Crystallization method

Abstract

The present invention provides a novel crystallization method. A crystallization method according to an embodiment of the present invention includes: a step for heating a solution containing a crystallization target compound having at least one crystal form and a solvent to a prescribed heating temperature; and a step for evaporating the solvent from the solution under normal pressure while lowering the temperature of the solution from the heating temperature.

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 for precipitating such crystals, in which a solution of the specific compound is heated to the boiling point of the solvent and the solvent is evaporated while maintaining a constant temperature (see Patent Document 1). This dries the solution, yielding crystals of the specific compound.

[0003] Patent No. 5714228

[0004] In recent years, there has been a demand for the crystallization of a variety of compounds. Since the appropriate crystallization method may vary depending on the compound, the development of new crystallization methods is desired. The main object of the present invention is to provide a novel crystallization method.

[0005] [1] A crystallization method according to an embodiment of the present invention includes the steps of heating a solution containing a compound to be crystallized having at least one crystalline form and a solvent to a predetermined heating temperature, and evaporating the solvent from the solution under normal pressure while cooling the solution from the heating temperature. [2] In the crystallization method described in [1] above, the step of evaporating the solvent from the solution may involve drying the solution to obtain crystals of the compound to be crystallized. [3] In the crystallization method described in [1] or [2] above, the step of evaporating the solvent from the solution may involve using a container whose opening is larger than the liquid level. [4] In the crystallization method described in any of [1] to [3] above, the step of evaporating the solvent from the solution may involve obtaining crystals of the compound to be crystallized within 24 hours. [5] In the crystallization method described in any of [1] to [4] above, the step of evaporating the solvent from the solution may involve irradiating the solution with infrared rays. [6] In the crystallization method according to [5] above, the infrared rays may include the absorption wavelength band of the solvent. [7] In the crystallization method according to [5] or [6] above, the infrared rays may include the absorption wavelength band of the compound to be crystallized. [8] In the crystallization method according to any one of [1] to [7] above, in the step of evaporating the solvent from the solution, the heat source may be the heating temperature −20° C. or lower. [9] In the crystallization method according to any one of [1] to [8] above, the heating temperature may be the boiling point of the solvent −15° C. or higher.

[10] In the crystallization method according to any one of [1] to [9] above, an additive may be added to the solution.

[0006] According to embodiments of the present invention, a novel crystallization method can be realized.

[0007] Figure 1 is a schematic diagram illustrating a crystallization method according to one embodiment of the present invention. Figure 2 shows X-ray diffraction charts of the terfenadine crystals obtained in Examples 1 to 7 and Comparative Examples 1 to 3. Figure 3 shows X-ray diffraction charts of the indomethacin crystals obtained in Examples 9 to 14 and Comparative Examples 5 to 7.

[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 Compound to be Crystallized The crystallization method in one embodiment of the present invention includes a heating step and an evaporation step. In the heating step, a solution containing a compound to be crystallized having at least one crystalline form and a solvent is heated to a predetermined heating temperature. In the evaporation step, the solvent is evaporated from the solution under normal pressure while the solution containing the compound to be crystallized and the solvent is cooled from the heating temperature. This allows stable precipitation of crystals of the compound to be crystallized.

[0010] A compound to be crystallized typically has two or more crystalline forms, in other words, crystalline polymorphism. A compound to be crystallized that has crystalline polymorphism can have different crystalline forms depending on the crystallization conditions, even if it has the same chemical composition. Different crystalline forms can have different properties. Examples of properties that can differ depending on the crystalline form include solubility, bioavailability, and stability. In one embodiment, the crystallization method controls the crystalline polymorphism of the compound to be crystallized to produce crystals of the compound to be crystallized that have properties appropriate for the intended use. In particular, since crystals of the compound to be crystallized that have the same chemical composition but different properties (e.g., solubility) can be produced, this crystallization method can be suitably applied to the production of solid pharmaceuticals.

[0011] A-1. Heating Step As described above, in the heating step, a solution of the compound to be crystallized is heated to a predetermined temperature. The solution of the compound to be crystallized is prepared, for example, by dissolving the compound to be crystallized in a solvent.

[0012] Any suitable organic compound can be used as the compound to be crystallized. Examples of organic compounds include terfenadine, indomethacin, febuxostat, ibuprofen, loxoprofen, caffeine, diclofenac, and carbamazepine. 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, preferred are terfenadine and indomethacin. When the compound to be crystallized includes terfenadine or indomethacin, crystals of terfenadine or indomethacin having a novel crystalline form can be produced.

[0013] 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 may be used alone or in combination. Among the solvents, organic solvents are preferred, alcohol-based solvents and ester-based solvents are more preferred, and IPA is even more preferred.

[0014] To dissolve a compound to be crystallized in a solvent, for example, the compound to be crystallized is added to a solvent, and then heated to any appropriate temperature as needed, followed by stirring and mixing. This prepares a solution of the compound to be crystallized. The concentration of the compound to be crystallized in the solution is, for example, 1 mg / mL or more, preferably 5 mg / mL or more, more preferably 15 mg / mL or more, and even more preferably 20 mg / mL or more. When the solution contains the compound to be crystallized at such a concentration, crystals of the compound to be crystallized can be stably precipitated in the evaporation step. Meanwhile, the concentration of the compound to be crystallized in the solution is, for example, 500 mg / mL or less, or, for example, 250 mg / mL or less.

[0015] An additive may be added to such a solution of the 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 compound to be crystallized.

[0016] Next, the obtained solution of the compound to be crystallized is heated to a predetermined heating temperature while stirring by any appropriate means. The heating temperature is, for example, (the boiling point of the solvent - 40°C) or higher, preferably (the boiling point of the solvent - 20°C) or higher, more preferably (the boiling point of the solvent - 15°C) or higher, and even more preferably (the boiling point of the solvent - 5°C) or higher. When the solution of the compound to be crystallized is heated to such a temperature, the solvent can be stably evaporated in the evaporation step while the solution of the compound to be crystallized is cooled. Meanwhile, the upper limit of the heating temperature is typically (the boiling point of the solvent).

[0017] The heating step is typically carried out under any appropriate environmental pressure. The environmental pressure in the heating step is, for example, 0.08 MPa (absolute pressure) to 0.12 MPa (absolute pressure). The duration of the heating step (heating time) is set arbitrarily and appropriately. The heating time is, for example, 5 to 20 minutes.

[0018] A-2. Evaporation Step Next, in the evaporation step, the solvent is evaporated from the heated solution of the compound to be crystallized under normal pressure while the temperature of the solution is lowered from the heating temperature.

[0019] In this specification, "normal pressure" means 0.08 MPa (absolute pressure) to 0.12 MPa (absolute pressure). The temperature lowering rate of the solution of the compound to be crystallized in the evaporation step is, for example, 0.1°C / min to 10°C / min, and preferably 1°C / min to 5°C / min.

[0020] The evaporation step is typically carried out until the solution 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.

[0021] In one embodiment, in the evaporation step, the temperature of the solution of the compound to be crystallized is appropriately controlled by using a heat source, such as a Peltier element or a hot plate.

[0022] 1 is a schematic diagram illustrating a crystallization method according to one embodiment of the present invention. In one embodiment, a solution of a compound to be crystallized (hereinafter referred to as solution 1) adjusted to the heating temperature described above is poured into a container 3, and the container 3 containing solution 1 is placed on a heat source 2. In the illustrated example, a Peltier element 2a is used as the heat source 2.

[0023] The container 3 typically has an opening that is larger than or equal to the liquid level of the solution 1. Examples of the container 3 include a Petri dish and a watch glass, and a Petri dish is preferred.

[0024] The container 3 is preferably heated before the solution 1 is poured into it. The range of the heating temperature of the container 3 is, for example, the same as the range of the heating temperature of the solution 1 in the heating step described above. The absolute value of the difference between the heating temperature of the solution 1 and the heating temperature of the container 3 is, for example, 10°C or less, preferably 5°C or less. On the other hand, the lower limit of the absolute value of the difference between the heating temperature of the solution 1 and the heating temperature of the container 3 is typically 0°C. If the temperature difference between the solution and the container when the solution is poured into the container is within this range, the solution can be prevented from being cooled by the container when poured into the container. Therefore, the solvent can be evaporated more stably in the evaporation step.

[0025] 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.

[0026] Furthermore, the heat source 2 (in the illustrated example, a Peltier element 2a) is typically adjusted to any appropriate heat source temperature before the container 3 is placed thereon. The container 3 containing the solution 1 is then placed on the heat source 2 (Peltier element 2a), and the heat source 2 is maintained at the heat source temperature until the evaporation step is complete. The heat source temperature is, for example, less than the heating temperature of the solution 1, preferably not more than (the heating temperature of the solution 1 - 20°C), more preferably not more than (the heating temperature of the solution 1 - 30°C), and even more preferably not more than (the heating temperature of the solution 1 - 50°C). When the heat source has such a heat source temperature, the solvent can be sufficiently evaporated under normal pressure while the solution of the compound to be crystallized is stably cooled from the heating temperature during the evaporation step. As a result, crystals of the compound to be crystallized having the desired crystalline form can be produced. On the other hand, the heat source temperature is, for example, not less than (the heating temperature of the solution 1 - 80°C), and preferably not less than (the heating temperature of the solution 1 - 70°C).

[0027] In the illustrated example, a container 3 is used, and the container 3 containing the solution 1 is placed on the heat source 2, but the evaporation step is not limited to this. The solution 1 heated to the above heating temperature may be directly dropped onto the heat source 2 (typically, a Peltier element 2a) adjusted to the above heat source temperature.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] In this way, crystals of the target compound for crystallization are produced. The crystals of the target compound for crystallization typically have a desired crystal form. The crystallite size of the target compound for crystallization is, for example, 10 μm to 500 μm, and preferably 100 μm to 200 μm.

[0034] The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.

[0035] Examples 1 to 3 Terfenadine (1-(p-tert-butylphenyl)-4-[4'-(hydroxydiphenylmethyl)-1'-piperidinyl]butanol) was dissolved in isopropanol (IPA) to a concentration shown in Table 1 to prepare a solution of terfenadine in IPA. The IPA solution of terfenadine was then heated to the heating temperature shown in Table 1, i.e., to the boiling point of IPA (heating step). Separately, a Petri dish (outer diameter: 32 mm, height: 15 mm) was heated to the heating temperature shown in Table 1. 1 ml of the heated IPA solution of terfenadine was then poured into the heated Petri dish. The Petri dish was then placed on a Peltier element adjusted to the heat source temperature shown in Table 1, and the IPA was evaporated under normal pressure (0.1 MPa) until the IPA solution in the Petri dish was dried up (evaporation step). The heat source temperature was set lower than the heating temperature. The difference between the heating temperature and the heat source temperature is shown in Table 1. Terfenadine crystals were obtained in this manner. The evaporation step in Example 3 was carried out for 180 minutes.

[0036] Examples 4 and 5 Crystals of terfenadine were obtained in the same manner as in Example 3, except that in the evaporation step, the IPA solution of terfenadine was irradiated with infrared light having the maximum peak wavelength shown in Table 1. The evaporation times in Examples 4 and 5 are shown in Table 1.

[0037] Example 6 Crystals of terfenadine were obtained in the same manner as in Example 2, except that the heating temperature of the IPA solution of terfenadine in the heating step was changed to 65°C, and the heat source temperature of the Peltier element in the evaporation step was changed to 35°C.

[0038] Example 7 Crystals of terfenadine were obtained in the same manner as in Example 2, except that the heating temperature of the IPA solution of terfenadine in the heating step was changed to 65°C.

[0039] Example 8 An amorphous form of terfenadine was obtained in the same manner as in Example 1, except that the concentration of the IPA solution of terfenadine was changed to 10 mg / ml and the heating temperature of the IPA solution of terfenadine in the heating step was changed to 45°C.

[0040] Examples 9 to 12 Indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-H-indole-3-acetic acid) was dissolved in IPA to a concentration shown in Table 1 to prepare an IPA solution of indomethacin. The IPA solution of indomethacin was then heated to the heating temperature shown in Table 1, i.e., the boiling point of IPA (heating step). Separately, a Petri dish (outer diameter: 32 mm, height: 15 mm) was heated to the heating temperature shown in Table 1. 1 mL of the heated IPA solution of indomethacin was then poured into the heated Petri dish. The Petri dish was then placed on a Peltier element adjusted to the heat source temperature shown in Table 1, and the IPA was evaporated until the IPA solution in the Petri dish was solidified (evaporation step). The heat source temperature was set lower than the heating temperature. The difference between the heating temperature and the heat source temperature is shown in Table 1. As a result, indomethacin crystals were obtained. The evaporation step in Example 11 was carried out for 253 minutes.

[0041] Example 13 Crystals of indomethacin were obtained in the same manner as in Example 11, except that in the evaporation step, the IPA solution of indomethacin was irradiated with infrared light having the maximum peak wavelength shown in Table 1. The evaporation time in Example 13 was 57 minutes.

[0042] Example 14 Indomethacin was dissolved in ethyl acetate to a concentration shown in Table 1 to prepare an indomethacin-ethyl acetate solution. The indomethacin-ethyl acetate solution was then heated to the heating temperature shown in Table 1, i.e., the boiling point of ethyl acetate (heating step). Separately, a Petri dish (outer diameter: 32 mm, height: 15 mm) was heated to the heating temperature shown in Table 1. 1 mL of the heated indomethacin-ethyl acetate solution was poured into the heated Petri dish. The Petri dish was then placed on a Peltier element adjusted to the heat source temperature shown in Table 1, and the ethyl acetate was evaporated until the indomethacin-ethyl acetate solution in the Petri dish was dried up (evaporation step). The heat source temperature was set lower than the heating temperature. The difference between the heating temperature and the heat source temperature is shown in Table 1. This resulted in the production of indomethacin crystals.

[0043] <<Comparative Example 1>> Crystals of terfenadine were obtained in the same manner as in Example 1, except that the heat source temperature of the Peltier element in the evaporation step was changed to 89°C. That is, in Comparative Example 1, the heat source temperature was set higher than the heating temperature (= the boiling point of IPA). Therefore, in Comparative Example 1, IPA was evaporated under normal pressure while the IPA solution of terfenadine was maintained at the boiling point of IPA.

[0044] <<Comparative Example 2>> Crystals of terfenadine were obtained in the same manner as in Example 2, except that the heat source temperature of the Peltier element in the evaporation step was changed to 89° C. Therefore, also in Comparative Example 2, IPA was evaporated under normal pressure while the IPA solution of terfenadine was maintained at the boiling point of IPA.

[0045] <<Comparative Example 3>> Crystals of terfenadine were obtained in the same manner as in Example 2, except that the heating temperature of the IPA solution of terfenadine in the heating step was changed to 65° C., and the heat source temperature of the Peltier element in the evaporation step was changed to 65° C. Therefore, in Comparative Example 3, IPA was evaporated under normal pressure while the IPA solution of terfenadine was maintained at 65° C.

[0046] <<Comparative Example 4>> An amorphous form of terfenadine was obtained in the same manner as in Example 2, except that the concentration of the IPA solution of terfenadine was changed to 10 mg / mL and the heating temperature of the IPA solution of terfenadine in the heating step was changed to 25° C. That is, in Comparative Example 4, IPA was evaporated under normal pressure while the IPA solution of terfenadine was maintained at 25° C.

[0047] <<Comparative Example 5>> Crystals of indomethacin were obtained in the same manner as in Example 10, except that the concentration of the indomethacin IPA solution was changed to 40 mg / mL and the heat source temperature of the Peltier element in the evaporation step was changed to 89°C. That is, in Comparative Example 5, the heat source temperature was set higher than the heating temperature (= the boiling point of IPA). Therefore, in Comparative Example 5, IPA was evaporated under normal pressure while the indomethacin IPA solution was maintained at the boiling point of IPA.

[0048] Comparative Example 6 Indomethacin crystals were obtained in the same manner as in Example 14, except that the heat source temperature of the Peltier element in the evaporation step was changed to 80° C. That is, in Comparative Example 6, the heat source temperature was set higher than the heating temperature (= the boiling point of ethyl acetate). Therefore, in Comparative Example 6, ethyl acetate was evaporated under normal pressure while the temperature of the indomethacin-ethyl acetate solution was maintained at the boiling point of ethyl acetate.

[0049] <<Comparative Example 7>> Crystals of indomethacin were obtained in the same manner as in Example 14, except that the concentration of the indomethacin ethyl acetate solution was changed to 25 mg / mL, the heating temperature of the indomethacin ethyl acetate solution in the heating step was changed to 40° C., and the heat source temperature of the Peltier element in the evaporation step was changed to 40° C. That is, in Comparative Example 7, ethyl acetate was evaporated under normal pressure while the indomethacin ethyl acetate solution was maintained at 40° C.

[0050]

[0051] <Evaluation> The terfenadine crystals obtained in Examples 1 to 7 and Comparative Examples 1 to 3 were analyzed using an X-ray diffraction (XRD) device (Rigaku Corporation, Ultima IV, measurement range: 3 to 30°, X-ray generator: Cu). As a result, it was confirmed that the terfenadine crystals obtained in Comparative Examples 1 and 2 had the known Form 1 (F1), and the terfenadine crystals obtained in Comparative Example 3 had the known Form 2 (F2). On the other hand, it was confirmed that the terfenadine crystals obtained in Examples 1 to 7 had an unknown crystal form different from Forms 1 and 2. Figure 2 shows X-ray diffraction charts of terfenadine crystals (Form 1, Form 2, and novel crystals).

[0052] The indomethacin crystals obtained in Examples 9 to 14 and Comparative Examples 5 to 7 were analyzed using an X-ray diffraction (XRD) apparatus and an electron beam diffractometer (Rigaku Corporation, XtaLAB Synergy-ED, measurement range: 3 to 30°). As a result, it was confirmed that the indomethacin crystals obtained in Example 9 and Comparative Example 5 had the known Form α, while the indomethacin crystals obtained in Comparative Examples 6 and 7 had both the known Form α and the known Form γ. On the other hand, it was confirmed that the indomethacin crystals obtained in Examples 10 to 14 had an unknown crystalline form different from Form α and Form γ. Figure 3 shows the X-ray diffraction chart of the indomethacin crystals.

[0053] 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.

Claims

1. A crystallization method comprising the steps of: heating a solution containing a compound to be crystallized, having at least one crystalline form, and a solvent to a predetermined heating temperature; and evaporating the solvent from the solution under normal pressure while cooling the solution from the heating temperature.

2. The crystallization method according to claim 1, wherein in the step of evaporating the solvent from the solution, the solution is dried to solidify and crystals of the compound to be crystallized are isolated.

3. The crystallization method according to claim 1 or 2, wherein a container having an opening larger than the liquid level is used in the step of evaporating the solvent from the solution.

4. The crystallization method according to claim 1 or 2, wherein in the step of evaporating the solvent from the solution, the crystals of the compound to be crystallized are taken out within 24 hours.

5. The crystallization method according to claim 1 or 2, wherein the solution is irradiated with infrared rays in the step of evaporating the solvent from the solution.

6. The crystallization method according to claim 5, wherein the infrared radiation includes the absorption wavelength band of the solvent.

7. The crystallization method according to claim 5, wherein the infrared light includes an absorption wavelength band of the compound to be crystallized.

8. The crystallization method according to claim 1 or 2, wherein in the step of evaporating the solvent from the solution, the heat source is the heating temperature −20° C. or lower.

9. The crystallization method according to claim 1 or 2, wherein the heating temperature is equal to or higher than the boiling point of the solvent minus 15°C.

10. The crystallization method according to claim 1 or 2, wherein an additive is added to the solution.

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