A crystal form of indolepropionic acid-metformin salt, its preparation method and uses

Abstract

The application discloses a crystal form of indolepropionic acid-metformin salt and a preparation method and application thereof, and belongs to the technical field of chemical medicines and crystal form processes. The X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at 8.8°±0.2°, 12.7°±0.2°, 14.1°±0.2°, 17.2°±0.2°, 18.0°±0.2°, 18.5°±0.2° and 19.6°±0.2°. The crystal form of indolepropionic acid-metformin salt provided by the application has good stability, improved solubility and dissolution rate compared with indolepropionic acid, can solve the problem of low solubility of indolepropionic acid, and combines metformin and indolepropionic acid which have a blood sugar lowering effect, and is expected to promote the design of indolepropionic acid preparations and the application in the clinical aspect, can have a pharmacological synergistic effect in the treatment of diabetes, and has the potential to develop a drug for treating diabetes.

Description

Technical Field

[0001] This application relates to the field of chemical drugs and crystal form processing technology, and in particular to a crystal form of indolepropionic acid-metformin salt, its preparation method and uses. Background Technology

[0002] Diabetes is a chronic metabolic disease, mainly classified into type 1 diabetes, type 2 diabetes, and gestational diabetes. Its main characteristic is elevated blood glucose levels, accompanied by disturbances in fat and protein metabolism. The disease is difficult to cure and easily leads to complications in multiple organs (such as blood vessels, nerves, heart, and kidneys).

[0003] Indole-3-propionic acid, with a molecular weight of 189.21, has the following chemical structural formula:

[0004] .

[0005] Indolepropionic acid (IVPA) is considered a potential biomarker associated with the development of type 2 diabetes, and it may prevent the development of type 2 diabetes by protecting pancreatic β-cell function. Studies have shown that IVPA intake can significantly reduce fasting blood glucose and plasma insulin levels in rats, while improving insulin sensitivity and glucose metabolism. Therefore, IVPA is considered a potential candidate drug for treating metabolic disorders caused by insulin resistance. In addition, IVPA also has potential applications in treating various diseases such as cancer, colitis, tuberculosis, and kidney disease. Although IVPA has diverse physiological activities, its low solubility (intrinsic solubility of 0.35 g / L) presents many challenges in its pharmacokinetics in vivo and formulation design, and its potential toxicity also raises significant concerns. Summary of the Invention

[0006] Based on this, the main objective of this application is to provide a crystal form of indolepropionic acid-metformin salt, which has improved solubility and dissolution rate, thereby solving the problem of low solubility of indolepropionic acid and is expected to promote the design of indolepropionic acid formulations and their clinical application.

[0007] The first aspect of this application provides a crystal form of indolepropionic acid-metformin salt, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 8.8°±0.2°, 12.7°±0.2°, 14.1°±0.2°, 17.2°±0.2°, 18.0°±0.2°, 18.5°±0.2° and 19.6°±0.2°.

[0008] In some embodiments, its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ angles: one or more of 22.2°±0.2°, 24.3°±0.2°, 24.7°±0.2°, 27.7°±0.2° and 32.7°±0.2°.

[0009] In some embodiments, the X-ray powder diffraction pattern of the crystal form is substantially as follows: Figure 5 or Figure 6 or Figure 7 As shown.

[0010] In some embodiments, the crystal data of the indolepropionic acid-bismethylguanidine salt includes: monoclinic system; space group P21 / n; an asymmetric unit containing one indolepropionic acid anion and one bismethylguanidine cation, the indolepropionic acid anion and the bismethylguanidine cation being combined in a 1:1 molar ratio; cell parameters a = 10.517(4); b = 9.392(6); c = 17.126, α = 90.00°; β = 105.030°; γ = 90.00°; cell volume 1633.9 Å. 3 The number of molecules in the unit cell Z = 4.

[0011] In some embodiments, the crystal form of the indolepropionic acid-metformin salt satisfies one or more of the following conditions:

[0012] (1) The calculated crystal density of the indolepropionic acid-metformin salt is 1.293 g / cm³. 3 ;

[0013] (2) The crystal form of the indolepropionic acid-metformin salt was determined by differential scanning calorimetry to have a melting onset temperature of 181±5 ℃ and a melting peak value of 183±5 ℃ during heating at a heating rate of 10 ℃ / min.

[0014] (3) According to thermogravimetric analysis, the crystal form of the indolepropionic acid-metformin salt began to lose weight at 200±5℃ during the heating process from 20℃ / min to 400℃, and lost 80±1% of its weight at 395±5℃.

[0015] (4) The infrared absorption spectrum of the crystal form of the indolepropionic acid-metformin salt is at least at 3493 cm⁻¹. -1 1557 cm -1 1379 cm -1 and 1048 cm -1 It has an absorption peak.

[0016] A second aspect of this application provides a method for preparing the crystal form of indolepropionic acid-metformin salt, comprising the following steps:

[0017] Indolepropionic acid, a first solvent, and metformin free base are mixed and reacted, the solvent is removed, and the mixture is dried to prepare the crystal form of the indolepropionic acid-metformin salt.

[0018] In some embodiments, the step of mixing and reacting indolepropionic acid, the first solvent, and metformin free base includes:

[0019] The metformin free base is mixed with the first solvent to form a metformin free base solution, and the metformin free base solution is mixed with the indolepropionic acid;

[0020] Alternatively, the metformin free base and the indolepropionic acid can be added to the first solvent and mixed.

[0021] In some embodiments, the solvent removal step includes at least one of solid-liquid separation, natural evaporation, and rotary evaporation; optionally, the solid-liquid separation includes filtration and / or centrifugation.

[0022] In some embodiments, the mixing includes stirring and / or grinding;

[0023] Optionally, the stirring conditions include: stirring temperature 10-40 ℃, stirring time 1-24 h, and stirring speed 50-1000 rpm;

[0024] Optionally, the grinding is ball milling, and the ball milling time is 30-90 minutes.

[0025] In some embodiments, the drying includes at least one of natural drying, vacuum drying, and freeze drying.

[0026] Optionally, the vacuum drying conditions are: drying at 10-60 ℃ for 12-40 h.

[0027] In some embodiments, the molar ratio of indolepropionic acid to the metformin free base is 0.3-3:1; optionally 0.5-2:1, further optionally 0.9-1.1:1, and particularly optionally 1:1.

[0028] In some embodiments, the molar volume ratio of the metformin free base to the first solvent is 0.1 mol: (0.5-10) mL.

[0029] In some embodiments, the first solvent comprises water and / or an organic solvent; the organic solvent comprises at least one of alcohols, ketones, esters, nitriles, ethers, alkanes, aromatics, and halogenated hydrocarbons.

[0030] Optionally, the organic solvent includes at least one selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, and dichloromethane.

[0031] Optionally, the organic solvent includes at least one of isopropanol, acetone, acetonitrile, and dichloromethane.

[0032] In some embodiments, the preparation of the metformin free base includes the following steps:

[0033] Metformin hydrochloride, an alkali, and a second solvent are mixed and reacted, followed by solid-liquid separation to obtain the free alkali of metformin.

[0034] In some embodiments, the alkali includes at least one of sodium hydroxide, potassium hydroxide, and calcium hydroxide;

[0035] And / or, the molar ratio of metformin hydrochloride to the base is 1:0.5-2;

[0036] And / or, the second solvent includes water and / or an alcohol solvent; optionally, at least one of water, methanol and ethanol.

[0037] A third aspect of this application provides the crystal form of indolepropionic acid-metformin salt prepared by the preparation method described in the second aspect.

[0038] A fourth aspect of this application provides a pharmaceutical composition comprising the crystal form of the indolepropionic acid-metformin salt described in the first or third aspect, and pharmaceutically acceptable excipients.

[0039] In some embodiments, the dosage form of the pharmaceutical composition includes tablets, capsules, pills, gels, emulsions, or suspensions; tablets or capsules are optional.

[0040] The fifth aspect of this application provides the use of the crystal form of the indolepropionic acid-metformin salt described in the first or third aspect, or the pharmaceutical composition described in the fourth aspect, in the preparation of a medicament for treating metabolic diseases of the endocrine system.

[0041] In some embodiments, metabolic diseases of the endocrine system include diabetes.

[0042] The beneficial effects of this application are:

[0043] 1. The crystal form of indolepropionic acid-metformin salt provided in this application has good stability and improved solubility and dissolution rate compared with indolepropionic acid. It can solve the problem of low solubility of indolepropionic acid and is expected to promote the design of indolepropionic acid formulations and their clinical application.

[0044] 2. The crystal form of indolepropionic acid-metformin salt provided in this application combines metformin and indolepropionic acid, which have hypoglycemic effects, and has improved solubility and dissolution rate. It may have a synergistic pharmacological effect in the treatment of diabetes and has the potential to develop drugs for the treatment of diabetes. Attached Figure Description

[0045] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. The drawings are only used to illustrate preferred embodiments and are not intended to limit this application. Throughout the drawings, the same reference numerals denote the same parts, wherein "salt" in the drawings refers to "the crystal form of indolepropionic acid-metformin salt". In the drawings:

[0046] Figure 1 These are comparative powder X-ray diffraction patterns of the crystal form, single-crystal simulation, and free base of indolepropionic acid and metformin obtained in Example 1 of this application.

[0047] Figure 2 This is a comparison of the crystal form of the indolepropionic acid-metformin salt obtained in Example 1 of this application, and the Fourier transform infrared spectra of indolepropionic acid and metformin free base.

[0048] Figure 3 This is a comparative thermogravimetric analysis (TGA) spectrum of the crystal form of indolepropionic acid-metformin salt obtained in Example 1 of this application, and of indolepropionic acid and metformin free base.

[0049] Figure 4 This is a comparative differential scanning calorimetry (DSC) spectrum of the crystal form of indolepropionic acid-metformin salt obtained in Example 1 of this application, and the indolepropionic acid and metformin free base.

[0050] Figure 5 This is the powder X-ray diffraction pattern of the crystal form of indolepropionic acid-bismethylguanidine salt obtained in Example 4 of this application.

[0051] Figure 6 This is the powder X-ray diffraction pattern of the crystal form of indolepropionic acid-bismethylguanidine salt obtained in Example 5 of this application.

[0052] Figure 7 This is the powder X-ray diffraction pattern of the crystal form of indolepropionic acid-bismethylguanidine salt obtained in Example 6 of this application.

[0053] Figure 8 This is a comparison of the crystal form of indolepropionic acid-bismethylguanidine salt prepared in Example 1 in pH 2.0 buffer with the dissolution curve of indolepropionic acid.

[0054] Figure 9This is a comparison of the crystal form of indolepropionic acid-metformin salt prepared in Example 1 in pH 4.5 buffer with the dissolution curve of indolepropionic acid.

[0055] Figure 10 This is a comparison of the crystal form of indolepropionic acid-metformin salt prepared in Example 1 in pH 6.8 buffer with the dissolution curve of indolepropionic acid.

[0056] Figure 11 The crystal form of indolepropionic acid-metformin salt obtained in Example 1 of this application was subjected to forced degradation under forced degradation conditions (60°C, 92.5% RH, and light irradiation of 5500 lx, 90 μW / cm²). 2 Comparative powder X-ray diffraction patterns under ( ).

[0057] Figure 12 This is the powder X-ray diffraction pattern of the sample obtained in Comparative Example 1 of this application.

[0058] Figure 13 This is the powder X-ray diffraction pattern of the sample obtained in Comparative Example 2 of this application. Detailed Implementation

[0059] To make the objectives, technical solutions, and advantages of this application clearer and to provide a more thorough and comprehensive understanding of the disclosure of this application, the technical solutions of this application will be clearly and completely described below in conjunction with specific embodiments and corresponding drawings. The described embodiments are only some embodiments of this application, and not all embodiments.

[0060] The implementation of this application will be described in detail below with reference to the accompanying drawings. This embodiment is implemented based on the technical solution of this application, and provides detailed implementation methods and specific operation processes, but the protection scope of this application is not limited to the following embodiments.

[0061] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0062] the term

[0063] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0064] In this application, the terms "multiple" or "various" are used unless otherwise specified, referring to a quantity greater than or equal to 2. For example, "one or more" or "at least one" means one or more of two.

[0065] In this application, terms such as "further" and "especially" are used to describe purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0066] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0067] In this application, when numerical intervals (i.e., numerical ranges) are mentioned, unless otherwise specified, the distribution of selectable numerical values ​​within the numerical interval is considered continuous, and includes the two endpoints of the numerical interval (i.e., the minimum and maximum values), as well as every numerical value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that numerical interval, including the two endpoint integers of the numerical range, as well as every integer between the two endpoints, is equivalent to directly listing every integer. When multiple numerical ranges are provided to describe features or characteristics, these numerical ranges can be merged. In other words, unless otherwise specified, the numerical ranges disclosed herein should be understood to include any and all subranges included therein. The "numerical value" in the numerical interval can be any quantitative value, such as a number, percentage, ratio, etc. The term "numerical interval" can be broadly included to include numerical interval types such as percentage intervals, ratio intervals, and proportion intervals.

[0068] In this application, unless otherwise specified, the temperature parameters are permitted to be either constant-temperature treatment or variations within a certain temperature range. It should be understood that the constant-temperature treatment allows temperature fluctuations within the precision range of the instrument control. Fluctuations are permitted within ranges such as ±5℃, ±4℃, ±3℃, ±2℃, and ±1℃.

[0069] In this application, if the unit of a data range is only followed by the right endpoint, it indicates that the units of the left and right endpoints are the same. For example, 2-5h means that the units of the left endpoint "2" and the right endpoint "5" are both h (hours).

[0070] In this application, the terms “indolepropionic acid salt formation with metformin”, “crystal form of indolepropionic acid-metformin salt”, and “salt” are synonymous.

[0071] In this application, "room temperature" refers to a temperature range of 10-30 °C.

[0072] The first aspect of this application provides a crystal form of indolepropionic acid-metformin salt, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 8.8°±0.2°, 12.7°±0.2°, 14.1°±0.2°, 17.2°±0.2°, 18.0°±0.2°, 18.5°±0.2° and 19.6°±0.2°.

[0073] Optionally, its X-ray powder diffraction pattern also has characteristic diffraction peaks at the following 2θ angles: 22.2°±0.2°, 24.3°±0.2°, 24.7°±0.2°, 27.7°±0.2° and 32.7°±0.2°, or more.

[0074] The indolepropionic acid-metformin salt of this application has good stability and improved solubility and dissolution rate compared to indolepropionic acid. It can solve the problem of low solubility of indolepropionic acid and is expected to promote the design of indolepropionic acid formulations and their clinical application.

[0075] Optionally, the X-ray powder diffraction pattern of the crystal form is basically as follows: Figure 5 or Figure 6 or Figure 7 As shown.

[0076] Optionally, the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 8.8°, 12.7°, 14.1°, 17.2°, 18.0°, 18.5°, 19.6°, 22.2°, 24.3°, 24.7°, 27.7°, and 32.7°.

[0077] Optionally, the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 8.9°, 12.8°, 14.3°, 17.4°, 18.2°, 18.7°, 19.8°, 22.4°, 24.5°, 24.9° and 32.9°.

[0078] Optionally, the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 8.9°, 12.9°, 14.3°, 17.4°, 18.2°, 18.7°, 19.8°, 22.4°, 24.5°, 24.9° and 32.9°.

[0079] The indolepropionic acid-bismethylguanidine salt of this application has a single-crystal structure and exhibits good stability. Specifically, the crystal data of the indolepropionic acid-bismethylguanidine salt include: monoclinic crystal system; space group P21 / n; the asymmetric unit contains one indolepropionic acid anion and one bismethylguanidine cation, which are combined in a 1:1 molar ratio; cell parameters a = 10.517(4); b = 9.392(6); c = 17.126, α = 90.00°; β = 105.030°; γ = 90.00°; cell volume 1633.9 Å. 3 The number of molecules in the unit cell Z = 4.

[0080] Specifically, the calculated crystal density of the indolepropionic acid-metformin salt is 1.293 g / cm³. 3 The infrared absorption spectrum of the crystal form of the indolepropionic acid-bismethylguanidine salt is at least at 3493 cm⁻¹. -1 1557 cm -1 1379cm -1 and 1048 cm -1 It has an absorption peak.

[0081] The indolepropionic acid-metformin salt crystal form of this application exhibits good thermal stability. Specifically, by differential scanning calorimetry, the melting initiation temperature of the indolepropionic acid-metformin salt crystal form during heating at a rate of 10 °C / min is 181±5 °C, and the melting peak value is 183±5 °C. By thermogravimetric analysis, the indolepropionic acid-metformin salt crystal form during heating at a rate of 20 °C / min to 400 °C begins to lose weight at 200±5 °C, and loses 80±1% of its weight at 395±5 °C.

[0082] A second aspect of this application provides a method for preparing the crystal form of indolepropionic acid-metformin salt, comprising the following steps:

[0083] Indolepropionic acid, a first solvent, and metformin free base are mixed and reacted, the solvent is removed, and the mixture is dried to prepare the crystal form of the indolepropionic acid-metformin salt.

[0084] The crystal form of the indolepropionic acid-metformin salt of this application is obtained by mixing and reacting indolepropionic acid and metformin free base. The preparation process is simple, and it combines metformin and indolepropionic acid, which have hypoglycemic effects, and has improved solubility and dissolution rate. It can solve the problem of low solubility of indolepropionic acid and is expected to promote the design of indolepropionic acid preparations and their clinical application.

[0085] In this application, there is no specific requirement for the mixing order of indolepropionic acid, the first solvent, and the metformin free base; the goal is simply to achieve the dissolution and dispersion of indolepropionic acid and the metformin free base. For example, the metformin free base can be mixed with the first solvent to form a metformin free base solution, and then the metformin free base solution can be mixed with the indolepropionic acid; alternatively, the metformin free base and the indolepropionic acid can be added to the first solvent and mixed.

[0086] In this application, the solvent removal step serves to preliminarily remove the solvent to facilitate the subsequent drying process, and the method of solvent removal is not particularly limited. Specifically, the solvent removal step includes at least one of solid-liquid separation, natural evaporation, and rotary evaporation; wherein, solid-liquid separation may include filtration and / or centrifugation; the water bath temperature for rotary evaporation is 30-50 ℃, for example, 30 ℃, 40 ℃, 50 ℃, etc.

[0087] In this application, the purpose of drying is to remove moisture. There are no special limitations on the drying method, such as natural drying, vacuum drying or freeze drying. For example, the vacuum drying conditions can be: drying at 10-60 ℃ (e.g., 10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, etc.) for 12-40 h (e.g., 12 h, 16 h, 20 h, 24 h, 28 h, 32 h, 36 h, 40 h, etc.).

[0088] In this application, there are no special requirements for the mixing conditions; it is sufficient to achieve the dissolution and dispersion of indolepropionic acid and metformin free base. During the mixing process, stirring, grinding, and other methods can be used to promote the mixing effect. The stirring conditions include: stirring temperature 10-40 ℃, such as 10 ℃, 20 ℃, 30 ℃, 40 ℃, etc.; stirring time 1-24 h, such as 1 h, 4 h, 8 h, 12 h, 16 h, 20 h, 24 h, etc.; stirring speed 50-1000 rpm, such as 50 rpm, 100 rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm, 800 rpm, 1000 rpm, etc.; the grinding is ball milling, and the ball milling time is 30-90 min, such as 30 min, 40 min, 50 min, 60 min, 70 min, 80 min, 90 min, etc.

[0089] In this application, fluctuations in the molar ratio of indolepropionic acid to metformin free base within a certain range have no impact on the quality of the crystal form of indolepropionic acid-metformin salt. Specifically, the molar ratio of indolepropionic acid to metformin free base is 0.3-3:1; optionally 0.5-2:1, further optionally 0.9-1.1:1, and particularly optionally 1:1, such as 0.3:1, 0.5:1, 0.7:1, 0.9:1, 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, etc.

[0090] In this application, the role of the first solvent is to effectively dissolve or disperse indolepropionic acid and metformin free base, and there are no special limitations on the amount and type used.

[0091] Specifically, the molar volume ratio of the metformin free base to the first solvent is 0.1 mol: (0.5-10) mL, for example, 0.1 mol: 0.5 mL, 0.1 mol: 1 mL, 0.1 mol: 2 mL, 0.1 mol: 3 mL, 0.1 mol: 4 mL, 0.1 mol: 5 mL, 0.1 mol: 6 mL, 0.1 mol: 7 mL, 0.1 mol: 8 mL, 0.1 mol: 9 mL, 0.1 mol: 10 mL, etc.

[0092] Specifically, the first solvent includes water and / or an organic solvent; the organic solvent includes at least one of alcohols, ketones, esters, nitriles, ethers, alkanes, aromatics, and halogenated hydrocarbons; optionally, the organic solvent includes at least one of methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, and dichloromethane; more preferably, at least one of isopropanol, acetone, acetonitrile, and dichloromethane.

[0093] In this application, the metformin free base can be a commercially available product or can be prepared in-house. For example, the preparation of the metformin free base includes the following steps:

[0094] Metformin hydrochloride, an alkali, and a second solvent are mixed and reacted, followed by solid-liquid separation to obtain the free alkali of metformin.

[0095] Understandably, after the solid-liquid separation step, steps such as resolution, recrystallization, and drying may also be included. During the reaction of metformin hydrochloride, the base, and the second solvent, stirring can be used to improve reaction uniformity and efficiency. The stirring speed can be 50-1000 rpm, for example, 50 rpm, 100 rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm, 800 rpm, 1000 rpm, etc.

[0096] The metformin free base solution can be a solution obtained by redissolving the metformin free base, or a solution obtained by redissolving, recrystallizing and drying the metformin free base in the first solvent.

[0097] In this application, the base is used to react with metformin hydrochloride to obtain free metformin base. The specific type of base is not particularly limited, and the amount used can be adjusted according to actual needs. Specifically, the base includes at least one of sodium hydroxide, potassium hydroxide, and calcium hydroxide; the molar ratio of metformin hydrochloride to the base is 1:0.5-2, for example, 1:0.5, 1:1, 1:1.5, 1:2, etc.

[0098] In this application, the second solvent serves to dissolve or disperse metformin hydrochloride and the base; its specific type is not particularly required. Specifically, the second solvent includes water and / or alcohol solvents; preferably at least one of water, methanol, and ethanol.

[0099] Depending on the specific mixing and solvent removal processes, the preparation methods of this application can be divided into reaction crystallization, solvent evaporation, suspension, and solvent-assisted grinding.

[0100] The reaction crystallization method includes the following steps:

[0101] Metformin free base is dispersed in a first solvent to form a metformin free base solution; indolepropionic acid is added to the metformin free base solution, mixed, filtered, and the solid is dried to prepare the crystal form of the indolepropionic acid-metformin salt.

[0102] In the reaction crystallization method, a white solid precipitates after mixing and standing. The solvent is preferably an organic solvent with a certain solubility for the free base of metformin, such as ketones and / or nitriles, with acetone being particularly preferred.

[0103] The solvent evaporation method includes the following steps:

[0104] Indolepropionic acid and metformin free base are added to the first solvent, mixed and reacted, the solvent is allowed to evaporate naturally, and then dried to prepare the crystal form of the indolepropionic acid-metformin salt.

[0105] In the solvent evaporation method, the solvent is preferably a solvent with a certain solubility for indolepropionic acid and metformin free base, such as at least one of alcohols, ketones, esters, nitriles, ethers, alkanes, aromatic hydrocarbons and halogenated hydrocarbons, and especially preferably at least one of methanol, ethanol, isopropanol and acetonitrile; the solvent is allowed to evaporate naturally for 1-7 days, which can be carried out at room temperature.

[0106] The suspension method includes the following steps:

[0107] Indolepropionic acid and metformin free base are added to the first solvent, mixed and reacted, filtered, and the solid is dried to prepare the crystal form of the indolepropionic acid-metformin salt.

[0108] In the suspension method, the solvent is preferably a solvent with a certain solubility for indolepropionic acid and metformin free base, such as at least one of alcohols, ketones, esters, nitriles, ethers, alkanes, aromatic hydrocarbons and halogenated hydrocarbons, and especially preferably at least one of methanol, ethanol, isopropanol and acetonitrile.

[0109] The solvent-assisted grinding method includes the following steps:

[0110] Indolepropionic acid and metformin free base are mixed, a first solvent is added, the mixture is ground, the solvent is removed, and the mixture is dried to prepare the crystal form of the indolepropionic acid-metformin salt.

[0111] In the solvent-assisted grinding method, there are no special requirements for the solvent.

[0112] A third aspect of this application provides the crystal form of indolepropionic acid-metformin salt prepared by the preparation method described in the second aspect.

[0113] The crystal form of the indolepropionic acid-metformin salt of this application combines metformin and indolepropionic acid, which have hypoglycemic effects, and has improved solubility and dissolution rate. This can solve the problem of low solubility of indolepropionic acid and is expected to promote the design of indolepropionic acid formulations and their clinical application.

[0114] A fourth aspect of this application provides a pharmaceutical composition comprising the crystal form of the indolepropionic acid-metformin salt described in the first or third aspect, and pharmaceutically acceptable excipients.

[0115] The pharmaceutical composition of this application includes a crystal form of indolepropionic acid-metformin salt, which can solve the problem of low solubility of indolepropionic acid and is expected to promote the design and clinical application of indolepropionic acid formulations.

[0116] In this application, the dosage form of the pharmaceutical composition is not particularly limited and may include tablets, capsules, pills, gels, emulsions or suspensions; considering medication adherence, tablets or capsules are preferred.

[0117] The fifth aspect of this application provides the use of the crystal form of the indolepropionic acid-metformin salt described in the first or third aspect, or the pharmaceutical composition described in the fourth aspect, in the preparation of a medicament for treating metabolic diseases of the endocrine system.

[0118] The crystal form or pharmaceutical composition of indolepropionic acid-metformin salt of this application has good stability and improved solubility and dissolution rate compared with indolepropionic acid, which can solve the problem of low solubility of indolepropionic acid. It combines metformin and indolepropionic acid, which have hypoglycemic effects, and may have a pharmacological synergistic effect in the treatment of diabetes, and has the potential to develop drugs for the treatment of diabetes.

[0119] Specifically, metabolic diseases of the endocrine system include diabetes.

[0120] Unless otherwise specified, the raw materials used in the following experiments can be purchased from the market.

[0121] Information on the instruments and performance testing methods used in the examples and comparative examples is as follows:

[0122] X-ray powder diffraction patterns were obtained using a Shimadzu XRD-6000 X-ray powder diffractometer, which used Cu-Kα rays (λ = 1.5418 Å); the ray scanning range was 3 - 40°; the scanning speed was 2 ° / min; and the analysis software used was MDI Jade 6.0.

[0123] Single-crystal data were obtained using a Bruker D8 Advance single-crystal X-ray diffractometer with a graphite monochromator and Mo-Kα rays (λ = 0.71073 Å); the test temperature was 170 K; the single-crystal structure was reconstructed and analyzed using SAINT-5.0 and SHELXTL-2017 programs, and the absorption correction was performed using the SADABS program.

[0124] Differential scanning calorimetry was performed using a Netzsch DSC 3500 instrument with a heating rate of 10 °C / min.

[0125] Thermogravimetric analysis was performed using a Netzsch TG 209F3 instrument at a heating rate of 20 °C / min.

[0126] The Fourier transform infrared spectrometer used was a Nicolet iS50 device, with a scanning range of 4000-400 cm⁻¹. -1 4 cm resolution -1 .

[0127] High-performance liquid chromatography (HPLC) data were determined using a Shimadzu LC-20 HPLC system. The column was a C18 column (4.6 mm × 150 mm, 5 μm); the chromatographic index was 20 mmol·L⁻¹. -1 Sodium heptanesulfonate solution (pH 2.8) was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed according to Table 1. The flow rate was 1.0 mL / min, the column temperature was 40 ℃, the detection wavelength was 230 nm, and the injection volume was 10 μL.

[0128] Table 1 Elution gradient

[0129]

[0130] The following are specific examples.

[0131] Preparation Example 1

[0132] Preparation of metformin free alkaline solution:

[0133] 1) Add metformin hydrochloride (10 mmol) and sodium hydroxide (10 mmol) to an Erlenmeyer flask, add 100 mL of anhydrous ethanol, stir at 500 rpm for 1 hour at room temperature, filter to remove the white solid, and rotary evaporate the solution in a 40 ℃ water bath to obtain the white powder, which is the crude metformin free base.

[0134] 2) Dissolve the crude metformin free base obtained in step 1) in 100 mL of acetone and stir for 10 min. Filter to remove the white insoluble matter to obtain a colorless and transparent solution, which is the metformin free base solution.

[0135] Preparation Example 2

[0136] The metformin free base solution prepared in Preparation Example 1 was rotary evaporated to obtain a white powder, which is the metformin free base.

[0137] Example 1

[0138] Add indolepropionic acid (10 mmol) to the metformin free base solution (10 mmol metformin free base) obtained in step 2) of Preparation Example 1. After standing for a while, a white solid precipitates out. Filter and vacuum dry the filter at room temperature for 24 hours to obtain a white powder, which is the crystal form of indolepropionic acid-metformin salt.

[0139] The crystal form of the obtained indolepropionic acid-bismethylguanidine salt was characterized by powder X-ray diffraction, infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry. The comparison results of the crystal form of indolepropionic acid-bismethylguanidine salt with those of indolepropionic acid and the free base of bismethylguanidine are as follows: Figures 1-4 As shown, the crystal form of indolepropionic acid-metformin salt exhibits characteristic diffraction peaks at 8.8°, 12.7°, 14.1°, 17.2°, 18.0°, 18.5°, 19.6°, 22.2°, 24.3°, 24.7°, 27.7°, and 32.7°.

[0140] Example 2

[0141] Approximately 100 mg of the indolepropionic acid-metformin salt crystal form from Example 1 was added to 0.4 mL of water and heated to 40 °C until completely dissolved. The solution was then refrigerated at 4 °C, and transparent bulk single crystals were obtained after approximately one week.

[0142] Single-crystal X-ray diffraction analysis revealed that the obtained bulk single crystal belongs to the monoclinic system with space group P21 / n. The crystal lattice features are: a = 10.517(4), b = 9.392(6), c = 17.126, α = 90.00°, β = 105.030°, γ = 90.00°, and a cell volume of 1633.9 Å. 3The number of molecules per unit cell, Z = 4, yields a calculated crystal density of 1.293 g / cm³. 3 .

[0143] The powder X-ray diffraction results obtained from the single-crystal simulation in Example 2 are basically consistent with the powder X-ray diffraction pattern in Example 1, which verifies that the crystal has the same crystal form as the indolepropionic acid-bismethylguanidine salt obtained in Example 1.

[0144] Example 3

[0145] Metformin free base (0.1 mmol, Preparation Example 2) and indolepropionic acid (0.1 mmol) were added to 4 mL of acetonitrile and stirred at 1000 rpm for 1 hour at room temperature. After complete dissolution, the solvent was evaporated at room temperature, and a bulk single crystal was obtained after 3-4 days. The powder X-ray diffraction results obtained from the single crystal simulation were basically consistent with the powder X-ray diffraction pattern in Example 1, verifying that the crystal form of this crystal is the same as that of the indolepropionic acid-metformin salt obtained in Example 1.

[0146] Example 4

[0147] Metformin free base (Preparation Example 2, 0.1 mmol) and indolepropionic acid (0.1 mmol) were added to 4 mL of isopropanol and stirred at 800 rpm for 1 hour at room temperature. After complete dissolution, the solvent was evaporated at room temperature, and a white powder was obtained after 7 days. The crystalline form of indolepropionic acid-metformin salt was obtained after vacuum drying at 60 °C for 24 hours. Its powder X-ray diffraction pattern is shown below. Figure 5 As shown, characteristic diffraction peaks are observed at 8.9°, 12.8°, 14.3°, 17.4°, 18.2°, 18.7°, 19.8°, 22.4°, 24.5°, 24.9°, and 32.9°, which are basically consistent with the powder X-ray diffraction pattern in Example 1, confirming that the same crystal form as in Example 1 was obtained.

[0148] Example 5

[0149] Metformin free base (0.1 mmol, Preparation Example 2) and indolepropionic acid (0.1 mmol) were added to 4 mL of acetone and stirred at 200 rpm for 12 hours at room temperature. The mixture was filtered, and the filtrate was vacuum dried at 40 °C for 24 hours to obtain a white powder, which is the crystalline form of indolepropionic acid-metformin salt. Its powder X-ray diffraction pattern is shown below. Figure 6 As shown, characteristic diffraction peaks are observed at 8.9°, 12.9°, 14.3°, 17.4°, 18.2°, 18.7°, 19.8°, 22.4°, 24.5°, 24.9°, and 32.9°, which are basically consistent with the powder X-ray diffraction pattern in Example 1, confirming that the same crystal form as in Example 1 was obtained.

[0150] Example 6

[0151] Metformin free base (Preparation Example 2, 0.1 mmol) and indolepropionic acid (0.2 mmol) were added to 4 mL of dichloromethane. The mixture was stirred at 50 rpm for 24 hours at room temperature, filtered, and the filtrate was vacuum dried at 20 °C for 24 hours to obtain a white powder, which is the crystalline form of indolepropionic acid-metformin salt. Its powder X-ray diffraction pattern is shown below. Figure 7 As shown, characteristic diffraction peaks were observed at 8.9°, 12.8°, 14.3°, 17.3°, 18.1°, 18.6°, 19.8°, 22.3°, 24.5°, 24.9°, and 32.8°, which were basically consistent with the powder X-ray diffraction pattern in Example 1, confirming that the same crystal form as in Example 1 was obtained.

[0152] Test Example 1

[0153] Comparison of the crystal forms of indolepropionic acid-methylbisguanidine salt and the solubility of indolepropionic acid monomer.

[0154] Weigh an excess of the indolepropionic acid-metformin salt crystal form and indolepropionic acid monomer obtained in Example 1 into buffer solutions at pH 2.0, 4.5, and 6.8. Incubate at 25 °C with a shaker at 250 rpm for 24 hours. After standing for 24 hours, centrifuge and collect the supernatant. Dilute 100 times with 20% acetonitrile and determine the concentration of indolepropionic acid in the solution using high-performance liquid chromatography (HPLC). This yields the crystal form of indolepropionic acid-metformin salt and the equilibrium solubility of indolepropionic acid in the monomer.

[0155] The experimental results are shown in Table 2:

[0156] Table 2. Crystal forms of indolepropionic acid-metformin salt and the relationship between indolepropionic acid in monomers in different pH buffer solutions.

[0157] Equilibrium solubility comparison

[0158]

[0159] As shown in Table 2, in pH 4.5 and pH 6.8 buffer solutions, the equilibrium solubility of the indolepropionic acid-metformin salt crystal form increased by 204 and 35 times, respectively, compared with the indolepropionic acid monomer. The higher equilibrium solubility can ensure that the drug maintains a higher supersaturation state in the digestive tract, allowing the drug to be rapidly absorbed through the digestive tract wall into the blood circulation, increasing the blood drug concentration, and thus helping to improve bioavailability and ensure the efficacy of the drug.

[0160] Test Example 2

[0161] Comparison of the crystal form of indolepropionic acid-metformin salt and the solubility of indolepropionic acid monomer

[0162] After passing the indolepropionic acid monomer and the indolepropionic acid-metformin salt crystal form prepared in Example 1 through a 100-mesh sieve, excess indolepropionic acid and the corresponding amount of indolepropionic acid-metformin salt crystal form were weighed and added to 10 mL of pH 2.0, pH 4.5, and pH 6.8 buffer solutions. The stirring speed was 150 rpm, and the solution temperature was 37 ℃. 300 μL of solution was collected at minutes 1, 3, 5, 10, 15, 20, 30, and 60, filtered through a 0.22 μm filter membrane, diluted 100 times with 20% acetonitrile, and the concentration of indolepropionic acid in the solution at each time point was determined by high-performance liquid chromatography (HPLC), repeated three times. The dissolution curves of the indolepropionic acid monomer and the indolepropionic acid-metformin salt crystal forms in pH 2.0, pH 4.5, and pH 6.8 buffer solutions were finally obtained, and the results are shown below. Figure 8 , Figure 9 and Figure 10 As shown.

[0163] from Figures 8-10 The results show that the crystal form of indolepropionic acid-metformin salt has higher apparent solubility and exhibits a faster dissolution rate, especially in buffer solutions at pH 4.5 and 6.8, where the dissolution advantage of the crystal form of indolepropionic acid-metformin salt is extremely significant, consistent with the solubility results in Test Example 1. The higher dissolution rate allows the drug to dissolve rapidly in the digestive tract, reaching supersaturation more quickly and reducing the time to peak plasma concentration (ts). max Higher apparent solubility can also allow drugs to be rapidly absorbed through the digestive tract wall into the bloodstream, increasing peak blood drug concentration (C0). max ), and may improve bioavailability.

[0164] Test Example 3

[0165] Evaluation of the crystal stability of indolepropionic acid-metformin salt

[0166] The indolepropionic acid-metformin salt crystal form obtained in Example 1 was passed through a 100-mesh sieve and subjected to high temperature (60 °C), high humidity (92.5% RH), and light irradiation (5500 lx, 90 μW / cm²). 2 Under the specified conditions, the salt was placed for 10 days. Powder X-ray diffraction (PXRD) and high-performance liquid chromatography (HPLC) analyses were performed on the crystal forms of the undegraded indolepropionic acid-metformin salt and the salts under various degradation conditions to evaluate the crystal form stability and chemical stability of indolepropionic acid-metformin salt. The results are shown in Table 3 below. Figure 11 As shown.

[0167] Table 3. Crystal form chemical stability of indolepropionic acid-methylguanidine salt

[0168]

[0169] Depend on Figure 11 It can be seen that the characteristic diffraction peaks of the crystal forms of indolepropionic acid-metformin salt under undegraded and various degradation conditions are relatively consistent, indicating that the crystal forms of indolepropionic acid-metformin salt have good stability under the three degradation conditions. As shown in Table 3, the amount of impurities detected in the crystal forms of indolepropionic acid-metformin salt under high temperature and high humidity conditions did not differ significantly, and no new degradation impurities were generated, showing good chemical stability. Under light conditions, a small amount of new impurity Imp1 was generated, suggesting that the crystal forms of indolepropionic acid-metformin salt need to be stored in the dark.

[0170] Comparative Example 1

[0171] Metformin hydrochloride (0.1 mmol) and indolepropionic acid (0.1 mmol) were added to 4 mL of isopropanol and stirred at 800 rpm for 1 hour at room temperature until completely dissolved. The solvent was then evaporated at room temperature, and a white powder was obtained after 7 days. The X-ray diffraction pattern of the powder after vacuum drying at 60 °C for 24 hours is shown below. Figure 12 As shown, compare it with Figure 5 Comparison revealed that no characteristic diffraction peaks of the indolepropionic acid-metformin salt crystal form were observed, making it impossible to obtain the crystal form of indolepropionic acid-metformin salt.

[0172] Comparative Example 2

[0173] Metformin hydrochloride (0.1 mmol) and indolepropionic acid (0.1 mmol) were added to 4 mL of acetone, stirred at 200 rpm for 12 hours at room temperature, filtered, and the filtrate was vacuum dried at 40 °C for 24 hours to obtain a white powder. Its powder X-ray diffraction pattern is shown below. Figure 13 As shown, compare it with Figure 5 Comparison revealed that no characteristic diffraction peaks of the indolepropionic acid-metformin salt crystal form were observed, making it impossible to obtain the crystal form of indolepropionic acid-metformin salt.

[0174] Comparative Examples 1 and 2 show that using metformin hydrochloride, the crystal form of indolepropionic acid-metformin salt could not be prepared by solvent evaporation or suspension methods.

[0175] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0176] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A crystalline form of an indolepropionic acid-biguanide salt characterized by, The X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ angles: 8.8°±0.2°, 12.7°±0.2°, 14.1°±0.2°, 17.2°±0.2°, 18.0°±0.2°, 18.5°±0.2° and 19.6°±0.2°.

2. The crystalline form of the indolepropionic acid-dimethylguanidine salt of claim 1, characterized in that, The X-ray powder diffraction pattern thereof further has one or more of the following characteristic diffraction peaks at the following 2θ angles: 22.2°±0.2°, 24.3°±0.2°, 24.7°±0.2°, 27.7°±0.2° and 32.7°±0.2°.

3. The crystalline form of an indolepropionic acid-dimethylguanidine salt of claim 1, characterized in that, The X-ray powder diffraction pattern thereof is substantially as shown in Figure 5 or Figure 6 or Figure 7.

4. The crystalline form of an indolepropionic acid-dimethylguanidine salt according to claim 1 or 2, characterized in that, The crystal data of the crystal form of the indolepropionic acid-metformin salt comprises: monoclinic system; space group P21 / n; one indolepropionic acid anion and one metformin cation are contained in an asymmetric unit, the indolepropionic acid anion and the metformin cation are combined in a 1:1 molar ratio to form; the cell parameters are a = 10.517(4); b = 9.392(6); c = 17.126, α = 90.00°; β = 105.030°; γ = 90.00°; the cell volume is 1633.9 Å 3 ; the number of molecules in the cell Z = 4.

5. The crystalline form of the indolepropionic acid-dimethylguanidine salt of claim 4, characterized in that, The crystal form of the indoline propionic acid-metformin salt satisfies one or more of the following conditions: (1) The calculated crystal density of the crystal form of the indolepropionic acid- metformin salt is 1.293 g / cm 3 ; (2) The crystal form of the indoline propionic acid-metformin salt has a melting onset temperature of 181±5 °C and a melting peak value of 183±5 °C during heating at a temperature rising rate of 10 °C / min, as determined by differential scanning calorimetry; (3) The crystal form of the indoline propionic acid-metformin salt starts to lose weight at 200±5 °C and loses 80±1% of weight at 395±5 °C during heating at a rate of 20 °C / min to 400 °C, as determined by a thermal gravimetric analyzer; (4) The infrared absorption spectrum of the crystal form of the indolepropionic acid- metformin salt has absorption peaks at least at 3493 cm -1 , 1557 cm -1 , 1379 cm -1 , and 1048 cm -1 .

6. A process for preparing a crystal form of an indolepropionic acid- metformin salt according to any one of claims 1 to 5, characterized in that, comprising the following steps: mixing and reacting indoline propionic acid, a first solvent and metformin free base, removing the solvent, and drying to prepare the crystal form of the indoline propionic acid-metformin salt.

7. The production method according to claim 6, wherein satisfying one or more of the following conditions: (1) the step of mixing and reacting the indoline propionic acid, the first solvent and the metformin free base comprises: mixing the metformin free base with the first solvent to form a metformin free base solution, and mixing the metformin free base solution with the indoline propionic acid; or adding the metformin free base and the indoline propionic acid into the first solvent and mixing; (2) the step of removing the solvent comprises at least one of solid-liquid separation, natural evaporation and rotary evaporation; (3) the mixing comprises stirring and / or grinding; (4) the drying comprises at least one of natural drying, vacuum drying and freeze drying; (5) the molar ratio of the indoline propionic acid to the metformin free base is 0.3-3:1; (6) the molar volume ratio of the metformin free base to the first solvent is 0.1 mol:(0.5-10) mL; (7) the first solvent comprises water and / or an organic solvent; the organic solvent comprises at least one of an alcohol solvent, a ketone solvent, an ester solvent, a nitrile solvent, an ether solvent, an alkane, an aromatic hydrocarbon and a halogenated hydrocarbon; (8) the preparation of the metformin free base comprises the following steps: mixing and reacting metformin hydrochloride, a base and a second solvent, and solid-liquid separation to obtain the metformin free base.

8. The production method according to claim 7, wherein The stirring conditions comprise a stirring temperature of 10-40 °C, a stirring time of 1-24 h and a stirring speed of 50-1000 rpm.

9. The production method according to claim 7, wherein The grinding is ball milling, and the ball milling time is 30-90 min.

10. The production method according to claim 7, wherein The vacuum drying conditions are drying at 10-60 °C for 12-40 h.

11. The production method according to claim 7, wherein The molar ratio of the indoline propionic acid to the metformin free base is 0.5-2:

1.

12. The production method according to claim 11, wherein The molar ratio of the indoline propionic acid to the metformin free base is 0.9-1.1:

1.

13. The production method according to claim 12, wherein The molar ratio of the indoline propionic acid to the metformin free base is 1:

1.

14. The production method according to claim 7, wherein The organic solvent comprises at least one of methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile and dichloromethane.

15. The production method according to claim 14, wherein The organic solvent comprises at least one of isopropanol, acetone, acetonitrile and dichloromethane.

16. The production method according to claim 7, wherein The base comprises at least one of sodium hydroxide, potassium hydroxide and calcium hydroxide.

17. The production method according to claim 7, wherein The molar ratio of the metformin hydrochloride to the base is 1:0.5-2.

18. The production method according to claim 7, wherein The second solvent comprises water and / or an alcoholic solvent.

19. The production method according to claim 7, wherein The second solvent is at least one of water, methanol and ethanol.

20. The crystal form of the indoline propionic acid-metformin salt prepared by the preparation method of any one of claims 6-19.

21. A pharmaceutical composition comprising, The crystal form of the indoline propionic acid-metformin salt of any one of claims 1-5 or claim 20, and a pharmaceutically acceptable excipient.

22. The pharmaceutical composition of claim 21, wherein, The dosage form of the pharmaceutical composition comprises a tablet, a capsule, a pill, a gel, an emulsion or a suspension.

23. The pharmaceutical composition of claim 22, wherein, The dosage form of the pharmaceutical composition is a tablet or a capsule.

24. Use of the crystal form of the indoline propionic acid-metformin salt of any one of claims 1-5 or claim 20 or the pharmaceutical composition of any one of claims 21-23 in the preparation of a medicament for treating a metabolic disease of the endocrine system.

25. The use of claim 24, wherein, The metabolic disease of the endocrine system comprises diabetes. The metabolic disease of the endocrine system comprises diabetes.

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