CN115403538B

CN115403538B - Epalrestat crystal form and preparation method and application thereof

Info

Publication number: CN115403538B
Application number: CN202211121627.3A
Authority: CN
Inventors: 姜侠; 何淑旺; 胡醒; 程中伟
Original assignee: Beijing Dayin High Tech Children Medicine Research Institute Co ltd; Shandong Dyne Marine Biopharmaceutical Co Ltd
Current assignee: Beijing Dayin High Tech Children Medicine Research Institute Co ltd; Shandong Dyne Marine Biopharmaceutical Co Ltd
Priority date: 2022-09-15
Filing date: 2022-09-15
Publication date: 2024-04-30
Anticipated expiration: 2042-09-15
Also published as: CN115403538A

Abstract

The application provides an epalrestat crystal form, a preparation method and application thereof, wherein the epalrestat crystal form has diffraction characteristic peaks ：7.93±0.2°,12.62±0.2°,15.87±0.2°,16.05±0.2°,16.43±0.2°,22.02±0.2°,23.89±0.2°,25.39±0.2°,27.71±0.2°,32.03±0.2°,35.39±0.2° at the following 2 theta angles and characteristic absorption peaks. The epalrestat crystal has complete appearance, even granularity, water solubility superior to other crystal forms, simple operation, easy filtering, washing and drying of crystal slurry, low labor intensity of technological operation and easy large-scale amplification.

Description

Epalrestat crystal form and preparation method and application thereof

Technical Field

The application relates to the technical field of medicines, in particular to an epalrestat crystal form and a preparation method and application thereof.

Background

The information disclosed in the background of the application is intended to enhance an understanding of the general background of the application, and this disclosure should not necessarily be taken as an acknowledgement or any form of suggestion that this information has become known to a person of ordinary skill in the art.

Epalrestat was originally developed and marketed by small wild japan as an aldose reductase inhibitor, and has a molecular formula of C ₁₅H₁₃NO₃S₂, a molecular weight of 319.40, and a chemical structural formula shown in the following figure.

Epalrestat can be used for treating peripheral nerve disorder and abnormal heartbeat caused by diabetes. Epalrestat is yellow or orange crystalline powder in appearance, soluble in DMF, slightly soluble in methanol and ethanol, and almost insoluble in water. The existing crystal form of epalrestat has poor water solubility, so that the in vivo dissolution and release amount are low, and the bioavailability of the medicine is further affected.

Although efficacy is a major concern for evaluating drugs, salt and solid state forms of drug candidates, such as crystalline or amorphous forms, are also particularly important for the physicochemical and pharmacological properties of the drug and its development as an API, as this is more practical, safe and economical to alter the structure of the drug. Polymorphism is a phenomenon commonly existing in medicines, and plays an important role in improving physicochemical properties of medicines. Different crystal forms of the same medicine often have different indexes such as solubility, stability and the like, and the properties can influence the clinical curative effect of the preparation product, so that the preparation has important significance for solid medicine development.

The conventional preparation methods of the drug crystal form comprise solution crystallization, solid grinding crystal transformation, solvent-mediated crystal transformation and the like, wherein the solution crystallization method is most common in industrial application due to the advantages of easiness in operation, low equipment requirement and the like. In the crystallization process of the solution, the supersaturation degree of the solution is reasonably regulated, and the directional preparation of the unstable crystal form, the metastable crystal form and the stable crystal form of the same kind of medicine can be realized through the differences of the dynamics, the thermodynamics and other behaviors of different crystal forms in the crystallization process, so that the aim of preparing the target crystal form is finally achieved.

Related studies have shown that epalrestat not only has polymorphism, but also can form eutectic products with other components. Researchers have found and prepared other crystalline forms of epalrestat through extensive research. Wherein, patent JP2004210702A and patent JP2004210703A disclose preparation methods of epalrestat crystal form A and epalrestat crystal form B respectively. Patent CN105272934A provides a preparation method of epalrestat crystal form C, and the crystal form C product with the purity of more than 99.9% can be obtained through two refining processes of methyl butanone and methyl isobutyl ketone, formic acid and acetic acid. Because the boiling point of the solvent prepared by the crystal form C is higher, the solvent residue in the product is easy to exceed the standard, and the crystal form C lacks clinical data, so that the application and popularization are difficult. Furthermore, solvent compounds such as epalrestat, DMF and the like are also reported successively. Meanwhile, the epalrestat eutectic compound also draws attention of research personnel, and patent WO2010011926 discloses a preparation method of epalrestat betaine eutectic compound; patent CN103951634B discloses a process for the preparation of crystalline salts of epalrestat hydrate and hydroxypiperidine co-crystals. Patent CN113277962a successfully prepares epalrestat-metformin salt hydrate by using an acetone aqueous solvent system, which greatly improves the dissolution rate of epalrestat and reduces the hygroscopicity of metformin, however, the new salt compound is still in a preclinical research stage at present, and finally, various uncertainties still exist whether the new salt compound can be successfully marketed.

Disclosure of Invention

As described in the background, each salt or each crystalline form of a drug candidate may have different physical properties, which may affect its pharmaceutical parameters as a pharmaceutically active ingredient, for example, storage stability and processability are important in formulation and product manufacture, while solubility and dissolution rate are more important factors in determining efficacy and bioavailability. Thus, different drug crystal forms can significantly affect many factors, including the choice of the compound as a drug substance (API), the final drug dosage form, the optimization of the manufacturing process, and the absorption of the drug. And finding the most suitable crystal form to further develop the medicament can reduce development time and cost, so that the development of the crystal form is more practical, safer and more economical.

The crystalline form of the drug may offer advantages over the free form of the compound, such as improvements in solubility, stability and processability, and of course may have more adverse pharmaceutical properties, the extent of which may vary from crystalline form to crystalline form. However, the crystalline form of the compound is unpredictable and is not always practical. There is no way to predict the nature of a particular crystal form of a compound before it is formed. Thus, finding suitable conditions to obtain a particular crystalline form of a compound having pharmaceutically acceptable properties can take a significant amount of time and effort, but once successful will also have great market value and social significance.

Therefore, the application provides an epalrestat crystal form and a preparation method thereof. The epalrestat crystal form provided by the application has the advantages of good water solubility, high crystallinity, good fluidity, simple preparation process, low labor intensity of process operation, capability of obtaining a product with the purity of more than 99.95%, and process yield of more than 85%.

In a first aspect of the application, the application provides a crystalline form of epalrestat having a diffraction-characteristic peak ：7.93±0.2°,12.62±0.2°,15.87±0.2°,16.05±0.2°,16.43±0.2°,22.02±0.2°,23.89±0.2°,25.39±0.2°,27.71±0.2°,32.03±0.2°,35.39±0.2° at the following 2θ angles, with the peak intensity being the strongest at a 2θ angle of 7.93±0.2°.

Further, the X-ray powder diffraction pattern of the epalrestat crystalline form has the following typical characteristic absorption peaks at 2θ:

No.	2θ/°	Peak intensity/counts	Relative peak intensity/%
				1	7.93±0.2°	153883	100
2	12.62±0.2°	38951	25.31
				3	15.87±0.2°	77457	50.33
4	16.05±0.2°	8845	5.75
				5	16.43±0.2°	4164	2.71
6	22.02±0.2°	3801	2.47
				7	23.89±0.2°	14153	9.20
8	25.39±0.2°	20871	13.56
				9	27.71±0.2°	2715	1.76
10	32.03±0.2°	111509	72.46
				11	35.39±0.2°	6475	4.21

In an embodiment of the present application, the X-ray powder diffraction pattern of the epalrestat crystalline form is shown in fig. 1.

In an embodiment of the present application, the crystalline form of epalrestat has a melting point of 225-227 ℃.

In an embodiment of the application, the epalrestat crystal form has one endothermic peak at 226+/-1 ℃ and no endothermic peak or exothermic peak between 0 ℃ and 130 ℃.

In a second aspect of the present application, there is provided a process for preparing the crystalline form of epalrestat as described in the first aspect above, comprising: adding epalrestat as raw material into 1, 4-dioxane mixed solvent, stirring at 70 deg.c to dissolve, filtering to decolorize, transferring the filtrate into crystallizer for temperature control crystallization, filtering, washing filter cake and drying to obtain the final product;

Wherein the temperature-controlled crystallization process comprises the processes of cooling, heating and cooling again, and the temperature of the whole temperature-controlled crystallization process is 0-30 ℃.

In one or more embodiments of the present application, the raw material epalrestat is one or more selected from epalrestat crystal form a, epalrestat crystal form B, epalrestat crystal form C and amorphous epalrestat, for example, epalrestat crystal form a, epalrestat crystal form B, epalrestat crystal form C or amorphous epalrestat crystal form C may be directly adopted to perform the above process of the present application.

In one or more embodiments of the present application, the raw material epalrestat is added to the 1, 4-dioxane mixed solvent, and the solid-to-liquid ratio of the solution is 0.01g/g to 0.05g/g.

In one or more embodiments of the present application, the raw material epalrestat is added to the 1, 4-dioxane mixed solvent, and the temperature of stirring dissolution is 60-70 ℃.

In one or more embodiments of the present application, the solvent mixture is a mixture of 1, 4-dioxane and one or more selected from the group consisting of water, formic acid, acetic acid and acetone; for example, the 1, 4-dioxane mixed solvent can be selected from one of the following solvent combinations: a solvent combination of 1, 4-dioxane and water, a solvent combination of 1, 4-dioxane and formic acid, a solvent combination of 1, 4-dioxane and acetic acid, a solvent combination of 1, 4-dioxane and acetone, a solvent combination of 1, 4-dioxane, water and acetone.

In one or more embodiments of the present application, the volume fraction of 1, 4-dioxane in the 1, 4-dioxane mixed solvent is 80% -98%.

In one or more embodiments of the application, the solvent used for washing is water.

In one or more embodiments of the application, the temperature-controlled crystallization process includes moving the filtrate into a crystallizer and rapidly cooling to 5-10 ℃ and stirring at constant temperature; heating to 20-30deg.C after stopping stirring, standing at constant temperature, starting stirring, and continuing to grow crystal at constant temperature; then cooling to 10-15 ℃, stopping stirring, and growing crystals at constant temperature; then stirring is started and the temperature is reduced to 0-5 ℃.

For example, in some embodiments, the temperature-controlled crystallization process includes: transferring the filtrate into a crystallizer, rapidly cooling to 5-10deg.C, and stirring at constant temperature for 20-40 min; stopping stirring, heating to 20-30deg.C at a heating rate of 3-6deg.C/hr, keeping the temperature for 30-45 min, stirring, and keeping the temperature for 15-30 min; then cooling to 10-15 ℃, wherein the cooling rate is 5-10 ℃/h, stopping stirring, and growing the crystal at the constant temperature for 60-90 minutes; then stirring is started and the temperature is reduced to 0-5 ℃, and the temperature reduction rate is 2-4 ℃/min.

In one or more embodiments of the present application, the drying conditions are: vacuum drying at 45-60deg.C under 0.08-0.1MPa for 7-10 hr.

In a third aspect of the present application, the present application provides a pharmaceutical composition or pharmaceutical formulation comprising the crystalline form of epalrestat as described in the first aspect above; or further comprises at least one pharmaceutically acceptable auxiliary material.

The pharmaceutical composition or pharmaceutical preparation related to the application contains the epalrestat crystal form and one or more pharmaceutical excipients. The crystalline forms of epalrestat described herein can be formulated into pharmaceutical compositions or pharmaceutical formulations by those skilled in the art using techniques well known in the art. For example, some embodiments of the application include methods of producing pharmaceutical compositions or formulations comprising mixing the crystalline forms of epalrestat of the application with pharmaceutical excipients, such as generally by uniformly mixing the active compound with liquid and/or finely divided solid excipients in the desired proportions, and then preparing the desired formulation, such as tablets or capsules, and if desired, forming the desired shape.

The epalrestat crystal form has improved water solubility and fluidity, thus having better drug property, better processability when being used for pharmaceutical preparations, and improved dissolution and bioavailability.

In a fourth aspect of the application, the present application provides the use of an epalrestat crystalline form as described in the first aspect above, or a pharmaceutical composition or pharmaceutical formulation comprising the epalrestat crystalline form, in the manufacture of an aldose reductase inhibitor medicament. In some embodiments, the medicament may be used to prevent, ameliorate and treat diabetic neuropathy, including but not limited to peripheral nerve disorders, abnormal heartbeats, etc. that are complicated by diabetes.

In a fifth aspect of the present application, there is provided a method for preventing, ameliorating and treating diabetic neuropathy comprising administering to a subject a therapeutically effective amount of a medicament having epalrestat as an active ingredient in the crystalline form of epalrestat described in the first aspect above.

By "subject" is meant an animal, preferably a mammal, especially a human, that has been the subject of treatment, observation or experiment. By "therapeutically effective amount" is meant that amount of epalrestat crystalline form described herein or a drug comprising epalrestat crystalline form described herein that can elicit the biological or medical response of a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other medical personnel, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.

Compared with the prior art, the application has the advantages that:

The epalrestat crystal form provided by the application has complete crystal appearance, uniform particle size distribution, easy crystal slurry filtration, washing and drying, and low labor intensity of process operation. The preparation method of the epalrestat crystal form provided by the application has stable preparation process, the HPLC content of the obtained product can reach more than 99.95%, the generation of other crystal forms can be avoided, the crystal form purity of the target crystal form product is ensured, meanwhile, the water solubility of the new crystal form is obviously superior to that of the other crystal forms, and the preparation process is simple and convenient to operate and easy to scale up.

In addition, the epalrestat crystal form provided by the application has good fluidity, the repose angle of particles is below 22.7 degrees, and the fluidity of the particles is obviously better than that of other crystal forms. Meanwhile, the particle compression coefficient of the epalrestat crystal form provided by the application is about 8%, and in the process of producing the medicine, the transfer, granulating and tabletting of the medicine are all related to the fluidity of medicine powder particles.

Drawings

The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. Embodiments of the present application are described in detail below with reference to the attached drawing figures, wherein:

fig. 1: x-ray powder diffraction pattern of epalrestat crystalline form;

fig. 2: DSC profile of epalrestat crystalline form;

fig. 3: epalrestat crystal form photomicrographs (. Times.500 times.) on a scale of 20. Mu.m.

Detailed Description

The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or materials used in the present application may be purchased in conventional manners, and unless otherwise indicated, they may be used in conventional manners in the art or according to the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.

The methods of differential scanning calorimetric analysis (DSC) and X-ray powder diffraction analysis (XRPD) described in the present application are performed as follows:

DSC method: instrument model: mettler Toledo DSC1, temperature range: scanning rate at 30-300 deg.c: 10 ℃/min, nitrogen flow rate: 20mL/min.

XRPD method: instrument model: rigku ULTIMA IV, target: cu-kα (40 kv,40 ma), sample-to-detector distance: 30cm, scan range: 2 ° -40 ° (2 theta value), scanning step size: 0.05-0.5s.

The term "substantially identical" or similar to the various analytical techniques and data resulting therefrom as described herein means that a particular set of analytical data is sufficiently similar to the data disclosed herein within an acceptable scientific range to enable one of ordinary skill in the art to understand that the compound is in the same form as the present application. It will be appreciated by those skilled in the art that certain analytical techniques, such as XRPD and DSC, do not produce exactly the same results each time due to instrument variations, sample preparation, scientific errors, etc. By way of example only, XRPD results (i.e., location of peaks, intensity, and/or presence of peaks) may vary somewhat from sample to sample, although within accepted scientific guidelines the form of the sample is the same, which may be due to, for example, orientation direction or different solvent or water content. Those skilled in the art are fully capable of viewing the data as a whole, knowing whether this difference is indicative of a different form, and thus determining whether it is substantially similar to the analytical data disclosed in the present application. In this regard, as is commonly done in the scientific community, it is not intended that the exemplary analytical data of the crystalline forms of epalrestat disclosed herein be satisfied literally, e.g., whether each peak of the exemplary XRPD patterns disclosed herein is present in the comparison data, is in the same location and/or has the same intensity, in order to determine whether the comparison data represents the same form as disclosed and claimed herein. Rather, as noted above, one skilled in the art will determine whether the data for comparison and analysis are the same or different forms of the crystalline form of epalrestat disclosed herein, based on the integrity of the data, using accepted scientific principles.

In an embodiment of the present invention, the angle of repose is measured using an FT-104BC powder particle flow analyzer. The method for measuring the compression coefficient comprises the following steps: according to the method in the section <0993> of Chinese pharmacopoeia 2020, the bulk density (ρ ₀) and tap density (ρ _t) of epalrestat are respectively measured, and the compression coefficient (C) thereof is calculated according to the following formula: c= (ρ _t-ρ₀)/ρ₀.

Example 1

20G of amorphous epalrestat is added into 630 g of mixed solvent of 1, 4-dioxane and water (the volume fraction of the 1, 4-dioxane is 92 percent), and the mixture is continuously stirred and dissolved for 40 minutes at 60 ℃, and then filtered and decolorized; transferring the filtrate into a crystallizer, quickly cooling to 5 ℃, and stirring for 30 minutes at the constant temperature of 5 ℃; stopping stirring, heating the solution to 26 ℃ at a heating rate of 3 ℃/hour, keeping the temperature for 30 minutes, starting stirring, and continuing to grow crystals at the constant temperature for 20 minutes; then cooling the solution to 11 ℃ at a speed of 5 ℃/hour, stopping stirring, and growing crystals at a constant temperature of 11 ℃ for 80 minutes; stirring was then turned on and the temperature was reduced to 3℃at a rate of 4℃per minute. The filter cake was filtered off with suction and washed with water and dried under vacuum at 60℃for 10 hours at a vacuum of 0.09MPa. The epalrestat crystal form product can be obtained, the yield is 89.2%, the HPLC purity is 99.96%, the melting point is 226.27 ℃, the X-ray powder diffraction pattern is shown in figure 1, the DSC pattern is shown in figure 2, the obtained epalrestat crystal has complete appearance and uniform particle size distribution, and the crystal form microscopic photograph (multiplied by 500) is shown in figure 3.

Wherein the X-ray powder diffraction pattern of the crystalline form of epalrestat has the following typical characteristic absorption peaks at 2θ:

Example 2

Adding 10g of epalrestat crystal form B into 200g of a mixed solvent of 1, 4-dioxane and formic acid (the volume fraction of the 1, 4-dioxane is 80%), continuously stirring and dissolving at 70 ℃ for 50 minutes, filtering, and decoloring; transferring the filtrate into a crystallizer, quickly cooling to 10 ℃, and stirring at the constant temperature of 10 ℃ for 20 minutes; stopping stirring, heating the solution to 25 ℃ at a heating rate of 6 ℃/hour, keeping the temperature for 45 minutes, starting stirring, and continuing to grow crystals at the constant temperature for 15 minutes; then cooling the solution to 15 ℃ at the speed of 10 ℃/hour, stopping stirring, and growing crystals at the constant temperature of 15 ℃ for 60 minutes; the stirring was then turned on and the temperature was reduced to 5℃at a rate of 2℃per minute. Suction filtration and washing the filter cake with water, and drying at 45℃under vacuum for 7 hours, the vacuum degree being 0.08MPa. The epalrestat crystal form product can be obtained with the yield of 88.9 percent and the HPLC purity of 99.96 percent, and the X-ray powder diffraction pattern is consistent with figure 1, and the melting point is 225.74 ℃.

Example 3

Adding 20g of epalrestat crystal form A into 500g of a mixed solvent of 1, 4-dioxane and acetic acid (the volume fraction of the 1, 4-dioxane is 90%), continuously stirring and dissolving at 66 ℃ for 30 minutes, filtering, and decoloring; transferring the filtrate into a crystallizer, quickly cooling to 8 ℃, and stirring for 30 minutes at the constant temperature of 8 ℃; stopping stirring, heating the solution to 30 ℃ at a heating rate of 4 ℃/hour, keeping the temperature for 40 minutes, starting stirring, and continuing to grow crystals at the constant temperature for 20 minutes; then cooling the solution to 14 ℃ at the speed of 8 ℃/hour, stopping stirring, and growing crystals at the constant temperature of 14 ℃ for 75 minutes; the stirring was then turned on and the temperature was reduced to 2℃at a rate of 3℃per minute. Suction filtration and washing the filter cake with water, and drying at 50℃under vacuum for 9 hours, the vacuum degree being 0.09MPa. The epalrestat crystal form product can be obtained with the yield of 87.3 percent and the HPLC purity of 99.96 percent, and the X-ray powder diffraction pattern is consistent with figure 1, and the melting point is 226.35 ℃.

Example 4

15G of epalrestat crystal form C is added into 500g of a mixed solvent of 1, 4-dioxane and acetone (the volume fraction of the 1, 4-dioxane is 95 percent), and the mixture is continuously stirred and dissolved for 40 minutes at 65 ℃, and then filtered and decolorized; transferring the filtrate into a crystallizer, quickly cooling to 6 ℃, and stirring at the constant temperature of 6 ℃ for 35 minutes; stopping stirring, heating the solution to 26 ℃ at a heating rate of 5 ℃/hour, keeping the temperature for 30 minutes, starting stirring, and continuing to grow crystals at the constant temperature for 30 minutes; then cooling the solution to 12 ℃ at a speed of 7 ℃/hour, stopping stirring, and growing crystals at a constant temperature of 12 ℃ for 70 minutes; stirring was then turned on and the temperature was reduced to 4℃at a rate of 4℃per minute. Suction filtration and washing the filter cake with water, and drying at 45℃under vacuum for 7 hours, the vacuum degree being 0.08MPa. The epalrestat crystal form product can be obtained with the yield of 85.1 percent and the HPLC purity of 99.97 percent, and the X-ray powder diffraction pattern is consistent with figure 1, and the melting point is 225.22 ℃.

Example 5

20G of epalrestat crystal form A is added into 2000g of a mixed solvent of 1, 4-dioxane and water (the volume fraction of the 1, 4-dioxane is 98 percent), and the mixture is continuously stirred and dissolved for 60 minutes at 60 ℃, and then filtered and decolorized; transferring the filtrate into a crystallizer, quickly cooling to 5 ℃, and stirring for 40 minutes at the constant temperature of 5 ℃; stopping stirring, heating the solution to 20 ℃ at a heating rate of 3 ℃/hour, keeping the temperature for 30 minutes, starting stirring, and continuing to grow crystals at the constant temperature for 30 minutes; then cooling the solution to 10 ℃ at a rate of 5 ℃/hour, stopping stirring, and growing crystals at a constant temperature of 10 ℃ for 90 minutes; stirring was then turned on and the temperature was reduced to 0℃at a rate of 4℃per minute. Filtering, washing the filter cake with water, and drying at 60 ℃ under vacuum for 10 hours, wherein the vacuum degree is 0.1MPa. The epalrestat crystal form product can be obtained with 86.3 percent of yield and 99.95 percent of HPLC purity, and the X-ray powder diffraction pattern is consistent with figure 1, and the melting point is 226.66 ℃.

Example 6

15G of epalrestat crystal form C is added into 500g of a ternary mixed solvent of 1, 4-dioxane, water and acetone (the volume fraction of the 1, 4-dioxane is 90 percent, the volume fraction of the water is 5 percent), and the mixture is continuously stirred and dissolved for 50 minutes at 60 ℃, and then filtered and decolorized; transferring the filtrate into a crystallizer, quickly cooling to 6 ℃, and stirring for 30 minutes at the constant temperature of 6 ℃; stopping stirring, heating the solution to 26 ℃ at a heating rate of 5 ℃/hour, keeping the temperature for 35 minutes, starting stirring, and continuing to grow crystals at the constant temperature for 20 minutes; then cooling the solution to 12 ℃ at a speed of 7 ℃/hour, stopping stirring, and growing crystals at a constant temperature of 12 ℃ for 90 minutes; stirring was then turned on and the temperature was reduced to 4℃at a rate of 4℃per minute. Suction filtration and washing the filter cake with water, and drying at 45℃under vacuum for 8 hours, the vacuum degree being 0.08MPa. The epalrestat crystal form product can be obtained with the yield of 87.3 percent and the HPLC purity of 99.96 percent, and the X-ray powder diffraction pattern is consistent with figure 1, and the melting point is 226.71 ℃.

Example 7

Adding 10g of epalrestat crystal form C into 200g of a mixed solvent of 1, 4-dioxane and formic acid (the volume fraction of the 1, 4-dioxane is 80%), continuously stirring and dissolving at 70 ℃ for 45 minutes, filtering, and decoloring; transferring the filtrate into a crystallizer, quickly cooling to 10 ℃, and stirring at the constant temperature of 10 ℃ for 20 minutes; stopping stirring, heating the solution to 25 ℃ at a heating rate of 6 ℃/hour, keeping the temperature for 45 minutes, starting stirring, and continuing to grow crystals at the constant temperature for 15 minutes; then cooling the solution to 15 ℃ at the speed of 10 ℃/hour, stopping stirring, and growing crystals at the constant temperature of 15 ℃ for 60 minutes; the stirring was then turned on and the temperature was reduced to 5℃at a rate of 2℃per minute. Suction filtration and washing the filter cake with water, and drying at 45℃under vacuum for 9 hours, the vacuum degree being 0.08MPa. The epalrestat crystal form product can be obtained with 86.3 percent of yield and 99.97 percent of HPLC purity, and the X-ray powder diffraction pattern is consistent with figure 1, and the melting point is 226.31 ℃.

Example 8

20G of amorphous epalrestat is added into 1700g of mixed solvent of 1, 4-dioxane and water (the volume fraction of the 1, 4-dioxane is 92 percent), and the mixture is continuously stirred and dissolved for 50 minutes at 60 ℃, and then filtered and decolorized; transferring the filtrate into a crystallizer, quickly cooling to 5 ℃, and stirring at constant temperature of 5 ℃ for 20 minutes; stopping stirring, heating the solution to 26 ℃ at a heating rate of 3 ℃/hour, keeping the temperature for 35 minutes, starting stirring, and continuing to grow crystals at the constant temperature for 15 minutes; then cooling the solution to 11 ℃ at a speed of 5 ℃/hour, stopping stirring, and growing crystals at a constant temperature of 11 ℃ for 60 minutes; stirring was then turned on and the temperature was reduced to 3℃at a rate of 4℃per minute. Filtering, washing the filter cake with water, and drying at 60 ℃ under vacuum for 10 hours, wherein the vacuum degree is 0.1MPa. The epalrestat crystal form product can be obtained with the yield of 87.3 percent and the HPLC purity of 99.95 percent, and the X-ray powder diffraction pattern is consistent with figure 1, and the melting point is 226.38 ℃.

Test examples

Taking 10mg of epalrestat crystal form product obtained in examples 1-8, placing in a 250mL triangular flask with a plug, adding 100mL of water, performing ultrasound for 30min (light-shielding operation in the ultrasound process), standing to room temperature (25 ℃) after the ultrasound is finished, and filtering to obtain a subsequent filtrate as a sample solution.

Preparing a reference substance solution: taking reference substance 10mg, precisely weighing, placing into a 100mL measuring flask, adding 30mL of methanol for ultrasonic dissolution, adding flow for dilution to scale, and shaking uniformly.

Conditions for high performance liquid chromatography detection: octadecylsilane chemically bonded silica is used as a filler, methanol and acetic acid solution with the volume concentration of 0.4 percent are used as the filler according to the volume ratio of 65: the mixed solution of 35 is taken as a mobile phase for isocratic elution; the flow rate is 1.0mL/min; the detection wavelength is 290nm; the column temperature is 30 ℃; the sample volume was 20. Mu.L.

Precisely measuring the sample solution and the reference substance solution, respectively injecting into high performance liquid chromatograph, detecting according to the detection conditions of the high performance liquid chromatograph, and recording the chromatogram to 3 times of the retention time of the main component peak. And calculating the content of epalrestat in the test sample according to an external standard method and the peak area.

The solubility of epalrestat form a, form B, form C in water (25 ℃) was measured according to the above method, respectively.

Wherein, epalrestat form a was prepared according to the method described in example 1 of patent JP2004210702a, epalrestat form B was prepared according to the method described in example 1 of patent CN201810070470.3, and epalrestat form C was prepared according to the method described in example 1 of patent CN 201510649032.9.

The solubility data of the different crystalline forms of epalrestat in water are shown in table 1.

TABLE 1 solubility of epalrestat in water (25 ℃ C.)

Crystal form	Solubility/(μg/mL)
		Epalrestat crystal forms	2.768
Epalrestat crystal form A	1.789
		Epalrestat crystal form B	1.821
Epalrestat crystal form C	1.816

The solubility of epalrestat crystal forms obtained in examples 1-8 of the present application in water is 2.7-2.8 μg/mL (average at 2.768 μg/mL). In combination with the solubility data for the other forms in table 1, epalrestat forms are significantly better than the existing forms a, B and C. Since epalrestat is orally taken, the improvement of epalrestat water solubility can help the epalrestat to absorb in human body, and has important significance for the development of downstream preparations.

In addition, the particle repose angles of the epalrestat crystal forms prepared in the examples 1-8 are all below 22.7 degrees, and the particle mobility is obviously superior to that of the existing crystal forms A, B and C. Meanwhile, the particle compression coefficients of the epalrestat crystal forms prepared in the embodiments 1-8 are about 8%, and the epalrestat crystal forms have great advantages in preparation links, particularly in granulating and tabletting links. Obviously, the epalrestat crystal form is superior to the existing crystal form product.

The foregoing description is only a preferred embodiment of the present application, and the present application is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present application has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A crystalline form of epalrestat having a powder XRD characteristic peak angle of 2Θ of ：7.93±0.2°,12.62±0.2°,15.87±0.2°,16.05±0.2°,16.43±0.2°,22.02±0.2°,23.89±0.2°,25.39±0.2°,27.71±0.2°,32.03±0.2°,35.39±0.2°, wherein the relative peak intensity at 2Θ angle of 7.93 ± 0.2 ° is strongest.

2. Crystalline form of epalrestat according to claim 1, characterized by the X-ray powder diffraction pattern shown in figure 1.

3. The crystalline form of epalrestat according to claim 1, wherein the melting point of the crystalline form is 225-227 ℃.

4. The crystalline form of epalrestat according to claim 3, having an endothermic peak at 226±1 ℃ and no endothermic or exothermic peak at 0 to 130 ℃.

5. A process for preparing the crystalline form of epalrestat as claimed in any one of claims 1 to 4, comprising: adding epalrestat as raw material into 1, 4-dioxane mixed solvent, stirring at 70 deg.c to dissolve, filtering to decolorize, transferring the filtrate into crystallizer for temperature control crystallization, filtering, washing filter cake and drying to obtain the final product;

Wherein the temperature-controlled crystallization process comprises the processes of cooling, heating and cooling again, and the temperature of the whole temperature-controlled crystallization process is 0-30 ℃;

The raw material epalrestat is added into the 1, 4-dioxane mixed solvent, and the solid-to-liquid ratio of the solution is 0.01 g/g-0.05 g/g;

The 1, 4-dioxane mixed solvent is selected from one of the following solvent combinations: 1, 4-dioxane and water, 1, 4-dioxane and formic acid, 1, 4-dioxane and acetic acid, 1, 4-dioxane and acetone, 1, 4-dioxane and water and acetone;

In the 1, 4-dioxane mixed solvent, the volume fraction of the 1, 4-dioxane is 80-98%;

The temperature-controlled crystallization process comprises the following steps: transferring the filtrate into a crystallizer, rapidly cooling to 5-10deg.C, and stirring at constant temperature for 20-40 min; stopping stirring, heating to 20-30deg.C at a heating rate of 3-6deg.C/hr, keeping the temperature for 30-45 min, stirring, and keeping the temperature for 15-30 min; then cooling to 10-15 ℃, wherein the cooling rate is 5-10 ℃/h, stopping stirring, and growing the crystal at the constant temperature for 60-90 minutes; then stirring is started and the temperature is reduced to 0-5 ℃, and the temperature reduction rate is 2-4 ℃/min.

6. The method of claim 5, wherein the raw epalrestat is one or more selected from epalrestat form a, epalrestat form B, epalrestat form C and amorphous epalrestat.

7. The method according to claim 5, wherein the raw material epalrestat is added into the 1, 4-dioxane mixed solvent, and the temperature of stirring dissolution is 60-70 ℃.

8. The method according to claim 5, wherein the solvent used for washing is water.

9. The method of claim 5, wherein the drying conditions are: vacuum drying at 45-60deg.C under 0.08-0.1MPa for 7-10 hr.

10. A pharmaceutical composition or pharmaceutical formulation comprising the crystalline form of epalrestat as claimed in any one of claims 1 to 4.

11. Use of the crystalline form of epalrestat as claimed in any one of claims 1 to 4 or the pharmaceutical composition or pharmaceutical formulation as claimed in claim 10 for the preparation of an aldose reductase inhibitor medicament.

12. The use according to claim 11, wherein the medicament is for the prevention, amelioration and treatment of diabetic neuropathy.

13. The use according to claim 12, wherein the diabetic neurological disorder comprises a peripheral neurological disorder or a heart beat abnormality that is complicated by diabetes.