CN117383998A

CN117383998A - Preparation method of eutectic

Info

Publication number: CN117383998A
Application number: CN202311281200.4A
Authority: CN
Inventors: 陈嘉媚; 李顺宇; 李艺; 黄昭荣
Original assignee: Tianjin University of Technology
Current assignee: Tianjin University of Technology
Priority date: 2023-09-28
Filing date: 2023-09-28
Publication date: 2024-01-12

Abstract

The invention discloses a preparation method of eutectic, which comprises the following steps: after the poor solvent and the good solvent are mixed, solid reactant and eutectic formation are added for suspension, and the eutectic is obtained. Compared with a suspension method, the preparation method of the eutectic can obtain purer and higher-yield eutectic, can effectively inhibit the generation of solvates, has wide applicability, and is suitable for milligram-scale eutectic screening, gram-scale eutectic sample preparation and kilogram-scale eutectic pilot scale production.

Description

Preparation method of eutectic

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of eutectic.

Background

A eutectic is a single crystalline phase material composed of two or more different solid state compounds in stoichiometric proportions. Typically, the various components of the co-crystal are neutral molecules; when proton transfer occurs between different components in the eutectic, the crystal lattice contains charged ions, so that salt is formed; when the co-crystal contains both neutral molecules and charged ions, an ionic co-crystal is formed. If one component of the co-crystal is an Active Pharmaceutical Ingredient (API) and the other component is a pharmaceutically acceptable co-crystal former (CCF), such co-crystal is referred to as a pharmaceutical co-crystal. Since the co-crystals can regulate the photoelectric, mechanical, physicochemical and biological properties of substances and enrich the solid forms of the substances, they are receiving increasing attention in various solid material fields, especially in the pharmaceutical field.

The formation of co-crystals involves co-crystallization of two or more solid components, and the synthesis of co-crystals presents a greater challenge than crystallization of a single component because the different components tend to be of different polarity and different properties. Many methods for producing a eutectic crystal have been reported, and can be roughly classified into a method using a solvent (for example, evaporation method, cooling crystallization method, anti-solvent crystallization method, suspension method, etc.) and a method using no or only a small amount of a solvent (for example, melt crystallization method, hot melt extrusion method, grinding method, etc.). In contrast, the eutectic preparation method using a solvent is more advantageous in on-line monitoring of the reaction process, control of product quality and industrial scale-up (Rodrigues et al, "Pharmaceutical cocrystallization technologies. Advances and changes", int. J. Pharm.2018,547,404-420, DOI:10.1016/j. Ijpharm. 2018.06.024). However, for some components that readily form Solvates, when solvents are used to prepare the co-crystals, it is common to obtain Solvates or co-crystals mixed with Solvates (Johnston et al, "Carbamazepine N, N-dimethylformamide solvate", acta crystal grogr.E 2005,61, O1509-O1511, 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 solvents", org.ProcessRes. Dev.2005,9,902-910, DOI:10.1021/op0500990; fleischet al, "Crystal engineering of the composition of pharmaceutical phases: multiple-component crystalline solids involving Carbamazepine", cryst. Grow Des.2003,3,909-919, DOI:10.1021/c 034035).

The suspension method is a widely used method for preparing a eutectic using a solvent, i.e. solid reactants and a eutectic formation are suspended in a solvent according to a certain proportion to form a eutectic (Zhang et al, "effect 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 co-crystals or some of the components thereof in the solvent is large, excessive dosing is often required to obtain the co-crystals (Rodriguez-Hornedo et al, "Reaction crystallization of pharmaceutical molecular complexes", mol. Pharmaceuticals 2006,3,362-367, DOI:10.1021/mp050099 m), which tends to reduce the utilization of the raw materials and also to bring about more impurities in the residual mother liquor.

The anti-solvent crystallization method is another eutectic preparation method using a solvent, namely, solid reactants and eutectic formations are jointly dissolved in a certain good solvent, then the anti-solvent is added to enable the eutectic in the solution to be supersaturated and to be separated out of the solution (Zhang Jianjun et al, edition, crystal form drug research theory and application, 2019, p 191), and the anti-solvent crystallization method requires miscibility of the poor solvent and the good solvent (Douromics et al, "Advanced methodologies for cocrystal synthesis", adv. Drug delivery Rev.2017,117,178-195, DOI:10.1016/j. Addr. 2017.07.008).

Another challenge of eutectic preparation is the applicability of the preparation method. The preparation method is difficult to be suitable for mg-scale eutectic screening and gram-scale eutectic sample preparation, and is also suitable for kg-scale eutectic pilot scale production to larger-scale industrial scale production.

Therefore, a novel eutectic preparation method is developed, the defects of the suspension method can be overcome, the method has wide applicability, and the method is suitable for milligram-scale eutectic screening and gram-scale eutectic sample preparation, and is suitable for kilogram-scale eutectic pilot scale production, thereby having important practical significance.

Disclosure of Invention

The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, compared with the suspension method, the anti-solvent suspension method can obtain the eutectic with purer and higher yield, can effectively inhibit the generation of solvates, and has wide applicability.

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

after the poor solvent and the good solvent are mixed, solid reactant and eutectic formation are added for suspension, and the eutectic is obtained.

In some embodiments of the invention, the poor solvent comprises an alkane.

In some embodiments of the invention, the alkane comprises at least one of n-heptane, n-hexane, cyclohexane.

In some embodiments of the invention, the good solvent comprises at least one of water, alcohol, ester, ketone, nitrile, ether, DMSO, DMF.

In some embodiments of the invention, the alcohol comprises at least one of methanol, ethanol, isopropanol.

In some embodiments of the invention, the esters include ethyl acetate, isopropyl acetate.

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

In some embodiments of the invention, the nitrile comprises acetonitrile.

In some embodiments of the invention, the ether comprises at least one of methyl tertiary butyl ether, tetrahydrofuran, 1, 4-dioxane.

In some embodiments of the invention, the poor solvent and the good solvent are immiscible.

In some embodiments of the invention, the poor solvent comprises an alkane and the poor solvent comprises at least one of water, methanol, acetonitrile, DMSO, DMF.

In some embodiments of the invention, the solid reactant comprises at least one of carbamazepine, theophylline, mebendazole, urea, temozolomide, carbazole, picolinamide, isoniazid.

In some embodiments of the invention, the co-crystal former comprises at least one of carboxylic acid, amide, saccharin, urea, pyridines, cyano compounds, inorganic salts.

In some embodiments of the invention, the co-crystal former comprises 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, 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-hydroxybenzoamide, saccharin, urea, 4' -bipyridine, 7, 8-Tetracyanoquinodimethane (TCNQ), magnesium sulfate.

In some embodiments of the invention, the molar ratio of solid reactant to eutectic formation is 1 to 4:1.

in some embodiments of the invention, the volume ratio of the good solvent to the poor solvent is 1:5 to 200.

In some embodiments of the invention, the volume ratio of the good solvent to the poor solvent is 1:10 to 100.

In some embodiments of the invention, the ratio of the total amount of solid reactant and eutectic formation to the total amount of solvent is 1g: (5-500) mL.

In some embodiments of the invention, the ratio of the total amount of solid reactant and eutectic formation to the total amount of solvent is 1g: (10-100) mL.

In some embodiments of the present invention, the method for preparing the eutectic specifically includes the following steps:

mixing the poor solvent and the good solvent, adding the solid reactant and the eutectic formation, stirring, filtering and drying to obtain the eutectic.

In some embodiments of the invention, the stirring time is from 0.3 to 48 hours.

In some embodiments of the invention, the temperature of the agitation is 15 to 35 ℃.

In a second aspect of the invention, the application of the preparation method of the eutectic in the preparation of the eutectic is provided.

Compared with the prior art, the invention has the following beneficial effects:

(1) The antisolvent suspension method adopted by the invention does not need to carry out complicated solubility measurement on reactants, and can obtain products with higher purity and higher yield.

(2) The anti-solvent suspension method can effectively inhibit the generation of solvates.

(3) The antisolvent suspension method has wide applicability, can be suitable for milligram-scale eutectic screening and gram-scale eutectic sample preparation, is also suitable for kilogram-scale eutectic pilot scale production, and has wide application prospects in eutectic screening, preparation and production processes.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of the sample prepared in example 1 and comparative example 1 of the present invention.

FIG. 2 is an X-ray powder diffraction pattern of the samples prepared in example 2 and comparative example 2 of the present invention.

FIG. 3 is an X-ray powder diffraction pattern of the samples prepared in example 3 and comparative example 3 of the present invention.

FIG. 4 is an X-ray powder diffraction pattern of the samples prepared in example 4 and comparative example 4 of the present invention.

FIG. 5 is an X-ray powder diffraction pattern of the samples prepared in example 5 and comparative example 5 of the present invention.

FIG. 6 is an X-ray powder diffraction pattern of the samples prepared in example 6 and comparative example 6 of the present invention.

FIG. 7 is an X-ray powder diffraction pattern of the samples prepared in example 7 and comparative example 7 of the present invention.

FIG. 8 is an X-ray powder diffraction pattern of the samples prepared in example 8 and comparative example 8 of the present invention.

FIG. 9 is an X-ray powder diffraction pattern of the samples prepared in example 9 and comparative example 9 of the present invention.

FIG. 10 is an X-ray powder diffraction pattern of the samples prepared in example 10 and comparative example 10 of the present invention.

FIG. 11 is an X-ray powder diffraction pattern of the samples prepared in example 11 and comparative example 11 of the present invention.

FIG. 12 is an X-ray powder diffraction pattern of the samples prepared in example 12 and comparative example 12 of the present invention.

FIG. 13 is an X-ray powder diffraction pattern of a sample prepared in example 13 of the present invention.

Detailed Description

The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention. The test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.

In the description of the present invention, the descriptions of the terms "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

In the present invention, "suspension" is a common term in the art of pharmaceutical preparation and generally refers to the mechanical or fluid treatment of a solid drug substance such that the solid drug substance is dispersed or suspended in a solvent.

An X-ray powder diffraction pattern detection instrument and method: the X-ray powder diffraction analysis was carried out by using a diffractometer, cu K.alpha.ray, of Rigaku SmartLab 9KW, japan Physics Co., ltdThe voltage is 40 kilovolts, the current is 150 milliamperes, the step size is 0.01 degrees, the scanning speed is 20 degrees/min, the scanning range is 5.0-40.0 degrees, and the testing temperature is room temperature.

Carbamazepine, theophylline, mebendazole, temozolomide, pyridine amide and isoniazid are all active drug molecules, urea, carbazole and TCNQ are organic compounds and magnesium sulfate is an inorganic compound, and eutectic reports exist on the carbamazepine, the theophylline, the mebendazole, the temozolomide, the pyridine amide and the isoniazid, wherein the pyridine amide, the isoniazid and the fumaric acid can form ternary eutectic. Additionally, carbamazepine can form a variety of solvates. The invention takes the eutectic of the solid compound as a research model, and utilizes the anti-solvent suspension method of the invention to prepare the eutectic.

Example 1

Carbamazepine (0.70 mmol) and malonic acid (0.35 mmol) were added to a mixture of 1mL n-heptane and 10. Mu.L DMF and stirred at room temperature for 24 hours, filtered and the solid dried in vacuo to give pure carbamazepine-malonic acid co-crystals (2:1) in 89% yield with an X-ray powder diffraction pattern as shown in FIG. 1.

Comparative example 1

Carbamazepine (0.70 mmol) and malonic acid (0.35 mmol) were added to 1mL DMF and stirred at room temperature for 24 hours, filtered and the solid dried in vacuo to give the DMF solvate of carbamazepine, no carbamazepine-malonic acid co-crystals (2:1) were obtained and the X-ray powder diffraction pattern is shown in FIG. 1.

Example 2

Carbamazepine (0.32 mmol) and 4,4 '-bipyridine (0.16 mmol) were added to a mixture of 1mL cyclohexane and 10. Mu.L acetone, stirred at room temperature for 48 hours, filtered and the solid dried in vacuo to give pure carbamazepine-4, 4' -bipyridine co-crystals (2:1) in 89% yield with X-ray powder diffraction pattern as shown in FIG. 2.

Comparative example 2

Carbamazepine (0.32 mmol) and 4,4 '-bipyridine (0.16 mmol) were added to 1mL of acetone, stirred at room temperature for 48 hours, filtered, and the solid dried in vacuo to give the acetone solvate of carbamazepine, no carbamazepine-4, 4' -bipyridine co-crystals (2:1) were obtained, the X-ray powder diffraction pattern of which is shown in FIG. 2.

Example 3

Theophylline (0.55 mmol) and oxalic acid (0.55 mmol) were added to a mixed solvent of 1mL of n-heptane and 10 μl of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure theophylline-oxalic acid co-crystals (1:1) in 92% yield, with X-ray powder diffraction pattern as shown in figure 3.

Comparative example 3

Theophylline (0.55 mmol) and oxalic acid (0.55 mmol) were added to 1mL ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried under vacuum to give 60mg of powder, which was subjected to X-ray powder diffraction analysis, and characteristic peaks of theophylline were observed at 12.5 °, indicating that theophylline-oxalic acid co-crystals (1:1) mixed with theophylline were obtained, the X-ray powder diffraction pattern of which is shown in fig. 3.

Example 4

Mebendazole (0.23 mmol) and glutaric acid (0.23 mmol) were added to a mixed solvent of 2mL of n-hexane and 20 μl of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure mebendazole-glutaric acid co-crystals (1:1) in 82% yield, with X-ray powder diffraction pattern as shown in fig. 4.

Comparative example 4

Mebendazole (0.23 mmol) and glutaric acid (0.23 mmol) were added to 2mL ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give 35mg of powder, which was subjected to X-ray powder diffraction analysis, showing only the characteristic peaks of mebendazole, indicating that mebendazole was obtained, whose X-ray powder diffraction pattern was shown in fig. 4.

Example 5

Mebendazole (0.24 mmol) and maleic acid (0.24 mmol) were added to a mixed solvent of 2mL of n-hexane and 50 μl of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure mebendazole-maleate (1:1) in 88% yield, with X-ray powder diffraction pattern as shown in fig. 5.

Comparative example 5

Mebendazole (0.24 mmol) and maleic acid (0.24 mmol) were added to 2mL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give 37mg of powder, which was subjected to X-ray powder diffraction analysis, showing only the characteristic peaks of mebendazole, indicating that mebendazole was obtained, and the X-ray powder diffraction pattern thereof was shown in fig. 5.

Example 6

Urea (0.75 mmol) and adipic acid (0.38 mmol) were added to a mixture of 1mL of n-heptane and 10. Mu.L of water, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure urea-adipic acid co-crystals (2:1) in 80% yield, with an X-ray powder diffraction pattern as shown in FIG. 6.

Comparative example 6

Urea (0.75 mmol) and adipic acid (0.38 mmol) were added to 1mL of water, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give 3mg of a powder, which was subjected to X-ray powder diffraction analysis, showing only characteristic peaks of adipic acid, indicating that adipic acid was obtained, and its X-ray powder diffraction pattern was shown in FIG. 6.

Example 7

Urea (1.1 mmol) and magnesium sulfate (0.28 mmol) were added to a mixed solvent of 1mL cyclohexane and 5. Mu.L water, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give a pure urea-magnesium sulfate co-crystal (4:1) product in 81% yield with an X-ray powder diffraction pattern as shown in FIG. 7.

Comparative example 7

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

Example 8

Carbamazepine (0.35 mmol) and nicotinamide (0.35 mmol) were added to a mixture of 4mL n-hexane and 40. Mu.L ethyl acetate, stirred at room temperature for 24 hours, filtered and the solid dried in vacuo to give pure carbamazepine-nicotinamide co-crystals (1:1) in 87% yield as shown in FIG. 8 as an X-ray powder diffraction pattern.

Comparative example 8

Carbamazepine (0.35 mmol) and nicotinamide (0.35 mmol) were added to 4mL ethyl acetate and stirred at room temperature for 24 hours, filtered and the solid dried in vacuo to give pure carbamazepine-nicotinamide co-crystals (1:1) in 35% yield with an X-ray powder diffraction pattern as shown in FIG. 8.

Example 9

Temozolomide (0.22 mmol) and baicalein (0.21 mmol) are added into a mixed solvent of 1mL of n-heptane and 100 mu L of methanol, stirred at room temperature for 24 hours, filtered, and the solid is dried in vacuum to obtain pure temozolomide-baicalein eutectic (1:1) with the yield of 84%, and the X-ray powder diffraction pattern of the pure temozolomide-baicalein eutectic is shown in figure 9.

Comparative example 9

Temozolomide (0.22 mmol) and baicalein (0.21 mmol) were added to 1mL of methanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure temozolomide-baicalein co-crystal (1:1) in 49% yield with an X-ray powder diffraction pattern as shown in fig. 9.

Example 10

A mixture of urea (0.39 mmol) and citric acid (0.39 mmol) was added to a mixed solvent of 1mL n-heptane and 10. Mu.L ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure urea-citric acid co-crystals (1:1) in 86% yield with an X-ray powder diffraction pattern as shown in FIG. 10.

Comparative example 10

A mixture of urea (0.39 mmol) and citric acid (0.39 mmol) was added to 1mL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure urea-citric acid co-crystals (1:1) in 45% yield with an X-ray powder diffraction pattern as shown in FIG. 10.

Example 11

Carbazole (0.27 mmol) and TCNQ (0.27 mmol) were added to a mixed solvent of 2mL of n-hexane and 100. Mu.L of methanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure carbazole-TCNQ cocrystal (1:1) in 85% yield with an X-ray powder diffraction pattern as shown in FIG. 11.

Comparative example 11

Carbazole (0.27 mmol) and TCNQ (0.27 mmol) were added to 2mL of ethanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure carbazole-TCNQ co-crystals (1:1) in 44% yield, with an X-ray powder diffraction pattern as shown in FIG. 11.

Example 12

Pyridine amide (0.1 mmol), isoniazid (0.1 mmol) and fumaric acid (0.2 mmol) were added to a mixed solvent of 1mL of n-hexane and 10 μl of methanol, stirred at room temperature for 24 hours, filtered, and the solid was dried in vacuo to give pure pyrazine amide-isoniazid-fumaric acid co-crystals (1:1:2) in 85% yield, with X-ray powder diffraction pattern as shown in fig. 12.

Comparative example 12

Pyridine amide (0.1 mmol), isoniazid (0.1 mmol) and fumaric acid (0.2 mmol) were added to 1mL methanol, stirred at room temperature for 24 hours, filtered and the solid was dried in vacuo to give pure pyrazine amide-isoniazid-fumaric acid co-crystals (1:1:2) in 45% yield with an X-ray powder diffraction pattern as shown in figure 12.

Example 13

Carbamazepine (0.070 mmol) and malonic acid (0.035 mmol) were added to a mixed solvent of 1mL of n-heptane and 5. Mu.L of water, or 1mL of n-heptane and 10. Mu.L of methanol, or 1mL of n-heptane and 10. Mu.L of acetonitrile, or 1mL of n-heptane and 10. Mu.L of ethyl acetate, or 1mL of n-heptane and 10. Mu.L of acetone, respectively, stirred at room temperature for 24 hours, filtered, and the solid was dried under air to give a pure carbamazepine-malonic acid co-crystal (2:1), the X-ray powder diffraction pattern of which is shown in FIG. 13.

Example 14

Carbamazepine (0.35 mol) and malonic acid (0.17 mol) were added to a mixture of 500mL of n-heptane and 50 μl of methanol, stirred at room temperature for 6 hours, filtered, and the solid was dried under vacuum, which showed by X-ray powder diffraction analysis, to give pure carbamazepine-malonic acid co-crystals (2:1) in 98% yield.

Example 15

Carbamazepine (3.5 mol) and malonic acid (1.7 mol) were added to a mixture of 5L of n-heptane and 0.5mL of methanol, stirred at room temperature for 12 hours, filtered, and the solid was dried under vacuum, which showed by X-ray powder diffraction analysis, pure carbamazepine-malonic acid co-crystals (2:1) were obtained in 99% yield.

Example 16

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

Example 17

Carbamazepine (0.055 mmol) and glutaric acid (0.055 mmol) were added to a mixture of 1mL n-heptane and 10. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-glutaric acid co-crystals (1:1).

Example 18

Carbamazepine (0.065 mmol) and adipic acid (0.032 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-adipic acid co-crystals (2:1).

Example 19

Carbamazepine (0.054 mmol) and L-malic acid (0.054 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-L-malic acid cocrystal (1:1).

Example 20

Carbamazepine (0.054 mmol) and DL-malic acid (0.054 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-DL-malic acid cocrystal (1:1).

Example 21

Carbamazepine (0.052 mmol) and L-tartaric acid (0.052 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-L-tartaric acid co-crystals (1:1).

Example 22

Carbamazepine (0.056 mmol) and benzoic acid (0.056 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-benzoic acid co-crystals (1:1).

Example 23

Carbamazepine (0.052 mmol) and cinnamic acid (0.052 mmol) were added to a mixture of 1mL n-heptane and 10. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-cinnamic acid co-crystals (1:1).

Example 24

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

Example 25

Carbamazepine (0.053 mmol) and 4-hydroxybenzoic acid (0.053 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-4-hydroxybenzoic acid co-crystals (1:1).

Example 26

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

Example 27

Carbamazepine (0.051 mmol) and 2, 4-dihydroxybenzoic acid (0.051 mmol) were added to a mixture of 1mL n-heptane and 10. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-2, 4-dihydroxybenzoic acid cocrystal (1:1).

Example 28

Carbamazepine (0.051 mmol) and 2, 5-dihydroxybenzoic acid (0.051 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-2, 5-dihydroxybenzoic acid cocrystal (1:1).

Example 29

Carbamazepine (0.051 mmol) and 2, 6-dihydroxybenzoic acid (0.051 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-2, 6-dihydroxybenzoic acid cocrystal (1:1).

Example 30

Carbamazepine (0.056 mmol) and benzamide (0.056 mmol) were added to a mixture of 1mL n-heptane and 10. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-benzamide co-crystals (1:1).

Example 31

Carbamazepine (0.056 mmol) and nicotinamide (0.056 mmol) were added to a mixture of 1mL n-heptane and 10. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-nicotinamide co-crystals (1:1).

Example 32

Carbamazepine (0.056 mmol) and isonicotinamide (0.056 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-isonicotinamide co-crystals (1:1).

Example 33

Carbamazepine (0.054 mmol) and 4-hydroxybenzoamide (0.054 mmol) were added to a mixture of 1mL of n-heptane and 20. Mu.L of water, or 1mL of n-heptane and 10. Mu.L of methanol, or 1mL of n-heptane and 10. Mu.L of acetonitrile, or 1mL of n-heptane and 10. Mu.L of ethyl acetate, or 1mL of n-heptane and 10. Mu.L of acetone, respectively, stirred at room temperature for 24 hours, filtered, and the solid was dried in air, and X-ray powder diffraction analysis showed that pure carbamazepine-4-hydroxybenzoamide co-crystals (1:1) were obtained.

Example 34

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

Example 35

Carbamazepine (0.053 mmol) and salicylic acid (0.054 mmol) were added to a mixture of 1mL n-heptane and 10. Mu.L water, or 1mL n-heptane and 10. Mu.L methanol, or 1mL n-heptane and 10. Mu.L acetonitrile, or 1mL n-heptane and 10. Mu.L ethyl acetate, or 1mL n-heptane and 10. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-salicylic acid co-crystals (1:1).

Example 36

Carbamazepine (0.048 mmol) and acetylsalicylic acid (0.048 mmol) were added to a mixture of 1mL n-heptane and 5. Mu.L water, or 1mL n-heptane and 40. Mu.L methanol, or 1mL n-heptane and 40. Mu.L acetonitrile, or 1mL n-heptane and 100. Mu.L ethyl acetate, or 1mL n-heptane and 40. Mu.L acetone, respectively, and stirred at room temperature for 24 hours, filtered, and the solid was dried in air, as shown by X-ray powder diffraction analysis, yielding pure carbamazepine-acetylsalicylic acid co-crystals (1:1).

Example 37

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

By comparing examples 1-2 and corresponding comparative examples, it can be found that, by taking carbamazepine-malonic acid eutectic (2:1) and carbamazepine-4, 4' -bipyridine eutectic (2:1) as models, solid reactants and eutectic formations with stoichiometric ratios are respectively used for preparing eutectic by an anti-solvent suspension method and a suspension method, and the anti-solvent suspension method can be used for obtaining pure eutectic; however, the use of suspension method does not give a co-crystal, but only a solvate of carbamazepine.

By comparing examples 3-7 with corresponding comparative examples, it can be found that, with theophylline-oxalic acid eutectic (1:1), mebendazole-glutaric acid eutectic (1:1), mebendazole maleate (1:1), urea-adipic acid eutectic (2:1), urea-magnesium sulfate eutectic (4:1) as a model, solid reactants and eutectic formations in stoichiometric ratio are used for preparing eutectic by anti-solvent suspension method and suspension method respectively, and the anti-solvent suspension method of the invention can be found to obtain pure eutectic or salt; and pure eutectic crystals or salts cannot be obtained by using the suspension method.

By comparing examples 8-12 with corresponding comparative examples, it was found that the yield obtained by the antisolvent suspension method of the present invention was higher by modeling the solid reactant and the eutectic formation in stoichiometric ratios with carbamazepine-nicotinamide eutectic (1:1), temozolomide-baicalein eutectic (1:1), urea-citric acid eutectic (1:1), carbazole-TCNQ eutectic (1:1), pyrazinamide-isoniazid-fumaric acid eutectic (1:1:2), and the antisolvent suspension method and suspension method, respectively.

As can be seen from comparative examples 13-15, the anti-solvent suspension method of the present invention can produce pure co-crystals from micro-reactions (mg-scale charge) to macro-reactions (kg-scale charge) using carbamazepine-malonic acid co-crystals as a model.

As can be seen from comparative examples 1-37, when the co-crystal former is oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, fumaric acid, maleic acid, tartaric acid, malic acid, citric 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-hydroxybenzoamide, saccharin, urea, 4' -bipyridine, TCNQ, magnesium sulfate, the co-crystal can be prepared using the antisolvent suspension method.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. The preparation method of the eutectic is characterized by comprising the following steps of: after the poor solvent and the good solvent are mixed, solid reactant and eutectic formation are added for suspension, and the eutectic is obtained.

2. The method of producing a co-crystal according to claim 1, wherein the poor solvent comprises an alkane, and the poor solvent comprises at least one of water, an alcohol, an ester, a ketone, a nitrile, an ether, DMSO, DMF.

3. The method of producing a co-crystal according to claim 1, wherein the poor solvent and the good solvent are not miscible.

4. The method of claim 3, wherein the poor solvent comprises an alkane, and the poor solvent comprises at least one of water, methanol, acetonitrile, DMSO, and DMF.

5. The method of preparing a co-crystal according to claims 1-4, wherein the solid reactant comprises at least one of carbamazepine, theophylline, mebendazole, urea, temozolomide, carbazole, picolinamide, isoniazid;

and/or the eutectic formation comprises at least one of carboxylic acid, amide, saccharin, urea, pyridine compound, cyano compound and inorganic salt.

6. The method of producing a co-crystal according to claim 5, wherein the co-crystal former comprises 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, 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-hydroxybenzoamide, saccharin, urea, 4' -bipyridine, TCNQ, magnesium sulfate.

7. The method of producing a co-crystal according to claim 1 to 4, wherein the volume ratio of the good solvent to the poor solvent is 1:5 to 200;

and/or the ratio of the total amount of solid reactant and eutectic formation to the total amount of solvent is 1g: (5-50) mL;

and/or the mole ratio of the solid reactant and the eutectic formation is 1-4: 1.

8. the method for preparing the eutectic according to claim 1, comprising the following steps:

9. The method of producing a co-crystal according to claim 8, wherein the temperature of the stirring is 15 to 35 ℃;

and/or the stirring time is 0.3-48 h.

10. Use of the method for the preparation of co-crystals according to any one of claims 1 to 9 for the preparation of co-crystals.