Crystals of specific shapes of compounds and their manufacturing method

Abstract

To provide a method for obtaining a specifically-shaped crystal (specifically, spherocrystal) of a compound with good reproducibility.SOLUTION: This method for producing a specifically-shaped crystal (specifically spherocrystal) of a compound comprises the steps of: (1) preparing a supersaturated solution of a compound having a degree of supersaturation equal to or higher than a critical degree of supersaturation; and (2) precipitating a specifically-shaped crystal (specifically spherocrystal) of the compound from the supersaturated solution.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a specific shaped crystal of a compound and a method for producing the same, and in particular to a spherulite of a compound and a method for producing the same. [Background technology]

[0002] The powder properties of a compound are significantly affected by its crystalline shape, so methods for controlling the crystalline shape have broad potential applications in fields such as pharmaceutical manufacturing, agricultural chemical manufacturing, food manufacturing, printing technology, and organic electronic devices.

[0003] The crystalline shape of a compound is closely related to the crystal growth mechanism. As the driving force for crystal growth or the amount of impurities increases, the crystal changes from a single polyhedral crystal to a skeletal crystal (a crystal with depressions on the crystal face) and then to a symmetrical dendrite through spiral growth or two-dimensional nucleation growth. If the driving force or the amount of impurities increases further, the crystal changes to an asymmetrical polycrystalline dendrite through accretion growth, and finally to a spherulite (Non-Patent Document 1).

[0004] Because spherulites are the crystalline form with the smallest specific surface area, they offer various advantages in the manufacturing processes of many chemical products, including pharmaceuticals, pesticides, food, and electronic materials. Specifically, during solid-liquid separation in the crystallization process, their high filterability shortens the operation time, and washing procedures are highly efficient, allowing for the production of highly pure crystals. Furthermore, their high packing ability into manufacturing equipment allows for increased throughput during these operations. Furthermore, improved fluidity and packing properties are expected to improve productivity in the processing of spherulites. For example, in the manufacturing process of pharmaceutical formulations, fine pharmaceutical active ingredients can sometimes be difficult to formulate as is due to their poor adhesion and cohesion, fluidity, packing, and wettability. In such cases, various excipients are typically added and the active ingredient is granulated into granules or other particles before formulation. However, spherulites, which have high fluidity and packing properties, eliminate the need for such granulation procedures and offer the advantage of direct tableting and coating (Patent Document 1).

[0005] In contrast to the spherical crystallization method, which produces spherulites by radial crystallization from a homogeneous solution of a single compound, another known method is the spherical granulation method, which involves adding an immiscible organic solvent (e.g., dichloromethane) containing the compound to water and a water-miscible organic solvent (e.g., ethanol) to form a pseudo-emulsion. The microcrystals obtained by solvent diffusion are then directly accumulated in the system to produce spherical agglomerates (Patent Documents 1 and 2). This method is limited to compounds that are soluble in halogenated solvents such as dichloromethane. In pharmaceutical manufacturing, strict residual solvent management is required due to the high toxicity of halogenated solvents. On the other hand, a method of forming emulsions using surfactants instead of halogenated solvents is also known (Non-Patent Document 2). With this method, all compounds dissolved in a good solvent crystallize, essentially eliminating the purification effect of crystallization. Therefore, the raw material must be a highly purified compound, making it unsuitable for improving the productivity of chemical manufacturing processes. From the above, the spherical crystallization method, which obtains spherulites from a homogeneous solution of a single compound, has a wider range of application and is therefore highly useful industrially. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Unexamined Patent Publication No. 58-143832 [Patent Document 2] Japanese Patent Application Publication No. 1-279869 [Non-patent literature]

[0007] [Non-Patent Document 1] Ichiro Sunagawa, "Crystals: Growth, Shape, Perfection", Kyoritsu Shuppan (Tokyo, 2003), Chapter 3, pp. 47-48 [Non-patent document 2] F. Espitalier, B. Biscans, J.-R. Authelin, C. Laguerrie, Institution of Chemical Engineers, 1997, 75(2), pp.257-267 [Non-patent document 3] L. Granasy, et al., Nature Materials 2004, vol. 3, pp. 645-650 Summary of the Invention [Problem to be solved by the invention]

[0008] Currently, there is no universal method for preparing crystals of desired shapes as needed. In particular, because spherulites of compounds are highly useful industrially as described above, a method for producing spherulites of any compound with good reproducibility is desired.

[0009] Spherulites are a crystalline form commonly observed regardless of the type of compound. However, they are often obtained from compounds such as polymers, minerals, and inorganic materials, while relatively few examples are obtained from molecular compounds such as active pharmaceutical ingredients, intermediates, and pesticides. Furthermore, there are many examples of spherulites being obtained from supercooled compounds. Theoretical studies suggest that as the degree of supercooling increases, rotational motion becomes relatively slower than translational motion, leading to nucleation in non-crystallographic orientations on the crystal surface, resulting in branching and polycrystallization, ultimately resulting in spherulites (Non-Patent Document 3). Meanwhile, crystallization from supersaturated solutions of compounds is a common crystallization process in the production of fine chemicals and is of great industrial importance. However, there are few examples of spherulites being obtained, and theoretical research has been insufficient. Therefore, the challenge of reproducibly obtaining spherulites from supersaturated solutions of compounds is difficult to achieve in a unified manner and largely relies on trial and error. This significantly hinders shortening product development times. Therefore, systematic research and development of methods for obtaining spherulites from supersaturated solutions of compounds would be industrially useful.

[0010] An object of the present invention is to provide a method for reproducibly obtaining crystals of a compound having a desired shape, and in particular, to provide a method for reproducibly obtaining spherulites of a compound. [Means for solving the problem]

[0011] In view of the above-mentioned problems, the present inventors have conducted extensive research and have found that there exists a minimum degree of supersaturation (referred to herein as "critical supersaturation") required to obtain crystals of a specific shape of a compound. Furthermore, the present inventors have found that crystals of a specific shape can be reproducibly obtained from a supersaturated solution of a compound having a degree of supersaturation equal to or greater than the critical supersaturation. Furthermore, the present inventors have developed a statistical model of critical supersaturation by machine learning data on the critical supersaturation and crystallization conditions of a large number of newly obtained compounds, and have clarified the physical quantity that determines the critical supersaturation. As a result, they have found that the critical supersaturation of any compound can be predicted during crystallization from solution without trial and error.

[0012] One or more embodiments of the invention include the following. <1> A method for producing spherulites of a compound, comprising the steps of: (1) preparing a supersaturated solution of the compound having a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites of the compound; and (2) A step of precipitating spherulites of the compound from the supersaturated solution. A method comprising: <2> The step (1) is carried out under conditions that do not cause nucleation until a supersaturation level equal to or higher than a critical supersaturation level is reached. <1> The method described below. <3> The method further includes a step of removing crystal nuclei generated in the step (1) before the supersaturation reaches a critical supersaturation or higher. <1> The method described below. <4> Information on compounds obtained as spherulites, At least one of the following: information on the solvent used for crystallization and the solution temperature during crystallization The method further comprises inputting the data including the following into a prediction model of the critical supersaturation required to obtain spherulites of the compound, and outputting a predicted value of the critical supersaturation from the prediction model; The critical supersaturation in the step (1) is the predicted value. <1> ~ <3> 10. The method according to claim 9, wherein <5> When the predicted value is output as a numerical range, the critical supersaturation in step (1) is the lower limit of the numerical range. <4> The method described below. <6> The critical supersaturation is an actual measured value. <1> ~ <3> 10. The method according to claim 9, wherein <7> The sphericity of the spherulites is 0.60 or more. <1> ~ <6> 10. The method according to claim 9, wherein <8> The compound obtained as spherulites is a compound selected from the following (1) and (2): <1> ~ <7> Either one of the following methods: (1) A compound represented by the following formula I, or a tautomer thereof, or an optical isomer thereof, or a salt thereof, or a solvate thereof: [ka] [In the formula, X is CH or N; R 1 is a hydrogen atom or an optionally substituted C 1-6 is an alkoxy group, R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 an alkoxy group or an optionally substituted amino group; (2) Azithromycin, duloxetine, clarithromycin, lanthanum carbonate, glutamic acid, clopidogrel, ketotifen, escitalopram, dabigatran etexilate, theophylline, teneligliptin, pilsicainide, tramadol, vildagliptin, linagliptin, glutathione, mirabegron, tolvaptan, valacyclovir, bepotastine, olopatadine, or an optical isomer thereof, or a salt thereof, or a solvate thereof. <9> The compound obtained as spherulites is esomeprazole or lansoprazole, or a salt thereof, or a solvate thereof. <1> ~ <8> 10. The method according to claim 9, wherein <10> The compound obtained as spherulites is esomeprazole magnesium trihydrate. <1> ~ <9> 10. The method according to claim 9, wherein <11> <1> ~ <10> 10. A spherulite of a compound produced by any one of the methods described above. <12> Spherulites of a compound selected from (1) and (2) below: (1) A compound represented by the following formula I, or a tautomer thereof, or an optical isomer thereof, or a salt thereof, or a solvate thereof: [ka] [In the formula, X is CH or N; R 1 is a hydrogen atom or an optionally substituted C 1-6 is an alkoxy group, R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 an alkoxy group or an optionally substituted amino group; (2) Azithromycin, duloxetine, clarithromycin, lanthanum carbonate, glutamic acid, clopidogrel, ketotifen, escitalopram, dabigatran etexilate, theophylline, teneligliptin, pilsicainide, tramadol, vildagliptin, linagliptin, glutathione, mirabegron, tolvaptan, valacyclovir, bepotastine, olopatadine, or an optical isomer thereof, or a salt thereof, or a solvate thereof. <13> The compound selected from (1) and (2) above is esomeprazole or lansoprazole, or a salt thereof, or a solvate thereof. <12> The spherulites described in <14> The compound selected from (1) and (2) above is esomeprazole magnesium trihydrate. <12> or <13> The spherulites described in <15> The sphericity is 0.60 or more. <12> ~ <14> 3. The spherulite according to any one of claims 1 to 2. <16> a memory unit that records a pre-trained prediction model of critical supersaturation that receives input data including information on a compound obtained as spherulites, information on a solvent used for crystallization, and at least one of the solution temperature during crystallization, and outputs a predicted value of critical supersaturation required to obtain spherulites of the compound; and a calculation unit that inputs data including information about the target compound obtained as spherulites, information about the solvent used to crystallize the target compound, and at least one of the solution temperature during crystallization into the prediction model, and calculates a predicted value of the critical supersaturation required to obtain spherulites of the target compound; A device for predicting the critical supersaturation required to obtain spherulites of a target compound, comprising: <17> A method for predicting the critical supersaturation required to obtain spherulites of a compound, comprising: A method comprising the steps of inputting data including information about a compound obtained as spherulites, information about the solvent used for crystallization, and at least one of the solution temperature during crystallization, into a prediction model for the critical supersaturation required to obtain spherulites of the compound, and outputting a predicted value of the critical supersaturation from the prediction model. <18> A computer program for predicting the critical supersaturation required to obtain spherulites of a compound, which causes a computer to execute a process including the step of inputting data including information about the compound obtained as spherulites, information about the solvent used for crystallization, and at least one of the solution temperature during crystallization into a prediction model for the critical supersaturation required to obtain spherulites of the compound, and outputting a predicted value of the critical supersaturation from the prediction model. <19> A method for producing a crystal of a specific shape of a compound, comprising: (1) preparing a supersaturated solution of the compound having a degree of supersaturation equal to or greater than the critical degree of supersaturation required to obtain crystals of a specific shape of the compound; and (2) A step of precipitating crystals of a specific shape of the compound from the supersaturated solution. A method comprising: <20> a storage unit that records a prediction model of critical supersaturation that has been pre-trained to input data including information about a compound obtained as a crystal of a specific shape, information about a solvent used in crystallization, and at least one of the solution temperature during crystallization, and to output a predicted value of critical supersaturation required to obtain a crystal of the specific shape of the compound; and a calculation unit that inputs data including information about a target compound obtained as a crystal of a specific shape, and at least one of information about a solvent used to crystallize the target compound and a solution temperature during crystallization into the prediction model, and calculates a predicted value of the critical supersaturation required to obtain a crystal of the target compound of a specific shape; A device for predicting the critical supersaturation required to obtain crystals of a specific shape of a target compound, comprising: <21> A method for predicting the critical supersaturation required to obtain a specific crystal shape of a compound, comprising: A method comprising the steps of inputting data including information about a compound obtained as a crystal of a specific shape, and at least one of information about the solvent used for crystallization and the solution temperature during crystallization, into a prediction model of the critical supersaturation required to obtain crystals of the compound of a specific shape, and outputting a predicted value of the critical supersaturation from the prediction model. <22> A computer program for predicting the critical supersaturation required to obtain crystals of a specific shape of a compound, which causes a computer to execute a process including the step of inputting data including information about the compound to be obtained as crystals of a specific shape, and at least one of information about the solvent used for crystallization and the solution temperature during crystallization into a prediction model of the critical supersaturation required to obtain crystals of the specific shape of the compound, and outputting a predicted value of the critical supersaturation from the prediction model. [Effects of the Invention]

[0013] By using the method of the present invention, crystals (particularly spherulites) of a specific shape of a compound can be obtained with good reproducibility. Because these spherulites have high fluidity and packing properties, the time required for solid-liquid separation during the manufacturing process is short, and crystal washing is highly effective. Furthermore, when using these to manufacture pharmaceuticals, they can be directly tableted without adding additives to form granules. Furthermore, these spherulites can be uniformly coated using a small amount of substrate. Furthermore, because the specific surface area of ​​these spherulites is small, adhesion to the punch surface during tableting can be suppressed. Therefore, tableting problems can be reduced. Therefore, the spherulites produced by the method of the present invention can improve both the quality and productivity of pharmaceuticals. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows a scanning electron microscope (SEM) image of the crystals of ketotifen fumarate obtained in Example 1. [Figure 2] 1 shows the results of powder X-ray diffraction of the spherulites of ketotifen fumarate obtained in Example 1. [Figure 3] 1 shows the dissolution profiles and regression models of spherulites and non-spherulites of esomeprazole magnesium trihydrate of Example 8. [Figure 4] 1 shows an SEM image of a cut spherulite of azithromycin monohydrate obtained in Example 12. [Figure 5] 1 shows an SEM image of spherulites of esomeprazole magnesium trihydrate obtained in Example 2. [Figure 6] 1 shows the results of powder X-ray diffraction of spherulites of esomeprazole magnesium trihydrate obtained in Example 2. [Figure 7] 1 shows the particle size distribution of spherulites of esomeprazole magnesium trihydrate obtained in Example 2. [Figure 8] 1 shows an SEM image of spherulites of esomeprazole magnesium trihydrate obtained in Example 3. [Figure 9] 1 shows an SEM image of spherulites of esomeprazole magnesium trihydrate obtained in Example 4. [Figure 10] 1 shows an SEM image of spherulites of esomeprazole magnesium trihydrate obtained in Example 5. [Figure 11] 1 shows the results of powder X-ray diffraction of spherulites of esomeprazole magnesium trihydrate obtained in Example 5. [Figure 12] 1 shows the particle size distribution results of spherulites of esomeprazole magnesium trihydrate obtained in Example 5. [Figure 13] 1 shows an SEM image of spherulites of esomeprazole magnesium trihydrate obtained in Example 6. [Figure 14] 1 shows the results of powder X-ray diffraction of spherulites of esomeprazole magnesium trihydrate obtained in Example 6. [Figure 15] 1 shows the particle size distribution results of spherulites of esomeprazole magnesium trihydrate obtained in Example 6. [Figure 16] 1 shows an SEM image of spherulites of esomeprazole magnesium trihydrate obtained in Example 7. [Figure 17] 1 shows the results of powder X-ray diffraction of spherulites of esomeprazole magnesium trihydrate obtained in Example 7. [Figure 18]1 shows the particle size distribution results of spherulites of esomeprazole magnesium trihydrate obtained in Example 7. [Figure 19] 1 shows an SEM image of spherulites of lansoprazole obtained in Example 11. [Figure 20] 1 shows the results of powder X-ray diffraction of the spherulites of lansoprazole obtained in Example 11. [Figure 21] 1 shows an SEM image of spherulites of azithromycin monohydrate obtained in Example 12. [Figure 22] 1 shows the results of powder X-ray diffraction of spherulites of azithromycin monohydrate obtained in Example 12. [Figure 23] 1 shows the particle size distribution results of spherulites of azithromycin monohydrate obtained in Example 12. [Figure 24] 1 shows an SEM image of clarithromycin spherulites obtained in Example 13. [Figure 25] 1 shows the results of powder X-ray diffraction of the clarithromycin spherulites obtained in Example 13. [Figure 26] 1 shows the particle size distribution results of clarithromycin spherulites obtained in Example 13. [Figure 27] 1 shows an SEM image of spherulites of DL-glutamic acid obtained in Example 14. [Figure 28] 1 shows the results of powder X-ray diffraction of the spherulites of DL-glutamic acid obtained in Example 14. [Figure 29] 1 shows the particle size distribution results of spherulites of ketotifen fumarate obtained in Example 15. [Figure 30] 1 shows an SEM image of spherulites of duloxetine hydrochloride obtained in Example 15. [Figure 31] 1 shows the results of powder X-ray diffraction of the spherulites of duloxetine hydrochloride obtained in Example 15. [Figure 32] 1 shows the particle size distribution results of duloxetine hydrochloride spherulites obtained in Example 15. [Figure 33] 1 shows an SEM image of spherulites of clopidogrel sulfate obtained in Example 16. [Figure 34]1 shows the results of powder X-ray diffraction of the spherulites of clopidogrel sulfate obtained in Example 16. [Figure 35] 1 shows the particle size distribution of spherulites of clopidogrel sulfate obtained in Example 16. [Figure 36] 1 shows an SEM image of spherulites of lanthanum carbonate octahydrate obtained in Example 17. [Figure 37] 1 shows the results of powder X-ray diffraction of spherulites of lanthanum carbonate octahydrate obtained in Example 17. [Figure 38] 1 shows the particle size distribution of spherulites of lanthanum carbonate octahydrate obtained in Example 17. [Figure 39] FIG. 1 is a diagram illustrating an example of a schematic configuration of an information processing device 100 used in a step of predicting a critical supersaturation degree. [Figure 40] 10 shows a flowchart illustrating an example of the operation of the overall processing. [Figure 41] This figure plots the predicted versus experimental critical supersaturation values, with the dashed lines representing the 95% confidence interval. [Figure 42] FIG. 10 is a diagram illustrating a method for calculating sphericity. [Figure 43] FIG. 10 is a diagram showing the relationship between RMSE value and sphericity. [Figure 44] 1 shows an SEM image of spherulites of esomeprazole magnesium trihydrate obtained in Example 8(1). [Figure 45] 1 shows the results of powder X-ray diffraction of spherulites of esomeprazole magnesium trihydrate obtained in Example 8(1). [Figure 46] 1 shows the results of particle size distribution of spherulites of esomeprazole magnesium trihydrate obtained in Example 8(1). [Figure 47] 1 shows an SEM image of non-spherulites of esomeprazole magnesium trihydrate used in Example 8(2). [Figure 48] FIG. 1 shows the results of powder X-ray diffraction of non-spherulites of esomeprazole magnesium trihydrate used in Example 8(2). [Figure 49] 1 shows the results of particle size distribution of non-spherulites of esomeprazole magnesium trihydrate used in Example 8(2). [Figure 50] 1 shows an SEM image of spherulites of esomeprazole magnesium trihydrate obtained in Example 10(1). [Figure 51] 1 shows the results of particle size distribution of spherulites of esomeprazole magnesium trihydrate obtained in Example 10(1). [Figure 52] 1 shows an SEM image of the crystals of esomeprazole magnesium trihydrate obtained in Example 10(2). [Figure 53] 1 shows the particle size distribution results for the crystals of esomeprazole magnesium trihydrate obtained in Example 10(2). [Figure 54] 1 shows an SEM image of the crystals of escitalopram oxalate obtained in Example 19. [Figure 55] 1 shows the results of powder X-ray diffraction of the crystals of escitalopram oxalate obtained in Example 19. [Figure 56] 1 shows the results of particle size distribution of escitalopram oxalate crystals obtained in Example 19. [Figure 57] 1 shows an SEM image of the crystals of vildagliptin obtained in Example 20. [Figure 58] 1 shows the results of powder X-ray diffraction of the crystals of vildagliptin obtained in Example 20. [Figure 59] 1 shows the particle size distribution results of vildagliptin crystals obtained in Example 20. [Figure 60] 1 shows an SEM image of the linagliptin crystals obtained in Example 21. [Figure 61] 1 shows the results of powder X-ray diffraction of the linagliptin crystals obtained in Example 21. [Figure 62] 1 shows the particle size distribution results of linagliptin crystals obtained in Example 21. [Figure 63] 1 shows an SEM image of the crystals of teneligliptin hydrobromide hydrate obtained in Example 22. [Figure 64] 1 shows the results of powder X-ray diffraction of the crystals of teneligliptin hydrobromide hydrate obtained in Example 22. [Figure 65]1 shows the results of particle size distribution of the crystals of teneligliptin hydrobromide hydrate obtained in Example 22. [Figure 66] 1 shows an SEM image of the glutathione crystals obtained in Example 23. [Figure 67] 1 shows the results of powder X-ray diffraction of the glutathione crystals obtained in Example 23. [Figure 68] 1 shows the particle size distribution results of glutathione crystals obtained in Example 23. [Figure 69] 1 shows an SEM image of the crystals of dabigatran etexilate methanesulfonate obtained in Example 24. [Figure 70] 1 shows the results of powder X-ray diffraction of the crystals of dabigatran etexilate methanesulfonate obtained in Example 24. [Figure 71] 1 shows the results of particle size distribution of the crystals of dabigatran etexilate methanesulfonate obtained in Example 24. [Figure 72] 1 shows an SEM image of the crystals of pilsicainide hydrochloride obtained in Example 25. [Figure 73] 1 shows the results of powder X-ray diffraction of the crystals of pilsicainide hydrochloride obtained in Example 25. [Figure 74] 1 shows the particle size distribution results of pilsicainide hydrochloride crystals obtained in Example 25. [Figure 75] 1 shows an SEM image of theophylline magnesium salt tetrahydrate crystals obtained in Example 26. [Figure 76] 1 shows the results of powder X-ray diffraction of the crystals of theophylline magnesium salt tetrahydrate obtained in Example 26. [Figure 77] 1 shows the particle size distribution results of theophylline magnesium salt tetrahydrate crystals obtained in Example 26. [Figure 78] 1 shows an SEM image of the mirabegron crystals obtained in Example 27. [Figure 79] 1 shows the results of powder X-ray diffraction of the mirabegron crystals obtained in Example 27. [Figure 80] 1 shows the particle size distribution results of the mirabegron crystals obtained in Example 27. [Figure 81] 1 shows an SEM image of the tolvaptan crystals obtained in Example 28. [Figure 82] 1 shows the results of powder X-ray diffraction of the tolvaptan crystals obtained in Example 28. [Figure 83] 1 shows an SEM image of the tramadol hydrochloride crystals obtained in Example 29. [Figure 84] 1 shows the results of powder X-ray diffraction of the tramadol hydrochloride crystals obtained in Example 29. [Figure 85] 1 shows an SEM image of the crystals of bepotastine besylate obtained in Example 30. [Figure 86] 1 shows the results of powder X-ray diffraction of the crystals of bepotastine besilate obtained in Example 30. [Figure 87] 1 shows the results of particle size distribution of the crystals of bepotastine besilate obtained in Example 30. [Figure 88] 1 shows an SEM image of the crystals of olopatadine obtained in Example 31. [Figure 89] 1 shows the results of powder X-ray diffraction of the crystalline olopatadine obtained in Example 31. [Figure 90] This figure plots the predicted versus experimental critical supersaturation values, with the dashed lines representing the 95% confidence interval. [Figure 91] 10 shows a flowchart illustrating an example of the operation of the overall processing. DETAILED DESCRIPTION OF THE INVENTION

[0015] The method of the present invention is a method for producing a specific crystalline form of a compound, comprising the following steps: (1) preparing a supersaturated solution of the compound having a degree of supersaturation equal to or greater than the critical degree of supersaturation required to obtain crystals of a specific shape of the compound; and (2) A step of precipitating crystals of a specific shape of the compound from the supersaturated solution.

[0016] In the present invention, "crystal of a compound" means a single crystal or polycrystal of the compound. Furthermore, in the present invention, "a crystal of a specific shape of a compound" is not particularly limited as long as it is a known shape of a single crystal or polycrystal of the compound. Specific examples include plate-like crystals, needle-like crystals, columnar crystals, skeletal crystals, symmetrical dendrites, asymmetrical dendrites, and spherulites. Spherulites are preferred.

[0017] The compound obtained as a crystal of a specific shape by the method of the present invention is not particularly limited, and may be either an organic compound or an inorganic compound.

[0018] When the compound obtained as a crystal of a specific shape by the method of the present invention is an organic compound, it may be in the form of a free form (i.e., a form in which it is not complexed with other substances), a salt thereof, or a solvate thereof, or a mixture thereof.When the compound obtained as a crystal of a specific shape by the method of the present invention is an inorganic compound, it may be in the form of a free form, a solvate thereof, or a mixture thereof.

[0019] In this specification, the "salt" of an organic compound is not particularly limited, and examples thereof include salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and nitric acid; salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, benzenesulfonic acid (besylic acid), methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, and naphthalene-2-sulfonic acid; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, and aluminum ion; and salts with amines such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, and benzathine.

[0020] As used herein, the "solvate" of an organic compound or an inorganic compound is not particularly limited, and examples thereof include hydrates, alcohol solvates (e.g., methanol solvate, ethanol solvate, 1-propanol solvate, 2-propanol solvate), ketone solvates (e.g., acetone solvate, methyl ethyl ketone solvate, methyl isopropyl ketone solvate, methyl isobutyl ketone solvate), nitrile solvates (e.g., acetonitrile solvate, propionitrile solvate), ester solvates (e.g., ethyl acetate solvate, isopropyl acetate solvate), ether solvates (e.g., ethyl ether solvate, tert-butyl methyl ether solvate), aliphatic hydrocarbon solvates (e.g., n-pentane solvate, n-hexane solvate, cyclohexane solvate, n-heptane solvate, isooctane solvate), toluene solvates, N,N-dimethylformamide solvates, and dimethyl sulfoxide solvates.

[0021] When the compound obtained as crystals of a specific shape by the method of the present invention is an organic compound, its molecular weight is not particularly limited, but from the viewpoint of the operation of dissolving the compound once, crystallizing it, and drying it under reduced pressure, the molecular weight is preferably 100 to 2000, more preferably 200 to 1500. When the compound obtained as crystals of a specific shape by the method of the present invention is an inorganic compound, its formula weight is not particularly limited, but from the same viewpoint as above, it is preferably 50 to 2000, more preferably 200 to 1500.

[0022] The compound obtained as a crystal of a specific shape by the method of the present invention is preferably a compound selected from the following (1) and (2): (1) A compound represented by the following formula I, or a tautomer thereof, or an optical isomer thereof, or a salt thereof, or a solvate thereof: [ka] [In the formula, X is CH or N; R 1is a hydrogen atom or an optionally substituted C 1-6 is an alkoxy group, R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 an alkoxy group or an optionally substituted amino group; (2) Azithromycin, duloxetine, clarithromycin, lanthanum carbonate (La2(CO3)3), glutamic acid, clopidogrel, ketotifen, escitalopram, dabigatran etexilate, theophylline, teneligliptin, pilsicainide, tramadol, vildagliptin, linagliptin, glutathione, mirabegron, tolvaptan, valacyclovir, bepotastine, olopatadine or their optical isomers (if any), or their salts (if any), or their solvates.

[0023] As used herein, "C 1-6 The term "alkyl group" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms. 1-6 Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and isomers thereof. 1-6 If the alkyl group is substituted, it may be monosubstituted or polysubstituted. If polysubstituted, the substituents may be the same or different. 1-6 The substituent on the alkyl group is not particularly limited, but examples thereof include halogen, a hydroxy group, an amino group, C 1-6 Examples include alkoxy groups.

[0024] As used herein, "C 1-6 "Alkoxy group" refers to an oxygen atom having one of the above C 1-6 The alkyl group is a substituted group. 1-6 Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, and isomers thereof. 1-6When the alkoxy group is substituted, it may be mono-substituted or poly-substituted. When poly-substituted, the substituents may be the same or different. 1-6 The substituent on the alkoxy group is not particularly limited, but examples thereof include halogen, a hydroxy group, an amino group, C 1-6 Examples include alkoxy groups.

[0025] As used herein, the term "halogen" refers to a monovalent group of a halogen atom, and specific examples include a fluoro group, a chloro group, a bromo group, and an iodo group.

[0026] In the present specification, when an amino group is substituted, it may be mono-substituted or di-substituted. When it is di-substituted, the substituents may be the same or different. The substituents on the amino group are not particularly limited, but examples thereof include C 1-6 Examples of suitable alkyl groups include:

[0027] Compounds obtained as crystals of a specific shape include omeprazole (X = CH, R 1 = methoxy, R 2 = methyl, R 3 = methoxy, R 4 = methyl), lansoprazole (X = CH, R 1 = hydrogen atom, R 2 = methyl, R 3 = 2,2,2-trifluoroethoxy, R 4 = hydrogen atom), tenatoprazole (X = N, R 1 = methoxy, R 2 = methyl, R 3 = methoxy, R 4 = methyl), pantoprazole (X = CH, R 1 = difluoromethoxy, R 2 = methoxy, R 3 = methoxy, R 4 = hydrogen atom), esomeprazole (X = CH, R 1 = methoxy, R 2 = methyl, R 3 = methoxy, R 4 = methyl), dexlansoprazole (X = CH, R 1= hydrogen atom, R 2 = methyl, R 3 = 2,2,2-trifluoroethoxy, R 4 = hydrogen atom), rabeprazole (X = CH, R 1 = hydrogen atom, R 2 = methyl, R 3 = 3-methoxypropoxy, R 4 = hydrogen atom) and leminoprazole (X = CH, R 1 = hydrogen atom, R 2 = N-methyl-N-(2-methylpropyl)amino, R 3 = hydrogen atom, R 4 = hydrogen atom), and salts thereof, and solvates thereof are preferred, and esomeprazole and lansoprazole, and salts thereof, and solvates thereof are more preferred.

[0028] In the method of the present invention, the compound used as the starting material (also referred to herein as the "compound to be crystallized" or "substrate") may be the same as or different from the "compound obtained as a crystal of a specific shape" by the method. For example, the compound used as the starting material may be a potassium salt crystal, and the compound obtained as a crystal of a specific shape may be a magnesium salt (see Example 6). For example, the compound used as the starting material may be a dihydrate crystal, and the compound obtained as a crystal of a specific shape may be a monohydrate (see Example 12). The compound used as the starting material may also be amorphous. The compound obtained as a crystal of a specific shape may also be formed in the supersaturated solution during preparation of the solution (see Examples 15 to 17).

[0029] As used herein, a "spherulite" refers to a crystal aggregate (polycrystal) that has a radial or concentric lamellar structure and exhibits a spherical external shape. Whether the crystal obtained by the method of the present invention is a spherulite can be determined, for example, by observing the external shape of the crystal with an SEM. Alternatively, it can be determined, for example, by cutting the crystal aggregate and observing its internal structure with an SEM. The sphericity of the spherulite obtained by the method of the present invention is usually 0.60 or more, preferably 0.70 or more, more preferably 0.80 or more, particularly preferably 0.90 or more, and most preferably 0.95 or more. The sphericity can be calculated by the following method.

[0030] When analyzing particle images captured with an SEM using the image processing software ImageJ, a set of coordinates representing the pixel positions forming the particle's contour is obtained. Let the length of the coordinate set be N, and let p[i] (1≦i≦N) be the coordinate of one pixel on each contour. Let θ(k) (-180°<θ<180°) be the angle between the line l(k) connecting two points p[k] and p[k + N / D] and the line m(k) connecting two points p[k + N / D] and p[k + 2N / D] (1≦k≦N, 1≦D≦N). Here, D is the number of contour divisions. If N / D is not a natural number, the quotient obtained by dividing N by D is used. By calculating this angle for k = 1 to N, N values ​​of θ can be obtained. Figure 42 shows the positions of θ(k).

[0031] There are several ways to calculate θ(k). For example, if the slope of the line l(k) is a(k) and the slope of the line m(k) is b(k), it can be calculated using the following formula:

number

number

number

[0032] In this specification, 10 is a value obtained by a particle size distribution measuring device, and indicates the particle size of the particles that make up the cumulative 10% from the small particle side of the particle size distribution, based on volume.

[0033] In this specification, 50 is a value obtained by a particle size distribution measuring device, and indicates the particle size of particles that are 50% cumulatively from the small particle side of the particle size distribution, based on volume.

[0034] In this specification, 90 is a value obtained using a particle size distribution analyzer, and indicates the particle size of the particles that make up the cumulative 90% from the small particle side of the particle size distribution, based on volume.

[0035] The specific shape of the crystal obtained by the method of the present invention 50 The lower limit of d of the crystals of a specific shape obtained by the method of the present invention is not particularly limited, but is preferably 1 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, or 50 μm. 50 The upper limit of d is not particularly limited, but is preferably 100 μm, 120 μm, 150 μm, 200 μm, 250 μm, 300 μm, 500 μm, or 1000 μm. 50 is 1 to 500 μm or 10 to 300 μm.

[0036] As used herein, the "equivalent circle diameter" refers to the diameter of a perfect circle corresponding to the area of ​​an individual particle in a particle image taken with an SEM, and is calculated using image processing software ImageJ from 5 to 800 randomly selected particles. The equivalent circle diameter of the spherulites obtained by the method of the present invention is preferably 25 μm or more, 30 μm or more, 35 μm or more, 40 μm or more, 45 μm or more, or 50 μm or more, and 100 μm or less, 120 μm or less, 150 μm or less, 200 μm or less, 250 μm or less, 300 μm or less, 500 μm or less, or 1000 μm or less. More preferably, the equivalent circle diameter is 25 to 500 μm or 30 to 300 μm.

[0037] In this specification, the "sharpness index" is an index that indicates the uniformity of particle diameters of particles in a powder, with 1.0 being the powder with the most uniform particle diameter. The closer the sharpness index is to 1.0, the more uniform the particle diameters of the powder are. Specifically, the sharpness index is the d measured by a particle size distribution measuring device. 10 , d 50 , d 90 The value is calculated using the following formula from the value of

number

[0038] The sharpness index of the crystals of a specific shape obtained by the method of the present invention is preferably 1.0 to 5.0, more preferably 1.0 to 4.0, even more preferably 1.0 to 3.0, still more preferably 1.0 to 2.5, particularly preferably 1.0 to 2.0, and most preferably 1.0 to 1.5.

[0039] Whether or not the crystals having a specific shape obtained by the method of the present invention are crystals can be determined, for example, by observing the diffraction peaks in powder X-ray diffraction or by SEM observation.

[0040] As used herein, the term "supersaturated solution" refers to a solution that contains a solute at or above its solubility. The degree of supersaturation can be expressed as "degree of supersaturation." The degree of supersaturation, S, can be expressed by the following formula, where C is the concentration (mass concentration (g / g)) of a compound dissolved in a supersaturated solution, and Cs is the solubility of the compound.

number

[0041] In the method of the present invention, when the compound obtained as a crystal of a specific shape is a solvate, the degree of supersaturation of the compound is calculated by dividing the concentration of the solvate of the compound dissolved in the supersaturated solution by the solubility of the solvate of the compound.

[0042] As used herein, "critical supersaturation" refers to the minimum degree of supersaturation required to obtain crystals of a specific shape. The inventors have discovered that spherulites of a specific shape of a compound can be reproducibly obtained from a supersaturated solution of the compound having a degree of supersaturation equal to or greater than the critical supersaturation. That is, when supersaturated solutions with different degrees of supersaturation are prepared using the same compound and the same solvent or the same combination of solvents and crystallized, crystals of the desired specific shape are produced from all supersaturated solutions with degrees of supersaturation above the critical supersaturation. However, crystals of the specific shape are not produced from supersaturated solutions below the critical supersaturation. The value of the critical supersaturation varies depending on the shape of the crystal. For example, the critical supersaturation required to obtain plate-shaped crystals, the critical supersaturation required to obtain needle-shaped crystals, and the critical supersaturation required to obtain spherulites all have different values. The critical supersaturation required to obtain spherulites is higher than the critical supersaturation required to obtain plate-shaped crystals or needle-shaped crystals.

[0043] In the method of the present invention, the "critical supersaturation" may be an actual measured value obtained by a measurement method described below, or may be a predicted value output from a prediction model of the critical supersaturation described below. Here, when the predicted value is output as a numerical range having an upper and lower limit, the "critical supersaturation" may be the lower limit of the predicted value, the upper limit, or any value between the upper and lower limits. In this case, the "critical supersaturation" is preferably the lower limit of the predicted value.

[0044] The actual value of the critical supersaturation (S*) can be measured as follows. (1) Observe 100 particles using an SEM. (2) Select 5 to 10 particles that are close to the desired specific shape and evaluate their shape. In particular, if the desired specific shape is spherical, evaluate their sphericity. (3) Based on the shape evaluation index, it is determined whether the selected particles have a desired specific shape. In particular, if the desired specific shape is a sphere, it is determined to be a spherulite if the sphericity is 0.60 or more. (4) The above procedure is carried out for each sample with a different degree of supersaturation during crystallization, and the minimum value of the degree of supersaturation with particles of the specific shape is determined as the critical degree of supersaturation, provided that the difference between the maximum value of the degree of supersaturation without particles of the specific shape and the critical degree of supersaturation is 20% or less.

[0045] The step of preparing a supersaturated solution at or above the critical supersaturation level can be carried out under conditions that prevent nucleation before the critical supersaturation level is reached (i.e., under conditions that prevent the formation of crystal nuclei of crystals of a desired shape before the critical supersaturation level required to obtain crystals of a desired shape is reached). For example, the step can be carried out by preparing a supersaturated solution faster than the formation of crystal nuclei of crystals of a desired shape.

[0046] Furthermore, even if crystal nuclei of crystals not of the desired shape are formed before the critical degree of supersaturation is reached during the preparation of a supersaturated solution, a supersaturated solution can be prepared by separating the crystal nuclei from the solution by a method such as filtration before the supersaturated state is completely eliminated.

[0047] The preparation process of a supersaturated solution having a degree of supersaturation equal to or greater than the critical supersaturation is not particularly limited as long as a solution having a degree of supersaturation equal to or greater than the critical supersaturation can be prepared (e.g., the rate of addition of a poor solvent to a compound solution, the rate of addition of a compound solution to a poor solvent, the rate of addition of a reaction reagent to a compound precursor solution, the rate of addition of a compound precursor to a reaction reagent solution, the crystallization temperature, the stirring rate, the stirring time, etc.). This supersaturated solution preparation process can be carried out, for example, by the following methods (1) to (6).

[0048] (1) Preparation of supersaturated solution by back-drop A supersaturated solution of the compound to be crystallized, which has a degree of supersaturation equal to or greater than the critical degree of supersaturation, can be prepared by back-dropping a solution of the compound in a good solvent into a poor solvent. The combination of the good solvent and the poor solvent used can be appropriately changed depending on the compound to be crystallized.

[0049] (2) Preparation of supersaturated solution by sequential dropwise addition By adding a poor solvent dropwise to a solution in which the compound to be crystallized is dissolved in a good solvent, a supersaturated solution of the compound, which has a degree of supersaturation equal to or greater than the critical degree of supersaturation and is obtained as crystals of a specific shape, can be prepared. In this case, if amorphous forms of the compound are precipitated in the supersaturated solution, the solution may be filtered. The combination of the good solvent and poor solvent used can be appropriately changed depending on the compound to be crystallized.

[0050] (3) Preparation of supersaturated solution by neutralization reaction When the compound to be crystallized is an acidic compound, a supersaturated solution of the compound, which is obtained as crystals of a specific shape and has a degree of supersaturation equal to or greater than the critical degree of supersaturation, can be prepared by (i) preparing a suspension of the compound to be crystallized in a good solvent, (ii) adding a base to the suspension prepared in (i) to prepare a solution of a base addition salt of the compound, and (iii) adding a poor solvent containing an acid to the solution of the base addition salt. The combination of the good solvent and poor solvent used can be changed as appropriate depending on the compound to be crystallized. The base used can be selected as appropriate depending on the compound to be crystallized.

[0051] Furthermore, when the compound to be crystallized is a basic compound, a supersaturated solution of the compound, which is obtained as crystals of a specific shape and has a degree of supersaturation equal to or greater than the critical degree of supersaturation, can be prepared by (i) preparing a suspension of the compound to be crystallized in a good solvent, (ii) adding an acid to the suspension prepared in (i) to prepare a solution of an acid addition salt of the compound, and (iii) adding a poor solvent containing a base to the solution of the acid addition salt. The combination of the good solvent and poor solvent used can be changed as appropriate depending on the compound to be crystallized. The acid used can be selected as appropriate depending on the compound to be crystallized.

[0052] (4) Preparation of supersaturated solutions by salt formation When the compound obtained as crystals of a specific shape is a salt of an organic compound and the free form of the organic compound is a basic compound, a supersaturated solution of the salt of the organic compound having a degree of supersaturation equal to or greater than the critical degree of supersaturation can be prepared by (i) preparing a solution in which the free form of the organic compound is dissolved in a solvent, and (ii) adding an acid to the solution prepared in (i). The acid used can be appropriately selected depending on the free form of the organic compound.

[0053] Furthermore, when the compound obtained as crystals of a specific shape is a salt of an organic compound and the free form of the organic compound is an acidic compound, a supersaturated solution of the salt of the organic compound having a degree of supersaturation equal to or greater than the critical degree of supersaturation can be prepared by (i) preparing a solution in which the free form of the organic compound is dissolved in a solvent, and (ii) adding a base to the solution prepared in (i). The base used can be appropriately selected depending on the free form of the organic compound.

[0054] (5) Preparation of supersaturated solutions by chemical transformation When a compound obtained as a crystal of a specific shape is a compound obtained by chemical conversion of a precursor compound, a supersaturated solution of the compound obtained by the chemical conversion, having a degree of supersaturation equal to or greater than the critical degree of supersaturation, can be prepared by (i) preparing a solution in which the precursor compound is dissolved in a solvent, and (ii) adding a conversion reagent to the solution prepared in (i). The conversion reagent used can be appropriately selected depending on the precursor compound.

[0055] (6) Preparation of supersaturated solutions by ion exchange When the compound obtained as crystals of a specific shape is a salt with a cation, (i) a solution of the compound salted with a different cation from the aforementioned cation is prepared, and (ii) a solution containing the cation constituting the compound obtained as crystals of a specific shape is added to the solution prepared in (i) to prepare a supersaturated solution of the compound obtained as crystals of a specific shape having a degree of supersaturation equal to or greater than the critical degree of supersaturation. The solvent used can be appropriately changed depending on the compound to be crystallized. The cation used can be appropriately selected depending on the compound.

[0056] When the compound obtained as a crystal of a specific shape is a salt with an anion, (i) a solution of the compound salted with a different anion from the anion described above is prepared, and (ii) a solution containing the anion constituting the compound obtained as a crystal of a specific shape is added to the solution prepared in (i) to prepare a supersaturated solution of the compound obtained as a crystal of a specific shape having a degree of supersaturation equal to or greater than the critical degree of supersaturation. The solvent used can be changed as appropriate depending on the compound to be crystallized. The anion used can be selected as appropriate depending on the compound.

[0057] The solvent used in the method of the present invention is not particularly limited and is determined based on the solubility of the compound to be crystallized and the compound to be obtained as crystals of a specific shape. Examples of the solvent include water, alcohols (e.g., linear or branched monohydric, dihydric, or trihydric alcohols having 1 to 6 carbon atoms, specifically, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, propylene glycol, glycerin, diethylene glycol, and diethylene glycol monoethyl ether), tetrahydrofuran, ketones (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, and methyl isobutyl ketone), acetonitrile, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, toluene, aliphatic hydrocarbons (e.g., n-pentane, n-hexane, cyclohexane, n-heptane, and isooctane), aromatic hydrocarbons (e.g., toluene), N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof.

[0058] The preparation of the supersaturated solution can be carried out at room temperature, but can also be carried out under cooling or heating, for example, at a temperature of from -30°C to the boiling point of the solvent, preferably from 0°C to 100°C.

[0059] In the method of the present invention, the step of precipitating crystals of a specific shape from a supersaturated solution (crystallization step) may be carried out by leaving the supersaturated solution to stand or by stirring. This step is preferably carried out for 0.1 to 400 hours, more preferably 0.1 to 200 hours, and even more preferably 0.1 to 100 hours. This step may also be carried out by inoculating the supersaturated solution with seed crystals of the compound. The shape of the seed crystals is not particularly limited, and they may or may not be crystals of the same shape as the crystals to be precipitated. The amount of seed crystals to be inoculated is preferably 0.00001 to 10% (w / w), more preferably 0.00005 to 1% (w / w), even more preferably 0.0001 to 0.5% (w / w), and particularly preferably 0.0001 to 0.1% (w / w), relative to the amount of compound in the supersaturated solution. The particle size of the obtained crystals can be adjusted by the amount of seed crystals added.

[0060] In the method of the present invention, the step of precipitating crystals of a specific shape from a supersaturated solution can be carried out at room temperature, but can also be carried out under cooling or heating. This step can be carried out at a crystallization temperature of, for example, −70°C to the boiling point of the solvent, preferably −20°C to 60°C, and more preferably −10°C to 40°C.

[0061] The method of the present invention may further include a step of isolating the precipitated crystals of a specific shape by, for example, filtration, centrifugation, or decantation after the step of precipitating the crystals of a specific shape from the supersaturated solution, and may also include a step of washing the isolated crystals of a specific shape with an appropriate solvent, if necessary.

[0062] The method of the present invention may further comprise, after the step of isolating and washing the crystals of a particular shape, a step of drying the wet crystals, for example, by air drying, ventilation drying, vacuum drying and / or freeze drying.

[0063] The size of the individual crystals constituting the crystals of a specific shape obtained by the method of the present invention can be controlled by the degree of supersaturation and the crystallization temperature during crystallization. For example, if the crystals of a specific shape are spherulites, by using a method in which the degree of supersaturation decreases as the crystals grow, the individual crystals will gradually grow larger and grow radially, resulting in the formation of polycrystalline spherulites with the finest crystals at the center of the spherulite (see Example 12). This characteristic can be observed by cutting the spherulite and observing it with an SEM (see Figure 4). As another example, by using a method in which a high degree of supersaturation is maintained during crystal growth, the spherulites will be formed while the size of the individual crystals remains small. By controlling the crystal size inside the spherulite, the dissolution profile can be controlled.

[0064] The dissolution profile can be described by the zero-order model, first-order model, Weibull model, Higuchi model, Hixson-Crowell model, Korsmeyer-Peppas model, Baker-Lonsdale model, Hopfenberg model, etc. The Weibull model is expressed by the following equation:

[0065]

number

[0066] In this specification, "particle density" refers to the mass per unit volume of a polycrystalline particle when the volume of the particle includes the volume of the substance itself as well as the volumes of open and closed voids. For example, when the polycrystalline particles are spherical, the density is calculated using the average mass and volume of the polycrystalline particles according to the following formula:

[0067]

number

[0068] Here, the average mass of polycrystalline particles is calculated by measuring the number of polycrystalline particles contained in a sample of 1.0 mg or more, preferably 5.0 mg or more, and more preferably 10.0 mg or more using a scanner or the like. The average volume of crystal particles is calculated by photographing 500 or more, preferably 1,000 or more, and more preferably 5,000 or more crystal particles using an optical microscope or the like, and then averaging the volumes calculated using the equivalent circle diameters obtained from the projected areas of the polycrystalline particles, assuming that the polycrystalline particles are spherical. In this case, it is desirable that the distribution of the equivalent circle diameters be unimodal and the sharpness value be less than 1.5.

[0069] When the crystals obtained by the method of the present invention are polycrystals (e.g., spherulites), the particle density and particle strength of the polycrystals can be controlled by the degree of supersaturation, stirring speed, and crystallization temperature during crystallization. This is also related to the control of crystal size mentioned above. For example, if the crystals are spherulites, maintaining a high degree of supersaturation during crystal growth will result in small individual crystals and densely packed spherulites. As another example, decreasing the degree of supersaturation as the crystals grow will result in gradually larger individual crystals, and therefore the particle density will not increase.

[0070] When the crystals of a particular shape obtained by the method of the present invention are polycrystalline (e.g., spherulites), the preferred particle density is 0.6 g / cm 3 More preferably, 0.7 g / cm 3 More preferably, 0.9 g / cm 3 More preferably, 1.0 g / cm 3 That's all.

[0071] In this specification, the "particle packing ratio" of polycrystals is a value calculated by the following formula.

[0072]

number

[0073] Here, the "true density of a compound" refers to the density of the substance itself, excluding voids. When there are absolutely no voids inside or on the surface of a particle, the particle packing ratio is 100%. The true density of a compound can be obtained by dry density measurement using the constant volume expansion method. An example of a measuring device is the dry automatic density meter Accupyc II1340-10CC manufactured by Shimadzu Corporation.

[0074] When the crystals of a specific shape obtained by the method of the present invention are polycrystals (for example, spherulites), the particle packing ratio is preferably 30% or more, more preferably 50% or more, even more preferably 60% or more, and particularly preferably 80% or more.

[0075] Furthermore, polycrystals with high particle density also have high particle strength. When polycrystals, particularly spherulites, are used as raw materials for pharmaceutical production, wear during the formulation process can result in a decrease in yield, quality, or both. In this respect, polycrystals with high particle strength are advantageous. When the crystals of a specific shape obtained by the present invention are polycrystals, the particle strength is preferably 1.0 MPa or more, more preferably 1.5 MPa or more, even more preferably 2.0 MPa, even more preferably 2.5 MPa or more, and particularly preferably 3.0 MPa or more. Particle strength is calculated by measuring the particle size and the force at which a particle breaks when a load is applied to a single particle. Specifically, it is calculated using the following formula in accordance with JIS R 1639-5. Examples of measuring devices include the New Grano particle hardness measuring device manufactured by Okada Seiko Co., Ltd. and the MCT microcompression tester manufactured by Shimadzu Corporation.

[0076]

number

[0077] The filtration rate of particles increases with the spherical shape of the particles to be filtered and the larger the particle diameter. Also, the more spherical the particle shape, the thinner the cake thickness and the smaller the difference between before and after compression.

[0078] In one embodiment, the method of the present invention comprises: Information about compounds obtained as crystals of a particular shape; At least one of the following: information on the solvent used for crystallization and the solution temperature during crystallization into a prediction model of the critical supersaturation required to obtain a crystal of a specific shape of the compound, and outputting a predicted value of the critical supersaturation from the prediction model (hereinafter also referred to as a "step of predicting the critical supersaturation").

[0079] In the step of predicting the critical supersaturation, the information about the compound and solvent may be arbitrarily used from the mol file or sdf file of the compound structure, variables about the compound and / or solvent used by paid or free descriptor calculation software such as alvaDesc, RDKit, Dragon, Chemopy, MOE, cinfony, PaDEL-descriptor, modred, etc., or information based on the chemical structure of the compound and / or solvent. In yet another embodiment, variables about the compound and / or solvent and information based on the chemical structure of the compound and / or solvent may be used in combination.

[0080] The variables related to the compound and / or solvent may be one or more variables belonging to at least one parameter selected from: 1) molecular-related parameters, such as molecular weight, atomic type / number, bond type / number, etc.; 2) topological parameters, such as molecular bond index, Hosoya index, etc.; 3) physical property-related parameters, such as molecular refractive index, parachor, LogP, etc.; and 4) other parameters, such as partial structure-related parameters (appearance information, appearance frequency, etc.) and partial charge parameters. In further detail, the variables describing the compounds and solvents include the above-mentioned descriptors: Constitutional indices, Ring descriptors, Topological indices, Walk and path counts, Connectivity indices, Information indices, 2D matrix-based descriptors, 2D autocorrelations, Burden eigenvalues, P_VSA-like descriptors, ETA indices, Edge adjacency indices, Geometrical descriptors, 3D matrix-based descriptors, 3D autocorrelations, RDF descriptors, 3D-MoRSE descriptors, and the like. descriptors, WHIM descriptors, GETAWAY descriptors, Randic molecular profiles, Functional group counts, Atom-centred fragments, Atom-type E-state indicesOne or more variables belonging to at least one category selected from the group consisting of molecular indices, pharmacophore descriptors, 2D atom pairs, 3D atom pairs, charge descriptors, molecular properties, drug-like indices, CATS 3D descriptors, 2D Monte Carlo descriptors, 3D Monte Carlo descriptors, and quantum-chemical descriptors may be used.

[0081] In the step of predicting the critical supersaturation, when variables related to the compound obtained as crystals of a specific shape and / or variables related to the solvent are used, the number of variables may be one or more. The variables related to the compound obtained as crystals of a specific shape and the solvent may be measured values ​​or values ​​calculated by calculation based on the molecular structure. Furthermore, when the solvent is a mixed solvent, not only the variables related to each solvent contained in the mixed solvent but also the mixing ratio of these solvents may be used as variables.

[0082] The variables related to compounds are, for example, the following descriptors (1905 types) calculated by calculation based on the molecular structure: MW,AMW,Sv,Se,Sp,Si,Mv,Me,Mp,Mi,GD,nAT,nSK,nTA,nBT,nBO,nBM,SCBO,RBN,RBF,nDB,nTB,nAB,nH,nC,nN,nO,nS,nF,nCL,nHM,nHet,nX,H%,C%,N% ,O%,X%,nCsp3,nCsp2,nCsp,max_conj_path,nCIC,nCIR,TRS,Rperim,Rbrid,MCD,RFD,RCI,NRS,NNRS,nR05,nR06,nR07,nR08,nR09,nR10,nR11,nBnz ,ARR,D / Dtr05,D / Dtr06,D / Dtr07,D / Dtr08,D / Dtr09,D / Dtr10,D / Dtr11,ZM1,ZM1V,ZM1Kup,ZM1Mad,ZM1Per,ZM1MulPer,ZM2,ZM2V,ZM2Kup,ZM2Mad,ZM2Per,ZM2MulPer,ON0,ON0V,ON1,ON1V,Qindex,BBI,DBI,SNar,HNar,GNar,Xt,Dz,Ram,BLI,Pol,LPRS,MSD,SPI,PJI2,ECC,AECC,DECC,MDDD,UNIP,C ENT,VAR,ICR,MaxTD,MeanTD,MaxDD,MeanDD,SMTI,SMTIV,GMTI,GMTIV,Xu,CSI,Wap,S1K,S2K,S3K,PHI,PW2,PW3,PW4,PW5,MAXDN,MAXDP,DELS,TIE,P mw C05,MWC06,MWC07,MWC08,MWC09,MWC10,SRW02,SRW04,SRW05,SRW06,SRW07,SRW08,SRW09,SRW10,MPC02,MPC03,MPC04,MPC05,MPC06,MPC07,MPC08,M PC09,MPC10,piPC01,piPC02,piPC03,piPC04,piPC05,piPC06,piPC07,piPC08,piPC09,piPC10,TWC,TPC,piID,PCR,PCD,CID,BID,X0,X1,X2,X3,X4,X5,X0A,X1A,X2A,X3A,X4A,X5A,X0v, X1v, CHI, RDSQ, X1Kup, X1Mad, X1Per, ndex,Yindex,IC0,IC1,IC2,IC3,IC4,IC5,TIC0,TIC1,TIC2,TIC3,TIC4,TIC5,SIC0,SIC1,SIC2,SIC3,SIC4,SIC5,CIC0,CIC1,CIC2,CIC3,CIC4,CIC 5,BIC0,BIC1,BIC2,BIC3,BIC4,BIC5,J_A,SpPos_A,SpPosLog_A,SpMax_A,SpMaxA_A,SpDiam_A,SpMAD_A,Ho_A,EE_A,VE1_A,VE2_A,VE3_A,VE1sign _A,VE2sign_A,VR1_A,VR2_A,VR3_A,Wi_D,AVS_D,H_D,Chi_D,ChiA_D,J_D,HyWi_D,SpPos_D,SpPosA_D,SpPosLog_D,SpMaxA_D,SpDiam_D,Ho_D,SM2_D,SM3_D,SM4_D,SM5_D,SM6_D,QW_L,TI1_L,TI2_L,STN_L,SpPosA_L,SpPosLog_L,SpMax_L,SpMaxA_L,SpDiam_L,SpAD_L,SpMAD_L,Ho_L,EE_L,SM2 _L,SM3_L,SM4_L,SM5_L,SM6_L,VE1_L,VE2_L,VE3_L,VE1sign_L,VE2sign_L,VE3sign_L,VR1_L,VR2_L,VR3_L,AVS_X,H_X,Chi_X,ChiA_X,J_X,HyWi _X,SpPos_X,SpPosA_X,SpPosLog_X,SpMaxA_X,SpDiam_X,SpMAD_X,Ho_X,EE_X,SM2_X,SM3_X,SM4_X,SM5_X,SM6_X,VE1_X,VE2_X,VE3_X,VE1sign_X,VE2sign_X,VR1_X,VR2_X,VR3_X,Wi_H2,WiA_H2,AVS_H2,Chi_H2,ChiA_H2,J_H2,HyWi_H2,SpPos_H2,SpPosA_H2,SpPosLog_H2,SpMax_H2,SpMaxA_H2,SpDiam_H2,Ho_H2,EE_H2,SM2_H2,SM3_H2,SM4_H2,SM5_H2,SM6_H2,VE1_H2,VE2_H2,VE3_H2,VE1sign_H2,VE2sign_H2,VR1_H2,VR2_H2,VR3_H2,Wi_Dt,AVS_Dt,H_Dt,Chi_Dt,ChiA_Dt,J_Dt,HyWi_Dt,SpPos_Dt,SpPosA_Dt,SpPosLog_Dt,SpMax_Dt,SpMaxA_Dt,SpDiam_Dt,Ho_Dt,SM2_Dt,SM3_Dt,SM4_Dt,SM5_Dt,SM6_Dt,Wi_D / Dt,WiA_D / Dt,AVS_D / Dt,H_D / Dt,Chi_D / Dt,ChiA_D / Dt,J_D / Dt,HyWi_D / Dt,SpPos_D / Dt,SpPosA_D / Dt,SpPosLog_D / Dt,SpMax_D / Dt,SpMaxA_D / Dt,SpDiam_D / Dt,Ho_D / Dt,EE_D / Dt,SM2_D / Dt,SM3_D / Dt,SM4_D / Dt,SM5_D / Dt,SM6_D / Dt,Wi_Dz(Z),WiA_Dz(Z),AVS_Dz(Z),H_Dz(Z),Chi_Dz(Z),ChiA_Dz(Z),J_Dz(Z),HyWi_Dz(Z),SpAbs_Dz(Z),SpPos_Dz(Z),SpPosA_Dz(Z),SpPosLog_Dz(Z),SpMax_Dz(Z),SpMaxA_Dz(Z),SpDiam_Dz(Z),SpAD_Dz(Z),SpMAD_Dz(Z),Ho_Dz(Z),SM1_Dz(Z),SM2_Dz(Z),SM3_Dz(Z),SM4_Dz(Z),SM5_Dz(Z),SM6_Dz(Z),VE1_Dz(Z),VE2_Dz(Z),VE3_Dz(Z),VE1sign_Dz(Z),VE2sign_Dz(Z),VR1_Dz(Z),VR2_Dz(Z),VR3_Dz(Z),Wi_Dz(m),WiA_Dz(m),AVS_Dz(m),H_Dz(m),Chi_Dz(m),ChiA_Dz(m),J_Dz(m),HyWi_Dz(m),SpAbs_Dz(m),SpPos_Dz(m),SpPosA_Dz(m),SpPosLog_Dz(m),SpMax_Dz(m),SpMaxA_Dz(m),SpDiam_Dz(m),SpAD_Dz(m),SpMA D_Dz(m),Ho_Dz(m),SM1_Dz(m),SM2_Dz(m),SM3_Dz(m),SM4_Dz(m),SM5_Dz(m),SM6_Dz(m),VE1_Dz(m),VE2_Dz(m),VE3_Dz(m),VE1_Dz(m),VE2 sign_Dz(m),VR1_Dz(m),VR2_Dz(m),VR3_Dz(m),Wi_Dz(v),WiA_Dz(v),AVS_Dz(v),H_Dz(v),Chi_Dz(v),ChiA_Dz(v),J_Dz(v),HyWi_Dz(v),SpAbs_Dz(v),SpPos_Dz(v),SpPosA_Dz(v),SpPosLog_Dz(v),SpMaxA_Dz(v),SpDiam_Dz(v),SpAD_Dz(v),SpMAD_Dz(v),Ho_Dz(v),EE_Dz(v),SM1_Dz(v),S M2_Dz(v),SM3_Dz(v),SM4_Dz(v),SM5_Dz(v),SM6_Dz(v),VE1_Dz(v),VE2_Dz(v),VE3_Dz(v),VE1sign_Dz(v),VE2sign_Dz(v),VE3sign_Dz(v),VR1_Dz(v),VR2_Dz(v),VR3_Dz(v),Wi_Dz(e),WiA_Dz(e),AVS_Dz(e),H_Dz(e),Chi_Dz(e),ChiA_Dz(e),J_Dz(e),HyWi_Dz(e),SpAbs_Dz(e),SpPos_Dz (e),SpPosA_Dz(e),SpPosLog_Dz(e),SpMax_Dz(e),SpMaxA_Dz(e),SpDiam_Dz(e),SpAD_Dz(e),SpMAD_Dz(e),Ho_Dz(e),EE_Dz(e),SM1_Dz(e),SM2_Dz(e),SM3_Dz(e),SM4_Dz(e),SM5_Dz(e),SM6_Dz(e),VE1_Dz(e),VE2_Dz(e),VE3_Dz(e),VE1sign_Dz(e),VE2sign_Dz(e),VR1_Dz(e),VR2_Dz(e),VR3_Dz(e),Wi_Dz(p),WiA_Dz(p),AVS_Dz(p),H_Dz(p),Chi_Dz(p),ChiA_Dz(p),J_Dz(p),HyWi_Dz(p),SpAbs_Dz(p),SpPos_Dz(p),SpPosA_Dz(p),SpPosLog_Dz(p),SpMax_Dz(p),SpMaxA_Dz(p),SpDiam_Dz(p),SpAD_Dz(p),SpMAD_Dz(p),Ho_Dz(p),EE_Dz(p),SM1_Dz(p),SM2_Dz(p),SM3_Dz(p),SM4_Dz(p),SM5_Dz(p),SM6_Dz(p),VE1_Dz(p),VE2_Dz(p),VE3_Dz(p),VE1sign_Dz(p),VE2sign_Dz(p),VE3sign_Dz(p),VR1_Dz(p),VR2_Dz(p),VR3_Dz(p),Wi_Dz(i),WiA_Dz(i),AVS_Dz(i),H_Dz(i),Chi_Dz(i),ChiA_Dz(i),J_Dz(i),HyWi_Dz(i),SpAbs_Dz(i),SpPos_Dz(i),SpPosA_Dz(i),SpPosLog_Dz(i),SpMaxA_Dz(i),SpDiam_Dz(i),SpAD_Dz(i),SpMAD_Dz(i),Ho_Dz(i),EE_Dz(i),SM1_Dz(i),SM2_Dz(i),SM3_Dz(i),SM4_Dz(i),SM5_Dz(i),SM6_Dz(i),VE1_Dz(i),VE2_Dz(i),VE3_Dz(i),VE1sign_Dz(i),VE2sign_Dz(i),VR1_Dz(i),VR2_Dz(i),VR3_Dz(i),Wi_B(m),WiA_B(m),AVS_B(m),Chi_B(m),ChiA_B(m),J_B(m),HyWi_B(m),SpAbs_B(m),SpPos_B(m),SpPosA_B(m),SpPosLog_B(m),SpMax_B(m),SpMaxA_B(m),SpDiam_B(m),SpAD_B(m),SpMAD_B(m),Ho_B(m),EE_B(m),SM1_B(m),SM2_B(m),SM3_B(m),SM4_B(m),SM5_B(m),SM6_B(m),VE1_B(m),VE2_B(m),VE3_B(m),VE1sign_B(m),VE2sign_B(m),VE3sign_B(m),VR1_B(m),VR2_B(m),VR3_B(m),Wi_B(v),WiA_B(v),AVS_B(v),Chi_B(v),ChiA_B(v),J_B(v),HyWi_B(v),SpAbs_B(v),SpPos_B(v),SpPosA_B(v),SpPosLog_B(v),SpMax_B(v),SpMaxA_B(v),SpDiam_B(v),SpAD_B(v),SpMAD_B(v),Ho_B(v),EE_B(v),SM1_B(v),SM2_B(v),SM3_B(v),SM4_B(v),SM5_B(v),SM6_B(v),VE1_B(v),VE2_B(v),VE3_B(v),VE1sign_B(v),VE2sign_B(v),VE3sign_B(v),VR1_B(v),VR2_B(v),VR3_B(v),Wi_B(e),WiA_B(e),AVS_B(e),Chi_B(e),ChiA_B(e),J_B(e),HyWi_B(e),SpAbs_B(e),SpPos_B(e),SpPosA_B(e),SpPosLog_B(e),SpMax_B(e),SpMaxA_B(e),SpDiam_B(e),SpAD_B(e),SpMAD_B(e),Ho_B(e),EE_B(e),SM1_B(e),SM2_B(e),SM3_B(e),SM4_B(e),SM5_B(e),SM6_B(e),VE1_B(e),VE2_B(e),VE3_B(e),VE1sign_B(e),VE2sign_B(e),VE3sign_B(e),VR1_B(e),VR2_B(e),VR3_B(e),Wi_B(p),WiA_B(p),AVS_B(p),Chi_B(p),ChiA_B(p),J_B(p),HyWi_B(p),SpAbs_B(p),SpPos_B(p),SpPosA_B(p),SpPosLog_B(p),SpMax_B(p),SpMaxA_B(p),SpDiam_B(p),SpAD_B(p),SpMAD_B(p),Ho_B(p),EE_B(p),SM1_B(p),SM2_B(p),SM3_B(p),SM4_B(p),SM5_B(p),SM6_B(p),VE1_B(p),VE2_B(p),VE3_B(p),VE1sign_B(p),VE2sign_B(p),VE3sign_B(p),VR1_B(p),VR2_B(p),VR3_B(p),Wi_B(i),WiA_B(i),AVS_B(i),Chi_B(i),ChiA_B(i),J_B(i),HyWi_B(i),SpAbs_B(i),SpPos_B(i),SpPosA_B(i),SpPosLog_B(i),SpMax_B(i),SpMaxA_B(i),SpDiam_B(i),SpAD_B(i),SpMAD_B(i),Ho_B(i),EE_B(i),SM1_B(i),SM2_B(i),SM3_B(i),SM4_B(i),SM5_B(i),SM6_B(i),VE1_B(i),VE2_B(i),VE3_B(i),VE1sign_B(i),VE2sign_B(i),VE3sign_B(i),VR1_B(i),VR2_B(i),VR3_B(i),Wi_B(s),WiA_B(s),AVS_B(s),Chi_B(s),ChiA_B(s),J_B(s),HyWi_B(s),SpAbs_B(s),SpPos_B(s),SpPosA_B(s),SpPosLog_B(s),SpMax_B(s),SpMaxA_B(s),SpDiam_B(s),SpAD_B(s),SpMAD_B(s),Ho_B(s),EE_B(s),SM1_B(s),SM2_B(s),SM3_B(s),SM4_B(s),SM5_B(s),SM6_B(s),VE1_B(s),VE2_B(s),VE3_B(s),VE1sign_B(s),VE2sign_B(s),VE3sign_B(s),VR1_B(s),VR2_B(s),VR3_B(s),ATS1m,ATS2m,ATS3m,ATS4m,ATS5m,ATS6m,ATS7m,ATS8m,ATS1v,ATS2v,ATS3v,ATS4v,ATS5v,ATS6v,ATS7v,ATS8v,ATS1e,ATS2e,ATS3e,ATS4e,ATS5e,ATS6e,ATS7e,ATS8e,ATS1p,ATS2p,ATS3p,ATS4p,ATS5p,ATS6p,ATS7p,ATS8p,ATS1i,ATS2i,ATS3i,ATS4i,ATS5i,ATS6i,ATS7i,ATS8i,ATS1s,ATS2s,ATS3s,ATS4s,ATS5s,ATS6s,ATS7s,ATS8s,ATSC1m,ATSC2m,ATSC3m,ATSC4m,ATSC5m,ATSC6m,ATSC7m,ATSC8m,ATSC1v,ATSC2v,ATSC3v,ATSC4v,ATSC5v,ATSC6v,ATSC7v,ATSC8v,ATSC1e,ATSC2e,ATSC3e,ATSC4e,ATSC5e,ATSC6e,ATSC7e,ATSC8e,ATSC1p,ATSC2p,ATSC3p,ATSC4p,ATSC5p,ATSC6p,ATSC7p,ATSC8p,ATSC1i,ATSC2i,ATSC3i,ATSC4i,ATSC5i,ATSC6i,ATSC7i,ATSC8i,ATSC1s,ATSC2s,ATSC3s,ATSC4s,ATSC5s,ATSC6s,ATSC7s,ATSC8s,MATS1m,MATS2m,MATS3m,MATS4m,MATS5m,MATS6m,MATS7m,MATS8m,MATS1v,MATS2v,MATS3v,MATS4v,MATS5v,MATS6v,MATS7v,MATS8v,MATS1e,MATS2e,MATS3e,MATS4e,MATS5e,MATS6e,MATS7e,MATS8e,MATS1p,MATS2p,MATS3p,MATS4p,MATS5p,MATS6p,MATS7p,MATS8p,MATS1i,MATS2i,MATS3i,MATS4i,MATS5i,MATS6i,MATS7i,MATS8i,MATS1s,MATS2s,MATS3s,MATS4s,MATS5s,MATS6s,MATS7s,MATS8s,GATS1m,GATS2m,GATS3m,GATS4m,GATS5m,GATS6m,GATS7m,GATS8m,GATS1v,GATS2v,GATS3v,GATS4v,GATS5v,GATS6v,GATS7v,GATS8v,GATS1e,GATS2e,GATS3e,GATS4e,GATS5e,GATS6e,GATS7e,GATS8e,GATS1p,GATS2p,GATS3p,GATS4p,GATS5p,GATS6p,GATS7p,GATS8p,GATS1i,GATS2i,GATS3i,GATS4i,GATS5i,GATS6i,GATS7i,GATS8i,GATS1s,GATS2s,GATS3s,GATS4s,GATS5s,GATS6s,GATS7s,GATS8s,GGI1,GGI2,GGI3,GGI4,GGI5,GGI6,GGI7,GGI8,GGI9,GGI10,JGI1,JGI2,JGI3,JGI4,JGI5,JGI6,JGI7,JGI8,JGI9,JGI10,JGT,SpMax1_Bh(m),SpMax2_Bh( m),SpMax3_Bh(m),SpMax4_Bh(m),SpMax5_Bh(m),SpMax6_Bh(m),SpMax7_Bh(m),SpMax8_Bh(m),SpMax1_Bh(v),SpMax2_Bh(v),SpMax3_Bh(v),SpMax 4_Bh(v),SpMax5_Bh(v),SpMax6_Bh(v),SpMax7_Bh(v),SpMax8_Bh(v),SpMax1_Bh(e),SpMax2_Bh(e),SpMax3_Bh(e),SpMax4_Bh(e),SpMax5_Bh(e), SpMax6_Bh(e),SpMax7_Bh(e),SpMax8_Bh(e),SpMax1_Bh(p),SpMax2_Bh(p),SpMax3_Bh(p),SpMax4_Bh(p),SpMax5_Bh(p),SpMax6_Bh(p),SpMax7_B h(p),SpMax8_Bh(p),SpMax1_Bh(i),SpMax2_Bh(i),SpMax3_Bh(i),SpMax4_Bh(i),SpMax5_Bh(i),SpMax6_Bh(i),SpMax7_Bh(i),SpMax8_Bh(i),Sp Max1_Bh(s),SpMax2_Bh(s),SpMax3_Bh(s),SpMax4_Bh(s),SpMax5_Bh(s),SpMax6_Bh(s),SpMax7_Bh(s),SpMax8_Bh(s),SpMin1_Bh(m),SpMin2_Bh(s m),SpMin3_Bh(m),SpMin4_Bh(m),SpMin5_Bh(m),SpMin6_Bh(m),SpMin7_Bh(m),SpMin8_Bh(m),SpMin1_Bh(v),SpMin2_Bh(v),SpMin3_Bh(v),SpMin 4_Bh(v),SpMin5_Bh(v),SpMin6_Bh(v),SpMin7_Bh(v),SpMin8_Bh(v),SpMin1_Bh(e),SpMin2_Bh(e),SpMin3_Bh(e),SpMin4_Bh(e),SpMin5_Bh(e),SpMin6_Bh(e),SpMin7_Bh(e),SpMin8_Bh(e),SpMin1_Bh(p),SpMin2_Bh(p),SpMin3_Bh(p),SpMin4_Bh(p),SpMin5_Bh(p),SpMin6_Bh(p),SpMin7_Bh(p) Bh(p),SpMin8_Bh(p),SpMin1_Bh(i),SpMin2_Bh(i),SpMin3_Bh(i),SpMin4_Bh(i),SpMin5_Bh(i),SpMin6_Bh(i),SpMin7_Bh(i),SpMin8_Bh(i),S pMin1_Bh(s),SpMin2_Bh(s),SpMin3_Bh(s),SpMin4_Bh(s),SpMin5_Bh(s),SpMin6_Bh(s),SpMin7_Bh(s),SpMin8_Bh(s),P_VSA_LogP_1,P_VSA_Lo gP_2,P_VSA_LogP_3,P_VSA_LogP_4,P_VSA_LogP_5,P_VSA_LogP_6,P_VSA_LogP_7,P_VSA_LogP_8,P_VSA_MR_1,P_VSA_MR_2,P_VSA_MR_3,P_VSA_MR_ 4,P_VSA_MR_5,P_VSA_MR_6,P_VSA_MR_7,P_VSA_MR_8,P_VSA_m_1,P_VSA_m_2,P_VSA_m_3,P_VSA_m_4,P_VSA_v_2,P_VSA_v_3,P_VSA_e_2,P_VSA_e_3,P_VSA_e_4,P_VSA_e_5,P_VSA_p_1,P_VSA_p_2,P_VSA_i_1,P_VSA_i_2,P_VSA_i_3,P_VSA_i_4,P_VSA_s_2,P_VSA_s_3,P_VSA_s_4,P_VSA_s_5,P_ VSA_s_6,P_VSA_ppp_L,P_VSA_ppp_P,P_VSA_ppp_N,P_VSA_ppp_D,P_VSA_ppp_A,P_VSA_ppp_ar,P_VSA_ppp_con,P_VSA_ppp_hal,P_VSA_ppp_cyc,P _VSA_ppp_ter,Eta_alpha,Eta_alpha_A,Eta_epsi,Eta_epsi_A,Eta_betaS,Eta_betaS_A,Eta_betaP,Eta_betaP_A,Eta_beta,Eta_beta_A,Eta_C,Eta_C_A,Eta_L,Eta_L_A,Eta_F,Eta_F_A,Eta_FL,Eta_FL_A,Eta_B,Eta_B_A,Eta_sh_p,Eta_sh_y,Eta_sh_x,Eta_D_AlphaA,Eta_D_AlphaB,Eta_epsi_2,Eta_epsi_3,Eta_epsi_4,Eta_epsi_5,Eta_D_epsiA,Eta_D_epsiB,Eta_D_epsiC,Eta_D_epsiD,Eta_psi1,Eta_D_psiA,Eta_D_beta,Eta_D_beta_A,SpMax_EA, ,SpMaxA_EA,SpDiam_EA,SpAD_EA,SpMAD_EA,SpMax_EA(ed),SpMaxA_EA(ed),SpDiam_EA(ed),SpAD_EA(ed),SpMAD_EA(ed),SpMax_EA(bo),SpMaxA_EA(bo),SpDiam_EA(bo),SpAD_EA(bo),SpMAD_EA(bo),SpMax_EA(dm),SpMaxA_EA(dm),SpDiam_EA(dm),SpAD_EA(dm),SpMAD_EA(dm),SpMax(ri ),SpMaxA_EA(ri),SpDiam_EA(ri),SpAD_EA(ri),SpMAD_EA(ri),SpMax_AEA(ed),SpMaxA_AEA(ed),SpDiam_AEA(ed),SpAD_AEA(ed),SpMAD_AEA(ed ),SpMax_AEA(bo),SpMaxA_AEA(bo),SpDiam_AEA(bo),SpAD_AEA(bo),SpMAD_AEA(bo),SpMax_AEA(dm),SpMaxA_AEA(dm),SpDiam_AEA(dm),SpAD_AE A(dm),SpMAD_AEA(dm),SpMax_AEA(ri),SpMaxA_AEA(ri),SpDiam_AEA(ri),SpAD_AEA(ri),SpMAD_AEA(ri),Chi0_EA,Chi1_EA,Chi0_EA(ed),Chi1_EA(ed),Chi0_EA(bo),Chi1_EA(bo),Chi0_EA(dm),Chi1_EA(dm),Chi0_EA(ri),Chi1_EA(ri),SM02_EA,SM03_EA,SM04_EA,SM05_EA,SM06_EA,SM07 _EA,SM08_EA,SM09_EA,SM10_EA,SM11_EA,SM12_EA,SM13_EA,SM14_EA,SM15_EA,SM02_EA(ed),SM03_EA(ed),SM04_EA(ed),SM05_EA(ed),SM06_EA(ed),SM07_EA(ed),SM08_EA(ed),SM09_EA(ed),SM10_EA(ed),SM11_EA(ed),SM12_EA(ed),SM13_EA(ed),SM14_EA(ed),SM15_EA(ed),SM02_EA(bo),SM03_EA(bo),SM04_EA(bo),SM05_EA(bo),SM06_EA(bo),SM07_EA(bo),SM08_EA(bo),SM09_EA(bo),SM10_EA(bo),SM11_EA(bo),SM12_EA(bo),SM13_EA(bo),SM14_EA(bo),SM15_EA(bo),SM02_EA(dm),SM03_EA(dm),SM04_EA(dm),SM05_EA(dm),SM06_EA(dm),SM07_EA(dm),SM08_EA(dm),SM09_EA(d m),SM10_EA(dm),SM11_EA(dm),SM12_EA(dm),SM13_EA(dm),SM14_EA(dm),SM15_EA(dm),SM02_EA(ri),SM03_EA(ri),SM04_EA(ri),SM05_EA(ri),SM 06_EA(ri),SM07_EA(ri),SM08_EA(ri),SM09_EA(ri),SM10_EA(ri),SM11_EA(ri),SM12_EA(ri),SM13_EA(ri),SM14_EA(ri),SM15_EA(ri),SM02_AE A(ed),SM03_AEA(ed),SM04_AEA(ed),SM05_AEA(ed),SM06_AEA(ed),SM07_AEA(ed),SM08_AEA(ed),SM09_AEA(ed),SM10_AEA(ed),SM11_AEA(ed),SM 12_AEA(ed),SM13_AEA(ed),SM14_AEA(ed),SM15_AEA(ed),SM02_AEA(bo),SM03_AEA(bo),SM04_AEA(bo),SM05_AEA(bo),SM06_AEA(bo),SM07_AEA(b o),SM08_AEA(bo),SM10_AEA(bo),SM11_AEA(bo),SM12_AEA(bo),SM13_AEA(bo),SM14_AEA(bo),SM15_AEA(bo),SM02_AEA(dm),SM03_AEA(dm),SM04_ AEA(dm),SM05_AEA(dm),SM06_AEA(dm),SM07_AEA(dm),SM08_AEA(dm),SM09_AEA(dm),SM11_AEA(dm),SM12_AEA(dm),SM13_AEA(dm),SM14_AEA(dm),SM15_AEA(dm),SM02_AEA(ri),SM03_AEA(ri),SM04_AEA(ri),SM05_AEA(ri),SM06_AEA(ri),SM07_AEA(ri),SM08_AEA(ri),SM09_AEA(ri),SM10_A EA(ri),SM12_AEA(ri),SM13_AEA(ri),SM14_AEA(ri),SM15_AEA(ri),Eig06_EA,Eig11_EA,Eig14_EA,Eig05_EA(ed),Eig10_EA(ed),Eig13_EA(ed) ,Eig14_EA(ed),Eig02_EA(bo),Eig05_EA(bo),Eig06_EA(bo),Eig07_EA(bo),Eig08_EA(bo),Eig09_EA(bo),Eig10_EA(bo),Eig11_EA(bo),Eig12_EA EA(bo),Eig13_EA(bo),Eig14_EA(bo),Eig15_EA(bo),Eig01_EA(dm),Eig02_EA(dm),Eig03_EA(dm),Eig04_EA(dm),Eig05_EA(dm),Eig06_EA(dm), Eig07_EA(dm),Eig08_EA(dm),Eig09_EA(dm),Eig10_EA(dm),Eig11_EA(dm),Eig12_EA(dm),Eig13_EA(dm),Eig14_EA(dm),Eig02_EA(ri),Eig03_E A(ri),Eig04_EA(ri),Eig05_EA(ri),Eig06_EA(ri),Eig07_EA(ri),Eig08_EA(ri),Eig09_EA(ri),Eig10_EA(ri),Eig11_EA(ri),Eig12_EA(ri),E ig13_EA(ri),Eig14_EA(ri),Eig15_EA(ri),Eig01_AEA(ed),Eig02_AEA(ed),Eig03_AEA(ed),Eig04_AEA(ed),Eig05_AEA(ed),Eig06_AEA(ed),Eig06_AEA(ed) g07_AEA(ed),Eig08_AEA(ed),Eig09_AEA(ed),Eig10_AEA(ed),Eig11_AEA(ed),Eig12_AEA(ed),Eig13_AEA(ed),Eig14_AEA(ed),Eig15_AEA(ed),Eig02_AEA(both),Eig03_AEA(both),Eig04_AEA(both),Eig05_AEA(both),Eig06_AEA(both),Eig07_AEA(both),Eig08_AEA(both),Eig09_AEA(both),Eig10_AEA(both ). dm),Eig05_AEA(dm),Eig06_AEA(dm),Eig07_AEA(dm),Eig08_AEA(dm),Eig09_AEA(dm),Eig10_AEA(dm),Eig11_AEA(dm),Eig12_AEA(dm),Eig13_A A(dm),Eig14_AEA(dm),Eig15_AEA(dm),Eig02_AEA(ri),Eig03_AEA(ri),Eig04_AEA(ri),Eig05_AEA(ri),Eig06_AEA(ri),Eig07_AEA(ri),Eig08_A EA(ri),Eig09_AEA(ri),Eig10_AEA(ri),Eig11_AEA(ri),Eig12_AEA(ri),Eig13_AEA(ri),Eig14_AEA(ri),Eig15_AEA(ri),nCp,nCs,nCt,nCq,nCr s,nCrt,nCrq,nCar,nCbH,nCb-,nCconj,nR=Ct,nRCOOH,nRCOOR,nRCONHR,nArCONHR,nRCONR2,nArCONR2,nCONN,nN=CN<,nRNH2,nRNHR,nRNR2,n ,nN(CO)2,nROH,nOHs,nOHt,nROR,nArOR,nSO,nArX,nPyrrolidines,nImidazoles,nThiophenes,nPyridines,nHDon,nHAcc,C-001,C-002,C-003,C -005,C-006,C-007,C-008,C-009,C-011,C-024,C-025,C-026,C-027,C-0 28,C-029,C-033,C-034,C-035,C-040,C-041,C-042,C-044,H-046,H-047,H-048,H-049,H-050,H-051,H-052,H-053,H-054,O-056,O-058,O-059,O -060,N-067,N-068,N-072,N-073,N-074,N-075,S-107,S-109,SsCH3,Sss CH2,SaaCH,SsssCH,StsC,SdssC,SaasC,SaaaC,SsssC,SsNH2,SssNH,SsssN,SdsN,SaaN,StN,SaasN,SaaNH,SsOH,SdO,SssO,SaaS,SFs,Sss,SsCl ,NsCH3,NssCH2,NaaCH,NsssCH,NdssC,NaasC,NaaaC,NssssC,NssNH,NsssN,NdsN,NaaN,NtN,NaasN,NaaNH,NdO,NssO,NdssS,CATS2D_00DD,CADD_2_ D_03_DD,CATS2D_05_DD,CATS2D_06_DD,CATS2D_08_DD,CATS2D_09_DD,CATS2D_02_DA,CATS2D_03_DA,CATS2D_04_DA,CATS2D_05_DA,CATS2D_06_DA ,CATS2D_07_DA,CATS2D_08_DA,CATS2D_09_DA,CATS2D_03_DP,CATS2D_06_DP,CATS2D_02_DN,CATS2D_04_DN,CATS2D_05_DN,CATS2D_02_DL,CATS2 D_03_DL,CATS2D_04_DL,CATS2D_05_DL,CATS2D_06_DL,CATS2D_07_DL,CATS2D_08_DL,CATS2D_09_DL,CATS2D_00_AA,CATS2D_02_AA,CATS2D_03_AA ,CATS2D_04_AA,CATS2D_05_AA,CATS2D_06_AA,CATS2D_07_AA,CATS2D_08_AA,CATS2D_09_AA,CATS2D_02_AP,CATS2D_03_AP,CATS2D_04_AP,CATS2D _05_AP,CATS2D_06_AP,CATS2D_08_AP,CATS2D_09_AP,CATS2D_04_AN,CATS2D_05_AN,CATS2D_07_AN,CATS2D_08_AN,CATS2D_02_AL,CATS2D_03_AL,CATS2D_04_AL,CATS2D_05_AL,CATS2D_06_AL,CATS2D_07_AL,CATS2D_08_AL,CATS2D_09_AL,CATS2D_02_PN,CATS2D_04_PN,CATS2D_02_PL,CATS2D_03_PL,CATS2D_04_PL,CATS2D_05_PL,CATS2D_07_PL,CATS2D_08_PL,CATS2D_09_PL,CATS2D_00_NN,CATS2D_01_NL,CATS2D_02_NL,CATS2D_03_NL,CATS2D_04_NL,CATS2D_05_NL,CATS2D_06_NL,CATS2D_07_NL,CATS2D_08_NL,CATS2D_00_LL,CATS2D_01_LL,CATS2D_02_LL,CATS2D_03_LL,CATS2D_04_LL,CATS2D_05_LL,CATS2D_06_LL,CATS2D_07_LL,CATS2D_08_LL,CATS2D_09_LL,SHED_DD,SHED_DA,SHED_DP,SHED_DN,SHED_DL,SHED_AA,SHED_AP,SHED_AN,SHED_AL,SHED_PN,SHED_PL,SHED_NN,SHED_NL,SHED_LL,T(N..N),T(N..O),T(N..S),T(N..F),T(N..Cl),T(O..O),T(O..S),T(O..Cl),B01[C-O],B01[C-F],B01[O-S],B02[C-F],B02[N-N],B02[N-O],B02[N-S],B02[O-O],B03[N-N],B03[N-O],B03[N-S],B03[O-O],B04[C-S],B04[C-F],B04[N-N],B04[N-O],B04[N-S],B04[O-O],B04[O-S],B05[C-C],B05[C-O],B05[C-S],B05[C-F],B05[N-N],B05[N-O],B05[N-S],B05[O-O],B05[O-S],B05[O-Cl],B06[C-C],B06[C-N],B06[C-O],B06[C-F],B06[N-N],B06[N-O],B06[O-O],B07[C-C],B07[C-N],B07[C-O],B07[C-S],B07[C-F],B07[N-N],B07[N-O],B07[N-S],B07[O-O],B07[O-S],B08[C-C],B08[C-N],B08[C-O],B08[C-S],B08[N-N],B08[N-O],B08[O-O],B09[C-C],B09[C-N],B09[C-O],B09[C-S],B09[C-F],B09[C-Cl],B09[N-N],B09[N-O],B09[O-O],B10[C-C],B10[C-N],B10[C-O],B10[N-N],B10[N-O],B10[O-O],F01[C-C],F01[C-N],F01[C-O],F01[C-S],F01[O-S],F02[C-C],F02[C-N],F02[C-O],F02[C-S],F02[C-F],F02[N-N],F02[N-O],F02[N-S],F02[O-O],F03[C-C],F03[C-N],F03[C-O],F03[C-S],F03[C-Cl],F03[N-N],F03[N-O],F03[O-O],F04[C-C],F04[C-N],F04[C-O],F04[C-S],F04[C-Cl],F04[N-N],F04[N-O],F04[N-S],F04[O-O],F04[O-S],F05[C-C],F05[C-N],F05[C-O],F05[C-S],F05[C-F],F05[C-Cl],F05[N-N],F05[N-O],F05[N-S],F05[O-O],F05[O-Cl],F06[C-C],F06[C-N],F06[C-O],F06[C-S],F06[C-F],F06[C-Cl],F06[N-N],F06[N-O],F06[O-O],F07[C-C],F07[C-N],F07[C-O],F07[C-S],F07[C-F],F07[C-Cl],F07[N-N],F07[N-O],F07[O-O],F07[O-S],F08[C-C],F08[C-N],F08[C-O],F08[C-S],F08[C-Cl],F08[N-N],F08[N-O],F08[O-O],F09[C-C],F09[C-N],F09[C-O],F09[C-S],F09[C-Cl],F09[N-N],F09[N-O],F09[O-O],F10[C-C],F10[C-N],F10[C-O],F10[N-N],F10[N-O],F10[O-O],Uc,Ui,Hy,TPSA(NO),TPSA(Tot),MLOGP,MLOGP2,SAtot,SAacc,VvdwMG,VvdwZAZ,PDI,BLTD48,BL TA96,Ro5,DLS_01,DLS_02,DLS_03,DLS_04,DLS_05,DLS_06,DLS_07,DLS_cons,LLS_01,LLS_02, At least one variable for the descriptor selected from the group consisting of:

[0083] The above mentioned descriptors are: Constitutional indices, Ring descriptors, Topological indices, Walk and path counts, Connectivity indices, Information indices, 2D matrix-based descriptors, 2D autocorrelations, Burden eigenvalues, P_VSA-like descriptors, ETA indices, Edge adjacency indices, Geometrical descriptors, 3D matrix-based descriptors, 3D autocorrelations, RDF descriptors, 3D-MoRSE descriptors, WHIM descriptors, and They can be classified into: molecular properties, drug-like indices, pharmacophore descriptors, 2D atom pairs, 3D atom pairs, charge descriptors, molecular properties, drug-like indices, CATS 3D descriptors.All of the variables for the above-mentioned descriptors may be used, or a combination of variables for any selected descriptors may be used. When using variables for multiple descriptors, from the viewpoint of selecting descriptors with high explanatory power for the critical supersaturation, components (principal components) obtained by statistical processing such as principal component analysis, or descriptors selected by variable importance in LASSO (Least Absolute Shrinkage and Selection Operator) regression, genetic algorithms, Random Forest, Boruta, forward variable selection, backward variable selection, stepwise selection, or VIP (Variable Importance in Projection) values ​​in PLSR (Partial Least Squares Regression) can be used as variables. As a compound descriptor, for example, variables for at least one descriptor belonging to the 2D autocorrelation, P_VSA-like descriptor, drug-like index, edge adjacency index, topological descriptor, and Barden eigenvalue descriptors can be used. In particular, when a descriptor belonging to the 2D autocorrelation and / or both a descriptor belonging to the drug-like index and a descriptor belonging to the edge adjacency index are used, a model with high prediction accuracy can be constructed. In addition, models can be generated using descriptors in Table 10 that have a value of 0.50 or greater, such as 2D autocorrelation and edge adjacency index, or combinations of descriptors that have a value of 0.50 or greater, such as 2D autocorrelation and P_VSA-like descriptor, 2D autocorrelation and drug-like index, 2D autocorrelation and edge adjacency index, 2D autocorrelation and Burden eigenvalue, 2D autocorrelation and topological descriptor, 2D autocorrelation and others, P_VSA-like descriptor and edge adjacency index, drug-like index and edge adjacency index, drug-like index and Burden eigenvalue, drug-like index and topological descriptor, edge adjacency index and Burden eigenvalue, edge adjacency index and topological descriptor.From the viewpoint of constructing a model with higher predictive accuracy, a model can be generated using a descriptor with a value of 0.65 or greater in Table 10, such as 2D autocorrelation, or a combination of descriptors with a value of 0.65 or greater, such as 2D autocorrelation and P_VSA-like descriptor, 2D autocorrelation and drug-like index, 2D autocorrelation and edge adjacency index, 2D autocorrelation and Barden eigenvalue, 2D autocorrelation and topological descriptor, 2D autocorrelation and others, drug-like index and edge adjacency index.

[0084] Even more specifically, the following descriptors: Variables for descriptors including at least one descriptor selected from the group consisting of MATS5i, SM03_EA(dm), P_VSA_MR_6, MAXDP, MATS6m, DLS_04, P_VSA_s_3, GATS8s, ATSC1e, P_VSA_MR_8, GATS5i, SM13_AEA(ri), MATS2s, P_VSA_LogP_2, SpMax1_Bh(m), and SpMax1_Bh(p), or descriptors with substantially the same content, can be used.

[0085] These descriptors have the following specific meanings: [Table 1]

[0086] The solvent-related variables are, for example, the following descriptors (373 types) calculated by calculation based on the molecular structure: MW,AMW,Sv,Se,Sp,Si,Mv,Me,Mp,Mi,GD,RBF,H%,C%,O%,MCD,ZM1Kup,ZM1Mad,ZM1Per,ZM1MulPer,ZM2Kup,ZM2Mad,ZM2Per,ZMON0,ONP0Ver, 1,ON1V,DBI,SNar,HNar,GNar,Xt,Dz,LPRS,MSD,SPI,AECC,DECC,MDDD,ICR,MeanTD,MeanDD,S1K,S2K,S3K,PHI,PW2,PW3,PW4,PW5,MAXDN,MAXDP S,LOC,MWC01,MWC02,MWC03,MWC04,MWC05,MWC06,MWC07,MWC08,MWC09,MWC10,SRW02,SRW04,SRW06,SRW08,SRW10,MPC03,MPC01,MPC0 5,piPC01,piPC02,piPC03,piPC04,piPC05,TWC,TPC,piID,PCD,CID,BID,ISIZ,IAC,AAC,IDE,IDM,IDDE,IDDM,IDET,IDMT,IVDE,IVDM,HVcpx,HDcpx, Uindex,Vindex,Xindex,Yindex,IC0,IC1,IC2,IC3,IC4,IC5,TIC0,TIC1,TIC2,TIC3,TIC4,TIC5,SIC0,SIC1,SIC2,SIC3,SIC4,SIC5,CIC0,CIC1,CI C2,CIC3,CIC4,CIC5,BIC0,BIC1,BIC2,BIC3,BIC4,BIC5,ATS1m,ATS2m,ATS3m,ATS4m,ATS5m,ATS6m,ATS1v,ATS2v,ATS3v,ATS4v,ATS5v,ATS1v,ATS6 ,ATS2e,ATS3e,ATS4e,ATS5e,ATS6e,ATS1p,ATS2p,ATS3p,ATS4p,ATS5p,ATS6p,ATS1i,ATS2i,ATS3i,ATS4i,ATS5i,ATS6i,ATSC1m,SC3m,A, TSC4m,ATSC5m,ATSC6m,ATSC1v,ATSC2v,ATSC3v,ATSC4v,ATSC5v,ATSC6v,ATSC1e,ATSC2e,ATSC3e,ATSC4e,ATSC5e,ATSC6e,ATSC1p,ATSC2p,ATSC3p,ATSC4p,ATSC5p,ATSC6p,ATSC1i,ATSC2i,ATSC3i,ATSC4i,ATSC5i,ATSC6i,MATS1m,MATS2m,MATS3m,MATS4m,MATS5m,MATS6m,MATS1v,MATS2v,MATS 3v,MATS4v,MATS5v,MATS6v,MATS1e,MATS2e,MATS3e,MATS4e,MATS5e,MATS6e,MATS1p,MATS2p,MATS3p,MATS4p,MATS5p,MATS6p,MATS1i,MATS2i,MA TS3i,MATS4i,MATS5i,MATS6i,GATS1m,GATS2m,GATS3m,GATS4m,GATS5m,GATS1v,GATS2v,GATS3v,GATS4v,GATS5v,GATS1e,GATS2e,GATS3e,GATS4e ,GATS5e,GATS1p,GATS2p,GATS3p,GATS4p,GATS5p,GATS1i,GATS2i,GATS3i,GATS4i,GATS5i,GGI1,GGI2,GGI3,JGI1,JGI2,JGI3,JGT,SpMax1_Bh(m) ,SpMax2_Bh(m),SpMax3_Bh(m),SpMax4_Bh(m),SpMax5_Bh(m),SpMax6_Bh(m),SpMax7_Bh(m),SpMax8_Bh(m),SpMax1_Bh(v),SpMax2_Bh(v),SpMax 3_Bh(v),SpMax4_Bh(v),SpMax5_Bh(v),SpMax6_Bh(v),SpMax7_Bh(v),SpMax1_Bh(e),SpMax2_Bh(e),SpMax3_Bh(e),SpMax4_Bh(e),SpMax5_Bh(e) ,SpMax6_Bh(e),SpMax7_Bh(e),SpMax8_Bh(e),SpMax1_Bh(p),SpMax2_Bh(p),SpMax3_Bh(p),SpMax4_Bh(p),SpMax5_Bh(p),SpMax6_Bh(p),SpMax7 _Bh(p),SpMax8_Bh(p),SpMax1_Bh(i),SpMax2_Bh(i),SpMax3_Bh(i),SpMax4_Bh(i),SpMax5_Bh(i),SpMax6_Bh(i),SpMax7_Bh(i),SpMax8_Bh(i),SpMin1_Bh(m),SpMin2_Bh(m),SpMin3_Bh(m),SpMin4_Bh(m),SpMin5_Bh(m),SpMin1_Bh(v),SpMin2_Bh(v),SpMin3_ Bh(v),SpMin4_Bh(v),SpMin5_Bh(v),SpMin1_Bh(e),SpMin2_Bh(e),SpMin3_Bh(e),SpMin4_Bh(e),SpMin1_Bh(p),Sp Min2_Bh(p),SpMin3_Bh(p),SpMin4_Bh(p),SpMin5_Bh(p),SpMin1_Bh(i),SpMin2_Bh(i),SpMin3_Bh(i),SpMin4_Bh( i),P_VSA_LogP_1,P_VSA_LogP_2,P_VSA_LogP_3,P_VSA_LogP_4,P_VSA_LogP_5,P_VSA_LogP_7,P_VSA_MR_1,P_VSA_M R_2,P_VSA_MR_3,P_VSA_MR_5,P_VSA_MR_6,P_VSA_m_1,P_VSA_m_2,P_VSA_m_3,P_VSA_v_2,P_VSA_v_3,P_VSA_e_2,P _VSA_e_5,P_VSA_i_2,P_VSA_i_3,P_VSA_s_2,P_VSA_s_3,P_VSA_s_4,P_VSA_s_6,P_VSA_ppp_L,P_VSA_ppp_D,P_VSA_ ppp_cyc,P_VSA_ppp_ter,SsCH3,SssCH2,SsssCH,SdssC,SsOH,SdO,SssO,SHED_AL,SHED_LL,Uc,Ui,Hy,AMR,TPSA(NO) ,TPSA(Tot),MLOGP2,ALOGP,ALOGP2,SAtot,SAdon,VvdwMG,VvdwZAZ,PDI,BLTF96,DLS_02,DLS_04,DLS_05,DLS_cons, One or more variables for the descriptors selected from the group consisting of:

[0087] The above mentioned descriptors are: Constitutional indices, Ring descriptors, Topological indices, Walk and path counts, Connectivity indices, Information indices, 2D matrix-based descriptors, 2D autocorrelations, Burden eigenvalues, P_VSA-like descriptors, ETA indices, Edge adjacency indices, Geometrical descriptors, 3D matrix-based descriptors, 3D autocorrelations, RDF descriptors, 3D-MoRSE descriptors, WHIM descriptors, and They can be classified into: molecular properties, drug-like indices, pharmacophore descriptors, 2D atom pairs, 3D atom pairs, charge descriptors, molecular properties, drug-like indices, CATS 3D descriptors.All of the variables for the above-mentioned descriptors may be used, or a combination of variables for any selected descriptors may be used as needed. When using variables for multiple descriptors, from the perspective of selecting descriptors with high explanatory power for critical supersaturation, components (principal components) obtained by statistical processing such as principal component analysis, or descriptors selected by variable importance in LASSO regression, genetic algorithms, Random Forest, Boruta, variable forward selection, variable backward selection, Stepwise selection, or VIP values ​​in PLSR may be used as variables. As solvent descriptors, for example, variables for descriptors belonging to the Burden eigenvalue and 2D autocorrelation may be used.

[0088] Even more specifically, the following descriptors: Variables for descriptors including at least one descriptor selected from the group consisting of SpMax5_Bh(m), SpMax5_Bh(v), and MATS3v, or descriptors with substantially the same content, can be used. These descriptors specifically have the following meanings: [Table 2]

[0089] A descriptor with substantially the same content refers to a descriptor that has the same or similar content as the above-mentioned descriptor, but is expressed as a different descriptor due to differences in software, etc. For example, a descriptor that is ATSC1e in alvaDesc is expressed as ATSC1se in modred, but only the name is different; the content is the same. Furthermore, some software may use descriptors with similar definitions that differ only in the numerical values ​​used to define the descriptor. Therefore, a descriptor with similar content to a descriptor in 1 includes a descriptor that differs only in the numerical values ​​used to define it. For example, a descriptor that is P_VSA_logP_5 in alvaDesc is expressed as SlogP_VSA4+MR_VSA5+MR_VSA6+MR_VSA7 in the RDKit, but the domain of definition of logP is the same. Furthermore, although atomic properties have different numerical values ​​by definition, they represent the same physical quantity, and therefore are substantially the same. For example, in the case of "mordred," ATSC1se is based on Sanderson's electronegativity, and ATSC1pe is based on Pauling's electronegativity, and although the numerical values ​​are different, the content is the same.

[0090] In the step of predicting the critical supersaturation, the "solution temperature at the time of crystallization" refers to the temperature at which crystals precipitate in step (2) of the method of the present invention (the step of precipitating spherulites of a compound from a supersaturated solution).

[0091] The information based on the chemical structure is, for example, information based on the three-dimensional structure of a compound after structural optimization. Images of the compound can be used as the information based on the three-dimensional structure. That is, images of a compound whose three-dimensional structure has been constructed can be generated from multiple directions, and the generated images can be input as information about the compound and / or solvent.

[0092] The three-dimensional structure of a compound can be generated on a computer using known software, or a structure determined by crystal structure analysis can be used. The input chemical formula of the compound can be used to construct a three-dimensional structure taking into account conditions such as solvent, temperature, and pH, or a three-dimensional structure constructed without considering some or all of these conditions. A single three-dimensional structure can be created for a single compound, or multiple three-dimensional structures can be created by taking into account degrees of freedom. For the three-dimensional structure, various display methods are available, such as BallandStick display, which displays atoms as spheres and bonds as sticks, Wireframe display, which shows only bonds, Spacefill display, which fills the space with atoms, and Surface display, which shows the molecular surface exposed to the solvent. In such display methods, it is preferable to distinguish the types of atoms by color, which can improve the accuracy of predicting the physical properties of the compound.

[0093] Images of the 3D structure constructed on a computer can be taken using a virtual camera on the computer. Images can be taken from multiple directions. For example, images can be taken from the X-axis, Y-axis, and Z-axis directions, or images can be taken by rotating a predetermined angle around each axis. The multiple images taken in this way can be input into a prediction model as information about the compound and / or solvent.

[0094] In the step of predicting the critical supersaturation, the input data may be data including or consisting of information on a compound obtained as crystals of a specific shape and information on the solvent used for crystallization, or may be data including or consisting of information on a compound obtained as crystals of a specific shape and the solution temperature during crystallization, or may be data including or consisting of information on a compound obtained as crystals of a specific shape, information on the solvent used for crystallization, and the solution temperature during crystallization. The input data is preferably data including information on a compound obtained as crystals of a specific shape, information on the solvent used for crystallization, and the solution temperature during crystallization.

[0095] The step of predicting the critical supersaturation is performed using an information processing device. Fig. 39 is a diagram showing an example of the schematic configuration of an information processing device 100 used to predict the critical supersaturation in the method of the present invention.

[0096] The information processing device 100 is an information processing device such as a personal computer, and is used by a user. The information processing device 100 includes a communication device 101, an input device 102, a display device 103, a storage device 110, and a CPU (Central Processing Unit) 120. Each unit of the information processing device 100 will be described in detail below.

[0097] The communication device 101 has a communication interface circuit for communicating with a network such as a LAN. The communication device 101 transmits and receives data to and from an external server device (not shown) via the network. The communication device 101 supplies data received from the server device via the network to the CPU 120, and transmits data supplied from the CPU 120 to the server device via the network. The communication device 101 may be any device that can communicate with an external device. The communication device 101 may receive input data used in the critical supersaturation prediction step from an external server device and supply the input data to the CPU 120. The communication device 101 may also transmit the predicted value of the critical supersaturation output from the CPU 120 to the external device.

[0098] The input device 102 is an example of an operation unit, and includes input devices such as a touch panel input device, a keyboard, and a mouse, as well as an interface circuit that acquires signals from the input devices. The input device 102 accepts input from a user and outputs a signal corresponding to the user input to the CPU 120. Input data used in the critical supersaturation prediction step may be input from the input device 102.

[0099] The display device 103 is an example of a display unit, and includes a display configured of liquid crystal, organic EL (Electro-Luminescence), etc., and an interface circuit that outputs image data or various information to the display. The display device 103 is connected to the CPU 120, and displays the predicted value of the critical supersaturation output from the CPU 120 on the display.

[0100] The storage device 110 is an example of a storage unit. The storage device 110 includes a memory device such as a random access memory (RAM) or a read-only memory (ROM), a fixed disk device such as a hard disk, or a portable storage device such as a flexible disk or an optical disk. The storage device 110 also stores computer programs, databases, tables, and the like used for various processes of the information processing device 100. The computer programs may be installed from a computer-readable portable recording medium such as a compact disk read-only memory (CD-ROM) or a digital versatile disk read-only memory (DVD-ROM). The computer programs are installed in the storage device 110 using a known setup program or the like. The storage device stores a prediction model used in the critical supersaturation prediction process and a parameter set for describing the prediction model.

[0101] The CPU 120 operates based on a program stored in advance in the storage device 110. The CPU 120 may be a general-purpose processor. Note that instead of the CPU 120, a digital signal processor (DSP), a large scale integration (LSI), an application specific integrated circuit (ASIC), a field-programmable gate array (FPGA), or the like may be used.

[0102] The CPU 120 is connected to the communication device 101, the input device 102, the display device 103, and the storage device 110, and controls each of these components.

[0103] 40 and 91 are flowcharts showing examples of the overall processing operations performed by the information processing device 100.

[0104] An example of the overall processing operation by the information processing device 100 will be described below with reference to the flowchart shown in Fig. 40 or 91. The flow of the operation described below is executed mainly by the CPU 120 in cooperation with each element of the information processing device 100, based on a program stored in advance in the storage device 110.

[0105] First, preprocessing S100 may be performed to generate information about the compound obtained as crystals of a specific shape and information about the solvent used for crystallization, which are input to the input device 102. In one embodiment, in preprocessing S100, information about the compound obtained as crystals of a specific shape and information about the solvent used for crystallization are determined based on the descriptors and mixing ratios for each of the compound and the solvent. In yet another embodiment, in preprocessing S100, a virtual camera may be used on the computer to capture an image of the compound from a specific direction relative to a three-dimensional structure of the compound and / or solvent constructed on the computer, thereby acquiring an image. The preprocessing step S100 may be performed on the information processing device 100, or may be performed in advance on an information processing device other than the information processing device 100. When the preprocessing step S100 is performed on the information processing device 100, the information generated by preprocessing S100 is stored in the storage device 110. When the preprocessing step S100 is performed in advance on an information processing device other than the information processing device 100, the information generated by preprocessing S100 is input to the information processing device 100 via the input device 102 or the communication device 101.

[0106] The variables for the compound descriptors and the variables for the solvent descriptors determined in the preprocessing S100 may be input directly to the prediction model, or when constructing the prediction model, principal component analysis (PCA) may be performed on the various variables that are explanatory variables. One or more principal components generated by the PCA can be used as information.

[0107] Next, the CPU 120 accepts data including information about a compound to be obtained as a crystal of a specific shape, which has been input by a user using the input device 102, or received by the communication device 101 from an external server device, or stored in the memory device 110, and at least one of information about the solvent used for crystallization and the solution temperature during crystallization (step S101).

[0108] Next, CPU 120 calculates a predicted value of the critical supersaturation (step S102). CPU 120 calculates a predicted value of the critical supersaturation by inputting the received data into a prediction model that has been pre-trained to output a critical supersaturation for each data when data including information on a compound obtained as a crystal of a specific shape and at least one of information on a solvent used for crystallization and a solution temperature during crystallization is input.

[0109] Next, the CPU 120 displays the calculated predicted value of the critical supersaturation on the display device 103 (step S103).

[0110] The prediction model is stored in advance in the storage device 110. For example, by performing partial least squares regression as shown in Examples 18, 32, and / or 33 below, a set of weighting coefficients for various information can be obtained as a parameter set. A prediction model showing the relationship between various explanatory variables and the critical supersaturation can also be obtained. Note that the method for constructing the prediction model is not limited to the method described in Example 18. For example, known machine learning techniques such as deep learning may be used to learn the relationship between input information and the critical supersaturation. Deep learning is machine learning using a multilayered neural network consisting of an input layer, an intermediate layer, and an output layer. Each node in the input layer receives input data including information about a compound obtained as a crystal of a specific shape, information about the solvent used for crystallization, and at least one of the solution temperature during crystallization. Each node in the intermediate layer outputs the sum of values ​​obtained by multiplying each feature vector output from each node in the input layer by a weight, and the output layer outputs the sum of values ​​obtained by multiplying each feature vector output from each node in the intermediate layer by a weight. Through pre-learning, the weights are adjusted to learn so that the difference between the output value from the output layer and the critical saturation degree becomes small.

[0111] By preparing a supersaturated solution having a degree of supersaturation higher than the calculated predicted value of the critical supersaturation, it is possible to obtain crystals of a specific shape of a compound with good reproducibility.

[0112] One embodiment of the method of the present invention is a method for producing spherulites of a compound, comprising the steps of: (1) preparing a supersaturated solution of the compound having a degree of supersaturation equal to or greater than the critical degree of supersaturation required to obtain spherulitic crystals of the compound; and (2) A step of precipitating crystals containing spherulites of the compound from the supersaturated solution. Here, the proportion of spherulites in the precipitated crystals is, for example, greater than 0% by weight, 0.1% by weight or more, 1% by weight or more, 5% by weight or more, 10% by weight or more, 20% by weight or more, 30% by weight or more, 40% by weight or more, 50% by weight or more, 60% by weight or more, 70% by weight or more, 80% by weight or more, 90% by weight or more, or 95% by weight or more. Preferably, it is 50% by weight or more, more preferably 70% by weight or more, and particularly preferably 90% by weight or more. The proportion of spherulites in the precipitated crystals (by weight) can be calculated, for example, by classifying the precipitated crystals and measuring the weight of the spherulites and the weight of the other crystals. The proportion of spherulites in the precipitated crystals is, for example, more than 0%, 0.1% or more, 1% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more, based on the number of particles. Preferably, it is 50% or more, more preferably 70% or more, and particularly preferably 90% or more. The proportion of spherulites in the precipitated crystals (based on the number of particles) can be calculated using, for example, a dry dispersion-type image analyzer.

[0113] One embodiment of the method of the present invention is a method for producing spherulites of azithromycin monohydrate, comprising the steps of: (1) A step of dissolving azithromycin or a hydrate thereof in a water-miscible organic solvent (e.g., lower alcohols such as methanol and ethanol, tetrahydrofuran, acetone, and mixtures thereof) to prepare a solution of azithromycin; (2) adding the solution prepared in step (1) dropwise to water at 0°C to 55°C (e.g., over a period of 1 second to 3 hours) to prepare a supersaturated solution of azithromycin monohydrate; (3) A step of precipitating spherulites of azithromycin monohydrate at 0°C to 55°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in Nos. 11, 14, 15, 16, 17, or 18 of Table 3 below, the solution may have a degree of supersaturation equal to or greater than the measured critical supersaturation value listed in Nos. 11, 14, 15, 16, 17, or 18, a predicted critical supersaturation value, a 95% predicted lower limit of the critical supersaturation, or a 95% predicted upper limit of the critical supersaturation. In this production method, seed crystals of azithromycin monohydrate may be inoculated between steps (2) and (3). The volume ratio of the water-miscible organic solvent to water (water-miscible organic solvent:water) used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:20.

[0114] Another embodiment of the process of the present invention is a process for producing spherulites of lansoprazole, comprising the steps of: (1) dissolving lansoprazole or a hydrate thereof in a water-miscible organic solvent (e.g., lower alcohols such as methanol and ethanol, tetrahydrofuran, acetone, and mixtures thereof) to prepare a lansoprazole solution; (2) adding the solution prepared in step (1) dropwise to water at 0°C to 55°C (e.g., over a period of 1 second to 3 hours) to prepare a supersaturated solution of lansoprazole; (3) A step of precipitating spherulites of lansoprazole at 0°C to 55°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 2 or 20 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 2 or 20, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. Furthermore, in this production method, seed crystals of lansoprazole may be inoculated between steps (2) and (3). The volume ratio of the water-miscible organic solvent to water (water-miscible organic solvent:water) used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:20.

[0115] Another embodiment of the method of the present invention is a method for producing esomeprazole magnesium trihydrate spherulites, comprising the steps of: (1) dissolving esomeprazole magnesium or a hydrate thereof in a water-miscible organic solvent (e.g., lower alcohols such as methanol, ethanol, and 2-propanol, tetrahydrofuran, acetone, and mixtures thereof) to prepare a solution of esomeprazole magnesium; (2) adding the solution prepared in step (1) dropwise to water at 0°C to 55°C (e.g., over a period of 1 second to 3 hours) to prepare a supersaturated solution of esomeprazole magnesium trihydrate; (3) A step of precipitating spherulites of esomeprazole magnesium trihydrate at 0°C to 55°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 1 or 19 of Table 3 below, the solution may have a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 1 or 19, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. In this production method, seed crystals of esomeprazole magnesium trihydrate may be inoculated between steps (2) and (3). The volume ratio of the water-miscible organic solvent to water (water-miscible organic solvent:water) used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:20.

[0116] Another embodiment of the method of the present invention is a method for producing esomeprazole magnesium trihydrate spherulites, comprising the steps of: (1) A step of dissolving esomeprazole potassium in a water-miscible organic solvent (e.g., lower alcohols such as methanol, ethanol, and 2-propanol, tetrahydrofuran, acetone, and mixtures thereof) to prepare a solution of esomeprazole potassium; (2) adding dropwise an aqueous magnesium chloride solution to the solution prepared in step (1) at 0°C to 55°C to prepare a supersaturated solution of esomeprazole magnesium trihydrate; (3) filtering the supersaturated solution prepared in step 2; (4) A step of precipitating spherulites of esomeprazole magnesium trihydrate at 0°C to 55°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical degree of supersaturation required to obtain spherulites. In this production method, seed crystals of esomeprazole magnesium trihydrate may be added between steps (3) and (4). The volume ratio of the water-miscible organic solvent to water (water-miscible organic solvent:water) used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:20. Preferably, the present production method further comprises the step (5) of growing spherulites of esomeprazole magnesium trihydrate while preparing a supersaturated solution of esomeprazole magnesium by adding dropwise an aqueous magnesium chloride solution at 0° C. to 55° C. The amounts of magnesium chloride used in step (2) and (5) can be adjusted appropriately.

[0117] Another embodiment of the process of the present invention is a process for producing spherulites of duloxetine hydrochloride, comprising the steps of: (1) mixing duloxetine with a water-miscible organic solvent (e.g., lower alcohols such as methanol, ethanol, and 2-propanol, tetrahydrofuran, acetone, and mixtures thereof) and a surfactant (e.g., polyol ester) to prepare a solution of duloxetine; (2) adding dropwise (e.g., over a period of 1 second to 1 hour) a solvent containing hydrogen chloride (e.g., ethyl acetate, 1,4-dioxane, ethanol, water) to the solution prepared in step (1) at 0°C to 55°C to prepare a supersaturated solution of duloxetine hydrochloride; (3) A step of precipitating spherulites of duloxetine hydrochloride at 0°C to 55°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical degree of supersaturation required to obtain spherulites.

[0118] Another embodiment of the process of the present invention is a process for producing spherulites of ketotifen fumarate, comprising the steps of: (1) adding an organic solvent (e.g., a lower alcohol such as methanol or ethanol, tetrahydrofuran, acetonitrile, or a mixture thereof) to ketotifen fumarate to dissolve the salt, thereby preparing a solution of ketotifen fumarate; (2) adding dropwise (for example, over 1 second to 1 hour) the solution prepared in step (1) to another organic solvent (a lower alcohol such as 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, or tert-butanol, ethyl acetate, tert-butyl methyl ether, toluene, acetone, or a mixture thereof) at -20°C to 30°C to prepare a supersaturated solution of ketotifen fumarate; (3) A step of precipitating spherulites of ketotifen fumarate at -20°C to 30°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrates, solvents, solvent ratios, and crystallization temperatures listed in Nos. 4, 5, 6, and 7 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured critical supersaturation values ​​listed in Nos. 4, 5, 6, and 7, a degree of supersaturation equal to or greater than the predicted critical supersaturation values, a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation.

[0119] Another embodiment of the method of the present invention is a method for producing spherulites of lanthanum carbonate octahydrate, comprising the steps of: (1) dissolving lanthanum oxide in hydrochloric acid to prepare an aqueous solution of lanthanum chloride; (2) A step of adding an aqueous ammonium carbonate solution dropwise at 0°C to 55°C (for example, over 1 hour to 72 hours) to prepare a supersaturated solution of lanthanum carbonate octahydrate while precipitating lanthanum carbonate octahydrate spherulites. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical degree of supersaturation required to obtain spherulites.

[0120] Another embodiment of the method of the present invention is a method for producing clarithromycin spherulites, comprising the steps of: (1) A step of dissolving clarithromycin in a water-miscible organic solvent (e.g., lower alcohols such as methanol, ethanol, and 2-propanol, tetrahydrofuran, acetone, and mixtures thereof) to prepare a clarithromycin solution; (2) adding the solution prepared in step (1) dropwise to water at -20°C to 50°C (e.g., over a period of 1 second to 1 hour) to prepare a supersaturated solution of clarithromycin; (3) A step of precipitating clarithromycin spherulites at -20°C to 50°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 8, 9, or 10 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 8, 9, or 10, respectively, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation.

[0121] Another embodiment of the method of the present invention is a method for producing spherulites of DL-glutamic acid, comprising the steps of: (1) A step of adding and dissolving DL-glutamic acid in a water-miscible organic solvent (e.g., lower alcohols such as methanol, ethanol, and 2-propanol, tetrahydrofuran, acetone, and mixtures thereof) to prepare a solution of DL-glutamic acid; (2) adding the solution prepared in step (1) dropwise to water at -20°C to 50°C (e.g., over a period of 1 second to 1 hour) to prepare a supersaturated solution of DL-glutamic acid; (3) A step of precipitating spherulites of DL-glutamic acid at -20°C to 50°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 12 or 13 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 12 or 13, respectively, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation.

[0122] Another embodiment of the method of the present invention is a method for producing spherulites of escitalopram oxalate, comprising the steps of: (1) A step of dissolving escitalopram oxalate in water, an organic solvent (e.g., a lower alcohol such as methanol or ethanol, acetonitrile, or acetone), or a mixed solvent thereof, to prepare a solution of escitalopram oxalate; (2) adding dropwise the solution prepared in step (1) to another organic solvent (e.g., a lower alcohol such as 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, or tert-butanol, ethyl acetate, tert-butyl methyl ether, toluene, or a mixture thereof) at -20°C to 30°C to prepare a supersaturated solution of escitalopram oxalate; (3) A step of precipitating spherulites of escitalopram oxalate at -20°C to 30°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in Nos. 21, 22, or 23 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in Nos. 21, 22, or 23, respectively; a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation; or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation. In this production method, seed crystals of escitalopram oxalate may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:5 to 1:30.

[0123] Another embodiment of the method of the present invention is a method for producing spherulites of dabigatran etexilate methanesulfonate, comprising the following steps: (1) A step of dissolving dabigatran etexilate methanesulfonate in an organic solvent (e.g., alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and 1-hexanol, acetonitrile, and mixtures thereof) to prepare a solution of dabigatran etexilate methanesulfonate; (2) adding dropwise the solution prepared in step (1) to another organic solvent (e.g., acetate esters such as ethyl acetate, propyl acetate, and isopropyl acetate, tert-butyl methyl ether, toluene, tetrahydrofuran, acetone, and mixtures thereof) at -20°C to 40°C to prepare a supersaturated solution of dabigatran etexilate methanesulfonate; (3) A step of precipitating spherulites of dabigatran etexilate methanesulfonate at -20°C to 40°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrates, solvents, solvent ratios, and crystallization temperatures listed in Nos. 24, 25, 26, and 27 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in Nos. 24, 25, 26, and 27, respectively; a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation; or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation. In this production method, seed crystals of dabigatran etexilate methanesulfonate may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is preferably 1:3 to 1:1000, more preferably 1:5 to 1:20.

[0124] Another embodiment of the process of the present invention is a method for producing spherulites of theophylline magnesium salt, comprising the steps of: (1) A step of dissolving magnesium chloride hexahydrate in water, an organic solvent (e.g., a lower alcohol such as methanol or ethanol, acetone, acetonitrile, or dimethyl sulfoxide), or a mixed solvent thereof to prepare a magnesium chloride solution; (2) adding dropwise an aqueous solution of theophylline potassium salt to the solution prepared in step (1) at 0°C to 55°C to prepare a supersaturated solution of theophylline magnesium salt; (3) Precipitating spherulites of theophylline magnesium salt at -20°C to 50°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrates, solvents, solvent ratios, and crystallization temperatures listed in Nos. 28, 29, 30, and 31 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in Nos. 28, 29, 30, and 31, respectively; a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation; or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation. In this production method, seed crystals of theophylline magnesium salt may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:20.

[0125] Another embodiment of the process of the present invention is a method for producing teneligliptin hydrobromide hydrate spherulites, comprising the steps of: (1) adding and dissolving teneligliptin hydrobromide hydrate in water and an organic solvent (e.g., a lower alcohol such as methanol or ethanol) or a mixed solvent thereof to prepare a solution of teneligliptin hydrobromide hydrate; (2) adding dropwise the solution prepared in step (1) to another organic solvent (e.g., a lower alcohol such as 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, or tert-butanol, ethyl acetate, tert-butyl methyl ether, toluene, acetone, or a mixture thereof) at -20°C to 30°C to prepare a supersaturated solution of teneligliptin hydrobromide hydrate; (3) A step of precipitating spherulites of teneligliptin hydrobromide hydrate at -20°C to 30°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in Nos. 32, 33, or 34 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in Nos. 32, 33, or 34, respectively; a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation; or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation. Furthermore, in this production method, seed crystals of teneligliptin hydrobromide hydrate may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:5 to 1:30.

[0126] Another embodiment of the method of the present invention is a method for producing spherulites of pilsicainide hydrochloride, comprising the steps of: (1) adding and dissolving pilsicainide hydrochloride in an organic solvent (e.g., alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and 1-hexanol, acetonitrile, ethyl acetate, and mixtures thereof) to prepare a solution of pilsicainide hydrochloride; (2) adding the solution prepared in step (1) dropwise to another organic solvent (e.g., toluene, tert-butyl methyl ether, tetrahydrofuran, acetone, or a mixture thereof) at -20°C to 50°C to prepare a supersaturated solution of pilsicainide hydrochloride; (3) A step of precipitating spherulites of pilsicainide hydrochloride at -20°C to 50°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 35 of Table 3 below, the solution may have a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 35, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. Furthermore, in this production method, seed crystals of pilsicainide hydrochloride may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:20.

[0127] Another embodiment of the process of the present invention is a method for producing spherulites of tramadol hydrochloride, comprising the steps of: (1) A step of dissolving tramadol hydrochloride in water, an organic solvent (e.g., a lower alcohol such as methanol or ethanol, acetone, acetonitrile, or dimethyl sulfoxide), or a mixed solvent thereof, to prepare a solution of tramadol hydrochloride; (2) adding the solution prepared in step (1) dropwise to another organic solvent (e.g., acetone, tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, tert-butyl methyl ether, or a mixture thereof) at -10°C to 40°C to prepare a supersaturated solution of tramadol hydrochloride; (3) A step of precipitating spherulites of tramadol hydrochloride at -10°C to 40°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrates, solvents, solvent ratios, and crystallization temperatures listed in Nos. 36, 37, and 38 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in Nos. 36, 37, and 38, respectively; a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation; or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation. In this production method, seed crystals of tramadol hydrochloride may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:40.

[0128] Another embodiment of the process of the present invention is a method for preparing spherulites of vildagliptin, comprising the steps of: (1) adding and dissolving vildagliptin in an organic solvent (e.g., lower alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, and tert-butanol, acetone, 2-butanone, acetonitrile, and mixtures thereof) to prepare a vildagliptin solution; (2) adding the solution prepared in step (1) dropwise to another organic solvent (e.g., tert-butyl methyl ether, diisopropyl ether, toluene, ethyl acetate, isopropyl acetate, butyl acetate, cyclopentyl methyl ether, cyclohexane, heptane, and mixtures thereof) at -20°C to 30°C to prepare a supersaturated solution of vildagliptin; (3) A step of precipitating vildagliptin spherulites at -20°C to 30°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrates, solvents, solvent ratios, and crystallization temperatures listed in Nos. 39, 40, 41, 42, 43, or 44 in Table 3 below, the solution may have a degree of supersaturation equal to or greater than the measured critical supersaturation value listed in Nos. 39, 40, 41, 42, 43, or 44, respectively; a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation; or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation. Furthermore, in this production method, seed crystals of vildagliptin may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:0.5 to 1:50.

[0129] Another embodiment of the process of the present invention is a process for preparing spherulites of linagliptin, comprising the steps of: (1) A step of dissolving linagliptin in an organic solvent (e.g., a lower alcohol such as methanol or ethanol, tetrahydrofuran, or acetone) or a mixed solvent thereof to prepare a linagliptin solution; (2) adding the solution prepared in step (1) dropwise to another organic solvent (e.g., a lower alcohol such as 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, or tert-butanol, ethyl acetate, tert-butyl methyl ether, toluene, or a mixture thereof) at -20°C to 30°C to prepare a supersaturated solution of linagliptin; (3) A step of precipitating spherulites of linagliptin at -20°C to 30°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrates, solvents, solvent ratios, and crystallization temperatures listed in Nos. 45 and 46 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in Nos. 45 and 46, respectively, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. Furthermore, in this production method, seed crystals of linagliptin may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:20.

[0130] Another embodiment of the method of the present invention is a method for producing spherulites of glutathione, comprising the steps of: (1) A step of dissolving glutathione in water, an organic solvent (e.g., a lower alcohol such as methanol), or a mixed solvent thereof to prepare a glutathione solution; (2) adding dropwise the solution prepared in step (1) to another organic solvent (e.g., a lower alcohol such as 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, or tert-butanol, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, toluene, acetone, or a mixture thereof) at -20°C to 30°C to prepare a supersaturated solution of glutathione; (3) A process of precipitating mirabegron spherulites at -20°C to 30°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 47 of Table 3 below, the solution may have a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 47, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. Furthermore, in this production method, seed crystals of mirabegron may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:2 to 1:30.

[0131] Another embodiment of the method of the present invention is a method for producing spherulites of mirabegron, comprising the steps of: (1) A step of dissolving mirabegron in an organic solvent (lower alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, and tert-butanol, acetone, 2-butanone, acetonitrile, and mixtures thereof) to prepare a mirabegron solution; (2) adding dropwise the solution prepared in step (1) to water, another organic solvent (e.g., tert-butyl methyl ether, diisopropyl ether, toluene, ethyl acetate, isopropyl acetate, butyl acetate, cyclopentyl methyl ether, cyclohexane), or a mixed solvent thereof at -20°C to 40°C to prepare a supersaturated solution of mirabegron; (3) A process of precipitating mirabegron spherulites at -20°C to 40°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrates, solvents, solvent ratios, and crystallization temperatures listed in Nos. 48, 49, 50, 51, 52, or 53 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in Nos. 48, 49, 50, 51, 52, or 53, respectively; a degree of supersaturation equal to or greater than the predicted 95% lower limit of the critical supersaturation; or a degree of supersaturation equal to or greater than the predicted 95% upper limit of the critical supersaturation. Furthermore, in this production method, seed crystals of mirabegron may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:0.2 to 1:50.

[0132] Another embodiment of the method of the present invention is a method for producing spherulites of tolvaptan, comprising the steps of: (1) preparing a tolvaptan solution by adding and dissolving tolvaptan in a water-miscible organic solvent (e.g., lower alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol, and mixtures thereof); (2) adding the solution prepared in step (1) dropwise to water at -10°C to 50°C to prepare a supersaturated solution of tolvaptan; (3) Precipitating spherulites of tolvaptan at -10°C to 50°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 54 or 55 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 54 or 55, respectively, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. In this production method, seed crystals of tolvaptan may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:20, more preferably 1:0.1 to 1:10.

[0133] Another embodiment of the process of the present invention is a process for preparing spherulites of valacyclovir hydrochloride, comprising the steps of: (1) A step of dissolving valacyclovir hydrochloride in water, an organic solvent (e.g., a lower alcohol such as methanol, tert-butyl methyl ether, dimethyl sulfoxide), or a mixed solvent thereof to prepare a solution of valacyclovir hydrochloride; (2) adding the solution prepared in step (1) dropwise to another organic solvent (e.g., a lower alcohol such as 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, or tert-butanol, tetrahydrofuran, toluene, or a mixture thereof) at -10°C to 40°C to prepare a supersaturated solution of valacyclovir hydrochloride; (3) A step of precipitating spherulites of valacyclovir hydrochloride at -10°C to 40°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 56 of Table 3 below, the solution may have a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 56, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. In this production method, seed crystals of valacyclovir hydrochloride may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:1 to 1:50.

[0134] Another embodiment of the method of the present invention is a method for producing spherulites of bepotastine besylate, comprising the steps of: (1) A step of dissolving bepotastine besilate in water and an organic solvent (e.g., a lower alcohol such as methanol or ethanol) or a mixed solvent thereof to prepare a solution of bepotastine besilate; (2) adding dropwise the solution prepared in step (1) to another solvent (e.g., lower alcohols such as 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, toluene, acetone, and mixtures thereof) at -20°C to 30°C to prepare a supersaturated solution of bepotastine besilate; (3) A step of precipitating spherulites of bepotastine besilate at -20°C to 30°C. The solution obtained in step (2) of this production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 57 of Table 3 below are used, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 57, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. In this production method, seed crystals of bepotastine besilate may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in this production method is not particularly limited, but is preferably 1:0.1 to 1:100, more preferably 1:5 to 1:30.

[0135] Another embodiment of the method of the present invention is a method for producing spherulites of olopatadine, comprising the steps of: (1) A step of adding and dissolving olopatadine in an organic solvent (e.g., a lower alcohol such as methanol or ethanol, tetrahydrofuran, or a mixed solvent thereof) to prepare a solution of olopatadine; (2) adding dropwise the solution prepared in step (1) to another organic solvent (e.g., acetate esters such as ethyl acetate, propyl acetate, and isopropyl acetate; lower alcohols such as 1-propanol, 2-propanol, 1-butanol, and 2-butanol; tert-butyl methyl ether; toluene; acetone; and mixed solvents thereof) at -20°C to 40°C to prepare a supersaturated solution of olopatadine; (3) Precipitating spherulites of olopatadine at -20°C to 40°C. The solution obtained in step (2) of the present production method has a degree of supersaturation equal to or greater than the critical supersaturation required to obtain spherulites. For example, when using the substrate, solvent, solvent ratio, and crystallization temperature listed in No. 58 of Table 3 below, the solution has a degree of supersaturation equal to or greater than the measured value of the critical supersaturation listed in No. 58, a degree of supersaturation equal to or greater than the predicted value of the critical supersaturation, a degree of supersaturation equal to or greater than the predicted lower limit of 95% of the critical supersaturation, or a degree of supersaturation equal to or greater than the predicted upper limit of 95% of the critical supersaturation. Furthermore, in the present production method, seed crystals of olopatadine may be inoculated between steps (2) and (3). The volume ratio of the good solvent to the poor solvent used in the present production method is not particularly limited, but is preferably 1:3 to 1:100, more preferably 1:5 to 1:20. [Example]

[0136] The present invention will be described in more detail with reference to the following examples, but it goes without saying that the scope of the present invention is not limited to these examples.

[0137] Unless otherwise specified, the various reagents used in the examples were either commercially available products or those prepared by known methods.

[0138] Particle size distribution was measured dry using a Microtrac spray particle size distribution analyzer, Aerotrac LDSA-SPR3500A. Note that the particle size distribution in Examples 2 and 7 was measured dry using a Malvern Laser Diffraction Particle Size Analyzer, Mastersizer 3000. SEM images were measured using a JEOL JSM-IT100 scanning electron microscope. Optical microscope images were measured using an Olympus BX53M upright microscope and an Olympus DP74 microscope digital camera. Images for particle counting were acquired using an Epson GT-X830 scanner. Powder X-ray diffraction (XRD) was measured using a Rigaku MiniFlex300 desktop X-ray diffractometer. Specific surface area was measured using a Mountec Macsorb HM-1208 fully automated specific surface area analyzer by the BET flow method (using pure nitrogen gas). Moisture content was measured using a Hiranuma Sangyo AQ-2200 trace moisture analyzer. Dissolution profiles were measured using a Pion μDISS Profiler. Centrifugal classification was performed using a Seishin Enterprises high-efficiency precision airflow classifier, Labo Cruseal N-01. Image analysis was performed using ImageJ, an image processing software developed by the National Institutes of Health (NIH). Particle strength was measured using an Okada Seiko New Grano particle hardness measuring device. True density was measured using a Shimadzu Accupyc II 1340-10CC dry automatic density meter. Compound purity was measured using a Shimadzu LC-20A high-performance liquid chromatograph.

[0139] Example 1 Measurement of the critical supersaturation of spherulites The critical supersaturation of ketotifen fumarate spherulites was determined as follows. 2.0 g of ketotifen fumarate was added to 10 mL of methanol (5 v / w) and completely dissolved by reflux. This solution was added dropwise to 50 mL of isopropanol at 20°C to prepare a supersaturated solution of ketotifen fumarate. At the end of the dropwise addition, the supersaturation of the supersaturated solution was 9.0. Crystallization was then carried out. The crystals were collected by filtration and dried under reduced pressure at 40°C to obtain ketotifen fumarate crystals. The sphericity of the spherulites was 0.78±0.02.

[0140] To gradually decrease the supersaturation, the amounts of methanol were adjusted to 11.5 v / w and 13.5 v / w, and the amount of isopropanol was adjusted to 5 times the amount of methanol. After the dropwise addition, seed crystals were added and crystallization was performed. The supersaturation degrees were 4.0 and 3.4, respectively. Figure 1 shows the results of SEM observation of each sample. Spherulites with a sphericity of 0.60 or greater were observed at supersaturations of 9.0 to 4.0 (Figures 1(a)-(b)), but not at 3.4 (Figure 1(c)). Since the difference between 3.4, the maximum supersaturation at which no spherulites with a sphericity of 0.60 or greater existed, and the critical supersaturation of 4.0 is within 20% of the critical supersaturation, we determined 4.0 as the critical supersaturation degree for ketotifen fumarate crystallized in a 1:5 methanol:isopropanol mixture at 20°C (see Figures 1 and 2).

[0141] Similarly, when using substrates and solvents different from those mentioned above, samples with different degrees of supersaturation were prepared and crystallized, and the critical supersaturation of spherulites was measured. The results are shown in Table 3. [Table 3-1] [Table 3-2]

[0142] Example 2 Preparation of spherulites of esomeprazole magnesium trihydrate (crystallization under normal dropping conditions) 13.43 kg (17.0 L) of methanol was added to 1.7 kg of esomeprazole magnesium trihydrate and dissolved with stirring at room temperature. 51.0 kg (51.0 L) of water was added dropwise to the resulting solution at 25°C over 11 minutes to prepare a supersaturated solution of esomeprazole magnesium trihydrate. At the end of the dropwise addition, the degree of supersaturation of the resulting solution was 6.7. Amorphous precipitate of esomeprazole magnesium was observed in the resulting solution (the amorphous nature of the precipitate was confirmed by powder X-ray diffraction). 25.5 mg of esomeprazole magnesium trihydrate suspended in 2.6 mL of water was added to the resulting solution as seed crystals. The solution was allowed to stand at 35°C for 45 hours and then stirred for 3 hours. After the addition of the seed crystals, the amorphous phase in the supersaturated solution dissolved, and crystallization of esomeprazole magnesium trihydrate proceeded. The precipitate was then isolated by centrifugation, washed with a mixture of 1.3 kg (1.7 L) of methanol and 5.1 kg (5.1 L) of water, and then dried under reduced pressure at 40°C for 38 hours to obtain 1.4 kg of esomeprazole magnesium trihydrate spherulites (yield 80%). 50 The diameter was 56.1 μm and the sharpness index was 2.5. The obtained crystals were separated into fine powder and coarse powder by centrifugal classification. The obtained fine powder was classified into 235 mesh (M) (63 μm) and 390M (38 μm). The crystals above 390M (38 μm) were further processed using an aspirator to obtain spherulites of esomeprazole magnesium trihydrate. The diameter of the fine powder was 56.1 μm and the sharpness index was 2.5. The obtained fine powder was separated into fine powder and coarse powder by centrifugal classification. The obtained fine powder was classified into 235 mesh (M) (63 μm) and 390M (38 μm). The crystals above 390M (38 μm) were further processed using an aspirator to obtain spherulites of esomeprazole magnesium trihydrate. 50 The diameter was 54.6 μm, the sharpness index was 1.3, and the sphericity of the spherulites was 0.95 ± 0.03 (see Figures 5 to 7).

[0143] Example 3 Preparation of spherulites of esomeprazole magnesium trihydrate (crystallization under normal dropping conditions) 50 mL of methanol was added to 10 g of esomeprazole magnesium trihydrate and dissolved with stirring at room temperature. 150 mL of water was added dropwise to the solution at 25°C, followed by the addition of 0.1 mg of esomeprazole magnesium trihydrate and the stirring was stopped. The temperature was raised to 45°C and the mixture was allowed to stand for 3 hours. 100 mL of methanol was then added with stirring. The solid was then isolated by vacuum filtration and dried under reduced pressure at 40°C for 20 hours to obtain 1.84 g of esomeprazole magnesium trihydrate spherulites (18% yield). The resulting crystals were classified using 149 mesh (100 μm) and 390 mesh (38 μm) sieves. The crystals above the 390 mesh (38 μm) sieve were then filtered using an aspirator to obtain esomeprazole magnesium trihydrate spherulites. The sphericity of the spherulites was 0.97 ± 0.01, and the equivalent circle diameter was 58 ± 7 μm (see Figure 8).

[0144] Example 4 Preparation of spherulites of esomeprazole magnesium trihydrate (crystallization under normal dropping conditions) 50 mL of methanol was added to 5 g of esomeprazole magnesium trihydrate and dissolved with stirring at room temperature. 50 mL of water was added dropwise to the solution at 35°C, and the solid was removed by pressure filtration. 50 mg of esomeprazole magnesium trihydrate spherulites (circle equivalent diameter 51 ± 3 μm) were added to the resulting solution and stirred at 35°C for 114 hours. The solid was then isolated by vacuum filtration and dried under reduced pressure at 40°C for 20 hours to obtain esomeprazole magnesium trihydrate spherulites (quantitative yield 66%). The sphericity of the spherulites was 0.93 ± 0.02, and the circle equivalent diameter was 183 ± 8 μm (see Figure 9).

[0145] Example 5 Preparation of spherulites of esomeprazole magnesium trihydrate (crystallization under normal dropping conditions) 20.0 g of esomeprazole magnesium trihydrate was dissolved in 360 mL of methanol while stirring at room temperature. 360 mL of water was added dropwise to the solution at 35°C, and insoluble matter was removed by pressure filtration. 20.0 mg of esomeprazole magnesium trihydrate was added and the mixture was stirred at 35°C for 186 hours. The solid was then isolated by vacuum filtration and dried under reduced pressure at 40°C for 23 hours to obtain 3.66 g of esomeprazole magnesium trihydrate spherulites (yield 18%). The resulting crystals were classified at 149 M (100 μm). The sharpness index of the resulting crystals was 1.4, and d 50 was 149.9 μm, and the sphericity of the spherulites was 0.89 ± 0.05 (see Figures 10 to 12).

[0146] Example 6 Preparation of spherulites of esomeprazole magnesium trihydrate (crystallization by salt exchange) 23.7 g of esomeprazole potassium dimethanol salt (purity 98.59%) was dissolved in 30.3 mL of water and 66.4 mL of acetone at room temperature. This solution was stirred, and 28.08 g of 5.8% aqueous magnesium chloride solution was added dropwise over 30 minutes. The solution was filtered under pressure, and 1.1 mg of esomeprazole magnesium trihydrate was added to the filtrate. Stirring was continued for 22 hours, after which 65.43 g of 5.5% aqueous magnesium chloride solution was added dropwise over 16 hours. After stirring for 23 hours, the crystals were collected by filtration and dried under reduced pressure at 50°C for 7 hours to obtain 14.8 g of esomeprazole magnesium trihydrate spherulites (yield 73.0%, purity 99.90%). The sharpness index of the resulting crystals was 1.45, and d 50 The diameter of the spherulites was 91.5 μm, and the sphericity of the spherulites was 0.96 ± 0.01 (see Figures 13 to 15).

[0147] Example 7 Preparation of spherulites of esomeprazole magnesium trihydrate (crystallization by salt exchange) 0.88 g of esomeprazole magnesium trihydrate was added to 33 mL of acetone and 62 mL of water and stirred at 30°C for 2 hours to dissolve. After filtering to remove dust, 8.9 mg of ground esomeprazole magnesium trihydrate (D50: 1.8 μm) was added and stirred to prepare a suspension. A solution of 5.49 g of magnesium chloride hexahydrate dissolved in 17 mL of acetone and 31 mL of water and a solution of 23.7 g of esomeprazole potassium dimethanolate (purity 98.59%) dissolved in 17 mL of acetone and 31 mL of water were simultaneously added dropwise over 33 hours. After stirring for 11 hours from the completion of the addition, the crystals were collected by filtration and washed with a mixture of 21 mL of acetone and 38 mL of water. The mixture was dried under reduced pressure at 40°C for 20 hours to obtain 16.4 g of esomeprazole magnesium trihydrate spherulites (yield 77%, purity 99.87%). The sharpness index of the obtained crystals was 1.40, d50 was 189 μm, and the sphericity of the spherulites was 0.97±0.01 (see FIGS. 16 to 18).

[0148] Example 8 Dissolution profile measurement (1) Preparation of esomeprazole magnesium trihydrate spherulites 100 g of esomeprazole magnesium trihydrate was added to 1.0 L of methanol and dissolved under stirring at 35°C. 3.0 L of water was added dropwise to the solution at 35°C, after which 0.1 g of esomeprazole magnesium trihydrate was added and the mixture was allowed to stand for 46 hours. The solid was then isolated by vacuum filtration and dried under reduced pressure at 40°C for 63 hours to obtain 69.9 g of esomeprazole magnesium trihydrate spherulites (70% yield). The sharpness index of the resulting crystals was 2.2, and d 50 The diameter of the spherulites was 33.0 μm, and the sphericity of the spherulites was 0.95±0.03 (see Figures 44 to 46). (2) Measurement of spherulitic and non-spherulitic dissolution profiles of esomeprazole magnesium trihydrate At 37°C, 30 mg of the esomeprazole magnesium trihydrate spherulites prepared in (1) above were added to 10 mL of pH 6.8 phosphate buffer and stirred at 300 rpm. The solution concentration was measured over time using a μDISS Profiler. For comparison, a non-spherulitic pulverized sample of esomeprazole magnesium trihydrate (sphericity 0.45±0.23) was also measured in the same manner. Data for the pulverized sample are shown in Figures 47 to 49. Compared to the non-spherulites, the spherulites dissolve more quickly (see Figure 3). The particle size and specific surface area of ​​the samples used are shown in Table 4 below.

[0149] [Table 4]

[0150] Example 9 Particle density and particle strength measurements The particle density and particle strength of esomeprazole magnesium trihydrate spherulites (Sample 1) obtained in the same manner as in Example 2, esomeprazole magnesium trihydrate spherulites (Sample 2) obtained in the same manner as in Example 4, and esomeprazole magnesium trihydrate spherulites (Sample 3) obtained in the same manner as in Example 6 were measured. The true density of esomeprazole magnesium trihydrate is 1.37 g / cm 3 The measurement results are shown in Table 5 below.

[0151] [Table 5]

[0152] The particle strength of the esomeprazole magnesium trihydrate spherulites obtained in Example 2, Example 5, and Example 6 was measured. The results are shown in Table 6.

[0153] [Table 6]

[0154] Example 10 Measurement of filtration time and cake thickness (1) Preparation of esomeprazole magnesium trihydrate spherulites (crystallization by salt exchange) 23.7 g of esomeprazole potassium dimethanolate was dissolved in 30.3 mL of water and 66.4 mL of acetone at room temperature. While stirring, 28.08 g of 5.8% aqueous magnesium chloride solution was added dropwise over 30 minutes. The solution was filtered by pressure filtration, and 71.1 mg of esomeprazole magnesium trihydrate was added to the filtrate. After 2.5 hours of stirring, 65.43 g of 5.5% aqueous magnesium chloride solution was added dropwise over 12 hours. After 8 hours of stirring, the crystals were filtered under reduced pressure using a Nutsche filter (outer diameter 70 mm, filter paper retention particle size 1 μm) and washed with 20 mL of acetone / water (35:65). After drying under reduced pressure at 50°C for 4.5 hours, 17.4 g of esomeprazole magnesium trihydrate spherulites were obtained (80% yield). The sharpness index of the resulting crystals was 1.51, and d 50 The diameter of the crystals was 39.9 μm, and the sphericity of the spherulites was 0.97±0.01 (see FIGS. 50 and 51). All of the obtained crystals were spherulites as far as observation by SEM was concerned.

[0155] (2) Preparation of esomeprazole magnesium trihydrate crystals (crystallization by salt exchange) 23.7 g of esomeprazole potassium dimethanolate was dissolved in 30.3 mL of water and 66.4 mL of acetone at room temperature. While stirring, 28.08 g of 5.8% aqueous magnesium chloride solution was added dropwise over 30 minutes. The solution was filtered by pressure filtration, and 71.1 mg of esomeprazole magnesium trihydrate was added to the filtrate. After 2.5 hours of stirring, 65.43 g of 5.5% aqueous magnesium chloride solution was added dropwise over 30 minutes. After 14 hours of stirring, the crystals were filtered under reduced pressure using a Nutsche filter (outer diameter 70 mm, filter paper retention particle size 1 μm) and washed with 20 mL of acetone / water (35:65). After drying under reduced pressure at 50°C for 4.5 hours, 17.9 g of esomeprazole magnesium trihydrate crystals were obtained (yield 82%). The sharpness index of the resulting crystals was 1.48, and d 50The average diameter was 9.6 μm. The obtained crystals consisted of a mixture of spherulites and non-spherulites. SEM images and particle size distribution confirmed that the proportion of non-spherulites was higher than that of spherulites. The sphericity of the spherulites contained in the obtained crystals was 0.80 ± 0.05. The sphericity of the non-spherulites contained in the obtained crystals was 0.50 ± 0.06 (see Figures 52 and 53).

[0156] In the above (1) and (2), the filtration times and cake thicknesses when esomeprazole magnesium trihydrate was isolated are shown in Table 7 below.

[0157] [Table 7]

[0158] Example 11 Preparation of spherulites of lansoprazole (crystallization by sequential dropping) 20 mL of methanol was added to 1 g of lansoprazole and heated to 35°C to dissolve. This solution was added dropwise to 60 mL of water at 0 to 5°C over 10 minutes to prepare a supersaturated solution of lansoprazole. The degree of supersaturation of the resulting solution at the end of the dropwise addition was 35. This value was higher than the measured critical supersaturation value (10.9) shown in No. 2 of Table 1 above. Then, 0.1 mg of lansoprazole was added as seed crystals, and the mixture was allowed to stand at 0 to 5°C for 4 hours. The precipitate was then isolated by vacuum filtration and dried to obtain 0.17 g of lansoprazole spherulites (17% yield). SEM images and powder X-ray diffraction results of the resulting spherulites are shown in Figures 19 and 20. The sphericity of the spherulites was 0.94 ± 0.04.

[0159] Example 12 Preparation of spherulites of azithromycin monohydrate (crystallization by reverse dropping). 1.0 g of azithromycin dihydrate was added to 10 mL of ethanol and dissolved under stirring at room temperature. This solution was added dropwise to 100 mL of 0°C water over 100 minutes to prepare a supersaturated solution of azithromycin. Crystals precipitated when the temperature was raised to 8°C in 1 minute 18 seconds. The degree of supersaturation at this point was 13.5. The temperature was then raised to 20°C in 3 minutes 9 seconds and stirred for 3 hours. The precipitate was then isolated by vacuum filtration and dried under vacuum at 40°C for 17 hours, yielding 0.81 g of azithromycin monohydrate spherulites (81% yield). The d of the resulting crystals was 50 The diameter was 75 μm, the sharpness index was 1.5, and the sphericity of the spherulites was 0.89±0.02 (see Figures 21 to 23).

[0160] The spherulite of azithromycin monohydrate produced in Example 12 was cut and the cut surface was observed by SEM (FIG. 4). The crystal size at the outer edge was 5 to 10 μm, while the crystal size at the center was 0.2 to 1 μm.

[0161] Example 13 Preparation of clarithromycin spherulites (crystallization under reverse dripping). 2 mL of tetrahydrofuran was added to 1 g of clarithromycin and dissolved at 50°C. This solution was added dropwise to 50 mL of water at 10°C over approximately 5 seconds with stirring to prepare a supersaturated solution of clarithromycin. The degree of supersaturation of the supersaturated solution at the end of the addition was 86. This value was higher than the measured value (17) of the critical supersaturation shown in No. 10 in Table 1 above. Immediately after the addition was completed, precipitation of clarithromycin crystals began. Approximately 6 minutes after the addition was completed, the precipitated crystals were filtered and dried under reduced pressure at 40°C for 17 hours to obtain 0.73 g of clarithromycin spherulites (73% yield). The d of the obtained crystals 50 The diameter was 16 μm, the sharpness index was 4.6, and the sphericity of the obtained spherulites was 0.87±0.08 (see Figures 24 to 26).

[0162] Example 14 Preparation of DL-glutamic acid spherulites (crystallization by reverse dropping) 0.21 g of DL-glutamic acid was added to 4 mL of water (20 v / w) and completely dissolved at 60°C. This solution was added dropwise to 20 mL of acetone cooled to 0°C over 3 seconds to cause crystallization. The degree of supersaturation was 91. The crystals were collected by filtration and dried under reduced pressure at 40°C to obtain DL-glutamic acid spherulites. The sphericity of the spherulites was 0.95 ± 0.03 (see Figures 27 and 28).

[0163] Example 15 Preparation of spherulites of duloxetine hydrochloride (crystallization by salt formation) 50 mL of 2-propanol and 5 mL of Span 80 were added to 5 g of duloxetine and dissolved at room temperature. While stirring the solution, 16 mL of a 1 mol / L hydrogen chloride-ethyl acetate solution was added dropwise at 20°C over approximately 1 second to prepare a supersaturated solution of duloxetine hydrochloride. The degree of supersaturation of the supersaturated solution at the end of the addition was 73. Approximately 3 minutes after the end of the addition, precipitation of duloxetine hydrochloride crystals began. One hour after the end of the addition, the precipitated crystals were collected by filtration and dried under reduced pressure at 40°C for 16 hours, yielding 4.7 g of duloxetine hydrochloride spherulites (yield 84%). The d of the obtained crystals was 50 The diameter was 138 μm, the sharpness index was 4.7, and the sphericity of the spherulites was 0.92±0.07 (see Figures 30 to 32).

[0164] Example 16 Preparation of spherulites of clopidogrel sulfate (crystallization by salt formation) 2 g of clopidogrel was dissolved in 40 mL of 2-butanol and 180 μL of water at room temperature. While stirring the solution, 0.63 g of 98 wt % aqueous sulfuric acid solution was added dropwise over approximately 1 second to prepare a supersaturated solution of clopidogrel sulfate. The degree of supersaturation of the supersaturated solution at the end of the addition was 23. After the addition, 2 mg of seed crystals were seeded and the stirring was continued for 102 hours. The crystals were collected by filtration and dried under reduced pressure at 70°C for 16 hours to obtain 1.87 g of spherulites of clopidogrel sulfate (yield 94%). The d of the obtained crystals 50 The diameter was 133 μm, the sharpness index was 1.7, and the sphericity of the spherulites was 0.96±0.02 (see Figures 33 to 35).

[0165] Example 17 Preparation of spherulites of lanthanum carbonate octahydrate (crystallization by chemical transformation) 35.1 g of lanthanum oxide was dissolved in 140 mL of water and 119.4 g of 20% hydrochloric acid. The solution was filtered to remove dust. While stirring the filtered aqueous lanthanum chloride solution, an aqueous ammonium carbonate solution (prepared using 35.2 g of ammonium carbonate and 175.5 mL of water) was added dropwise to the solution at 40°C over 46 hours. Lanthanum carbonate crystals precipitated 3 hours after the start of the addition. Two hours after the end of the addition, the precipitated crystals were collected by filtration and washed five times with 526 mL of water. The crystals were dried under reduced pressure at 40°C to obtain 61.9 g of lanthanum carbonate octahydrate spherulites (yield 96%). The obtained crystals were classified using a 149 mesh (M) (100 μm) sieve. The d of the obtained crystals 50 The diameter was 105 μm, the sharpness index was 1.4, and the sphericity of the spherulites was 0.69±0.08 (see Figures 36 to 38).

[0166] Example 18 Development of a model for predicting critical supersaturation 50,000 compound structures were randomly extracted from the ChEMBL (https: / / www.ebi.ac.uk / chembl / ) database, chembl_23, and the PubChem (https: / / pubchem.ncbi.nlm.nih.gov / ) database. These structures were then removed and desalted, resulting in a total of 89,203 structures. These compounds, along with desalted forms of 21 active pharmaceutical ingredients (azithromycin, clarithromycin, DL-glutamic acid, esomeprazole, lansoprazole, clopidogrel, ketotifen, theophylline, vildagliptin, valacyclovir, tramadol, escitalopram, dabigatran etexilate, pilsicainide, linagliptin, glutathione, mirabegron, teneligliptin, tolvaptan, bepotastine, and olopatadine), totaling 89,224 compound data were used. Solvent data for 14 solvents (1-butanol, 2-butanol, 2-propanol, acetone, ethanol, ethyl acetate, heptane, isopropyl acetate, methanol, methyl ethyl ketone, tert-butyl methyl ether, tetrahydrofuran, toluene, and water) were used. Descriptors were calculated using alvaDesc1.0 (https: / / www.alvascience.com / alvadesc / ). After calculating all two-dimensional descriptors, we removed any descriptors that could not be calculated, descriptors with the same value for all structures, and pairs of two structural descriptors with a correlation coefficient of 1.0. We also removed descriptors whose values ​​were all integers, including those indicating specific substructures or atom ratios. This left 436 descriptors for compounds and 373 for solvents.

[0167] Compound descriptors (436 types) MW,AMW,Se,Sp,Si,Me,Mp,Mi,GD,SCBO,RBF,H%,C%,N%,O%,X%,MCD,RFD,RCI,NNRS,ARR,D / Dtr03,D / Dtr04,D / Dtr05,D / Dtr06,D, / Dtr r09,D / Dtr10,D / Dtr11,D / Dtr12,LPRS,MSD,SPI,AECC,DECC,MDDD,ICR,MeanTD,MeanDD,S1K,S2K,S3K,PHI,PW2,PW3,PW4,PW5,MAXDNLS,MAX C,MWC01,MWC02,MWC03,MWC04,MWC05,MWC06,MWC07,MWC08,MWC09,MWC10,SRW02,SRW03,SRW04,SRW05,SRW06,SRW07,SRW0,MPC,MP 03,MPC04,MPC05,MPC06,MPC07,MPC08,MPC09,MPC10,piPC01,piPC02,piPC03,piPC04,piPC05,piPC06,piPC07,piPC08,piPC09,piPC10,TWC,TPC,pi ID,PCD,CID,BID,ATS1m,ATS2m,ATS3m,ATS4m,ATS5m,ATS6m,ATS7m,ATS8m,ATS1e,ATS2e,ATS3e,ATS4e,ATS2p1p,AT, S3p,ATS4p,ATS5p,ATS6p,ATS7p,ATS8p,ATS1i,ATS2i,ATS3i,ATS4i,ATS5i,ATSC2m,ATSC3m,ATSC4m,ATSC5m,A,ATSC6 TSC7m,ATSC8m,ATSC1e,ATSC2e,ATSC3e,ATSC4e,ATSC5e,ATSC6e,ATSC7e,ATSC8e,ATSC1p,ATSC2p,ATSC3p,ATSC4p,ATSC5p,ATSC6p,ATSC7p,ATSC8p, ATSC1i,ATSC2i,ATSC3i,ATSC4i,ATSC5i,ATSC6i,ATSC7i,ATSC8i,MATS1m,MATS2m,MATS3m,MATS4m,MATS5m,MATS6m,MATS7m,MATS8m,MATS1e,MATS2e,MATS3e,MATS4e,MATS5e,MATS6e,MATS7e,MATS8e,MATS1p,MATS2p,MATS3p,MATS4p,MATS5p,MATS6p,MATS7p,MATS8p,MATS1i,MATS2i,MATS3i,MATS 4i,MATS5i,MATS6i,MATS7i,MATS8i,GATS1m,GATS2m,GATS3m,GATS4m,GATS5m,GATS6m,GATS7m,GATS8m,GATS1e,GATS2e,GATS3e,GATS4e,GATS5e,GA TS6e,GATS7e,GATS8e,GATS1p,GATS2p,GATS3p,GATS4p,GATS5p,GATS6p,GATS7p,GATS8p,GATS1i,GATS2i,GATS3i,GATS4i,GATS5i,GATS6i,GATS7i, GATS8i,GGI1,GGI2,GGI3,GGI4,GGI5,GGI6,GGI7,GGI8,GGI9,GGI10,JGI1,JGI2,JGI3,JGI4,JGI5,JGI6,JGI7,JGI8,JGI9,JGI10,JGT,SpMax1_Bh(m ),SpMax2_Bh(m),SpMax3_Bh(m),SpMax4_Bh(m),SpMax5_Bh(m),SpMax6_Bh(m),SpMax7_Bh(m),SpMax8_Bh(m),SpMax1_Bh(e),SpMax2_Bh(e),SpMax 3_Bh(e),SpMax4_Bh(e),SpMax5_Bh(e),SpMax6_Bh(e),SpMax7_Bh(e),SpMax8_Bh(e),SpMax1_Bh(p),SpMax2_Bh(p),SpMax3_Bh(p),SpMax4_Bh(p) ,SpMax5_Bh(p),SpMax6_Bh(p),SpMax7_Bh(p),SpMax8_Bh(p),SpMax1_Bh(i),SpMax2_Bh(i),SpMax3_Bh(i),SpMax4_Bh(i),SpMax5_Bh(i),SpMax6 _Bh(i),SpMax7_Bh(i),SpMax8_Bh(i),SpMin1_Bh(m),SpMin2_Bh(m),SpMin3_Bh(m),SpMin4_Bh(m),SpMin5_Bh(m),SpMin6_Bh(m),SpMin7_Bh(m),SpMin8_Bh(m),SpMin1_Bh(e),SpMin2_Bh(e),SpMin3_Bh(e),SpMin4_Bh(e),SpMin5_Bh(e),SpMin6_Bh(e),SpMin7_Bh(e),SpMin8_Bh(e),SpMin1_Bh(e) Bh(p),SpMin2_Bh(p),SpMin3_Bh(p),SpMin4_Bh(p),SpMin5_Bh(p),SpMin6_Bh(p),SpMin7_Bh(p),SpMin8_Bh(p),SpMin1_Bh(i),SpMin2_Bh(i),Sp Min3_Bh(i),SpMin4_Bh(i),SpMin5_Bh(i),SpMin6_Bh(i),SpMin7_Bh(i),SpMin8_Bh(i),P_VSA_LogP_1,P_VSA_LogP_2,P_VSA_LogP_3,P_VSA_Log P_4,P_VSA_LogP_5,P_VSA_LogP_6,P_VSA_LogP_7,P_VSA_LogP_8,P_VSA_MR_1,P_VSA_MR_2,P_VSA_MR_3,P_VSA_MR_4,P_VSA_MR_5,P_VSA_MR_6,P_VSA_MR_6 SA_MR_7,P_VSA_MR_8,P_VSA_m_1,P_VSA_m_2,P_VSA_m_3,P_VSA_m_4,P_VSA_m_5,P_VSA_v_2,P_VSA_v_3,P_VSA_v_4,P_VSA_e_1,P_VSA_e_2,P_VSA _e_3,P_VSA_e_4,P_VSA_e_5,P_VSA_e_6,P_VSA_p_1,P_VSA_p_2,P_VSA_p_3,P_VSA_p_4,P_VSA_i_1,P_VSA_i_2,P_VSA_i_3,P_VSA_i_4,P_VSA_s_1, P_VSA_s_2,P_VSA_s_3,P_VSA_s_4,P_VSA_s_5,P_VSA_s_6,P_VSA_ppp_L,P_VSA_ppp_P,P_VSA_ppp_N,P_VSA_ppp_D,P_VSA_ppp_A,P_VSA_ppp_ar,P_VSA_ppp_ar VSA_ppp_con,P_VSA_ppp_hal,P_VSA_ppp_cyc,P_VSA_ppp_ter,SsCH3,SdCH2,SssCH2,StCH,SdsCH,SaaCH,SsssCH,SddC,StsC,SdssC,SaasC,SaaaC,SssssC, SsNH2, SssNH, SdNH, SsssN, SdsN, SaaN, StN, SsNH3+, SssNH2+, SdNH2+, SsssNH+, SssssN+, SddsN, SaasN, SaaNH, SsOH, SdO, SssO, SaaO, SsssP, SdsssP, SsssssP, SsSH, SdS, SssS, SaaS, SdssS, SddssS, SsF, SsCl, SsBr, SsI, SsssB, SHED_DD, SHED_DA, SHED_DP, SHED_DN, SHED_DL, SHED_AA, SHED_AP, SHED_AN, SHED_AL, SHED_PP, SHED_PN, SHED_PL, SHED_NN, SHED_NL, SHED_LL, Ro5, cRo5, DLS_01, DLS_02, DLS_03, DLS_04, DLS_05, DLS_06, DLS_07, DLS_cons, LLS_01, LLS_02

[0168] Descriptors of solvents (373 types) MW,AMW,Sv,Se,Sp,Si,Mv,Me,Mp,Mi,GD,RBF,H%,C%,O%,MCD,ZM1Kup,ZM1Mad,ZM1Per,ZM1MulPer,ZM2Kup,ZM2Mad,ZM2Per,ZMON0,ONP0Ver, 1,ON1V,DBI,SNar,HNar,GNar,Xt,Dz,LPRS,MSD,SPI,AECC,DECC,MDDD,ICR,MeanTD,MeanDD,S1K,S2K,S3K,PHI,PW2,PW3,PW4,PW5,MAXDN,MAXDP S,LOC,MWC01,MWC02,MWC03,MWC04,MWC05,MWC06,MWC07,MWC08,MWC09,MWC10,SRW02,SRW04,SRW06,SRW08,SRW10,MPC03,MPC01,MPC0 5,piPC01,piPC02,piPC03,piPC04,piPC05,TWC,TPC,piID,PCD,CID,BID,ISIZ,IAC,AAC,IDE,IDM,IDDE,IDDM,IDET,IDMT,IVDE,IVDM,HVcpx,HDcpx, Uindex,Vindex,Xindex,Yindex,IC0,IC1,IC2,IC3,IC4,IC5,TIC0,TIC1,TIC2,TIC3,TIC4,TIC5,SIC0,SIC1,SIC2,SIC3,SIC4,SIC5,CIC0,CIC1,CI C2,CIC3,CIC4,CIC5,BIC0,BIC1,BIC2,BIC3,BIC4,BIC5,ATS1m,ATS2m,ATS3m,ATS4m,ATS5m,ATS6m,ATS1v,ATS2v,ATS3v,ATS4v,ATS5v,ATS1v,ATS6 ,ATS2e,ATS3e,ATS4e,ATS5e,ATS6e,ATS1p,ATS2p,ATS3p,ATS4p,ATS5p,ATS6p,ATS1i,ATS2i,ATS3i,ATS4i,ATS5i,ATS6i,ATSC1m,SC3m,A, TSC4m,ATSC5m,ATSC6m,ATSC1v,ATSC2v,ATSC3v,ATSC4v,ATSC5v,ATSC6v,ATSC1e,ATSC2e,ATSC3e,ATSC4e,ATSC5e,ATSC6e,ATSC1p,ATSC2p,ATSC3p,ATSC4p,ATSC5p,ATSC6p,ATSC1i,ATSC2i,ATSC3i,ATSC4i,ATSC5i,ATSC6i,MATS1m,MATS2m,MATS3m,MATS4m,MATS5m,MATS6m,MATS1v,MATS2v,MATS 3v,MATS4v,MATS5v,MATS6v,MATS1e,MATS2e,MATS3e,MATS4e,MATS5e,MATS6e,MATS1p,MATS2p,MATS3p,MATS4p,MATS5p,MATS6p,MATS1i,MATS2i,MA TS3i,MATS4i,MATS5i,MATS6i,GATS1m,GATS2m,GATS3m,GATS4m,GATS5m,GATS1v,GATS2v,GATS3v,GATS4v,GATS5v,GATS1e,GATS2e,GATS3e,GATS4e ,GATS5e,GATS1p,GATS2p,GATS3p,GATS4p,GATS5p,GATS1i,GATS2i,GATS3i,GATS4i,GATS5i,GGI1,GGI2,GGI3,JGI1,JGI2,JGI3,JGT,SpMax1_Bh(m) ,SpMax2_Bh(m),SpMax3_Bh(m),SpMax4_Bh(m),SpMax5_Bh(m),SpMax6_Bh(m),SpMax7_Bh(m),SpMax8_Bh(m),SpMax1_Bh(v),SpMax2_Bh(v),SpMax 3_Bh(v),SpMax4_Bh(v),SpMax5_Bh(v),SpMax6_Bh(v),SpMax7_Bh(v),SpMax1_Bh(e),SpMax2_Bh(e),SpMax3_Bh(e),SpMax4_Bh(e),SpMax5_Bh(e) ,SpMax6_Bh(e),SpMax7_Bh(e),SpMax8_Bh(e),SpMax1_Bh(p),SpMax2_Bh(p),SpMax3_Bh(p),SpMax4_Bh(p),SpMax5_Bh(p),SpMax6_Bh(p),SpMax7 _Bh(p),SpMax8_Bh(p),SpMax1_Bh(i),SpMax2_Bh(i),SpMax3_Bh(i),SpMax4_Bh(i),SpMax5_Bh(i),SpMax6_Bh(i),SpMax7_Bh(i),SpMax8_Bh(i),SpMin1_Bh(m),SpMin2_Bh(m),SpMin3_Bh(m),SpMin4_Bh(m),SpMin5_Bh(m),SpMin1_Bh(v),SpMin2_Bh(v),SpMin3_ Bh(v),SpMin4_Bh(v),SpMin5_Bh(v),SpMin1_Bh(e),SpMin2_Bh(e),SpMin3_Bh(e),SpMin4_Bh(e),SpMin1_Bh(p),Sp Min2_Bh(p),SpMin3_Bh(p),SpMin4_Bh(p),SpMin5_Bh(p),SpMin1_Bh(i),SpMin2_Bh(i),SpMin3_Bh(i),SpMin4_Bh( i),P_VSA_LogP_1,P_VSA_LogP_2,P_VSA_LogP_3,P_VSA_LogP_4,P_VSA_LogP_5,P_VSA_LogP_7,P_VSA_MR_1,P_VSA_M R_2,P_VSA_MR_3,P_VSA_MR_5,P_VSA_MR_6,P_VSA_m_1,P_VSA_m_2,P_VSA_m_3,P_VSA_v_2,P_VSA_v_3,P_VSA_e_2,P _VSA_e_5,P_VSA_i_2,P_VSA_i_3,P_VSA_s_2,P_VSA_s_3,P_VSA_s_4,P_VSA_s_6,P_VSA_ppp_L,P_VSA_ppp_D,P_VSA_ ppp_cyc,P_VSA_ppp_ter,SsCH3,SssCH2,SsssCH,SdssC,SsOH,SdO,SssO,SHED_AL,SHED_LL,Uc,Ui,Hy,AMR,TPSA(NO) ,TPSA(Tot),MLOGP2,ALOGP,ALOGP2,SAtot,SAdon,VvdwMG,VvdwZAZ,PDI,BLTF96,DLS_02,DLS_04,DLS_05,DLS_cons,

[0169] Principal component analysis (PCA) was performed on each of the compound descriptors and solvent descriptors to reduce the dimensions. Principal component analysis is a method for synthesizing a small number of uncorrelated variables (principal components) that best represent the overall variability from a large number of correlated variables. When the original variable is X, the principal component is T, and the residual is E, PCA can be expressed by the following formula:

number

number

number

number

[0170] Using this model, predicted values ​​and prediction intervals of critical supersaturation were calculated for the substrates in Table 1. The results output on a logarithmic scale were converted to a linear scale, and the values ​​obtained are shown in Table 6. Note that in the table, "verification" in the data type section indicates that the data was used as verification data, and "learning" indicates that the data was used as learning data. [Table 8-1] [Table 8-2]

[0171] Even when the crystallization temperature was not used as an explanatory variable, a prediction model for critical supersaturation could be created by partial least squares regression using the compound components, the components of two solvents, and the solvent ratio. It was confirmed that the critical supersaturation predicted based on the training data also fit well with the validation data. Furthermore, even when variables related to the solvent used in crystallization were not used, a prediction model for critical supersaturation could be created by partial least squares regression using the compound components and the solution temperature during crystallization. It was also confirmed that the critical supersaturation predicted based on the training data also fit well with the validation data.

[0172] Example 19 Escitalopram oxalate (crystallization by reverse dripping) 0.5 g of escitalopram oxalate was dissolved in 1 mL of water at 60°C. This solution was added dropwise to 15 mL of 2-butanol at 0°C over approximately 1 second to prepare a supersaturated solution of escitalopram oxalate. The degree of supersaturation of the resulting solution at the end of the addition was 7.4. This value was higher than the measured critical supersaturation value (3.7) shown in No. 22 in Table 1 above. Crystals began to precipitate 27 minutes after the end of the addition. After stirring for 2 hours, the crystals were filtered and dried under reduced pressure at room temperature for 15 hours to obtain spherulites of escitalopram oxalate (quantitative yield 86%, calculated by measuring the concentration of the supernatant of the mother liquor by HPLC). The d50 of the resulting crystals was 50.7 μm, the sharpness index was 4.87, and the sphericity was 0.98 ± 0.01 (see Figures 54 to 56).

[0173] Example 20 Vildagliptin (crystallization by reverse instillation) 0.8 g of vildagliptin was dissolved in 1.0 mL of ethanol at 80°C. This solution was added dropwise to 10 mL of 0°C t-butyl methyl ether over approximately 1 second to prepare a supersaturated solution of vildagliptin. The supersaturation ratio of the resulting solution at the end of the addition was 21.5. This value was higher than the measured critical supersaturation value (9.2) shown in No. 39 in Table 1 above. Crystals began to precipitate 20 minutes after the end of the addition. After stirring for 1 hour, the crystals were filtered and dried under reduced pressure at room temperature for 18 hours to obtain vildagliptin spherulites (0.187 g, 23%). The sharpness index of the resulting crystals was 1.66, the d50 was 246 μm, and the sphericity was 0.99 ± 0.01 (see Figures 57 to 59).

[0174] Example 21 Linagliptin (crystallization by reverse instillation) 0.5 g of linagliptin was dissolved in 2.5 mL of ethanol at 70°C. This solution was added dropwise to 37.5 mL of tert-butyl methyl ether at 0°C over approximately 1 second to prepare a supersaturated solution of linagliptin. The degree of supersaturation of the resulting solution at the end of the addition was 23.3. This value was higher than the measured critical supersaturation value (7.9) shown in No. 45 in Table 1 above. Crystals began to precipitate 32 minutes after the end of the addition. After stirring for 5 hours, the crystals were filtered and dried under reduced pressure at room temperature for 17 hours to obtain linagliptin spherulites (quantitative yield 93%, calculated by measuring the concentration of the supernatant of the mother liquor by HPLC). The d50 of the resulting crystals was 69.1 μm, the sharpness index was 2.42, and the sphericity was 0.98 ± 0.01 (see Figures 60 to 62).

[0175] Example 22 Teneligliptin Hydrobromide Hydrate (Crystallization by Reverse Dropping) 1.0 g of teneligliptin hydrobromide hydrate was dissolved in 4 mL of methanol at 60°C. This solution was added dropwise to 40 mL of 1-butanol at 20°C over approximately 1 second to prepare a supersaturated solution of teneligliptin hydrobromide hydrate. The degree of supersaturation of the resulting solution at the end of the dropwise addition was 13.7. This value was higher than the measured critical supersaturation value (7.9) shown in No. 33 in Table 1 above. After stirring for 18 hours, the crystals were filtered and dried under reduced pressure at room temperature for 24 hours to obtain spherulites of teneligliptin hydrobromide hydrate (quantitative yield 93%, calculated by measuring the concentration of the supernatant of the mother liquor by HPLC). The d50 of the resulting crystals was 33.5 μm, the sharpness index was 3.77, and the sphericity was 0.93 ± 0.04 (see Figures 63 to 65).

[0176] Example 23 Glutathione (crystallized by reverse dripping) 1.0 g of glutathione was dissolved in 10 mL of water at 30°C. This solution was added dropwise to 50 mL of ethanol at 20°C over approximately 3 seconds to prepare a supersaturated solution of glutathione. The degree of supersaturation of the resulting solution at the end of the addition was 46.1. This value was higher than the measured critical supersaturation value (18.7) shown in No. 47 in Table 1 above. After stirring for 20 hours, the crystals were filtered and dried under reduced pressure at room temperature for 24 hours to obtain glutathione spherulites (0.97 g, 97%; calculated by measuring the concentration of the supernatant of the mother liquor by HPLC). The d50 of the resulting crystals was 48.4 μm, the sharpness index was 2.27, and the sphericity was 0.85 ± 0.07 (see Figures 66 to 68).

[0177] Example 24 Preparation of spherulites of dabigatran etexilate methanesulfonate (crystallization by reverse dropping) 0.8 g of dabigatran etexilate methanesulfonate was dissolved in 4 mL of ethanol at 60°C. This solution was added dropwise to 40 mL of ethyl acetate at 20°C over approximately 3 seconds to prepare a supersaturated solution. The degree of supersaturation of the resulting solution at the end of the addition was 82. This value was higher than the measured critical supersaturation value (4.3) shown in No. 26 in Table 1 above. Crystals began to precipitate approximately 4 minutes after the end of the addition, and were collected by filtration 42 minutes later. The crystals were dried under reduced pressure at 40°C to obtain spherulites of dabigatran etexilate methanesulfonate (quantitative yield: 98.7%). The sharpness index of the resulting crystals was 2.61, the d50 was 61.3 μm, and the sphericity was 0.95 ± 0.03 (see Figures 69 to 71).

[0178] Example 25 Preparation of spherulites of pilsicainide hydrochloride (crystallization by reverse dropping) 1.5 g of pilsicainide hydrochloride hemihydrate was dissolved in 4.5 mL of isopropanol at 80°C. This solution was added dropwise to 45 mL of toluene at 5°C over approximately 3 seconds to prepare a supersaturated solution. The degree of supersaturation of the resulting solution at the end of the addition was 27. This was the same as the measured critical supersaturation value (27) shown in No. 35 in Table 1 above. Crystals began to precipitate approximately 3 minutes after the end of the addition and were collected by filtration 1 hour later. The crystals were dried under reduced pressure at 40°C to obtain spherulites of pilsicainide hydrochloride anhydrate (quantitative yield: 93.6%). The sharpness index of the resulting crystals was 2.29, the d50 was 116 μm, and the sphericity was 0.69 ± 0.18 (see Figures 72 to 74).

[0179] Example 26 Theophylline magnesium salt tetrahydrate (crystallized by salt formation) 0.333 g of magnesium chloride hexahydrate was dissolved in 2.50 mL of water and 2.50 mL of methanol at room temperature and cooled to 0°C. 0.236 g of theophylline was dissolved in 5.00 mL of water and 0.0734 g of potassium hydroxide at room temperature and the resulting solution was added dropwise to the magnesium chloride solution over 10 minutes. The supersaturation ratio of the resulting supersaturated solution immediately after addition was 8.4. This value was higher than the measured critical supersaturation value (3.5) shown in No. 28 in Table 1 above. Approximately 1 minute after the end of addition, crystals began to precipitate. After allowing to stand for 30 minutes, the crystals were filtered and dried under reduced pressure at room temperature for 18 hours to obtain spherulites of theophylline magnesium salt tetrahydrate (0.140 g, 47%). The sharpness index of the obtained crystals was 3.06, d50 was 43.0 μm, and sphericity was 0.95±0.02 (see Figures 75 to 77).

[0180] Example 27 Mirabegron (crystallization by reverse dripping) 0.051 g of mirabegron was dissolved in 1.0 mL of ethanol at 80°C. This solution was added dropwise to 10 mL of t-butyl methyl ether at 0°C over approximately 1 second to prepare a supersaturated solution of mirabegron, followed by the addition of 2000 ppm of seed crystals. The supersaturation ratio of the resulting solution at the end of the addition was 6.9. This value was higher than the measured critical supersaturation value (5.6) shown in No. 52 in Table 1 above. Crystals began to precipitate 35 minutes after seeding. After stirring for 19 hours, the crystals were collected by filtration and dried under reduced pressure at room temperature for 18 hours to obtain mirabegron spherulites (0.027 g, 53%). The sharpness index of the resulting crystals was 1.66, the d50 was 148 μm, and the sphericity was 0.98 ± 0.01 (see Figures 78-80).

[0181] Example 28 Tolvaptan (crystallization by sequential dropping) 0.1 g of tolvaptan was dissolved in 5.0 mL of methanol at room temperature. This solution was cooled to 0°C, and 2.0 mL of room-temperature water was added dropwise over approximately 1 second to prepare a supersaturated solution of tolvaptan. The supersaturation ratio of the resulting solution at the end of the addition was 6.6. This value was higher than the measured critical supersaturation value (4.8) shown in No. 54 in Table 1 above. Crystals began to precipitate approximately 1 hour after the addition was completed. After stirring for 1.5 hours, the crystals were filtered and dried under reduced pressure at room temperature for 18 hours to obtain tolvaptan spherulites (0.031 g, 31%). The average particle size of the resulting crystals was 145 μm, and the sphericity of the resulting crystals was 0.94 ± 0.02 (see Figures 81 and 82).

[0182] Example 29 Preparation of spherulites of tramadol hydrochloride (crystallization by reverse dripping) 0.5 g of tramadol hydrochloride was dissolved in 0.5 mL of methanol at 30°C. This solution was added dropwise to 10 mL of isopropyl acetate at 10°C over approximately 1 second to prepare a supersaturated solution. The degree of supersaturation of the resulting solution at the end of the addition was 13. This value was higher than the measured critical supersaturation value (4.2) shown in No. 36 in Table 1 above. Crystals had already precipitated 25 minutes after the end of the addition, and were collected by filtration 70 minutes later. The solution was dried under reduced pressure at room temperature to obtain tramadol hydrochloride spherulites. The average particle size of the resulting spherulites was 319 μm, and the sphericity of the spherulites was 0.90 ± 0.08 (see Figures 83 and 84).

[0183] Example 30 Bepotastine besilate (crystallization by reverse dripping) 1.0 g of bepotastine besilate was dissolved in 4 mL of ethanol under reflux conditions. This solution was added dropwise to 40 mL of isopropyl acetate at 0°C over approximately 3 seconds to prepare a supersaturated solution of bepotastine besilate. The degree of supersaturation of the resulting solution at the end of the dropwise addition was 143. This value was higher than the measured critical supersaturation value (36.4) shown in No. 57 in Table 1 above. After stirring for 15 hours, the crystals were filtered and dried under reduced pressure at room temperature for 24 hours to obtain spherulites of bepotastine besilate (0.99 g, 99%: calculated by measuring the concentration of the supernatant of the mother liquor by HPLC). The d50 of the resulting crystals was 105 μm, the sharpness index was 2.15, and the sphericity was 0.98 ± 0.01 (see Figures 85 to 87).

[0184] Example 31 Preparation of spherulites of olopatadine (crystallization by reverse dripping) 2.5 mL of methanol was added to 1.0 g of olopatadine and dissolved under reflux. This solution was added dropwise to 50 mL of ethyl acetate at 15°C over approximately 1 second to prepare a supersaturated solution. The degree of supersaturation of the supersaturated solution at the end of the addition was 15. This value was higher than the measured critical supersaturation value (9.7) shown in No. 58 in Table 1 above. Crystals had already precipitated 1 hour after the end of the addition, and were collected by filtration 3.5 hours later. The crystals were dried under reduced pressure at room temperature to obtain olopatadine spherulites. The average particle size of the resulting spherulites was 167 μm, and the sphericity of the spherulites was 0.96 ± 0.02 (see Figures 88 and 89).

[0185] Example 32 Development of a prediction model for critical supersaturation (II) Two-dimensional descriptors were calculated using alvaDesc1.0 for 21 compounds for which critical supersaturation values ​​were obtained. After deleting one of the following pairs of descriptors: those that were identical for all compounds, those that could not be calculated for one or more compounds, and those with a correlation coefficient of 1.0, 1,905 descriptors remained. Similarly, two-dimensional descriptors were calculated using alvaDesc1.0 for the 13 solvents used to obtain critical supersaturation values. After deleting one of the following pairs of descriptors: those that were identical for all solvents, those that could not be calculated for one or more solvents, and those with a correlation coefficient of 1.0, 373 descriptors remained. A dataset consisting of 58 data sets was created by arranging the compound descriptors, good solvent descriptors, poor solvent descriptors, solvent ratios, and crystallization temperatures. After deleting descriptors with values ​​that were identical for more than 80% of the datasets, a total of 2,100 variables remained.

[0186] Compound descriptors (1905 types) MW,AMW,Sv,Se,Sp,Si,Mv,Me,Mp,Mi,GD,nAT,nSK,nTA,nBT,nBO,nBM,SCBO,RBN,RBF,nDB,nTB,nAB,nH,nC,nN,nO,nS,nF,nCL,nHM,nHet,nX,H%,C%,N% ,O%,X%,nCsp3,nCsp2,nCsp,max_conj_path,nCIC,nCIR,TRS,Rperim,Rbrid,MCD,RFD,RCI,NRS,NNRS,nR05,nR06,nR07,nR08,nR09,nR10,nR11,nBnz ,ARR,D / Dtr05,D / Dtr06,D / Dtr07,D / Dtr08,D / Dtr09,D / Dtr10,D / Dtr11,ZM1,ZM1V,ZM1Kup,ZM1Mad,ZM1Per,ZM1MulPer,ZM2,ZM2V,ZM2Kup,ZM2Mad,ZM2Per,ZM2MulPer,ON0,ON0V,ON1,ON1V,Qindex,BBI,DBI,SNar,HNar,GNar,Xt,Dz,Ram,BLI,Pol,LPRS,MSD,SPI,PJI2,ECC,AECC,DECC,MDDD,UNIP,C ENT,VAR,ICR,MaxTD,MeanTD,MaxDD,MeanDD,SMTI,SMTIV,GMTI,GMTIV,Xu,CSI,Wap,S1K,S2K,S3K,PHI,PW2,PW3,PW4,PW5,MAXDN,MAXDP,DELS,TIE,P mw C05,MWC06,MWC07,MWC08,MWC09,MWC10,SRW02,SRW04,SRW05,SRW06,SRW07,SRW08,SRW09,SRW10,MPC02,MPC03,MPC04,MPC05,MPC06,MPC07,MPC08,M PC09,MPC10,piPC01,piPC02,piPC03,piPC04,piPC05,piPC06,piPC07,piPC08,piPC09,piPC10,TWC,TPC,piID,PCR,PCD,CID,BID,X0,X1,X2,X3,X4,X5,X0A,X1A,X2A,X3A,X4A,X5A,X0v, X1v, CHI, RDSQ, X1Kup, X1Mad, X1Per, ndex,Yindex,IC0,IC1,IC2,IC3,IC4,IC5,TIC0,TIC1,TIC2,TIC3,TIC4,TIC5,SIC0,SIC1,SIC2,SIC3,SIC4,SIC5,CIC0,CIC1,CIC2,CIC3,CIC4,CIC 5,BIC0,BIC1,BIC2,BIC3,BIC4,BIC5,J_A,SpPos_A,SpPosLog_A,SpMax_A,SpMaxA_A,SpDiam_A,SpMAD_A,Ho_A,EE_A,VE1_A,VE2_A,VE3_A,VE1sign _A,VE2sign_A,VR1_A,VR2_A,VR3_A,Wi_D,AVS_D,H_D,Chi_D,ChiA_D,J_D,HyWi_D,SpPos_D,SpPosA_D,SpPosLog_D,SpMaxA_D,SpDiam_D,Ho_D,SM2_D,SM3_D,SM4_D,SM5_D,SM6_D,QW_L,TI1_L,TI2_L,STN_L,SpPosA_L,SpPosLog_L,SpMax_L,SpMaxA_L,SpDiam_L,SpAD_L,SpMAD_L,Ho_L,EE_L,SM2 _L,SM3_L,SM4_L,SM5_L,SM6_L,VE1_L,VE2_L,VE3_L,VE1sign_L,VE2sign_L,VE3sign_L,VR1_L,VR2_L,VR3_L,AVS_X,H_X,Chi_X,ChiA_X,J_X,HyWi _X,SpPos_X,SpPosA_X,SpPosLog_X,SpMaxA_X,SpDiam_X,SpMAD_X,Ho_X,EE_X,SM2_X,SM3_X,SM4_X,SM5_X,SM6_X,VE1_X,VE2_X,VE3_X,VE1sign_X,VE2sign_X,VR1_X,VR2_X,VR3_X,Wi_H2,WiA_H2,AVS_H2,Chi_H2,ChiA_H2,J_H2,HyWi_H2,SpPos_H2,SpPosA_H2,SpPosLog_H2,SpMax_H2,SpMaxA_H2,SpDiam_H2,Ho_H2,EE_H2,SM2_H2,SM3_H2,SM4_H2,SM5_H2,SM6_H2,VE1_H2,VE2_H2,VE3_H2,VE1sign_H2,VE2sign_H2,VR1_H2,VR2_H2,VR3_H2,Wi_Dt,AVS_Dt,H_Dt,Chi_Dt,ChiA_Dt,J_Dt,HyWi_Dt,SpPos_Dt,SpPosA_Dt,SpPosLog_Dt,SpMax_Dt,SpMaxA_Dt,SpDiam_Dt,Ho_Dt,SM2_Dt,SM3_Dt,SM4_Dt,SM5_Dt,SM6_Dt,Wi_D / Dt,WiA_D / Dt,AVS_D / Dt,H_D / Dt,Chi_D / Dt,ChiA_D / Dt,J_D / Dt,HyWi_D / Dt,SpPos_D / Dt,SpPosA_D / Dt,SpPosLog_D / Dt,SpMax_D / Dt,SpMaxA_D / Dt,SpDiam_D / Dt,Ho_D / Dt,EE_D / Dt,SM2_D / Dt,SM3_D / Dt,SM4_D / Dt,SM5_D / Dt,SM6_D / Dt,Wi_Dz(Z),WiA_Dz(Z),AVS_Dz(Z),H_Dz(Z),Chi_Dz(Z),ChiA_Dz(Z),J_Dz(Z),HyWi_Dz(Z),SpAbs_Dz(Z),SpPos_Dz(Z),SpPosA_Dz(Z),SpPosLog_Dz(Z),SpMax_Dz(Z),SpMaxA_Dz(Z),SpDiam_Dz(Z),SpAD_Dz(Z),SpMAD_Dz(Z),Ho_Dz(Z),SM1_Dz(Z),SM2_Dz(Z),SM3_Dz(Z),SM4_Dz(Z),SM5_Dz(Z),SM6_Dz(Z),VE1_Dz(Z),VE2_Dz(Z),VE3_Dz(Z),VE1sign_Dz(Z),VE2sign_Dz(Z),VR1_Dz(Z),VR2_Dz(Z),VR3_Dz(Z),Wi_Dz(m),WiA_Dz(m),AVS_Dz(m),H_Dz(m),Chi_Dz(m),ChiA_Dz(m),J_Dz(m),HyWi_Dz(m),SpAbs_Dz(m),SpPos_Dz(m),SpPosA_Dz(m),SpPosLog_Dz(m),SpMax_Dz(m),SpMaxA_Dz(m),SpDiam_Dz(m),SpAD_Dz(m),SpMA D_Dz(m),Ho_Dz(m),SM1_Dz(m),SM2_Dz(m),SM3_Dz(m),SM4_Dz(m),SM5_Dz(m),SM6_Dz(m),VE1_Dz(m),VE2_Dz(m),VE3_Dz(m),VE1_Dz(m),VE2 sign_Dz(m),VR1_Dz(m),VR2_Dz(m),VR3_Dz(m),Wi_Dz(v),WiA_Dz(v),AVS_Dz(v),H_Dz(v),Chi_Dz(v),ChiA_Dz(v),J_Dz(v),HyWi_Dz(v),SpAbs_Dz(v),SpPos_Dz(v),SpPosA_Dz(v),SpPosLog_Dz(v),SpMaxA_Dz(v),SpDiam_Dz(v),SpAD_Dz(v),SpMAD_Dz(v),Ho_Dz(v),EE_Dz(v),SM1_Dz(v),S M2_Dz(v),SM3_Dz(v),SM4_Dz(v),SM5_Dz(v),SM6_Dz(v),VE1_Dz(v),VE2_Dz(v),VE3_Dz(v),VE1sign_Dz(v),VE2sign_Dz(v),VE3sign_Dz(v),VR1_Dz(v),VR2_Dz(v),VR3_Dz(v),Wi_Dz(e),WiA_Dz(e),AVS_Dz(e),H_Dz(e),Chi_Dz(e),ChiA_Dz(e),J_Dz(e),HyWi_Dz(e),SpAbs_Dz(e),SpPos_Dz (e),SpPosA_Dz(e),SpPosLog_Dz(e),SpMax_Dz(e),SpMaxA_Dz(e),SpDiam_Dz(e),SpAD_Dz(e),SpMAD_Dz(e),Ho_Dz(e),EE_Dz(e),SM1_Dz(e),SM2_Dz(e),SM3_Dz(e),SM4_Dz(e),SM5_Dz(e),SM6_Dz(e),VE1_Dz(e),VE2_Dz(e),VE3_Dz(e),VE1sign_Dz(e),VE2sign_Dz(e),VR1_Dz(e),VR2_Dz(e),VR3_Dz(e),Wi_Dz(p),WiA_Dz(p),AVS_Dz(p),H_Dz(p),Chi_Dz(p),ChiA_Dz(p),J_Dz(p),HyWi_Dz(p),SpAbs_Dz(p),SpPos_Dz(p),SpPosA_Dz(p),SpPosLog_Dz(p),SpMax_Dz(p),SpMaxA_Dz(p),SpDiam_Dz(p),SpAD_Dz(p),SpMAD_Dz(p),Ho_Dz(p),EE_Dz(p),SM1_Dz(p),SM2_Dz(p),SM3_Dz(p),SM4_Dz(p),SM5_Dz(p),SM6_Dz(p),VE1_Dz(p),VE2_Dz(p),VE3_Dz(p),VE1sign_Dz(p),VE2sign_Dz(p),VE3sign_Dz(p),VR1_Dz(p),VR2_Dz(p),VR3_Dz(p),Wi_Dz(i),WiA_Dz(i),AVS_Dz(i),H_Dz(i),Chi_Dz(i),ChiA_Dz(i),J_Dz(i),HyWi_Dz(i),SpAbs_Dz(i),SpPos_Dz(i),SpPosA_Dz(i),SpPosLog_Dz(i),SpMaxA_Dz(i),SpDiam_Dz(i),SpAD_Dz(i),SpMAD_Dz(i),Ho_Dz(i),EE_Dz(i),SM1_Dz(i),SM2_Dz(i),SM3_Dz(i),SM4_Dz(i),SM5_Dz(i),SM6_Dz(i),VE1_Dz(i),VE2_Dz(i),VE3_Dz(i),VE1sign_Dz(i),VE2sign_Dz(i),VR1_Dz(i),VR2_Dz(i),VR3_Dz(i),Wi_B(m),WiA_B(m),AVS_B(m),Chi_B(m),ChiA_B(m),J_B(m),HyWi_B(m),SpAbs_B(m),SpPos_B(m),SpPosA_B(m),SpPosLog_B(m),SpMax_B(m),SpMaxA_B(m),SpDiam_B(m),SpAD_B(m),SpMAD_B(m),Ho_B(m),EE_B(m),SM1_B(m),SM2_B(m),SM3_B(m),SM4_B(m),SM5_B(m),SM6_B(m),VE1_B(m),VE2_B(m),VE3_B(m),VE1sign_B(m),VE2sign_B(m),VE3sign_B(m),VR1_B(m),VR2_B(m),VR3_B(m),Wi_B(v),WiA_B(v),AVS_B(v),Chi_B(v),ChiA_B(v),J_B(v),HyWi_B(v),SpAbs_B(v),SpPos_B(v),SpPosA_B(v),SpPosLog_B(v),SpMax_B(v),SpMaxA_B(v),SpDiam_B(v),SpAD_B(v),SpMAD_B(v),Ho_B(v),EE_B(v),SM1_B(v),SM2_B(v),SM3_B(v),SM4_B(v),SM5_B(v),SM6_B(v),VE1_B(v),VE2_B(v),VE3_B(v),VE1sign_B(v),VE2sign_B(v),VE3sign_B(v),VR1_B(v),VR2_B(v),VR3_B(v),Wi_B(e),WiA_B(e),AVS_B(e),Chi_B(e),ChiA_B(e),J_B(e),HyWi_B(e),SpAbs_B(e),SpPos_B(e),SpPosA_B(e),SpPosLog_B(e),SpMax_B(e),SpMaxA_B(e),SpDiam_B(e),SpAD_B(e),SpMAD_B(e),Ho_B(e),EE_B(e),SM1_B(e),SM2_B(e),SM3_B(e),SM4_B(e),SM5_B(e),SM6_B(e),VE1_B(e),VE2_B(e),VE3_B(e),VE1sign_B(e),VE2sign_B(e),VE3sign_B(e),VR1_B(e),VR2_B(e),VR3_B(e),Wi_B(p),WiA_B(p),AVS_B(p),Chi_B(p),ChiA_B(p),J_B(p),HyWi_B(p),SpAbs_B(p),SpPos_B(p),SpPosA_B(p),SpPosLog_B(p),SpMax_B(p),SpMaxA_B(p),SpDiam_B(p),SpAD_B(p),SpMAD_B(p),Ho_B(p),EE_B(p),SM1_B(p),SM2_B(p),SM3_B(p),SM4_B(p),SM5_B(p),SM6_B(p),VE1_B(p),VE2_B(p),VE3_B(p),VE1sign_B(p),VE2sign_B(p),VE3sign_B(p),VR1_B(p),VR2_B(p),VR3_B(p),Wi_B(i),WiA_B(i),AVS_B(i),Chi_B(i),ChiA_B(i),J_B(i),HyWi_B(i),SpAbs_B(i),SpPos_B(i),SpPosA_B(i),SpPosLog_B(i),SpMax_B(i),SpMaxA_B(i),SpDiam_B(i),SpAD_B(i),SpMAD_B(i),Ho_B(i),EE_B(i),SM1_B(i),SM2_B(i),SM3_B(i),SM4_B(i),SM5_B(i),SM6_B(i),VE1_B(i),VE2_B(i),VE3_B(i),VE1sign_B(i),VE2sign_B(i),VE3sign_B(i),VR1_B(i),VR2_B(i),VR3_B(i),Wi_B(s),WiA_B(s),AVS_B(s),Chi_B(s),ChiA_B(s),J_B(s),HyWi_B(s),SpAbs_B(s),SpPos_B(s),SpPosA_B(s),SpPosLog_B(s),SpMax_B(s),SpMaxA_B(s),SpDiam_B(s),SpAD_B(s),SpMAD_B(s),Ho_B(s),EE_B(s),SM1_B(s),SM2_B(s),SM3_B(s),SM4_B(s),SM5_B(s),SM6_B(s),VE1_B(s),VE2_B(s),VE3_B(s),VE1sign_B(s),VE2sign_B(s),VE3sign_B(s),VR1_B(s),VR2_B(s),VR3_B(s),ATS1m,ATS2m,ATS3m,ATS4m,ATS5m,ATS6m,ATS7m,ATS8m,ATS1v,ATS2v,ATS3v,ATS4v,ATS5v,ATS6v,ATS7v,ATS8v,ATS1e,ATS2e,ATS3e,ATS4e,ATS5e,ATS6e,ATS7e,ATS8e,ATS1p,ATS2p,ATS3p,ATS4p,ATS5p,ATS6p,ATS7p,ATS8p,ATS1i,ATS2i,ATS3i,ATS4i,ATS5i,ATS6i,ATS7i,ATS8i,ATS1s,ATS2s,ATS3s,ATS4s,ATS5s,ATS6s,ATS7s,ATS8s,ATSC1m,ATSC2m,ATSC3m,ATSC4m,ATSC5m,ATSC6m,ATSC7m,ATSC8m,ATSC1v,ATSC2v,ATSC3v,ATSC4v,ATSC5v,ATSC6v,ATSC7v,ATSC8v,ATSC1e,ATSC2e,ATSC3e,ATSC4e,ATSC5e,ATSC6e,ATSC7e,ATSC8e,ATSC1p,ATSC2p,ATSC3p,ATSC4p,ATSC5p,ATSC6p,ATSC7p,ATSC8p,ATSC1i,ATSC2i,ATSC3i,ATSC4i,ATSC5i,ATSC6i,ATSC7i,ATSC8i,ATSC1s,ATSC2s,ATSC3s,ATSC4s,ATSC5s,ATSC6s,ATSC7s,ATSC8s,MATS1m,MATS2m,MATS3m,MATS4m,MATS5m,MATS6m,MATS7m,MATS8m,MATS1v,MATS2v,MATS3v,MATS4v,MATS5v,MATS6v,MATS7v,MATS8v,MATS1e,MATS2e,MATS3e,MATS4e,MATS5e,MATS6e,MATS7e,MATS8e,MATS1p,MATS2p,MATS3p,MATS4p,MATS5p,MATS6p,MATS7p,MATS8p,MATS1i,MATS2i,MATS3i,MATS4i,MATS5i,MATS6i,MATS7i,MATS8i,MATS1s,MATS2s,MATS3s,MATS4s,MATS5s,MATS6s,MATS7s,MATS8s,GATS1m,GATS2m,GATS3m,GATS4m,GATS5m,GATS6m,GATS7m,GATS8m,GATS1v,GATS2v,GATS3v,GATS4v,GATS5v,GATS6v,GATS7v,GATS8v,GATS1e,GATS2e,GATS3e,GATS4e,GATS5e,GATS6e,GATS7e,GATS8e,GATS1p,GATS2p,GATS3p,GATS4p,GATS5p,GATS6p,GATS7p,GATS8p,GATS1i,GATS2i,GATS3i,GATS4i,GATS5i,GATS6i,GATS7i,GATS8i,GATS1s,GATS2s,GATS3s,GATS4s,GATS5s,GATS6s,GATS7s,GATS8s,GGI1,GGI2,GGI3,GGI4,GGI5,GGI6,GGI7,GGI8,GGI9,GGI10,JGI1,JGI2,JGI3,JGI4,JGI5,JGI6,JGI7,JGI8,JGI9,JGI10,JGT,SpMax1_Bh(m),SpMax2_Bh( m),SpMax3_Bh(m),SpMax4_Bh(m),SpMax5_Bh(m),SpMax6_Bh(m),SpMax7_Bh(m),SpMax8_Bh(m),SpMax1_Bh(v),SpMax2_Bh(v),SpMax3_Bh(v),SpMax 4_Bh(v),SpMax5_Bh(v),SpMax6_Bh(v),SpMax7_Bh(v),SpMax8_Bh(v),SpMax1_Bh(e),SpMax2_Bh(e),SpMax3_Bh(e),SpMax4_Bh(e),SpMax5_Bh(e), SpMax6_Bh(e),SpMax7_Bh(e),SpMax8_Bh(e),SpMax1_Bh(p),SpMax2_Bh(p),SpMax3_Bh(p),SpMax4_Bh(p),SpMax5_Bh(p),SpMax6_Bh(p),SpMax7_B h(p),SpMax8_Bh(p),SpMax1_Bh(i),SpMax2_Bh(i),SpMax3_Bh(i),SpMax4_Bh(i),SpMax5_Bh(i),SpMax6_Bh(i),SpMax7_Bh(i),SpMax8_Bh(i),Sp Max1_Bh(s),SpMax2_Bh(s),SpMax3_Bh(s),SpMax4_Bh(s),SpMax5_Bh(s),SpMax6_Bh(s),SpMax7_Bh(s),SpMax8_Bh(s),SpMin1_Bh(m),SpMin2_Bh(s m),SpMin3_Bh(m),SpMin4_Bh(m),SpMin5_Bh(m),SpMin6_Bh(m),SpMin7_Bh(m),SpMin8_Bh(m),SpMin1_Bh(v),SpMin2_Bh(v),SpMin3_Bh(v),SpMin 4_Bh(v),SpMin5_Bh(v),SpMin6_Bh(v),SpMin7_Bh(v),SpMin8_Bh(v),SpMin1_Bh(e),SpMin2_Bh(e),SpMin3_Bh(e),SpMin4_Bh(e),SpMin5_Bh(e),SpMin6_Bh(e),SpMin7_Bh(e),SpMin8_Bh(e),SpMin1_Bh(p),SpMin2_Bh(p),SpMin3_Bh(p),SpMin4_Bh(p),SpMin5_Bh(p),SpMin6_Bh(p),SpMin7_Bh(p) Bh(p),SpMin8_Bh(p),SpMin1_Bh(i),SpMin2_Bh(i),SpMin3_Bh(i),SpMin4_Bh(i),SpMin5_Bh(i),SpMin6_Bh(i),SpMin7_Bh(i),SpMin8_Bh(i),S pMin1_Bh(s),SpMin2_Bh(s),SpMin3_Bh(s),SpMin4_Bh(s),SpMin5_Bh(s),SpMin6_Bh(s),SpMin7_Bh(s),SpMin8_Bh(s),P_VSA_LogP_1,P_VSA_Lo gP_2,P_VSA_LogP_3,P_VSA_LogP_4,P_VSA_LogP_5,P_VSA_LogP_6,P_VSA_LogP_7,P_VSA_LogP_8,P_VSA_MR_1,P_VSA_MR_2,P_VSA_MR_3,P_VSA_MR_ 4,P_VSA_MR_5,P_VSA_MR_6,P_VSA_MR_7,P_VSA_MR_8,P_VSA_m_1,P_VSA_m_2,P_VSA_m_3,P_VSA_m_4,P_VSA_v_2,P_VSA_v_3,P_VSA_e_2,P_VSA_e_3,P_VSA_e_4,P_VSA_e_5,P_VSA_p_1,P_VSA_p_2,P_VSA_i_1,P_VSA_i_2,P_VSA_i_3,P_VSA_i_4,P_VSA_s_2,P_VSA_s_3,P_VSA_s_4,P_VSA_s_5,P_ VSA_s_6,P_VSA_ppp_L,P_VSA_ppp_P,P_VSA_ppp_N,P_VSA_ppp_D,P_VSA_ppp_A,P_VSA_ppp_ar,P_VSA_ppp_con,P_VSA_ppp_hal,P_VSA_ppp_cyc,P _VSA_ppp_ter,Eta_alpha,Eta_alpha_A,Eta_epsi,Eta_epsi_A,Eta_betaS,Eta_betaS_A,Eta_betaP,Eta_betaP_A,Eta_beta,Eta_beta_A,Eta_C,Eta_C_A,Eta_L,Eta_L_A,Eta_F,Eta_F_A,Eta_FL,Eta_FL_A,Eta_B,Eta_B_A,Eta_sh_p,Eta_sh_y,Eta_sh_x,Eta_D_AlphaA,Eta_D_AlphaB,Eta_epsi_2,Eta_epsi_3,Eta_epsi_4,Eta_epsi_5,Eta_D_epsiA,Eta_D_epsiB,Eta_D_epsiC,Eta_D_epsiD,Eta_psi1,Eta_D_psiA,Eta_D_beta,Eta_D_beta_A,SpMax_EA, ,SpMaxA_EA,SpDiam_EA,SpAD_EA,SpMAD_EA,SpMax_EA(ed),SpMaxA_EA(ed),SpDiam_EA(ed),SpAD_EA(ed),SpMAD_EA(ed),SpMax_EA(bo),SpMaxA_EA(bo),SpDiam_EA(bo),SpAD_EA(bo),SpMAD_EA(bo),SpMax_EA(dm),SpMaxA_EA(dm),SpDiam_EA(dm),SpAD_EA(dm),SpMAD_EA(dm),SpMax(ri ),SpMaxA_EA(ri),SpDiam_EA(ri),SpAD_EA(ri),SpMAD_EA(ri),SpMax_AEA(ed),SpMaxA_AEA(ed),SpDiam_AEA(ed),SpAD_AEA(ed),SpMAD_AEA(ed ),SpMax_AEA(bo),SpMaxA_AEA(bo),SpDiam_AEA(bo),SpAD_AEA(bo),SpMAD_AEA(bo),SpMax_AEA(dm),SpMaxA_AEA(dm),SpDiam_AEA(dm),SpAD_AE A(dm),SpMAD_AEA(dm),SpMax_AEA(ri),SpMaxA_AEA(ri),SpDiam_AEA(ri),SpAD_AEA(ri),SpMAD_AEA(ri),Chi0_EA,Chi1_EA,Chi0_EA(ed),Chi1_EA(ed),Chi0_EA(bo),Chi1_EA(bo),Chi0_EA(dm),Chi1_EA(dm),Chi0_EA(ri),Chi1_EA(ri),SM02_EA,SM03_EA,SM04_EA,SM05_EA,SM06_EA,SM07 _EA,SM08_EA,SM09_EA,SM10_EA,SM11_EA,SM12_EA,SM13_EA,SM14_EA,SM15_EA,SM02_EA(ed),SM03_EA(ed),SM04_EA(ed),SM05_EA(ed),SM06_EA(ed),SM07_EA(ed),SM08_EA(ed),SM09_EA(ed),SM10_EA(ed),SM11_EA(ed),SM12_EA(ed),SM13_EA(ed),SM14_EA(ed),SM15_EA(ed),SM02_EA(bo),SM03_EA(bo),SM04_EA(bo),SM05_EA(bo),SM06_EA(bo),SM07_EA(bo),SM08_EA(bo),SM09_EA(bo),SM10_EA(bo),SM11_EA(bo),SM12_EA(bo),SM13_EA(bo),SM14_EA(bo),SM15_EA(bo),SM02_EA(dm),SM03_EA(dm),SM04_EA(dm),SM05_EA(dm),SM06_EA(dm),SM07_EA(dm),SM08_EA(dm),SM09_EA(d m),SM10_EA(dm),SM11_EA(dm),SM12_EA(dm),SM13_EA(dm),SM14_EA(dm),SM15_EA(dm),SM02_EA(ri),SM03_EA(ri),SM04_EA(ri),SM05_EA(ri),SM 06_EA(ri),SM07_EA(ri),SM08_EA(ri),SM09_EA(ri),SM10_EA(ri),SM11_EA(ri),SM12_EA(ri),SM13_EA(ri),SM14_EA(ri),SM15_EA(ri),SM02_AE A(ed),SM03_AEA(ed),SM04_AEA(ed),SM05_AEA(ed),SM06_AEA(ed),SM07_AEA(ed),SM08_AEA(ed),SM09_AEA(ed),SM10_AEA(ed),SM11_AEA(ed),SM 12_AEA(ed),SM13_AEA(ed),SM14_AEA(ed),SM15_AEA(ed),SM02_AEA(bo),SM03_AEA(bo),SM04_AEA(bo),SM05_AEA(bo),SM06_AEA(bo),SM07_AEA(b o),SM08_AEA(bo),SM10_AEA(bo),SM11_AEA(bo),SM12_AEA(bo),SM13_AEA(bo),SM14_AEA(bo),SM15_AEA(bo),SM02_AEA(dm),SM03_AEA(dm),SM04_ AEA(dm),SM05_AEA(dm),SM06_AEA(dm),SM07_AEA(dm),SM08_AEA(dm),SM09_AEA(dm),SM11_AEA(dm),SM12_AEA(dm),SM13_AEA(dm),SM14_AEA(dm),SM15_AEA(dm),SM02_AEA(ri),SM03_AEA(ri),SM04_AEA(ri),SM05_AEA(ri),SM06_AEA(ri),SM07_AEA(ri),SM08_AEA(ri),SM09_AEA(ri),SM10_A EA(ri),SM12_AEA(ri),SM13_AEA(ri),SM14_AEA(ri),SM15_AEA(ri),Eig06_EA,Eig11_EA,Eig14_EA,Eig05_EA(ed),Eig10_EA(ed),Eig13_EA(ed) ,Eig14_EA(ed),Eig02_EA(bo),Eig05_EA(bo),Eig06_EA(bo),Eig07_EA(bo),Eig08_EA(bo),Eig09_EA(bo),Eig10_EA(bo),Eig11_EA(bo),Eig12_EA EA(bo),Eig13_EA(bo),Eig14_EA(bo),Eig15_EA(bo),Eig01_EA(dm),Eig02_EA(dm),Eig03_EA(dm),Eig04_EA(dm),Eig05_EA(dm),Eig06_EA(dm), Eig07_EA(dm),Eig08_EA(dm),Eig09_EA(dm),Eig10_EA(dm),Eig11_EA(dm),Eig12_EA(dm),Eig13_EA(dm),Eig14_EA(dm),Eig02_EA(ri),Eig03_E A(ri),Eig04_EA(ri),Eig05_EA(ri),Eig06_EA(ri),Eig07_EA(ri),Eig08_EA(ri),Eig09_EA(ri),Eig10_EA(ri),Eig11_EA(ri),Eig12_EA(ri),E ig13_EA(ri),Eig14_EA(ri),Eig15_EA(ri),Eig01_AEA(ed),Eig02_AEA(ed),Eig03_AEA(ed),Eig04_AEA(ed),Eig05_AEA(ed),Eig06_AEA(ed),Eig06_AEA(ed) g07_AEA(ed),Eig08_AEA(ed),Eig09_AEA(ed),Eig10_AEA(ed),Eig11_AEA(ed),Eig12_AEA(ed),Eig13_AEA(ed),Eig14_AEA(ed),Eig15_AEA(ed),Eig02_AEA(both),Eig03_AEA(both),Eig04_AEA(both),Eig05_AEA(both),Eig06_AEA(both),Eig07_AEA(both),Eig08_AEA(both),Eig09_AEA(both),Eig10_AEA(both ). dm),Eig05_AEA(dm),Eig06_AEA(dm),Eig07_AEA(dm),Eig08_AEA(dm),Eig09_AEA(dm),Eig10_AEA(dm),Eig11_AEA(dm),Eig12_AEA(dm),Eig13_A A(dm),Eig14_AEA(dm),Eig15_AEA(dm),Eig02_AEA(ri),Eig03_AEA(ri),Eig04_AEA(ri),Eig05_AEA(ri),Eig06_AEA(ri),Eig07_AEA(ri),Eig08_A EA(ri),Eig09_AEA(ri),Eig10_AEA(ri),Eig11_AEA(ri),Eig12_AEA(ri),Eig13_AEA(ri),Eig14_AEA(ri),Eig15_AEA(ri),nCp,nCs,nCt,nCq,nCr s,nCrt,nCrq,nCar,nCbH,nCb-,nCconj,nR=Ct,nRCOOH,nRCOOR,nRCONHR,nArCONHR,nRCONR2,nArCONR2,nCONN,nN=CN<,nRNH2,nRNHR,nRNR2,n ,nN(CO)2,nROH,nOHs,nOHt,nROR,nArOR,nSO,nArX,nPyrrolidines,nImidazoles,nThiophenes,nPyridines,nHDon,nHAcc,C-001,C-002,C-003,C -005,C-006,C-007,C-008,C-009,C-011,C-024,C-025,C-026,C-027,C-0 28,C-029,C-033,C-034,C-035,C-040,C-041,C-042,C-044,H-046,H-047,H-048,H-049,H-050,H-051,H-052,H-053,H-054,O-056,O-058,O-059,O -060,N-067,N-068,N-072,N-073,N-074,N-075,S-107,S-109,SsCH3,Sss CH2,SaaCH,SsssCH,StsC,SdssC,SaasC,SaaaC,SsssC,SsNH2,SssNH,SsssN,SdsN,SaaN,StN,SaasN,SaaNH,SsOH,SdO,SssO,SaaS,SFs,Sss,SsCl ,NsCH3,NssCH2,NaaCH,NsssCH,NdssC,NaasC,NaaaC,NssssC,NssNH,NsssN,NdsN,NaaN,NtN,NaasN,NaaNH,NdO,NssO,NdssS,CATS2D_00DD,CADD_2_ D_03_DD,CATS2D_05_DD,CATS2D_06_DD,CATS2D_08_DD,CATS2D_09_DD,CATS2D_02_DA,CATS2D_03_DA,CATS2D_04_DA,CATS2D_05_DA,CATS2D_06_DA ,CATS2D_07_DA,CATS2D_08_DA,CATS2D_09_DA,CATS2D_03_DP,CATS2D_06_DP,CATS2D_02_DN,CATS2D_04_DN,CATS2D_05_DN,CATS2D_02_DL,CATS2 D_03_DL,CATS2D_04_DL,CATS2D_05_DL,CATS2D_06_DL,CATS2D_07_DL,CATS2D_08_DL,CATS2D_09_DL,CATS2D_00_AA,CATS2D_02_AA,CATS2D_03_AA ,CATS2D_04_AA,CATS2D_05_AA,CATS2D_06_AA,CATS2D_07_AA,CATS2D_08_AA,CATS2D_09_AA,CATS2D_02_AP,CATS2D_03_AP,CATS2D_04_AP,CATS2D _05_AP,CATS2D_06_AP,CATS2D_08_AP,CATS2D_09_AP,CATS2D_04_AN,CATS2D_05_AN,CATS2D_07_AN,CATS2D_08_AN,CATS2D_02_AL,CATS2D_03_AL,CATS2D_04_AL,CATS2D_05_AL,CATS2D_06_AL,CATS2D_07_AL,CATS2D_08_AL,CATS2D_09_AL,CATS2D_02_PN,CATS2D_04_PN,CATS2D_02_PL,CATS2D_03_PL,CATS2D_04_PL,CATS2D_05_PL,CATS2D_07_PL,CATS2D_08_PL,CATS2D_09_PL,CATS2D_00_NN,CATS2D_01_NL,CATS2D_02_NL,CATS2D_03_NL,CATS2D_04_NL,CATS2D_05_NL,CATS2D_06_NL,CATS2D_07_NL,CATS2D_08_NL,CATS2D_00_LL,CATS2D_01_LL,CATS2D_02_LL,CATS2D_03_LL,CATS2D_04_LL,CATS2D_05_LL,CATS2D_06_LL,CATS2D_07_LL,CATS2D_08_LL,CATS2D_09_LL,SHED_DD,SHED_DA,SHED_DP,SHED_DN,SHED_DL,SHED_AA,SHED_AP,SHED_AN,SHED_AL,SHED_PN,SHED_PL,SHED_NN,SHED_NL,SHED_LL,T(N..N),T(N..O),T(N..S),T(N..F),T(N..Cl),T(O..O),T(O..S),T(O..Cl),B01[C-O],B01[C-F],B01[O-S],B02[C-F],B02[N-N],B02[N-O],B02[N-S],B02[O-O],B03[N-N],B03[N-O],B03[N-S],B03[O-O],B04[C-S],B04[C-F],B04[N-N],B04[N-O],B04[N-S],B04[O-O],B04[O-S],B05[C-C],B05[C-O],B05[C-S],B05[C-F],B05[N-N],B05[N-O],B05[N-S],B05[O-O],B05[O-S],B05[O-Cl],B06[C-C],B06[C-N],B06[C-O],B06[C-F],B06[N-N],B06[N-O],B06[O-O],B07[C-C],B07[C-N],B07[C-O],B07[C-S],B07[C-F],B07[N-N],B07[N-O],B07[N-S],B07[O-O],B07[O-S],B08[C-C],B08[C-N],B08[C-O],B08[C-S],B08[N-N],B08[N-O],B08[O-O],B09[C-C],B09[C-N],B09[C-O],B09[C-S],B09[C-F],B09[C-Cl],B09[N-N],B09[N-O],B09[O-O],B10[C-C],B10[C-N],B10[C-O],B10[N-N],B10[N-O],B10[O-O],F01[C-C],F01[C-N],F01[C-O],F01[C-S],F01[O-S],F02[C-C],F02[C-N],F02[C-O],F02[C-S],F02[C-F],F02[N-N],F02[N-O],F02[N-S],F02[O-O],F03[C-C],F03[C-N],F03[C-O],F03[C-S],F03[C-Cl],F03[N-N],F03[N-O],F03[O-O],F04[C-C],F04[C-N],F04[C-O],F04[C-S],F04[C-Cl],F04[N-N],F04[N-O],F04[N-S],F04[O-O],F04[O-S],F05[C-C],F05[C-N],F05[C-O],F05[C-S],F05[C-F],F05[C-Cl],F05[N-N],F05[N-O],F05[N-S],F05[O-O],F05[O-Cl],F06[C-C],F06[C-N],F06[C-O],F06[C-S],F06[C-F],F06[C-Cl],F06[N-N],F06[N-O],F06[O-O],F07[C-C],F07[C-N],F07[C-O],F07[C-S],F07[C-F],F07[C-Cl],F07[N-N],F07[N-O],F07[O-O],F07[O-S],F08[C-C],F08[C-N],F08[C-O],F08[C-S],F08[C-Cl],F08[N-N],F08[N-O],F08[O-O],F09[C-C],F09[C-N],F09[C-O],F09[C-S],F09[C-Cl],F09[N-N],F09[N-O],F09[O-O],F10[C-C],F10[C-N],F10[C-O],F10[N-N],F10[N-O],F10[O-O],Uc,Ui,Hy,TPSA(NO),TPSA(Tot),MLOGP,MLOGP2,SAtot,SAacc,VvdwMG,VvdwZAZ,PDI,BLTD48,BL TA96,Ro5,DLS_01,DLS_02,DLS_03,DLS_04,DLS_05,DLS_06,DLS_07,DLS_cons,LLS_01,LLS_02,

[0187] Read more (373 pages) MW,AMW,Sv,Se,Sp,Si,Mv,Me,Mp,Mi,GD,RBF,H%,C%,O%,MCD,ZM1Kup,ZM1Mad,ZM1Per,ZM1MulPer,ZM2Kup,ZM2Mad,ZM2Per,ZMON0,ONP0Ver, 1,ON1V,DBI,SNar,HNar,GNar,Xt,Dz,LPRS,MSD,SPI,AECC,DECC,MDDD,ICR,MeanTD,MeanDD,S1K,S2K,S3K,PHI,PW2,PW3,PW4,PW5,MAXDN,MAXDP S,LOC,MWC01,MWC02,MWC03,MWC04,MWC05,MWC06,MWC07,MWC08,MWC09,MWC10,SRW02,SRW04,SRW06,SRW08,SRW10,MPC03,MPC01,MPC0 5,piPC01,piPC02,piPC03,piPC04,piPC05,TWC,TPC,piID,PCD,CID,BID,ISIZ,IAC,AAC,IDE,IDM,IDDE,IDDM,IDET,IDMT,IVDE,IVDM,HVcpx,HDcpx, Uindex,Vindex,Xindex,Yindex,IC0,IC1,IC2,IC3,IC4,IC5,TIC0,TIC1,TIC2,TIC3,TIC4,TIC5,SIC0,SIC1,SIC2,SIC3,SIC4,SIC5,CIC0,CIC1,CI C2,CIC3,CIC4,CIC5,BIC0,BIC1,BIC2,BIC3,BIC4,BIC5,ATS1m,ATS2m,ATS3m,ATS4m,ATS5m,ATS6m,ATS1v,ATS2v,ATS3v,ATS4v,ATS5v,ATS1v,ATS6 ,ATS2e,ATS3e,ATS4e,ATS5e,ATS6e,ATS1p,ATS2p,ATS3p,ATS4p,ATS5p,ATS6p,ATS1i,ATS2i,ATS3i,ATS4i,ATS5i,ATS6i,ATSC1m,SC3m,A, TSC4m,ATSC5m,ATSC6m,ATSC1v,ATSC2v,ATSC3v,ATSC4v,ATSC5v,ATSC6v,ATSC1e,ATSC2e,ATSC3e,ATSC4e,ATSC5e,ATSC6e,ATSC1p,ATSC2p,ATSC3p,ATSC4p,ATSC5p,ATSC6p,ATSC1i,ATSC2i,ATSC3i,ATSC4i,ATSC5i,ATSC6i,MATS1m,MATS2m,MATS3m,MATS4m,MATS5m,MATS6m,MATS1v,MATS2v,MATS 3v,MATS4v,MATS5v,MATS6v,MATS1e,MATS2e,MATS3e,MATS4e,MATS5e,MATS6e,MATS1p,MATS2p,MATS3p,MATS4p,MATS5p,MATS6p,MATS1i,MATS2i,MA TS3i,MATS4i,MATS5i,MATS6i,GATS1m,GATS2m,GATS3m,GATS4m,GATS5m,GATS1v,GATS2v,GATS3v,GATS4v,GATS5v,GATS1e,GATS2e,GATS3e,GATS4e ,GATS5e,GATS1p,GATS2p,GATS3p,GATS4p,GATS5p,GATS1i,GATS2i,GATS3i,GATS4i,GATS5i,GGI1,GGI2,GGI3,JGI1,JGI2,JGI3,JGT,SpMax1_Bh(m) ,SpMax2_Bh(m),SpMax3_Bh(m),SpMax4_Bh(m),SpMax5_Bh(m),SpMax6_Bh(m),SpMax7_Bh(m),SpMax8_Bh(m),SpMax1_Bh(v),SpMax2_Bh(v),SpMax 3_Bh(v),SpMax4_Bh(v),SpMax5_Bh(v),SpMax6_Bh(v),SpMax7_Bh(v),SpMax1_Bh(e),SpMax2_Bh(e),SpMax3_Bh(e),SpMax4_Bh(e),SpMax5_Bh(e) ,SpMax6_Bh(e),SpMax7_Bh(e),SpMax8_Bh(e),SpMax1_Bh(p),SpMax2_Bh(p),SpMax3_Bh(p),SpMax4_Bh(p),SpMax5_Bh(p),SpMax6_Bh(p),SpMax7 _Bh(p),SpMax8_Bh(p),SpMax1_Bh(i),SpMax2_Bh(i),SpMax3_Bh(i),SpMax4_Bh(i),SpMax5_Bh(i),SpMax6_Bh(i),SpMax7_Bh(i),SpMax8_Bh(i),SpMin1_Bh(m), SpMin2_Bh(m), SpMin3_Bh(m), SpMin4_Bh(m), SpMin5_Bh(m), SpMin1_Bh(v), SpMin2_Bh(v), SpMin3_Bh(v), SpMin4_Bh(v), SpMin5_Bh(v), SpMin1_Bh(e), SpMin2_Bh(e), SpMin3_Bh(e), SpMin4_Bh(e), SpMin1_Bh(p), SpMin2_Bh(p), SpMin3_Bh(p), SpMin4_Bh(p), SpMin5_Bh(p), SpMin1_Bh(i), SpMin2_Bh(i), SpMin3_Bh(i), SpMin4_Bh(i), P_VSA_LogP_1, P_VSA_LogP_2, P_VSA_LogP_3, P_VSA_LogP_4, P_VSA_LogP_5, P_VSA_LogP_7, P_VSA_MR_1, P_VSA_MR_2, P_VSA_MR_3, P_VSA_MR_5, P_VSA_MR_6, P_VSA_m_1, P_VSA_m_2, P_VSA_m_3, P_VSA_v_2, P_VSA_v_3, P_VSA_e_2, P_VSA_e_5, P_VSA_i_2, P_VSA_i_3, P_VSA_s_2, P_VSA_s_3, P_VSA_s_4, P_VSA_s_6, P_VSA_ppp_L, P_VSA_ppp_D, P_VSA_ppp_cyc, P_VSA_ppp_ter, SsCH3, SssCH2, SsssCH, SdssC, SsOH, SdO, SssO, SHED_AL, SHED_LL, Uc, Ui, Hy, AMR, TPSA(NO), TPSA(Tot), MLOGP2, ALOGP, ALOGP2, SAtot, SAdon, VvdwMG, VvdwZAZ, PDI, BLTF96, DLS_02, DLS_04, DLS_05, DLS_cons,

[0188] (Step 1) Identification of important descriptors by LASSO LASSO was applied to identify the descriptors from the 2,100 that are important for predicting critical supersaturation. Three-fold cross-validation was performed using 80% (46 types) of the 58 datasets as training data and 20% (12 types) as validation data. The coefficient of determination Q2 was used as the evaluation metric for cross-validation to determine the hyperparameter λ. To account for the randomness of data division, LASSO was repeated 1,000 times, and models with a coefficient of determination R2 of 0.50 or higher for the validation data were deemed to have high predictive accuracy and high validity. Models with an R2 of 0.50 or higher were constructed 223 times, with the average R2 of the top 100 being 0.71, and the average number of descriptors used to construct a model was 10.

[0189] LASSO is a linear regression method. In the least squares method, regression coefficients are determined so as to minimize the sum of squares of the error, but in LASSO, regression coefficients are set so as to minimize the sum of the sum of squares of the error and the absolute value of the regression coefficient. In other words, when the explanatory variable is X, the target variable is y, the regression coefficient is b, and the number of explanatory variables is m, the set of b that minimizes the following function G is found:

number

[0190] Descriptors selected in models with a high coefficient of determination (R2) and a large regression coefficient within the model are considered to be more important. Therefore, for each descriptor selected in models with an R2 of 0.50 or greater, the product of R2 and the regression coefficient was calculated, and the sum was defined as the importance score. Table 9 shows the results of the 20 descriptors sorted by importance score. The 20 descriptors are broken down as follows: 2D autocorrelation (6 types), P_VSA-like descriptors (4 types), edge adjacency index (2 types), Barden eigenvalues ​​(2 types), druglikeness index (1 type), and topological descriptor (1 type) for compound-related descriptors; Barden eigenvalues ​​(2 types) for good solvent-related descriptors; 2D autocorrelation (1 type) for poor solvent-related descriptors; and temperature for experimental conditions. For definitions of descriptors, see the non-patent literature Roberto Todeschini, Viviana Consonni (2009) "Molecular Descriptors for Chemoinformatics" Wiley-VCH Verlag GmbH & Co. KGaA. [Table 9]

[0191] Six descriptor groups containing descriptors selected as important descriptors for compounds, namely, Moran and Geary 2D autocorrelation (96 types), P_VSA-like descriptors (42 types), edge adjacency index (278 types), Barden eigenvalue (96 types), drug-like index (10 types), topological descriptors (54 types), and other descriptor groups (839 types) Seven descriptor groups consisting of 1 and 2, good solvent descriptors, poor solvent descriptors, solvent ratios, and temperature were used to perform LASSO 1000 times. The average R2 of the top 100 coefficients of determination R2 for validation data is shown in Table 10. In Table 10, descriptors or combinations of descriptors with an average R2 of the top 100 times of 0.50 or more, preferably 0.65 or more, are relatively important. Models with high predictive accuracy were constructed when using Moran and Geary's 2D autocorrelation or when using both the drug-like index and edge adjacency index. Models can be generated using descriptors with values ​​of 0.50 or higher in Table 10, such as the 2D autocorrelation and edge adjacency index, or combinations of descriptors with values ​​of 0.50 or higher, such as the 2D autocorrelation and P_VSA-like descriptor, the 2D autocorrelation and drug-like index, the 2D autocorrelation and edge adjacency index, the 2D autocorrelation and Burden eigenvalue, the 2D autocorrelation and topological descriptor, the 2D autocorrelation and others, the P_VSA-like descriptor and edge adjacency index, the drug-like index and edge adjacency index, the drug-like index and Burden eigenvalue, the drug-like index and topological descriptor, the edge adjacency index and Burden eigenvalue, and the edge adjacency index and topological descriptor. From the viewpoint of constructing a model with higher predictive accuracy, a model can be generated using a descriptor with a value of 0.65 or greater in Table 10, such as 2D autocorrelation, or a combination of descriptors with a value of 0.65 or greater, such as 2D autocorrelation and P_VSA-like descriptor, 2D autocorrelation and drug-like index, 2D autocorrelation and edge adjacency index, 2D autocorrelation and Barden eigenvalue, 2D autocorrelation and topological descriptor, 2D autocorrelation and others, drug-like index and edge adjacency index. [Table 10]

[0192] (Step 2) Semi-supervised learning using PCA-PLS 50,000 compounds were randomly extracted from the ChEMBL (https: / / www.ebi.ac.uk / chembl / ) database, chembl_23, and the PubChem (https: / / pubchem.ncbi.nlm.nih.gov / ) database. Of these, 88,881 compounds for which 16 important descriptors related to the compounds identified in Step 1 could be calculated, along with the 21 compounds mentioned above, totaling 88,902 compounds, were subjected to principal component analysis to reduce the dimension. The number of components was set to 11, the first component whose cumulative contribution rate exceeded 90%.

[0193] A total of 15 variables, including 11 compounds obtained by principal component analysis, two important descriptors for good solvents, one important descriptor for poor solvents, and crystallization temperature, were used as explanatory variables. Partial least squares regression (PLSR) was performed using the logarithm of the critical supersaturation as the objective variable.

[0194] Of the 58 types of experimental data, 70% (40 types) were randomly selected as training data, and 30% (18 types) were used as validation data. The number of PLS ​​components was determined using the Q2 value in 4-fold cross-validation as an evaluation function, and when the number of components was 3, a model with R2 = 0.856 for the training data and R2 = 0.856 for the validation data was obtained. Figure 90 is a plot of predicted values ​​against experimental values ​​of critical supersaturation.

[0195] Using this model, predicted values ​​and prediction intervals of critical supersaturation were calculated for the substrates in Table 3. The results output on a logarithmic scale were converted to a linear scale, and the values ​​obtained are shown in Table 11. Note that in the table, "Verification" in the data type section indicates that the data was used as verification data, and "Learning" indicates that the data was used as learning data. [Table 11-1] [Table 11-2]

[0196] Example 33 Development of a prediction model for critical supersaturation (III) First, using Jmol (http: / / jmol.sourceforge.net / ), a structural model of the compound is generated based on the SDF file. Five hundred and twelve captured images (snapshots, size: 512 x 512, 24 bpp) are then generated for each structural model, rotated in 45-degree increments around the X, Y, and Z axes. The SDF file of the training data is input, and images are generated for each compound. The images of each compound are stored in a designated folder that records the critical supersaturation, along with solvent information and the solution temperature during crystallization. The model is an unmodified AlexNet (University of Toronto) with the output layer replaced with SVR (Support Vector Regression), and the predictive model is transferred using Keras.

[0197] Furthermore, the prediction performance was confirmed by external validation using test data containing images of the compound, information about the solvent, and actual measured values ​​of critical supersaturation. Specifically, the test data images were input into the learning model, and the output predicted values ​​of critical supersaturation were compared with the actual measured values ​​contained in the test data to examine the correlation. [Industrial Applicability]

[0198] The method of the present invention makes it possible to reproducibly obtain crystals (particularly spherulites) of specific shapes of compounds. The spherulites of compounds have a wide range of potential applications in the fields of pharmaceutical production, agricultural chemical production, food production, printing technology, and organic electronic devices. [Explanation of symbols]

[0199] 100 Information processing device 102 Input Device 103 Display device 110 Storage device 120 CPU

Claims

1. A method for producing spherulites of a compound, comprising the steps of: (1) preparing a supersaturated solution of the compound having a degree of supersaturation equal to or greater than the critical degree of supersaturation required to obtain spherulites of the compound; and (2) A step of precipitating spherulites of the compound from the supersaturated solution. (with the proviso that said compounds exclude clopidogrel or a salt thereof).

2. The method according to claim 1, wherein the step (1) is carried out under conditions that do not cause nucleation until a supersaturation equal to or greater than a critical supersaturation is reached.

3. The method according to claim 1 or 2, wherein the critical supersaturation is an actual measured value.

4. The method according to any one of claims 1 to 3, wherein the spherulites have a sphericity of 0.60 or more.

5. The method according to any one of claims 1 to 4, wherein the compound obtained as spherulites is a compound selected from the following (1) and (2): (1) A compound represented by the following formula I, or a tautomer thereof, or an optical isomer thereof, or a salt thereof, or a solvate thereof: 【Chemistry 1】 [In the formula, X is CH or N; R 1 is a hydrogen atom or an optionally substituted C 1-6 is an alkoxy group, R 2 , R 3 and R 4 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 represents an alkoxy group or an optionally substituted amino group; (2) Azithromycin, duloxetine, clarithromycin, lanthanum carbonate, glutamic acid, ketotifen, escitalopram, dabigatran etexilate, theophylline, teneligliptin, pilsicainide, tramadol, vildagliptin, linagliptin, glutathione, mirabegron, tolvaptan, valacyclovir, bepotastine, olopatadine, or an optical isomer thereof, or a salt thereof, or a solvate thereof.

6. The method according to any one of claims 1 to 5, wherein the compound obtained as spherulites is esomeprazole or lansoprazole, or a salt thereof, or a solvate thereof.

7. The method according to any one of claims 1 to 6, wherein the compound obtained as spherulites is esomeprazole magnesium trihydrate.

8. A spherulite of a compound produced by the method according to any one of claims 1 to 7.

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