalline form of a polymorphic compound is significantly affected not only by the environmental conditions (e.g., temperature, pressure, humidity) during crystallization but also by the evaporation rate of the solvent. Therefore, after extensive research into the evaporation rate of the solvent during crystallization, they have found that by adjusting the temperature of the container during the evaporation process, the evaporation rate of the solvent throughout the solution can be adjusted to a range suitable for crystallization. More specifically, by adjusting the peripheral temperature / center temperature of the container during the evaporation process within the above-mentioned range, the temperature of the solution can be appropriately adjusted throughout, resulting in substantially uniform evaporation of the solvent from the entire solution. As a result, the crystal forms of the crystals precipitated in the center and peripheral portions of the container can be made to match each other. This allows the crystal form precipitated throughout the container to be uniformly controlled, enabling stable production of crystals having the desired crystal form. Such crystallization methods can produce crystals of the same chemical composition that exhibit different properties, such as solubility, bioavailability, and stability.Therefore, the crystallization method according to one embodiment can be particularly suitably applied to the production of solid pharmaceuticals.

[0010] A-1. Solution Placing Step As described above, in the solution placing step, a solution 1 of the compound to be crystallized is placed in a temperature-controlled container 3.

[0011] In one embodiment, first, a container 3 is prepared. The container 3 has any appropriate configuration capable of containing a solution 1 of the compound to be crystallized. The container 3 typically has an opening that is larger than the liquid level of the solution 1 to be contained. The outer shape of the container 3 when viewed vertically from above can be, for example, a circular or elliptical shape, and preferably a circular shape. When the container 3 has a circular outer shape, the diameter of the container 3 is, for example, 4 cm to 10 cm, and preferably 5 cm to 6 cm.

[0012] Examples of such a container 3 include a Petri dish, a watch glass, and an evaporating dish. In one embodiment, the container 3 is a watch glass 30. The watch glass 30 is composed of a plate-like member curved in an arc. The watch glass 30 typically has an upper surface 30a, a lower surface 30b, and a side surface 30c. The upper surface 30a can be used to place a solution 1 of the compound to be crystallized. The upper surface 30a has an arc-like shape that is concave downward. The radius of curvature of the upper surface 30a is, for example, 1 cm to 100 cm, preferably 3 cm to 10 cm. The lower surface 30b is located on the opposite side of the upper surface 30a in the thickness direction of the watch glass 30. The lower surface 30b has an arc-like shape that bulges downward. The upper surface 30a and the lower surface 30b are typically substantially parallel. The side surface 30c connects the periphery of the upper surface 30a to the periphery of the lower surface 30b. The thickness of the watch glass 30 is, for example, 1 mm to 20 mm, and preferably 5 mm to 10 mm.

[0013] The container 3 is made of any appropriate material. Examples of materials for the container 3 include glass such as borosilicate glass, metal materials such as aluminum and chromium, resin materials such as polytetrafluoroethylene (PEFE), and ceramic materials such as zirconia. Among these materials for the container 3, materials that are corrosion-resistant to the solution 1 are preferred, and glass and aluminum are more preferred, with borosilicate glass being even more preferred.

[0014] The thermal conductivity of the container 3 is, for example, 0.5 W / (m K) or more, preferably 1.0 W / (m K) or more. If the thermal conductivity of the container is equal to or higher than this lower limit, the peripheral temperature / central temperature of the container can be stably adjusted within the above-mentioned range during the evaporation step.

[0015] Next, the container 3 is adjusted (temperature-regulated) to any appropriate temperature. More specifically, the central portion 31 of the container 3 is adjusted to a predetermined initial temperature. The initial temperature is typically set arbitrarily and appropriately depending on the solvent used in the solution 1 of the compound to be crystallized. The initial temperature is, for example, equal to or lower than the boiling point of the solvent, preferably equal to or lower than the boiling point of the solvent minus 30°C. On the other hand, the initial temperature is, for example, equal to or higher than the boiling point of the solvent minus 70°C, preferably equal to or higher than the boiling point of the solvent minus 60°C.

[0016] In one embodiment, the temperature of the container 3 is adjusted by contacting the jig 4 placed on the heat source 2. The temperature of the heat source 2 is adjustable. The temperature of the heat source 2 is adjusted arbitrarily and appropriately so that the temperature of the center portion 31 of the container 3 is within the above range. Examples of the heat source 2 include a Peltier element and a hot plate. In the illustrated example, the heat source 2 is a Peltier element 2a.

[0017] The jig 4 is typically placed on the upper surface of the Peltier element 2a. In the illustrated example, the upper surface of the Peltier element 2a extends in the horizontal direction.

[0018] 2, in one embodiment, the jig 4 has a cylindrical shape extending in the vertical direction. In the illustrated example, the jig 4 has a recess 40. The recess 40 is typically provided on the upper surface of the jig 4. The recess 40 can accommodate the container 3 (see FIG. 1).

[0019] As shown in Fig. 1, the recess 40 has a bottom surface 40a and a side surface 40b. The bottom surface 40a of the recess 40 typically has a shape that follows the bottom surface of the container 3. In the illustrated example, the bottom surface 40a of the recess 40 has an arc shape that follows the bottom surface 30b of the watch glass 30. The side surface 40b of the recess 40 typically extends upward from the periphery of the bottom surface 40a and follows the side surface of the container 3. In the illustrated example, the side surface 40b of the recess 40 has a shape that follows the side surface 30c of the watch glass 30.

[0020] The jig 4 may be composed of a single member or multiple members. In one embodiment, the jig 4 includes a main body 41 and a side wall 42. The main body 41 is configured to be able to contact the bottom surface of the container during the evaporation process. The main body 41 typically has a disk shape. In the illustrated example, an arcuate surface corresponding to the bottom surface 40a of the recess 40 is provided on the upper surface of the main body 41. The side wall 42 is configured to be able to contact the side surface of the container during the evaporation process. The side wall 42 typically has a tubular portion 421 and a protruding portion 422. In the illustrated example, the tubular portion 421 has a cylindrical shape extending vertically. The protruding portion 422 protrudes radially inward from an upper portion of the inner surface of the tubular portion 421. The protruding portion 422 is provided over the entire circumferential surface of the inner surface of the tubular portion 421. The free end surface of the protrusion 422 corresponds to the side surface 40b of the recess 40. The lower portion of the cylindrical portion 421 is capable of accommodating the main body 41. When the cylindrical portion 421 accommodates the main body 41, the arc surface provided on the upper surface of the main body 41 and the free end surface of the protrusion 422 define the recess 40. In addition, the side wall 42 is detachable from the main body 41. This configuration allows for smooth installation and removal of the container relative to the jig.

[0021] The jig 4 is made of any appropriate material. Examples of materials for the jig 4 include glass such as borosilicate glass; metal materials such as gold, silver, copper, aluminum, chromium, and alloys thereof; and ceramic materials such as zirconia. Among such materials for the jig 4, metal materials are preferred, and copper is more preferred.

[0022] The thermal conductivity of the jig 4 is, for example, 20 W / (m K) or more, preferably 100 W / (m K) or more. If the thermal conductivity of the jig is equal to or higher than this lower limit, the peripheral temperature / central temperature of the container can be stably adjusted within the above-mentioned range during the evaporation process.

[0023] In one embodiment, the temperature of the container 3 is controlled while it is housed in the recess 40 of the jig 4. When the container 3 is housed in the recess 40, the proportion of the area of ​​the lower surface of the container 3 (typically the lower surface 30b of the watch glass 30) that is in contact with the bottom surface 40a of the recess 40 is, for example, 20% to 100%, and preferably 60% to 100%. When the container 3 is housed in the recess 40, the proportion of the area of ​​the side surface of the container 3 (typically the side surface 30c of the watch glass 30) that is in contact with the side surface 40b of the recess 40 is, for example, 10% to 100%, and preferably 40% to 100%. When the contact area of ​​the container with the jig is within this range, the temperature of the container can be controlled more stably.

[0024] The method for controlling the temperature of the container 3 is not limited to the above-described method. For example, the temperature may be controlled by providing an electric heating wire in the container 3, or by placing the container 3 in a water bath or oil bath.

[0025] Next, the solution 1 of the compound to be crystallized is poured into the temperature-controlled container 3. The solution 1 of the compound to be crystallized is prepared, for example, by dissolving the compound to be crystallized in a solvent.

[0026] Any suitable organic compound can be used as the compound to be crystallized. Examples of organic compounds include chlorpropamide and tolbutamide. Such compounds to be crystallized can be used alone or in combination. The compound to be crystallized is preferably used alone. Among the compounds to be crystallized, chlorpropamide is preferred.

[0027] The solvent is not particularly limited as long as it can dissolve the above-mentioned target compound for crystallization. Examples of the solvent include water and organic solvents. Examples of the organic solvent include alcohol-based solvents such as methanol, ethanol, 1-propanol, 2-propanol (isopropanol (IPA)), 1-butanol, 2-butanol, isobutanol, and tert-butanol; nitrile-based solvents such as acetonitrile and propionitrile; ether-based solvents such as diethyl ether and tetrahydrofuran; ketone-based solvents such as acetone and methyl ethyl ketone; halogen-based solvents such as dichloromethane and chloroform; ester-based solvents such as ethyl acetate and methyl acetate; aliphatic hydrocarbon-based solvents such as pentane, hexane, heptane, octane, and cyclohexane; and aromatic hydrocarbon-based solvents such as benzene, toluene, and xylene. Such solvents can be used alone or in combination. Among the solvents, organic solvents are preferred, alcohol-based solvents are more preferred, and 2-butanol is even more preferred.

[0028] To dissolve the target compound for crystallization in a solvent, for example, the target compound for crystallization is added to the solvent, and then heated to any appropriate temperature as necessary and stirred and mixed. This prepares a solution 1 of the target compound for crystallization. The concentration of the target compound for crystallization in the solution is, for example, 10 mg / mL to 600 mg / mL, preferably 350 mg / mL to 450 mg / mL.

[0029] An additive may be added to such a solution 1 of the target compound to be crystallized. Examples of additives include talc, polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), and polyvinylpyrrolidone (PVP). The additive is added in an amount of, for example, 0.1 to 20 parts by mass, and preferably 0.5 to 1 part by mass, per 100 parts by mass of the target compound to be crystallized.

[0030] The amount of solution 1 poured into container 3 is adjusted arbitrarily and appropriately. When the volume of container 3 is taken as 100%, the amount of solution 1 poured into container 3 is, for example, 10% to 80%, and preferably 20% to 50%. The amount of solution 1 poured into container 3 is, for example, 0.5 mL to 5 mL, and preferably 1 mL to 2 mL.

[0031] The temperature of the solution 1 poured into the container 3 may be equal to or higher than the initial temperature of the center 31 of the temperature-controlled container 3, or may be lower than the initial temperature of the center 31 of the temperature-controlled container 3. In one embodiment, the temperature of the solution 1 poured into the container 3 is equal to or higher than the initial temperature of the center 31 of the container 3. The absolute value of the difference between the temperature of the solution 1 and the initial temperature of the center 31 of the container 3 is, for example, 0°C to 40°C, preferably 0°C to 30°C, and more preferably 0°C to 10°C. When the temperature difference between the solution and the container at the time of pouring the solution is within this range, variation in crystal size can be reduced. The temperature of the solution 1 poured into the container 3 is, for example, 20°C to 100°C, and preferably 40°C to 90°C.

[0032] As a result, the solution 1 is placed in the container 3. In the illustrated example, the solution 1 is placed on the upper surface 30a of the watch glass 30.

[0033] A-2. Evaporation Process The evaporation process begins when the injection of the solution 1 into the container 3 is completed. As described above, the portion of the container 3 that comes into contact with the periphery of the solution 1 at the start of the evaporation process (i.e., when the injection of the solution 1 into the container 3 is completed) is referred to as the peripheral portion 32.

[0034] In one embodiment, the peripheral temperature / central temperature of the container 3 is maintained within the above-mentioned range from the start to the completion of the evaporation step by the above-mentioned temperature control method for the container 3. This can reduce the variation in the evaporation rate of the solvent in the solution of the compound to be crystallized, and can stably match the crystal shapes of the crystals precipitated in the central and peripheral parts of the container.

[0035] The temperature at the center of the container 3 in the evaporation step is, for example, the same as the range of the initial temperature of the center portion 31 of the container 3 described above. The temperature at the center of the container 3 in the evaporation step is, for example, 10°C to 100°C, and preferably 40°C to 60°C. The temperature at the periphery of the container 3 in the evaporation step is, for example, the same as the range of the temperature at the center of the container 3 described above.

[0036] The environmental temperature in such an evaporation step is, for example, 10°C to 40°C, and preferably 20°C to 30°C. The environmental pressure in the evaporation step is, for example, 0.06 MPa (absolute pressure) to 0.14 MPa (absolute pressure), and preferably 0.08 MPa (absolute pressure) to 0.12 MPa (absolute pressure). The environmental humidity in the evaporation step is, for example, 10% RH (relative humidity) to 90% RH, and preferably 20% RH to 60% RH.

[0037] The evaporation step is typically carried out until the solution 1 of the compound to be crystallized is dried up, and crystals of the compound to be crystallized are extracted. In one embodiment, the crystals of the compound to be crystallized are extracted within 24 hours of the evaporation step. The evaporation step is preferably carried out for 10 hours or less, more preferably 5 hours or less, even more preferably 3 hours or less, and particularly preferably 1 hour or less. On the other hand, the lower limit of the evaporation step is typically 5 minutes.

[0038] In this evaporation step, infrared rays may be irradiated onto the solution 1. When infrared rays are irradiated onto the solution in the evaporation step, the infrared rays are absorbed by the solvent, which can promote evaporation of the solvent. Therefore, the time required for the evaporation step can be shortened.

[0039] The infrared rays preferably include the absorption wavelength band of the solvent contained in Solution 1. When the infrared rays include the absorption wavelength band of the solvent, evaporation of the solvent can be further promoted. Furthermore, the infrared rays may include the absorption wavelength band of the compound to be crystallized contained in Solution 1. When the infrared rays include the absorption wavelength band of the compound to be crystallized, the crystalline form of the compound to be crystallized to be produced can be controlled.

[0040] In one embodiment, the wavelength of the infrared ray at which the normal emissivity reaches a maximum (maximum peak) is controlled. The maximum peak can be determined, for example, from an infrared emissivity curve obtained by plotting the wavelength of the infrared ray versus the normal emissivity.

[0041] The peak wavelength of the maximum peak is, for example, in the range of 2.0 μm to 10 μm, and for example, in the range of 3.0 μm to 7.0 μm. The normal emissivity of the maximum peak is, for example, 0.80 or more, preferably 0.85 or more, and more preferably 0.90 or more. On the other hand, the upper limit of the normal emissivity of the maximum peak is typically 1.0. Note that the normal emissivity of infrared light is calculated, for example, by applying Kirchhoff's law with transmittance set to a value of 0, using the following formula (1). Note that the normal reflectivity is measured, for example, using a Fourier transform infrared spectrometer (FT-IR) equipped with an integrating sphere: (Normal emissivity) = 1 - (Normal reflectivity) (1) The half-width of the maximum peak is, for example, 1.5 μm or less, and preferably 1.0 μm or less. On the other hand, the lower limit of the half-width of the maximum peak is typically 0 μm.

[0042] Such infrared rays with a controlled maximum peak wavelength are emitted to the solution 1 by, for example, any appropriate infrared emitting device (wavelength-controlled heater). Details of such an infrared emitting device are described in, for example, Japanese Patent No. 7096958, the disclosure of which is incorporated herein by reference.

[0043] The irradiation time of the infrared rays is, for example, 40% to 100%, and preferably 80% to 100%, when the execution time of the evaporation step is taken as 100%.

[0044] As a result, crystals of the compound to be crystallized are precipitated. The crystal shape of the crystals precipitated in the center of the container 3 is the same as that of the crystals precipitated in the peripheral portion of the container 3. The crystallite diameter of the compound to be crystallized is, for example, 10 μm to 500 μm, and preferably 100 μm to 200 μm.

[0045] The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.

[0046] Example 1: A jig shown in FIG. 1 was placed on a Peltier element whose heat source temperature was adjusted to the temperature shown in Table 1. The jig was made of copper. The thermal conductivity of the jig was approximately 400 W / (m·K). Next, a watch glass (outer diameter: 50 mm, thickness: 5 mm) was placed in the recess of the jig. This brought the entire bottom and side surfaces of the watch glass into contact with the jig. The thermal conductivity of the watch glass was approximately 1.1 W / (m·K). A 2-butanol solution of chlorpropamide was prepared by dissolving chlorpropamide (4-chloro-N-(propylcarbamoyl)benzenesulfonamide) in 2-butanol (boiling point: 99°C). The concentration of the 2-butanol solution of chlorpropamide was 400 mg / mL. The temperature of the 2-butanol solution of chlorpropamide was 80°C. Next, after adjusting the temperature of the center of the watch glass to the center temperature shown in Table 1, 1 mL of a 2-butanol solution of chlorpropamide was poured into the watch glass and placed on the top surface of the watch glass (solution placement step). At this time, the area of ​​the watch glass in contact with the periphery of the solution was defined as the periphery, and the temperature differences between the center and periphery of the watch glass and the Peltier element were measured using thermocouples. The temperatures of the center and periphery of the watch glass were then calculated from the measured temperature differences. Table 1 shows the temperature of the center of the watch glass, the temperature of the periphery of the watch glass, and the temperature ratio of the periphery to the center of the watch glass (peripheral temperature / center temperature). Subsequently, at room temperature (25°C) and atmospheric pressure (0.1 MPa), the center and periphery of the watch glass were maintained at the temperatures shown in Table 1, and the 2-butanol was evaporated until the 2-butanol solution of chlorpropamide was solidified (evaporation step). This resulted in the production of chlorpropamide crystals. The evaporation step in Example 1 lasted approximately 20 minutes.

[0047] <<Examples 2 and 3>> Chlorpropamide crystals were obtained in the same manner as in Example 1. Examples 2 and 3 were repeated experiments of Example 1.

[0048] Example 4 Crystals of chlorpropamide were obtained in the same manner as in Example 1, except that in the evaporation step, the heat source temperature of the Peltier element was changed to 42°C and the 2-butanol solution of chlorpropamide was irradiated with infrared light having a maximum peak wavelength of 3.3 μm. The evaporation step in Example 4 was carried out for about 15 minutes.

[0049] <<Comparative Example 1>> A Petri dish (outer diameter: 32 mm, height: 15 mm) was placed directly on a Peltier element adjusted to the heat source temperature shown in Table 1. The thermal conductivity of the Petri dish was approximately 1.0 W / (m·K). Chlorpropamide was also dissolved in 2-butanol to prepare a 2-butanol solution of chlorpropamide. The concentration of the 2-butanol solution of chlorpropamide was 400 mg / mL. The temperature of the 2-butanol solution of chlorpropamide was 80°C. Next, the temperature of the center of the Petri dish was adjusted to the center temperature shown in Table 1, and then 1 mL of the 2-butanol solution of chlorpropamide was poured into the Petri dish. At this time, the temperature difference between the center and the periphery of the Petri dish and the Peltier element was measured using a thermocouple, with the area of ​​the Petri dish in contact with the periphery of the solution being defined as the periphery. The temperatures of the center and periphery of the Petri dish were then calculated from the measured temperature difference. The temperature at the center of the Petri dish, the temperature at the periphery of the Petri dish, and the temperature ratio of the periphery to the center of the Petri dish (peripheral temperature / center temperature) are shown in Table 1. Thereafter, at room temperature (25°C) and atmospheric pressure (0.1 MPa), the center and periphery of the Petri dish were maintained at the temperatures shown in Table 1, and 2-butanol was evaporated until the 2-butanol solution of chlorpropamide was dried up (evaporation step). Thus, chlorpropamide crystals were obtained. The evaporation step in Comparative Example 1 was carried out for approximately 45 minutes.

[0050] <<Comparative Examples 2 and 3>> Chlorpropamide crystals were obtained in the same manner as in Comparative Example 1. Comparative Examples 2 and 3 were repeated experiments of Comparative Example 1.

[0051] Comparative Example 4 Crystals of chlorpropamide were obtained in the same manner as in Comparative Example 1, except that in the evaporation step, the heat source temperature of the Peltier element was changed to 39°C and the 2-butanol solution of chlorpropamide was irradiated with infrared light having a maximum peak wavelength of 3.3 μm. The evaporation step in Comparative Example 4 was carried out for approximately 40 minutes.

[0052] <<Comparative Examples 5 and 6>> Crystals of chlorpropamide were obtained in the same manner as in Example 1, except that the watch glass was placed directly on the Peltier element without using a jig. The evaporation step in each of Comparative Examples 5 and 6 lasted for approximately 40 minutes.

[0053] <Evaluation> In Examples 1 to 4 and Comparative Examples 1 to 6, the crystal forms of the chlorpropamide crystals precipitated in the central and peripheral regions of the containers were analyzed using an X-ray diffraction (XRD) device (Rigaku Corporation, Ultima IV, measurement range: 3 to 30°, X-ray generator: Cu). The results are shown in Table 1. Five types of chlorpropamide crystal forms are known: Form α, Form β, Form γ, Form δ, and Form ε (reference literature: Transitions among five polymorphs of chlorpropamide near the melting point, J. Therm. Anal. Calorim, vol. 93, 2008, 343-351).

[0054] As a result, it was confirmed that in Comparative Examples 1 to 3, 5, and 6, in which the peripheral temperature / core temperature ratio during the evaporation step was less than 0.85, and in Comparative Example 4, in which the peripheral temperature / core temperature ratio during the evaporation step exceeded 1.30, the chlorpropamide crystals precipitated at the center of the container (Petri dish or watch glass) and the chlorpropamide crystals precipitated at the periphery of the container had different crystal forms. In contrast, in Examples 1 to 4, in which the peripheral temperature / core temperature ratio during the evaporation step was 0.85 or more and 1.30 or less, the chlorpropamide crystals precipitated at the center of the container (watch glass) and the chlorpropamide crystals precipitated at the periphery of the container had the same crystal form. In particular, it was confirmed that the precipitated chlorpropamide crystals in Examples 1, 2, and 4 all had Form α.

[0055] The crystallization method according to the embodiment of the present invention can be suitably used to produce a compound to be crystallized having a specific crystal form.

[0056] REFERENCE SIGNS LIST 1 Solution 2 Heat source 3 Container 30 Watch glass 4 Jig 40 Recess 41 Main body 42 Side wall

Claims

1. A crystallization method comprising: placing a solution containing a compound to be crystallized and a solvent in a temperature-controlled container; and evaporating the solvent from the solution placed in the container, wherein, at the start of the solvent evaporation process, the temperature of the peripheral part relative to the temperature of the center of the container is adjusted to be 0.85 or more and 1.30 or less, when the part of the container that is in contact with the peripheral part of the solution is defined as the peripheral part.

2. The crystallization method according to claim 1, wherein the container is placed in contact with a jig placed on a temperature-controllable heat source.

3. The crystallization method according to claim 2, wherein the jig has a recess capable of accommodating the container.

4. The crystallization method according to claim 2, wherein the jig is made of a metal material.

5. The crystallization method described in claim 2, wherein the jig comprises a main body portion that contacts the bottom surface of the container during the process of evaporating the solvent, and a side wall portion that contacts the side surface of the container during the process of evaporating the solvent, and the side wall portion is removable from the main body portion.

6. The crystallization method according to claim 1, wherein the solution is irradiated with infrared rays in the step of evaporating the solvent.

7. The crystallization method according to claim 6, wherein the infrared radiation includes the absorption wavelength band of the solvent.

8. A crystallization method according to any one of claims 1 to 7, wherein the container is a watch glass.

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