Preparation method for eutectic crystal

Abstract

Disclosed in the present invention is a preparation method for a eutectic crystal. The preparation method comprises the following steps: mixing a poor solvent and a good solvent, then adding a solid reactant and a eutectic crystal former thereto for suspension, so as to obtain the eutectic crystal. Compared with a suspension method, the preparation method for the eutectic crystal of the present invention can obtain a eutectic crystal with higher purity and yield, can effectively inhibit the generation of solvates, and has wide applicability; in addition, same can be suitable for both milligram-scale eutectic crystal screening and gram-scale eutectic sample preparation, as well as kilogram-scale eutectic crystal pilot production.

Description

A method for preparing eutectic Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a method for preparing a cocrystal. Background Art

[0002] A cocrystal is a single crystalline material composed of two or more different solid-state compounds in a stoichiometric ratio. Typically, the components of a cocrystal are neutral molecules. When proton transfer occurs between the components, resulting in the inclusion of charged ions in the lattice, a salt is formed. When a cocrystal contains both neutral molecules and charged ions, an ionic cocrystal is formed. If one component of the cocrystal is an active pharmaceutical ingredient (API) and the other is a pharmaceutically acceptable cocrystal former (CCF), the cocrystal is called a pharmaceutical cocrystal. Cocrystals have attracted increasing attention in various solid materials fields, particularly in the pharmaceutical field, due to their ability to manipulate optoelectronic, mechanical, physicochemical, and biological properties and enrich their solid forms.

[0003] The formation of cocrystals involves the cocrystallization of two or more solid components. Compared to the crystallization of a single component, the synthesis of cocrystals faces greater challenges because the different components often have different polarities and properties. Many methods for preparing cocrystals have been reported, which can be roughly divided into methods using solvents (e.g., evaporation, cooling crystallization, antisolvent crystallization, and suspension methods) and methods using no or only a small amount of solvent (e.g., melt crystallization, hot melt extrusion, and grinding methods). In contrast, methods using solvents for preparing cocrystals have advantages in terms of online monitoring of the reaction process, product quality control, and industrial scale-up (Rodrigues et al, "Pharmaceutical cocrystallization techniques. Advances and challenges", Int. J. Pharm. 2018, 547, 404-420, DOI: 10.1016 / j.ijpharm.2018.06.024).However, for some components that easily form solvates, solvates or cocrystals mixed with solvates are often obtained when cocrystals are prepared using solvents (Johnston et al, "Carbamazepine N,N-dimethylformamide solvate", Acta Crystallogr. E 2005, 61, 01509-01511, DOI: 10.1107 / S1600536805012535; Burnett et al, "Investigating carbamazepine-acetone solvate formation via dynamic gravimetric vapor sorption", J. Therm. Anal. Calorim. 2007, 89, 693-698, DOI: 10.1007 / s10973-006-7957-8; Harris et al, "Structural Studies of the Polymorphs of Carbamazepine, Its Dihydrate, and Two Solvates", Org. Process Res.Dev.2005,9,902-910,DOI:10.1021 / op0500990; Fleischman et al, "Crystal engineering of the composition of pharmaceutical phases: Multiple-component crystalline solids involving carbamazepine", Cryst.Growth Des. 2003, 3, 909-919, DOI: 10.1021 / cg034035x).

[0004] The suspension method is a widely used solvent-based method for preparing cocrystals, in which solid reactants and cocrystal formers are suspended in a solvent in a specific ratio to form the cocrystal (Zhang et al, "Efficient Co-crystal Screening Using Solution-Mediated Phase Transformation", J. Pharm. Sci. 2007, 96, 990-995, DOI: 10.1002 / jps.20949). When the solubility of the cocrystal or certain components thereof in the solvent is high, excessive feeding is often required to obtain the cocrystal (Rodriguez-Hornedo et al, "Reaction crystallization of pharmaceutical molecular complexes", Mol. Pharmaceutics 2006, 3, 362-367, DOI: 10.1021 / mp050099m). This often reduces the utilization of the raw materials and also introduces a high level of impurities into the residual mother liquor.

[0005] Antisolvent crystallization is another method for preparing cocrystals using solvents. This involves dissolving the solid reactants and the cocrystal former in a certain good solvent. An antisolvent is then added to supersaturate the solution and precipitate the cocrystal from the solution (Zhang Jianjun et al., Theory and Application of Crystalline Drug Development, 2019, p191). The antisolvent crystallization method requires that the poor solvent and the good solvent are miscible (Douroumis et al., “Advanced methodologies for cocrystal synthesis”, Adv. Drug Deliver Rev. 2017, 117, 178-195, DOI: 10.1016 / j.addr.2017.07.008).

[0006] Another challenge in cocrystal preparation is the applicability of the preparation method. It is often difficult for a single preparation method to be suitable for milligram-scale cocrystal screening, gram-scale cocrystal sample preparation, kilogram-scale cocrystal pilot production, and even larger-scale industrial production.

[0007] Therefore, developing a new cocrystal preparation method can overcome the shortcomings of the above-mentioned suspension method and has wide applicability. It can be used for milligram-scale cocrystal screening, gram-scale cocrystal sample preparation, and kilogram-scale cocrystal pilot production, which has important practical significance.

[0008] Summary of the Invention

[0009] The present invention aims to address at least one of the technical problems existing in the prior art. To this end, the present invention provides a method for preparing cocrystals using an antisolvent suspension method. Compared to suspension methods, the antisolvent suspension method of the present invention can produce cocrystals with higher purity and yield, effectively inhibits the formation of solvates, and has wide applicability.

[0010] In a first aspect of the present invention, a method for preparing a eutectic is provided, comprising the following steps:

[0011] After mixing the poor solvent with the good solvent, the solid reactant and the eutectic former are added and suspended to obtain the eutectic.

[0012] In some embodiments of the present invention, the poor solvent comprises an alkane.

[0013] In some embodiments of the present invention, the alkane includes at least one of n-heptane, n-hexane, and cyclohexane.

[0014] In some embodiments of the present invention, the good solvent includes at least one of water, alcohol, ester, ketone, nitrile, ether, DMSO, and DMF.

[0015] In some embodiments of the present invention, the alcohol comprises at least one of methanol, ethanol, and isopropanol.

[0016] In some embodiments of the present invention, the ester includes ethyl acetate and isopropyl acetate.

[0017] In some embodiments of the present invention, the ketone comprises acetone or methyl tert-butyl ketone.

[0018] In some embodiments of the present invention, the nitrile comprises acetonitrile.

[0019] In some embodiments of the present invention, the ether includes at least one of methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane.

[0020] In some embodiments of the present invention, the poor solvent and the good solvent are immiscible.

[0021] In some embodiments of the present invention, the poor solvent includes alkanes, and the good solvent includes at least one of water, methanol, acetonitrile, DMSO, and DMF.

[0022] In some embodiments of the present invention, the solid reactant includes at least one of carbamazepine, theophylline, mebendazole, urea, temozolomide, carbazole, pyrazinamide, and isoniazid.

[0023] In some embodiments of the present invention, the eutectic former includes at least one of carboxylic acid, amide, saccharin, urea, pyridine compounds, cyano compounds, and inorganic salts.

[0024] In some embodiments of the present invention, the cocrystal former includes at least one of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid, maleic acid, tartaric acid, malic acid, citric acid, mandelic acid, mandelic acid, proline, benzoic acid, cinnamic acid, salicylic acid, acetylsalicylic acid, 1-hydroxy-2-naphthoic acid, 4-hydroxybenzoic acid, vanillic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, gallic acid, isonicotinamide, nicotinamide, benzamide, 4-hydroxybenzamide, saccharin, urea, 4,4'-bipyridine, 7,7,8,8-tetracyanoquinodimethane (TCNQ), and magnesium sulfate.

[0025] In some embodiments of the present invention, the molar ratio of the solid reactant to the eutectic former is (1-4):1.

[0026] In some embodiments of the present invention, the volume ratio of the good solvent to the poor solvent is 1:(5-200).

[0027] In some embodiments of the present invention, the volume ratio of the good solvent to the poor solvent is 1:(10-100).

[0028] In some embodiments of the present invention, the ratio of the total amount of the solid reactants and the eutectic former to the total amount of the solvent is 1 g: (5-500) mL.

[0029] In some embodiments of the present invention, the ratio of the total amount of the solid reactants and the eutectic former to the total amount of the solvent is 1 g: (10-100) mL.

[0030] In some embodiments of the present invention, the method for preparing the cocrystal specifically comprises the following steps:

[0031] After mixing the poor solvent with the good solvent, add the solid reactant and the eutectic former, stir, filter, and dry to obtain the eutectic.

[0032] In some embodiments of the present invention, the stirring time is 0.3 to 48 hours.

[0033] In some embodiments of the present invention, the stirring temperature is 15-35°C.

[0034] In a second aspect, the present invention provides an application of the method for preparing a co-crystal in preparing a co-crystal.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] (1) The anti-solvent suspension method adopted in the present invention does not require tedious solubility measurements of the reactants, and can obtain products with higher purity and higher yield.

[0037] (2) The anti-solvent suspension method of the present invention can effectively inhibit the formation of its solvate.

[0038] (3) The antisolvent suspension method of the present invention has a wide range of applicability. It can be applied to milligram-scale cocrystal screening, gram-scale cocrystal sample preparation, and kilogram-scale cocrystal pilot production. It has broad application prospects in the screening, preparation and production processes of cocrystals. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG1 is an X-ray powder diffraction pattern of samples obtained in Example 1 of the present invention and Comparative Example 1.

[0040] FIG2 is an X-ray powder diffraction pattern of samples obtained in Example 2 of the present invention and Comparative Example 2.

[0041] FIG3 is an X-ray powder diffraction pattern of samples obtained in Example 3 of the present invention and Comparative Example 3.

[0042] FIG4 is an X-ray powder diffraction pattern of samples obtained in Example 4 of the present invention and Comparative Example 4.

[0043] FIG5 is an X-ray powder diffraction pattern of samples obtained in Example 5 of the present invention and Comparative Example 5.

[0044] FIG6 is an X-ray powder diffraction pattern of the samples prepared in Example 6 of the present invention and Comparative Example 6.

[0045] FIG7 is an X-ray powder diffraction pattern of samples prepared in Example 7 of the present invention and Comparative Example 7.

[0046] FIG8 is an X-ray powder diffraction pattern of samples prepared in Example 8 of the present invention and Comparative Example 8.

[0047] FIG9 is an X-ray powder diffraction pattern of samples prepared in Example 9 of the present invention and Comparative Example 9.

[0048] FIG10 is an X-ray powder diffraction pattern of the samples prepared in Example 10 of the present invention and Comparative Example 10.

[0049] FIG11 is an X-ray powder diffraction pattern of the samples prepared in Example 11 of the present invention and Comparative Example 11.

[0050] FIG12 is an X-ray powder diffraction pattern of the samples prepared in Example 12 of the present invention and Comparative Example 12.

[0051] FIG13 is an X-ray powder diffraction pattern of the sample obtained in Example 13 of the present invention.

[0052] FIG14 is a flow chart of a method for preparing a eutectic. DETAILED DESCRIPTION

[0053] The following will clearly and completely describe the concept of the present invention and the technical effects produced in conjunction with the embodiments, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention. The test methods used in the embodiments are all conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can all be reagents and materials obtained from commercial channels.

[0054] In the description of the present invention, reference to terms such as "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples" means that the specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the exemplary expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

[0055] In the present invention, "suspension" is a common term in the field of drug preparation, which generally refers to the mechanization or fluidization of solid drug raw materials so that the solid drug is dispersed or suspended in a solvent.

[0056] X-ray powder diffraction pattern detection instrument and method: X-ray powder diffraction analysis uses a Rigaku SmartLab 9KW diffractometer from Japan Rigaku Co., Ltd., Cu Kα ray The voltage was 40 kV, the current was 150 mA, the step size was 0.01°, the scanning speed was 20° / min, the scanning range was 5.0-40.0°, and the test temperature was room temperature.

[0057] Carbamazepine, theophylline, mebendazole, temozolomide, pyrazinamide, and isoniazid are all active drug molecules; urea, carbazole, and TCNQ are organic compounds; and magnesium sulfate is an inorganic compound. Cocrystals have been reported for all of these compounds, with pyrazinamide, isoniazid, and fumaric acid forming ternary cocrystals. Furthermore, carbamazepine can form a variety of solvates. The present invention uses the cocrystals of these solid compounds as research models and utilizes the antisolvent suspension method of the present invention to prepare cocrystals. The preparation process is shown in Figure 14.

[0058] Example 1

[0059] Carbamazepine (0.70 mmol) and malonic acid (0.35 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of DMF, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure carbamazepine-malonic acid cocrystal (2:1) with a yield of 89%. Its X-ray powder diffraction pattern is shown in Figure 1.

[0060] Comparative Example 1

[0061] Carbamazepine (0.70 mmol) and malonic acid (0.35 mmol) were added to 1 mL of DMF, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to obtain a DMF solvate of carbamazepine. No carbamazepine-malonic acid cocrystal (2:1) was obtained, and its X-ray powder diffraction pattern is shown in Figure 1.

[0062] Example 2

[0063] Carbamazepine (0.32 mmol) and 4,4'-bipyridine (0.16 mmol) were added to a mixed solvent of 1 mL of cyclohexane and 10 μL of acetone, stirred at room temperature for 48 hours, filtered, and the solid was vacuum dried to obtain pure carbamazepine-4,4'-bipyridine cocrystal (2:1) with a yield of 89%. Its X-ray powder diffraction pattern is shown in Figure 2.

[0064] Comparative Example 2

[0065] Carbamazepine (0.32 mmol) and 4,4'-bipyridine (0.16 mmol) were added to 1 mL of acetone, stirred at room temperature for 48 hours, filtered, and the solid was vacuum dried to obtain an acetone solvate of carbamazepine. Carbamazepine-4,4'-bipyridine cocrystal (2:1) was not obtained. Its X-ray powder diffraction pattern is shown in Figure 2.

[0066] Example 3

[0067] Theophylline (0.55 mmol) and oxalic acid (0.55 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum-dried to obtain pure theophylline-oxalic acid cocrystal (1:1) with a yield of 92%. Its X-ray powder diffraction pattern is shown in Figure 3.

[0068] Comparative Example 3

[0069] Theophylline (0.55 mmol) and oxalic acid (0.55 mmol) were added to 1 mL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum-dried to obtain 60 mg of powder. X-ray powder diffraction analysis of the powder revealed a characteristic peak for theophylline at 12.5°, indicating that the obtained product was a theophylline-oxalic acid cocrystal (1:1) mixed with theophylline. The X-ray powder diffraction pattern is shown in Figure 3.

[0070] Example 4

[0071] Toluene imidazole (0.23 mmol) and glutaric acid (0.23 mmol) were added to a mixed solvent of 2 mL of n-hexane and 20 μL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum-dried to obtain pure toluene imidazole-glutaric acid cocrystal (1:1) with a yield of 82%. Its X-ray powder diffraction pattern is shown in Figure 4.

[0072] Comparative Example 4

[0073] Tobacillus thiophene (0.23 mmol) and glutaric acid (0.23 mmol) were added to 2 mL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain 35 mg of powder. X-ray powder diffraction analysis showed only the characteristic peaks of tobacillus thiophene, indicating that tobacillus thiophene was obtained. The X-ray powder diffraction pattern is shown in Figure 4.

[0074] Example 5

[0075] Toluene imidazole (0.24 mmol) and maleic acid (0.24 mmol) were added to a mixed solvent of 2 mL of n-hexane and 50 μL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure toluene imidazole-maleate (1:1) with a yield of 88%. Its X-ray powder diffraction pattern is shown in Figure 5.

[0076] Comparative Example 5

[0077] Tobacillus thiophene (0.24 mmol) and maleic acid (0.24 mmol) were added to 2 mL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain 37 mg of powder. X-ray powder diffraction analysis showed only the characteristic peaks of tobacillus thiophene, indicating that the obtained product was tobacillus thiophene. Its X-ray powder diffraction pattern is shown in Figure 5.

[0078] Example 6

[0079] Urea (0.75 mmol) and adipic acid (0.38 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of water, stirred at room temperature for 24 hours, filtered, and the solid was vacuum-dried to obtain pure urea-adipic acid cocrystal (2:1) with a yield of 80%. Its X-ray powder diffraction pattern is shown in Figure 6.

[0080] Comparative Example 6

[0081] Urea (0.75 mmol) and adipic acid (0.38 mmol) were added to 1 mL of water, stirred at room temperature for 24 hours, filtered, and the solid was vacuum-dried to obtain 3 mg of powder. X-ray powder diffraction analysis showed only the characteristic peaks of adipic acid, indicating that adipic acid was obtained. Its X-ray powder diffraction pattern is shown in Figure 6.

[0082] Example 7

[0083] Urea (1.1 mmol) and magnesium sulfate (0.28 mmol) were added to a mixed solvent of 1 mL of cyclohexane and 5 μL of water, stirred at room temperature for 24 hours, filtered, and the solid was vacuum-dried to obtain a pure urea-magnesium sulfate eutectic (4:1) product with a yield of 81%. Its X-ray powder diffraction pattern is shown in Figure 7.

[0084] Comparative Example 7

[0085] Urea (1.1 mmol) and magnesium sulfate (0.28 mmol) were added to 1 mL of water and stirred at room temperature for 24 hours until all the solids were dissolved.

[0086] Example 8

[0087] Carbamazepine (0.35 mmol) and nicotinamide (0.35 mmol) were added to a mixed solvent of 4 mL of n-hexane and 40 μL of ethyl acetate, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure carbamazepine-nicotinamide cocrystal (1:1) with a yield of 87%. Its X-ray powder diffraction pattern is shown in Figure 8.

[0088] Comparative Example 8

[0089] Carbamazepine (0.35 mmol) and nicotinamide (0.35 mmol) were added to 4 mL of ethyl acetate, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure carbamazepine-nicotinamide cocrystal (1:1) with a yield of 35%. Its X-ray powder diffraction pattern is shown in Figure 8.

[0090] Example 9

[0091] Temozolomide (0.22 mmol) and baicalein (0.21 mmol) were added to a mixed solvent of 1 mL of n-heptane and 100 μL of methanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure temozolomide-baicalein cocrystal (1:1) with a yield of 84%. Its X-ray powder diffraction pattern is shown in Figure 9.

[0092] Comparative Example 9

[0093] Temozolomide (0.22 mmol) and baicalein (0.21 mmol) were added to 1 mL of methanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure temozolomide-baicalein cocrystal (1:1) with a yield of 49%. Its X-ray powder diffraction pattern is shown in Figure 9.

[0094] Example 10

[0095] A mixture of urea (0.39 mmol) and citric acid (0.39 mmol) was added to a mixed solvent of 1 mL of n-heptane and 10 μL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum-dried to obtain pure urea-citric acid cocrystal (1:1) with a yield of 86%. Its X-ray powder diffraction pattern is shown in Figure 10.

[0096] Comparative Example 10

[0097] A mixture of urea (0.39 mmol) and citric acid (0.39 mmol) was added to 1 mL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure urea-citric acid cocrystal (1:1) with a yield of 45%. Its X-ray powder diffraction pattern is shown in Figure 10.

[0098] Example 11

[0099] Carbazole (0.27 mmol) and TCNQ (0.27 mmol) were added to a mixed solvent of 2 mL of n-hexane and 100 μL of methanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure carbazole-TCNQ cocrystal (1:1) with a yield of 85%. Its X-ray powder diffraction pattern is shown in Figure 11.

[0100] Comparative Example 11

[0101] Carbazole (0.27 mmol) and TCNQ (0.27 mmol) were added to 2 mL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure carbazole-TCNQ cocrystal (1:1) with a yield of 44%. Its X-ray powder diffraction pattern is shown in Figure 11.

[0102] Example 12

[0103] Pyrazinamide (0.1 mmol), isoniazid (0.1 mmol), and fumaric acid (0.2 mmol) were added to a mixed solvent of 1 mL of n-hexane and 10 μL of methanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum-dried to obtain pure pyrazinamide-isoniazid-fumaric acid cocrystal (1:1:2) with a yield of 85%. Its X-ray powder diffraction pattern is shown in Figure 12.

[0104] Comparative Example 12

[0105] Pyrazinamide (0.1 mmol), isoniazid (0.1 mmol), and fumaric acid (0.2 mmol) were added to 1 mL of methanol, stirred at room temperature for 24 hours, filtered, and the solid was vacuum dried to obtain pure pyrazinamide-isoniazid-fumaric acid cocrystal (1:1:2) with a yield of 45%. Its X-ray powder diffraction pattern is shown in Figure 12.

[0106] Example 13

[0107] Carbamazepine (0.070 mmol) and malonic acid (0.035 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air to obtain pure carbamazepine-malonic acid cocrystal (2:1), the X-ray powder diffraction analysis pattern of which is shown in Figure 13.

[0108] Example 14

[0109] Carbamazepine (0.35 mol) and malonic acid (0.17 mol) were added to a mixed solvent of 500 mL of n-heptane and 50 μL of methanol, stirred at room temperature for 6 hours, filtered, and the solid was vacuum dried. X-ray powder diffraction analysis showed that pure carbamazepine-malonic acid cocrystal (2:1) was obtained with a yield of 98%.

[0110] Example 15

[0111] Carbamazepine (3.5 mol) and malonic acid (1.7 mol) were added to a mixed solvent of 5 L n-heptane and 0.5 mL methanol, stirred at room temperature for 12 hours, filtered, and the solid was vacuum dried. X-ray powder diffraction analysis showed that pure carbamazepine-malonic acid cocrystal (2:1) was obtained with a yield of 99%.

[0112] Example 16

[0113] Carbamazepine (0.068 mmol) and succinic acid (0.034 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-succinic acid cocrystal (2:1) was obtained.

[0114] Example 17

[0115] Carbamazepine (0.055 mmol) and glutaric acid (0.055 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-glutaric acid cocrystal (1:1) was obtained.

[0116] Example 18

[0117] Carbamazepine (0.065 mmol) and adipic acid (0.032 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-adipic acid cocrystal (2:1) was obtained.

[0118] Example 19

[0119] Carbamazepine (0.054 mmol) and L-malic acid (0.054 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-L-malic acid cocrystal (1:1) was obtained.

[0120] Example 20

[0121] Carbamazepine (0.054 mmol) and DL-malic acid (0.054 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-DL-malic acid cocrystal (1:1) was obtained.

[0122] Example 21

[0123] Carbamazepine (0.052 mmol) and L-tartaric acid (0.052 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-L-tartaric acid cocrystal (1:1) was obtained.

[0124] Example 22

[0125] Carbamazepine (0.056 mmol) and benzoic acid (0.056 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-benzoic acid cocrystal (1:1) was obtained.

[0126] Example 23

[0127] Carbamazepine (0.052 mmol) and cinnamic acid (0.052 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-cinnamic acid cocrystal (1:1) was obtained.

[0128] Example 24

[0129] Carbamazepine (0.047 mmol) and 1-hydroxy-2-naphthoic acid (0.047 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-1-hydroxy-2-naphthoic acid cocrystal (1:1) was obtained.

[0130] Example 25

[0131] Carbamazepine (0.053 mmol) and 4-hydroxybenzoic acid (0.053 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-4-hydroxybenzoic acid cocrystal (1:1) was obtained.

[0132] Example 26

[0133] Carbamazepine (0.050 mmol) and vanillic acid (0.049 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 40 μL of acetonitrile, or 1 mL of n-heptane and 100 μL of ethyl acetate, or 1 mL of n-heptane and 100 μL of acetone, respectively. The mixture was stirred at room temperature for 24 hours, filtered, and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-vanillic acid cocrystal (1:1) was obtained.

[0134] Example 27

[0135] Carbamazepine (0.051 mmol) and 2,4-dihydroxybenzoic acid (0.051 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-2,4-dihydroxybenzoic acid cocrystal (1:1) was obtained.

[0136] Example 28

[0137] Carbamazepine (0.051 mmol) and 2,5-dihydroxybenzoic acid (0.051 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-2,5-dihydroxybenzoic acid cocrystal (1:1) was obtained.

[0138] Example 29

[0139] Carbamazepine (0.051 mmol) and 2,6-dihydroxybenzoic acid (0.051 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-2,6-dihydroxybenzoic acid cocrystal (1:1) was obtained.

[0140] Example 30

[0141] Carbamazepine (0.056 mmol) and benzamide (0.056 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively. The mixture was stirred at room temperature for 24 hours, filtered, and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-benzamide cocrystal (1:1) was obtained.

[0142] Example 31

[0143] Carbamazepine (0.056 mmol) and nicotinamide (0.056 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively. The mixture was stirred at room temperature for 24 hours, filtered, and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-nicotinamide cocrystal (1:1) was obtained.

[0144] Example 32

[0145] Carbamazepine (0.056 mmol) and isonicotinamide (0.056 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-isonicotinamide cocrystal (1:1) was obtained.

[0146] Example 33

[0147] Carbamazepine (0.054 mmol) and 4-hydroxybenzamide (0.054 mmol) were added to a mixed solvent of 1 mL of n-heptane and 20 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-4-hydroxybenzamide cocrystal (1:1) was obtained.

[0148] Example 34

[0149] Carbamazepine (0.048 mmol) and saccharin (0.048 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-saccharin cocrystal (1:1) was obtained.

[0150] Example 35

[0151] Carbamazepine (0.053 mmol) and salicylic acid (0.054 mmol) were added to a mixed solvent of 1 mL of n-heptane and 10 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively. The mixture was stirred at room temperature for 24 hours, filtered, and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-salicylic acid cocrystal (1:1) was obtained.

[0152] Example 36

[0153] Carbamazepine (0.048 mmol) and acetylsalicylic acid (0.048 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 40 μL of methanol, or 1 mL of n-heptane and 40 μL of acetonitrile, or 1 mL of n-heptane and 100 μL of ethyl acetate, or 1 mL of n-heptane and 40 μL of acetone, respectively, and stirred at room temperature for 24 hours. The mixture was filtered and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-acetylsalicylic acid cocrystal (1:1) was obtained.

[0154] Example 37

[0155] Carbamazepine (0.063 mmol) and 4,4'-bipyridine (0.032 mmol) were added to a mixed solvent of 1 mL of n-heptane and 5 μL of water, or 1 mL of n-heptane and 10 μL of methanol, or 1 mL of n-heptane and 10 μL of acetonitrile, or 1 mL of n-heptane and 10 μL of ethyl acetate, or 1 mL of n-heptane and 10 μL of acetone, respectively. The mixture was stirred at room temperature for 24 hours, filtered, and the solid was dried in air. X-ray powder diffraction analysis showed that pure carbamazepine-4,4'-bipyridine cocrystal (2:1) was obtained.

[0156] By comparing Examples 1-2 and the corresponding comparative examples, it can be found that, using carbamazepine-malonic acid cocrystal (2:1) and carbamazepine-4,4'-bipyridine cocrystal (2:1) as models, solid reactants and cocrystal formers in stoichiometric ratios are used to prepare cocrystals using the antisolvent suspension method and the suspension method, respectively. It is found that the antisolvent suspension method of the present invention can obtain pure cocrystals; while the suspension method cannot obtain cocrystals, and only the solvate of carbamazepine can be obtained.

[0157] By comparing Examples 3-7 and the corresponding comparative examples, it can be found that, using theophylline-oxalic acid eutectic (1:1), tobendazole-glutaric acid eutectic (1:1), tobendazole maleate (1:1), urea-adipic acid eutectic (2:1), and urea-magnesium sulfate eutectic (4:1) as models, solid reactants and eutectic formers in stoichiometric ratios were used to prepare eutectics using the antisolvent suspension method and the suspension method, respectively. It was found that the antisolvent suspension method of the present invention can obtain pure eutectic or salt; while the suspension method cannot obtain pure eutectic or salt.

[0158] By comparing Examples 8-12 and the corresponding comparative examples, it can be found that, using carbamazepine-nicotinamide cocrystal (1:1), temozolomide-baicalein cocrystal (1:1), urea-citric acid cocrystal (1:1), carbazole-TCNQ cocrystal (1:1), and pyrazinamide-isoniazid-fumaric acid cocrystal (1:1:2) as models, solid reactants and cocrystal formers in stoichiometric ratios were used to prepare cocrystals using the antisolvent suspension method and the suspension method, respectively. It was found that the antisolvent suspension method of the present invention obtained a higher yield.

[0159] By comparing Examples 13-15, it can be found that, using carbamazepine-malonic acid cocrystal as a model, the antisolvent suspension method of the present invention can prepare pure cocrystals from trace reactions (milligram-level feed) to large-scale reactions (kilogram-level feed).

[0160] By comparing Examples 1-37, it can be found that when the cocrystal formers are oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid, maleic acid, tartaric acid, malic acid, citric acid, mandelic acid, mandelic acid, proline, benzoic acid, cinnamic acid, salicylic acid, acetylsalicylic acid, 1-hydroxy-2-naphthoic acid, 4-hydroxybenzoic acid, vanillic acid, 2,4-dihydroxybenzoic acid, benzamide, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, gallic acid, isonicotinamide, nicotinamide, 4-hydroxybenzamide, saccharin, urea, 4,4'-bipyridine, TCNQ, and magnesium sulfate, the cocrystals can be prepared using the antisolvent suspension method.

[0161] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A method for preparing a eutectic, characterized in that: The method comprises the following steps: after mixing a poor solvent with a good solvent, adding a solid reactant and a eutectic former for suspension to obtain a eutectic.

2. The method for preparing a eutectic according to claim 1, characterized in that: The poor solvent includes alkanes, and the good solvent includes at least one of water, alcohol, ester, ketone, nitrile, ether, DMSO, and DMF.

3. The method for preparing a eutectic according to claim 1, characterized in that: The poor solvent and the good solvent are immiscible.

4. The method for preparing a eutectic according to claim 3, characterized in that: The poor solvent includes alkane, and the good solvent includes at least one of water, methanol, acetonitrile, DMSO, and DMF.

5. The method for preparing a co-crystal according to any one of claims 1 to 4, characterized in that: The solid reactant comprises at least one of carbamazepine, theophylline, mebendazole, urea, temozolomide, carbazole, pyrazinamide and isoniazid; And / or, the eutectic former includes at least one of carboxylic acid, amide, saccharin, urea, pyridine compounds, cyano compounds, and inorganic salts.

6. The method for preparing a eutectic according to claim 5, characterized in that: The eutectic former includes at least one of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid, maleic acid, tartaric acid, malic acid, citric acid, mandelic acid, mandelic acid, proline, benzoic acid, cinnamic acid, salicylic acid, acetylsalicylic acid, 1-hydroxy-2-naphthoic acid, 4-hydroxybenzoic acid, vanillic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, gallic acid, isonicotinamide, nicotinamide, benzamide, 4-hydroxybenzamide, saccharin, urea, 4,4'-bipyridine, TCNQ, and magnesium sulfate.

7. The method for preparing a co-crystal according to any one of claims 1 to 4, characterized in that: The volume ratio of the good solvent to the poor solvent is 1:(5-200); and / or, the ratio of the total amount of the solid reactants and the eutectic formers to the total amount of the solvent is 1 g: (5-50) mL; And / or, the molar ratio of the solid reactant to the eutectic former is (1-4):

1.

8. The method for preparing a eutectic according to claim 1, characterized in that: The specific steps include: After the poor solvent and the good solvent are mixed, the solid reactant and the eutectic former are added, stirred, filtered and dried to obtain the eutectic.

9. The method for preparing a eutectic according to claim 8, characterized in that: The stirring temperature is 15 to 35° C. And / or, the stirring time is 0.3 to 48 hours.

10. Use of the method for preparing a co-crystal according to any one of claims 1 to 9 in preparing a co-crystal.

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