A crystalline form of a hypoxia-inducible factor prolyl hydroxylase inhibitor and methods of making the same

Abstract

The present application relates to the field of pharmaceutical chemistry, and in particular to a crystal form of a hypoxia-inducible factor prolyl hydroxylase inhibitor and a preparation method thereof.The X-ray powder diffraction pattern of the crystal form comprises diffraction peaks at 2theta angles of 14.26, 19.83 and 27.42 degrees, or comprises diffraction peaks at 2theta angles of 15.71, 22.28 and 26.42 degrees, or comprises diffraction peaks at 2theta angles of 16.72, 25.17 and 27.29 degrees, or comprises diffraction peaks at 2theta angles of 12.67, 15.95 and 20.42 degrees.The crystal form has good performance and can be used for treating or preventing anemia.The preparation method of the crystal form is simple, convenient to operate and mild in conditions.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a crystal form of a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor and its preparation method. Background Technology

[0002] Vadedustat (CAS No.: 1000025-07-9), chemically named {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, was developed by Akebia and is used to treat or prevent anemia. Its mechanism of action is as a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor. It is currently in phase III clinical trials for the treatment of anemia caused by secondary chronic kidney disease. Its structural formula is shown below:

[0003]

[0004] The original developer, Akebia, disclosed valdustat crystal forms A, B, and C in patent WO2015073779A1. Crystal form B may convert to crystal form A in a slurry at high temperatures. Crystal form A is a stable crystal form, but its solubility in water is very poor. Crystal form B has poor crystallinity and stability. Crystal form C is difficult to reproduce using conventional methods, and its preparation conditions are harsh, resulting in poor reproducibility. Furthermore, patent WO2015073779A1 did not conduct further screening research on the crystal forms of valdustat.

[0005] Therefore, there is still a need in the field to systematically and comprehensively develop different crystal forms of valdustat in order to find new crystal forms and / or co-crystals that are more suitable for drug development. Summary of the Invention Invention Overview

[0007] This invention provides a new crystal form of valdextrin, its preparation method, and its composition.

[0008] On one hand, the present invention provides a crystal form of vardurostat, referred to as the vardurostat-piperazine eutectic crystal form. The X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 14.26, 19.83, and 27.42 degrees.

[0009] Thermogravimetric analysis curves show that the crystal form loses weight at 200℃-270℃, with a weight loss of 1.0%-15.0%.

[0010] The differential scanning calorimetry curve of the crystal form has an endothermic peak at 200℃-260℃.

[0011] The present invention also provides a method for preparing the vardurostat-piperazine eutectic crystal form, comprising: dissolving vardurostat in a solvent, then adding piperazine hexahydrate to the solution, stirring, filtering, and drying to constant weight to obtain the vardurostat-piperazine eutectic crystal form.

[0012] On one hand, the present invention provides a crystal form of vardurostat, referred to as vardurostat-isoniacin eutectic crystal form I. The X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 15.71, 22.28, and 26.42 degrees.

[0013] Thermogravimetric analysis curves show that the crystal form experiences weight loss at 120℃-200℃, with a weight loss of 0.1%-2.5%.

[0014] The differential scanning calorimetry curve of the crystal form has an endothermic peak in the range of 140℃-200℃.

[0015] The present invention also provides a method for preparing the vardurostat-isoniazid eutectic crystal form I, comprising: dissolving vardurostat in a solvent, then adding isoniazid to the solution, precipitating a white solid, filtering, and drying to constant weight to obtain vardurostat-isoniazid eutectic crystal form I.

[0016] On one hand, the present invention provides a crystal form of vardurostat, referred to as vardurostat-isoniacin eutectic crystal form II. The X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 16.72, 25.17, and 27.29 degrees.

[0017] Thermogravimetric analysis curves show that the crystal form experiences weight loss at 120℃-200℃, with a weight loss of 0.1%-1.5%.

[0018] The differential scanning calorimetry curve of the crystal form has an endothermic peak in the range of 110℃-170℃.

[0019] The present invention also provides a method for preparing the vardurostat-isoniazid eutectic form II, comprising: dissolving vardurostat in a solvent, then adding isoniazid to the solution, stirring, precipitating a white solid, filtering, and drying to constant weight to obtain vardurostat-isoniazid eutectic form II.

[0020] On one hand, the present invention provides a crystal form of vardurostat, referred to as vardurostat-isoniacin eutectic crystal form III. The X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 12.67, 15.95, and 20.42 degrees.

[0021] Thermogravimetric analysis curves show that the crystal form experiences weight loss at temperatures ranging from 80℃ to 150℃, with a weight loss of 0.2% to 2.5%.

[0022] The differential scanning calorimetry curve of the crystal form has an endothermic peak in the range of 80℃-150℃.

[0023] The present invention also provides a method for preparing the vardurostat-isoniazid eutectic crystal form III, which includes: placing vardurostat-isoniazid eutectic crystal form I or vardurostat-isoniazid eutectic crystal form II in a solvent and slurrying, filtering, and drying to constant weight to obtain vardurostat-isoniazid eutectic crystal form III.

[0024] On one hand, the present invention provides a crystalline form of vardurostat, referred to as vardurostat-p-toluenesulfonate. The X-ray powder diffraction pattern of the crystalline form contains diffraction peaks at 2θ angles of 4.82, 16.75, and 22.78 degrees.

[0025] On one hand, the present invention provides a crystalline form of vardurostat, referred to as vardurostat-camphor sulfonate. The X-ray powder diffraction pattern of the crystalline form contains diffraction peaks at 2θ angles of 5.62, 18.81, and 29.57 degrees.

[0026] On the other hand, the present invention also provides a composition comprising any one or more of the aforementioned varodrustae crystal forms. In some embodiments, the composition comprises at least 90% of the crystal form of varodrustae by weight. In some embodiments, the crystal form in the composition does not exceed 0.5%-5% of varodrustae by weight.

[0027] Terminology Definition

[0028] The terms “comprising” or “including” are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0029] The term "crystal form" is used to describe the state of existence of a solid compound. It is a collection of various parameters describing the composition of ions, atoms or molecules, symmetry properties and periodic arrangement within the crystal.

[0030] The term "relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strongest peak in a set of diffraction peaks belonging to a certain crystal form, when the intensity of the first strongest peak is defined as 100%.

[0031] The term "basically as shown" means that at least 70%, at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern are shown in the pattern.

[0032] In the context of this invention, the 2θ (also known as 2theta or diffraction peak) values ​​in X-ray powder diffraction patterns are expressed in degrees (°).

[0033] When referring to spectra and / or data in figures, the term "diffraction peak" refers to a feature that a person skilled in the art would not attribute to background noise.

[0034] The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern of the crystal form is subject to experimental error. The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern may vary slightly between different machines and between different samples. The experimental error or difference may be + / - 0.2 units, + / - 0.1 units, or + / - 0.05 units. Therefore, the value of the 2θ or diffraction peaks cannot be considered absolute.

[0035] The differential scanning calorimetry (DSC) curves of the crystal form are subject to experimental error. The position and peak value of the endothermic peak may vary slightly between different machines and between different samples. The experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute.

[0036] Thermogravimetric analysis (TGA) of the crystal form is subject to experimental error. The weight loss temperature and the amount of weight loss may vary slightly between one machine and between one sample. The experimental error or difference may be approximately + / - 0.1 units, approximately + / - 0.05 units, or approximately + / - 0.01 units. Therefore, the values ​​of weight loss temperature and the amount of weight loss cannot be considered absolute.

[0037] In the context of this invention, all figures disclosed herein are approximate values, regardless of whether the words “approximately” or “about” are used, and the value of each figure may vary by ±1%, ±2%, or ±5%.

[0038] "Room temperature" refers to a temperature between approximately 15°C and 32°C, or approximately 20°C and 30°C, or approximately 23°C and 28°C, or approximately 28°C.

[0039] In this invention, when drying solids, the solids are dried to a constant weight. Invention Details

[0041] The inventors developed the crystal form of the compound vardurostat and its preparation method through research.

[0042] The crystalline forms of vardurostat provided by this invention are called vardurostat-piperazine co-crystal crystalline forms, vardurostat-isoniazid co-crystal crystalline form I, vardurostat-isoniazid co-crystal crystalline form II, vardurostat-isoniazid co-crystal crystalline form III, vardurostat-p-toluenesulfonate, or vardurostat-camphorsulfonate. These crystalline forms have good properties, high solubility, and high bioavailability; and / or good stability, which is beneficial for storage and thus meets the requirements for drug stability; low hygroscopicity, and / or good electrostatic properties, which is beneficial for operation in the production process.

[0043] In a first aspect, the present invention provides a new crystal form of vardurostat, called the vardurostat-piperazine eutectic crystal form.

[0044] The vardurostat-piperazine eutectic crystal form has the following characteristics: its X-ray powder diffraction pattern contains diffraction peaks with 2θ angles of 14.26, 19.83 and 27.42 degrees.

[0045] In some embodiments, the vardurostat-piperazine eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 12.88, 14.26, 19.83, 21.68, 24.86 and 27.42 degrees.

[0046] In some embodiments, the valdustat-piperazine eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 12.88, 14.26, 16.56, 16.75, 17.25, 19.58, 19.83, 20.40, 20.97, 21.68, 22.76, 23.20, 23.37, 24.00, 24.44, 24.86, 26.96, 27.42, 28.82, 29.62, and 29.97 degrees.

[0047] In some embodiments, the vardurostat-piperazine eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 12.88, 17.25, 20.97, 23.37, 27.42 and 29.97 degrees.

[0048] In some embodiments, the vardurostat-piperazine eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 14.26, 16.75, 19.58, 22.76, 24.86 and 29.62 degrees.

[0049] In some embodiments, the vardurostat-piperazine eutectic crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 16.56, 19.83, 21.68, 23.20, 24.00 and 28.82 degrees.

[0050] In some embodiments, the vardurostat-piperazine eutectic crystal form has an X-ray powder diffraction pattern containing at least one, at least two, or three peaks selected from diffraction peaks with 2θ angles of 14.26, 19.83, and 27.42 degrees.

[0051] In some specific implementations, the X-ray powder diffraction pattern of the vardurostat-piperazine eutectic crystal is essentially as follows: Figure 1 As shown.

[0052] The vardurostat-piperazine eutectic crystal form is a eutectic of vardurostat and piperazine. In some embodiments, the molar ratio of vardurostat to piperazine is 1:1.

[0053] The valdustat-piperazine eutectic crystal form also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystal form experiences weight loss of 1.0%-15.0% at 200℃-270℃. In some specific embodiments, the TGA shows that the crystal form experiences weight loss of approximately 7.7% at 200℃-270℃. In one specific embodiment, the TGA curve is essentially as follows: Figure 2 As shown.

[0054] The vardurostat-piperazine eutectic crystal form also has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 200℃-260℃. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 220℃-240℃. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 227℃-237℃. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 230℃-234℃, with the endothermic peak reaching a peak value of 232℃. In a specific embodiment, the DSC curve of the vardurostat-piperazine eutectic crystal form is substantially as follows: Figure 2 As shown.

[0055] Secondly, the present invention provides a method for preparing the vardulstat-piperazine eutectic crystal form.

[0056] The method for preparing the vardulstat-piperazine eutectic crystal form described in this invention is simple, convenient, mild, has high yield and high purity, and is suitable for industrial production.

[0057] A method for preparing the vardurostat-piperazine eutectic crystal form includes: dissolving vardurostat in a solvent, then adding piperazine hexahydrate to the solution, stirring, filtering, and drying to constant weight to obtain the vardurostat-piperazine eutectic crystal form.

[0058] In some embodiments, the solvent includes at least one selected from acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMF, and DMSO. In some embodiments, the solvent includes acetone. In some embodiments, the solvent is acetone.

[0059] In some embodiments, during the preparation of the vardurostat-piperazine co-crystal, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-300 mg / ml. In some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-200 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-100 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-50 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-200 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-100 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-50 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 20 mg / ml-100 mg / ml.

[0060] Thirdly, the present invention provides a new crystal form of vardurostat, called vardurostat-isoniacin eutectic crystal form I.

[0061] The vardurostat-isocyanate eutectic crystal type I has the following characteristics: its X-ray powder diffraction pattern contains diffraction peaks with 2θ angles of 15.71, 22.28 and 26.42 degrees.

[0062] In some embodiments, the vardurostat-isoniacin eutectic crystal form I has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 9.80, 15.71, 18.64, 22.28, 26.42 and 31.75 degrees.

[0063] In some embodiments, the valdustat-isoniacin eutectic crystal form I has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 6.99, 7.69, 9.30, 9.80, 13.91, 15.71, 18.23, 18.64, 22.28, 24.65, 25.35, 26.42, 29.13, 29.64, 31.75, and 34.52 degrees.

[0064] In some embodiments, the vardurostat-isoniacin eutectic crystal form I has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 7.69, 15.71, 24.65, 25.35, 29.13 and 34.52 degrees.

[0065] In some embodiments, the vardurostat-isoniacin eutectic crystal form I has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 6.99, 9.80, 13.91, 18.23, 29.64 and 31.75 degrees.

[0066] In some embodiments, the vardurostat-isoniacin eutectic crystal form I has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 9.30, 18.23, 18.64, 22.28, 29.64 and 34.52 degrees.

[0067] In some embodiments, the vardurostat-isocyanate eutectic crystal form I has an X-ray powder diffraction pattern containing at least one, at least two, or three peaks among diffraction peaks with 2θ angles of 15.71, 22.28, and 26.42 degrees.

[0068] In some specific embodiments, the X-ray powder diffraction pattern of the vardurostat-isoniazid eutectic crystal form I is essentially as follows: Figure 3 As shown.

[0069] The vardurostat-isoniacin eutectic crystal form I is a eutectic of vardurostat and isoniazid. In some embodiments, the molar ratio of vardurostat to isoniazid is 1:1.

[0070] The vardurostat-isocyanate eutectic form I also has the following characteristics: thermogravimetric analysis (TGA) curves show that the crystal form experiences weight loss of 0.1%-2.5% at 120℃-200℃. In some specific embodiments, the TGA curves show that the crystal form experiences weight loss of approximately 1.3% at 120℃-200℃. In one specific embodiment, the TGA curve is essentially as follows: Figure 4 As shown.

[0071] The vardurostat-isoniacin eutectic crystal form I also has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 140℃-200℃. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 155℃-185℃. In some embodiments, the differential scanning calorimetry curve of the crystal form has an endothermic peak at 165℃-169℃, with a peak value of 167℃. In a specific embodiment, the DSC curve of the vardurostat-isoniacin eutectic crystal form I is substantially as follows: Figure 4 As shown.

[0072] Fourthly, the present invention provides a method for preparing the vardurostat-isocyanamide eutectic crystal form I.

[0073] The preparation method of vardurostat-isoniacin co-crystal form I described in this invention is simple, convenient to operate, mild under mild conditions, high yield, and high purity, and is suitable for industrial production.

[0074] A method for preparing the vardurostat-isoniacin eutectic crystal form I includes: dissolving vardurostat in a solvent, then adding isoniacin to the solution, precipitating a white solid, filtering, and drying to constant weight to obtain the vardurostat-isoniacin eutectic crystal form I.

[0075] In some embodiments, the solvent includes at least one selected from acetone, butanone, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMF, and DMSO. In some embodiments, the solvent includes acetone. In some embodiments, the solvent is acetone.

[0076] In some embodiments, during the preparation of the vardulfostat-isoniazid eutectic crystal form I, the concentration of vardulfostat after complete dissolution in the solvent is 5 mg / ml-300 mg / ml. In some embodiments, the concentration of vardulfostat after complete dissolution in the solvent is 5 mg / ml-200 mg / ml; in some embodiments, the concentration of vardulfostat after complete dissolution in the solvent is 5 mg / ml-100 mg / ml; in some embodiments, the concentration of vardulfostat after complete dissolution in the solvent is 5 mg / ml-50 mg / ml; in some embodiments, the concentration of vardulfostat after complete dissolution in the solvent is 10 mg / ml-200 mg / ml; in some embodiments, the concentration of vardulfostat after complete dissolution in the solvent is 10 mg / ml-100 mg / ml; in some embodiments, the concentration of vardulfostat after complete dissolution in the solvent is 10 mg / ml-50 mg / ml; in some embodiments, the concentration of vardulfostat after complete dissolution in the solvent is 20 mg / ml-100 mg / ml.

[0077] Fifthly, the present invention provides a new crystal form of vardurostat, called vardurostat-isoniacin eutectic crystal form II.

[0078] The valdustat-isocyanate eutectic type II has the following characteristics: its X-ray powder diffraction pattern contains diffraction peaks with 2θ angles of 16.72, 25.17 and 27.29 degrees.

[0079] In some embodiments, the vardurostat-isoniacin eutectic crystal form II has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 15.60, 16.72, 25.17, 26.11, 27.29 and 32.13 degrees.

[0080] In some embodiments, the valdustat-isoniacin eutectic crystal form II has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 11.97, 12.33, 14.32, 15.60, 15.99, 16.72, 17.82, 19.67, 23.92, 25.17, 26.11, 27.29, 28.74, 29.47, 30.24, and 32.13 degrees.

[0081] In some embodiments, the vardurostat-isoniacin eutectic crystal form II has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 11.97, 12.33, 15.60, 16.72, 23.92 and 30.24 degrees.

[0082] In some embodiments, the vardurostat-isoniacin eutectic crystal form II has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 14.32, 17.82, 25.17, 26.11 and 29.47 degrees.

[0083] In some embodiments, the vardurostat-isoniacin eutectic crystal form II has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 15.99, 19.67, 27.29, 28.74 and 32.13 degrees.

[0084] In some embodiments, the vardurostat-isocyanate eutectic type II has an X-ray powder diffraction pattern containing at least one, at least two, or three peaks among diffraction peaks with 2θ angles of 16.72, 25.17, and 27.29 degrees.

[0085] In some specific implementations, the X-ray powder diffraction pattern of the valdustat-isoniazid eutectic crystal form II is essentially as follows: Figure 5 As shown.

[0086] The vardurostat-isoniacin eutectic crystal form II is a eutectic of vardurostat and isoniazid. In some embodiments, the molar ratio of vardurostat to isoniazid is 1:1.

[0087] The vardurostat-isocyanate eutectic form II also has the following characteristics: thermogravimetric analysis (TGA) curves show that the crystal form experiences weight loss of 0.1%-1.5% at 120℃-200℃. In some specific embodiments, the TGA curves show that the crystal form experiences weight loss of approximately 0.45% at 120℃-200℃. In one specific embodiment, the TGA curve is essentially as follows: Figure 6 As shown.

[0088] The vardurostat-isoniacin eutectic crystal form II also has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 110℃-170℃. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 125℃-155℃. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 132℃-146℃. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 137℃-141℃, with a peak value of 139℃. In a specific embodiment, the DSC curve of the vardurostat-isoniacin eutectic crystal form II is substantially as follows: Figure 6 As shown.

[0089] In a sixth aspect, the present invention provides a method for preparing the vardurostat-isocyanamide eutectic crystal form II.

[0090] The preparation method of vardurostat-isoniacin co-crystal II described in this invention is simple, convenient, mild, has high yield and high purity, and is suitable for industrial production.

[0091] A method for preparing the vardurostat-isoniacin eutectic form II includes: dissolving vardurostat in a solvent, then adding isoniacin to the solution, stirring, precipitating a white solid, filtering, and drying to constant weight to obtain the vardurostat-isoniacin eutectic form II.

[0092] In some embodiments, the solvent comprises at least one selected from ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMF, and DMSO. In some embodiments, the solvent comprises ethyl acetate. In some embodiments, the solvent is ethyl acetate.

[0093] In some embodiments, during the preparation of the vardurostat-isoniacin eutectic form II, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-300 mg / ml. In some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-200 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-100 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-50 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-200 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-100 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-50 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 20 mg / ml-100 mg / ml.

[0094] In a seventh aspect, the present invention provides a new crystal form of vardurostat, called vardurostat-isoniacin eutectic crystal form III.

[0095] The vardurostat-isocyanate eutectic type III has the following characteristics: its X-ray powder diffraction pattern contains diffraction peaks with 2θ angles of 12.67, 15.95 and 20.42 degrees.

[0096] In some embodiments, the vardurostat-isoniacin eutectic crystal form III has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 12.67, 13.18, 14.63, 15.95, 16.78 and 20.42 degrees.

[0097] In some embodiments, the valdustat-isoniacin eutectic crystal form III has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 6.32, 12.67, 13.18, 14.63, 15.95, 16.78, 18.32, 19.05, 19.40, 20.42, 22.94, 24.11, 25.62, 26.55, 27.80, 29.30, and 39.39 degrees.

[0098] In some embodiments, the vardurostat-isoniacin eutectic crystal form III has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 12.67, 13.18, 18.32, 19.05, 26.55 and 27.80 degrees.

[0099] In some embodiments, the vardurostat-isoniacin eutectic crystal form III has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 6.32, 14.63, 15.95, 19.40, 22.94 and 24.11 degrees.

[0100] In some embodiments, the vardurostat-isoniacin eutectic crystal form III has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 16.78, 20.42, 25.62, 29.30 and 39.39 degrees.

[0101] In some embodiments, the vardurostat-isocyanate eutectic crystal type III has an X-ray powder diffraction pattern containing at least one, at least two, or three peaks selected from diffraction peaks with 2θ angles of 12.67, 15.95, and 20.42 degrees.

[0102] In some specific implementations, the X-ray powder diffraction pattern of the valdustat-isoniazid eutectic crystal form III is essentially as follows: Figure 7 As shown.

[0103] The vardurostat-isoniacin eutectic crystal type III is a eutectic of vardurostat and isoniazid. In some embodiments, the molar ratio of vardurostat to isoniazid is 1:1.

[0104] The vardurostat-isocyanate eutectic form III also has the following characteristics: thermogravimetric analysis (TGA) curves show that the crystal form experiences weight loss of 0.2%-2.5% at 80℃-150℃. In some specific embodiments, the TGA curves show that the crystal form experiences weight loss of approximately 1.5% at 80℃-150℃. In one specific embodiment, the TGA curve is essentially as follows: Figure 8 As shown.

[0105] The vardurostat-isoniacin eutectic crystal form III also has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 80°C-150°C. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 100°C-130°C. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 110°C-120°C. In some embodiments, the DSC curve of the crystal form has an endothermic peak at 113°C-117°C, with a peak value of 115°C. In a specific embodiment, the DSC curve of the vardurostat-isoniacin eutectic crystal form III is substantially as follows: Figure 8 As shown.

[0106] Eighthly, the present invention provides a method for preparing the vardurostat-isocyanamide eutectic crystal form III.

[0107] The preparation method of vardurostat-isoniacin eutectic crystal form III described in this invention is simple, convenient to operate, mild under mild conditions, high yield, and high purity, and is suitable for industrial production.

[0108] A method for preparing the vardurostat-isoniacin co-crystal form III includes: placing vardurostat-isoniacin co-crystal form I or vardurostat-isoniacin co-crystal form II in a solvent and slurrying, filtering, and drying to constant weight to obtain vardurostat-isoniacin co-crystal form III.

[0109] In some embodiments, the solvent comprises at least one selected from water, n-hexane, cyclohexane, n-heptane, diethyl ether, and petroleum ether. In some embodiments, the solvent comprises water. In some embodiments, the solvent is water.

[0110] In some embodiments, during the preparation of the vardurostat-isoniacin eutectic form III, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-300 mg / ml. In some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-200 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-100 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml-50 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-200 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-100 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 10 mg / ml-50 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 20 mg / ml-100 mg / ml.

[0111] In a ninth aspect, the present invention provides a new crystal form of vardurostat, called vardurostat-p-toluenesulfonate.

[0112] In some embodiments, the vardurostat-p-toluenesulfonate has the following characteristic: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 9.60, 13.69, 16.75, 17.80, 21.17, 22.78 and 32.38 degrees.

[0113] In some embodiments, the vardurostat-p-toluenesulfonate has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 4.82, 8.35, 9.60, 13.69, 14.49, 16.75, 17.31, 17.80, 18.68, 19.40, 19.93, 21.17, 21.44, 22.78, 23.22, 23.72, 24.22, 26.44, 27.85, 28.02, 29.10, 30.49, 31.98, 32.38, 34.72, 35.04, 35.90, 37.71, and 38.42 degrees.

[0114] In some specific implementations, the X-ray powder diffraction pattern of vardurostat-p-toluenesulfonate is essentially as follows: Figure 9 As shown.

[0115] The vardurostat-p-toluenesulfonate is a salt form of vardurostat and p-toluenesulfonate. In some embodiments, the molar ratio of vardurostat to p-toluenesulfonate is 1:1.

[0116] The vardurostat-p-toluenesulfonate also has the following characteristics: thermogravimetric analysis (TGA) shows that the crystalline form experiences weight loss of 1.0%-6.0% at 100℃-160℃. In some specific embodiments, the TGA shows that the crystalline form experiences weight loss of approximately 3.2% at 100℃-160℃. In one specific embodiment, the TGA curve is essentially as follows: Figure 10 As shown.

[0117] The vardurostat-p-toluenesulfonate also has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 110°C-170°C. In some embodiments, the DSC curve of the crystalline form has an endothermic peak at 130°C-150°C. In some embodiments, the DSC curve of the crystalline form has an endothermic peak at 137°C-141°C, with a peak value of 139°C. In a specific embodiment, the DSC curve of the vardurostat-p-toluenesulfonate is substantially as follows: Figure 10 As shown.

[0118] In a tenth aspect, the present invention provides a method for preparing the vardulstat-p-toluenesulfonate.

[0119] The preparation method of vardurostat-p-toluenesulfonate described in this invention is simple, convenient to operate, mild under mild conditions, high yield, and high purity, and is suitable for industrial production.

[0120] A method for preparing the vardurostat-p-toluenesulfonate comprises: dissolving vardurostat in a solvent, adding p-toluenesulfonic acid monohydrate, stirring, precipitating a white solid, filtering, and drying to constant weight to obtain vardurostat-p-toluenesulfonate.

[0121] In some embodiments, the solvent includes at least one selected from acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMF, and DMSO. In some embodiments, the solvent is acetone.

[0122] In some embodiments, during the preparation of vardurostat-p-toluenesulfonate, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml to 300 mg / ml. In some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml to 200 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml to 100 mg / ml; and in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml to 50 mg / ml.

[0123] In the eleventh aspect, the present invention provides a new crystal form of vardurostat, called vardurostat-camphor sulfonate.

[0124] In some embodiments, the vardurostat-camphor sulfonate has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 5.62, 11.24, 13.93, 16.90, 18.81, 19.95, 22.60, 24.08, 24.66 and 29.57 degrees.

[0125] In some embodiments, the varduristar camphor sulfonate has the following characteristics: the X-ray powder diffraction pattern of the crystal form contains diffraction peaks with 2θ angles of 5.19, 5.62, 9.97, 11.24, 13.93, 14.73, 15.61, 16.00, 16.47, 16.90, 18.21, 18.81, 19.95, 21.17, 21.44, 22.05, 22.60, 22.90, 24.08, 24.66, 25.24, 25.96, 26.30, 26.69, 28.81, 29.57, 30.28, 31.55, 32.98, 33.82, 34.19, 35.21, 36.83, and 38.11 degrees.

[0126] In some specific implementations, the X-ray powder diffraction pattern of vardurostat-camphor sulfonate is essentially as follows: Figure 11 As shown.

[0127] The vardurostat-camphor sulfonate is a salt form of vardurostat and camphor sulfonate. In some embodiments, the molar ratio of vardurostat to p-toluenesulfonate is 1:1.

[0128] The vardurostat-camphor sulfonate also has the following characteristics: thermogravimetric analysis (TGA) curves show that the crystalline form experiences weight loss of 1.0%-5.0% at 50°C-200°C. In some specific embodiments, the TGA curves show that the crystalline form experiences weight loss of approximately 2.3% at 50°C-200°C. In one specific embodiment, the TGA curve is substantially as follows: Figure 12 As shown.

[0129] The vardurostat-camphor sulfonate also has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 165°C-225°C. In some embodiments, the DSC curve of the crystalline form has an endothermic peak at 185°C-205°C. In some embodiments, the DSC curve of the crystalline form has an endothermic peak at 192°C-196°C, with a peak value of 194°C. In a specific embodiment, the DSC curve of the vardurostat-camphor sulfonate is substantially as follows: Figure 12 As shown.

[0130] In a twelfth aspect, the present invention provides a method for preparing the vardulstat-camphor sulfonate.

[0131] The preparation method of vardurostat-camphor sulfonate described in this invention is simple, convenient to operate, mild under mild conditions, high yield, and high purity, and is suitable for industrial production.

[0132] A method for preparing the vardoxat-camphor sulfonate includes: dissolving vardoxat in a solvent, adding camphor sulfonic acid, stirring, precipitating a white solid, filtering, and drying to constant weight to obtain vardoxat-camphor sulfonate.

[0133] In some embodiments, the solvent includes at least one selected from acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMF, and DMSO. In some embodiments, the solvent is acetone.

[0134] In some embodiments, during the preparation of the vardurostat-camphor sulfonate, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml to 300 mg / ml. In some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml to 200 mg / ml; in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml to 100 mg / ml; and in some embodiments, the concentration of vardurostat after complete dissolution in the solvent is 5 mg / ml to 50 mg / ml.

[0135] In a thirteenth aspect, the present invention also provides a composition comprising any of the aforementioned valdustat crystal forms and / or salts.

[0136] In the composition, the crystalline form or salt is at least 90% of vardurostat by weight, or the crystalline form or salt does not exceed 0.5%-5% of vardurostat.

[0137] In some embodiments, the composition comprises: at least one of the aforementioned crystalline forms or salts, and a pharmaceutically acceptable excipient or carrier; wherein, by weight, the crystalline form or salt is at least 90% of vardostatine, or the crystalline form or salt does not exceed 0.5%-5% of vardostatine.

[0138] In some embodiments, by weight ratio, a composition comprises the aforementioned vardrusstat crystalline form, wherein the crystalline form is at least 90% vardrusstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardrusstat crystalline form, wherein the crystalline form is at least 95% or at least 99% vardrusstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardrusstat crystalline form, wherein the crystalline form is at least 0.5%-5% vardrusstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardrusstat crystalline form, wherein the crystalline form is at least 5% vardrusstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardrusstat crystalline form, wherein the crystalline form does not exceed 0.5%-5% vardrusstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardrusstat crystalline form, wherein the crystalline form does not exceed 5% vardrusstat.

[0139] In some embodiments, a composition comprises at least one of the aforementioned vardurostat crystalline forms, namely, vardurostat-piperazine co-crystalline form, vardurostat-isoniazid co-crystalline form I, vardurostat-isoniazid co-crystalline form II, vardurostat-isoniazid co-crystalline form III, vardurostat-p-toluenesulfonate, and vardurostat-camphorsulfonate. In some embodiments, a composition comprises at least one of the aforementioned vardurostat crystalline forms, namely, vardurostat-piperazine co-crystalline form, vardurostat-isoniazid co-crystalline form I, vardurostat-isoniazid co-crystalline form II, vardurostat-isoniazid co-crystalline form III, vardurostat-p-toluenesulfonate, and / or vardurostat-camphorsulfonate.

[0140] In some embodiments, by weight ratio, a composition comprises at least one of the aforementioned vardulstat-piperazine eutectic form, vardulstat-isoniazid eutectic form I, vardulstat-isoniazid eutectic form II, vardulstat-isoniazid eutectic form III, vardulstat-p-toluenesulfonate, and vardulstat-camphorsulfonate; wherein, based on vardulstat, the crystalline form or salt constitutes at least 90% of vardulstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardulstat-piperazine eutectic form, vardulstat-isoniazid eutectic form I, vardulstat-isoniazid eutectic form II, vardulstat-isoniazid eutectic form III, vardulstat-p-toluenesulfonate, and / or vardulstat-camphorsulfonate, wherein the crystalline form constitutes at least 90% of vardulstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardulstat-piperazine cocrystalline form, vardulstat-isoniazid cocrystalline form I, vardulstat-isoniazid cocrystalline form II, vardulstat-isoniazid cocrystalline form III, vardulstat-p-toluenesulfonate and / or vardulstat-camphorsulfonate, wherein the crystalline form is at least 95% or at least 99% of vardulstat.

[0141] In some embodiments, by weight ratio, a composition comprises at least one of the aforementioned vardulstat-piperazine eutectic form, vardulstat-isoniazid eutectic form I, vardulstat-isoniazid eutectic form II, vardulstat-isoniazid eutectic form III, vardulstat-p-toluenesulfonate, and vardulstat-camphorsulfonate; wherein, based on vardulstat, the crystalline form or salt is at least 0.5%-5% of vardulstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardulstat-piperazine eutectic form, vardulstat-isoniazid eutectic form I, vardulstat-isoniazid eutectic form II, vardulstat-isoniazid eutectic form III, vardulstat-p-toluenesulfonate, and / or vardulstat-camphorsulfonate, wherein the crystalline form is at least 0.5%-5% of vardulstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardulstat-piperazine cocrystalline form, vardulstat-isoniazid cocrystalline form I, vardulstat-isoniazid cocrystalline form II, vardulstat-isoniazid cocrystalline form III, vardulstat-p-toluenesulfonate, and / or vardulstat-camphorsulfonate, wherein the crystalline form is at least 5% vardulstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardulstat-piperazine cocrystalline form, vardulstat-isoniazid cocrystalline form I, vardulstat-isoniazid cocrystalline form II, vardulstat-isoniazid cocrystalline form III, vardulstat-p-toluenesulfonate, and / or vardulstat-camphorsulfonate, wherein the crystalline form does not exceed 0.5%-5% of vardulstat. In some embodiments, by weight ratio, a composition comprises the aforementioned vardulstat-piperazine cocrystalline form, vardulstat-isoniazid cocrystalline form I, vardulstat-isoniazid cocrystalline form II, vardulstat-isoniazid cocrystalline form III, vardulstat-p-toluenesulfonate and / or vardulstat-camphorsulfonate, wherein the crystalline form does not exceed 5% of vardulstat.

[0142] The composition may further include pharmaceutically acceptable excipients or carriers. These pharmaceutically acceptable excipients or carriers may include fillers, diluents, lubricants, etc. In some embodiments, the composition further includes pharmaceutically acceptable excipients or carriers, including lubricants. In some embodiments, the lubricant is magnesium stearate.

[0143] The composition can be prepared into any suitable pharmaceutical formulation, such as tablets, capsules, granules, suspensions, or injections. Attached Figure Description

[0144] Figure 1 X-ray powder diffraction (XRPD) pattern of the svaldulstat-piperazine eutectic crystal form;

[0145] Figure 2Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of the svaldulstat-piperazine eutectic crystal form;

[0146] Figure 3 X-ray powder diffraction (XRPD) pattern of svaldulstat-isocyanamide eutectic crystal form I;

[0147] Figure 4 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of valvastatin-isocyanate eutectic form I;

[0148] Figure 5 X-ray powder diffraction (XRPD) pattern of svaldulstat-isocyanamide eutectic crystal form II;

[0149] Figure 6 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of svaldulstat-isocyanamide eutectic crystal form II;

[0150] Figure 7 X-ray powder diffraction (XRPD) pattern of svaldulstat-isocyanamide eutectic crystal form III;

[0151] Figure 8 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of svaldulstat-isocyanamide eutectic crystal form III;

[0152] Figure 9 X-ray powder diffraction (XRPD) pattern of svaldulstat-p-toluenesulfonate;

[0153] Figure 10 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of svaldulstat-p-toluenesulfonate;

[0154] Figure 11 X-ray powder diffraction (XRPD) pattern of svaldulstat-camphor sulfonate;

[0155] Figure 12 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of svaldulstat-camphor sulfonate;

[0156] Figure 13 X-ray powder diffraction (XRPD) patterns of the svaldulstat-piperazine eutectic crystal form before and after 15 days of exposure to high temperature, high humidity, and light (from bottom to top: 0 days, 15 days of high temperature, 15 days of high humidity, and 15 days of light exposure).

[0157] Figure 14X-ray powder diffraction (XRPD) patterns of svaldulstat-isoniacin eutectic crystal form I before and after 15 days under high temperature, high humidity and light conditions (from bottom to top: 0 days, 15 days of high temperature, 15 days of high humidity, 15 days of light).

[0158] Figure 15 X-ray powder diffraction (XRPD) patterns of svaldulstat-isoniacin eutectic crystal form II before and after 15 days under high temperature, high humidity and light conditions (from bottom to top: 0 days, 15 days of high temperature, 15 days of high humidity, 15 days of light).

[0159] Figure 16 X-ray powder diffraction (XRPD) patterns of svaldulstat-isoniacin eutectic crystal form III before and after 15 days under high temperature, high humidity and light conditions (from bottom to top: 0 days, 15 days of high temperature, 15 days of high humidity, 15 days of light).

[0160] Figure 17 X-ray powder diffraction (XRPD) patterns of svaldulstat-p-toluenesulfonate before and after 15 days of storage under high temperature, high humidity and light conditions (from bottom to top: 0 days, 15 days of high temperature, 15 days of high humidity, 15 days of light).

[0161] Figure 18 X-ray powder diffraction (XRPD) patterns of svaldulstat-camphor sulfonate before and after 15 days of exposure to high temperature, high humidity, and light (from bottom to top: 0 days, 15 days of high temperature, 15 days of high humidity, and 15 days of light). Detailed Implementation

[0162] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0163] All reagents used in this invention can be purchased commercially or prepared by existing methods or by the methods described in this invention.

[0164] In this invention, ℃ represents degrees Celsius, mg represents milligrams, mL represents milliliters, h represents hours, min represents minutes, DMF is N,N-dimethylformamide, and DMSO is dimethyl sulfoxide.

[0165] Instrument parameters

[0166] Unless otherwise specified in the parameters, all the following analyses are performed at room temperature.

[0167] X-ray powder diffraction (XRPD)

[0168] X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero-background sample holder and a transmission / reflection sample stage. The radiation source used was (Cu, kα, Kα1) 1.540598; Kα2 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage is set at 45KV and the current at 40mA. The X-ray beam divergence, i.e., the effective size of the X-ray confinement on the sample, is 10mm. A continuous θ-θ scanning mode is used to obtain an effective 2θ range of 3° to 60°. An appropriate amount of sample is placed in the circular groove of the zero-background sample holder under ambient conditions (approximately 18℃ to 32℃), and gently pressed with a clean glass slide to obtain a flat surface. The zero-background sample holder is then fixed. A conventional XRPD pattern is generated within the range of 3 to 60°2θ ± 0.2° using a scanning step size of 0.0167°. Data collection software is Data Colector, and data is analyzed and displayed using Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the vertical axis represents the diffraction intensity expressed in counts, and the horizontal axis represents the diffraction angle 2θ expressed in degrees (°).

[0169] Differential scanning calorimetry (DSC)

[0170] Using TA Instruments TM The Q2000 model uses a sealed disc apparatus. The sample (approximately 1–3 mg) is weighed in an aluminum disc, capped with a Tzero, and precisely recorded to the nearest hundredth of a milligram. The sample is then transferred to the instrument for measurement. The instrument is purged with nitrogen at 50 mL / min. Data are collected between room temperature and 300°C at a heating rate of 10°C / min. A graph is plotted with the endothermic peak pointing downwards, and the data are analyzed and presented using TA Universal Analysis. In the DSC plot, the horizontal axis represents temperature (°C), and the vertical axis represents the heat flow per unit mass of the substance (W / g).

[0171] Thermogravimetric Analysis (TGA)

[0172] TGA measurements at TA Instruments TMThe experiment was conducted using a model Q500. The procedure involved removing the tare from an empty crucible, placing approximately 10 mg of the solid sample into the tare crucible, and spreading it evenly. After the instrument stabilized, data was collected under nitrogen purging at a heating rate of 10 °C / min between room temperature and 300 °C, and the resulting spectra were recorded. In the TGA graph, the horizontal axis represents temperature (°C), and the vertical axis represents mass percentage (%).

[0173] Preparation of Vadadustat-piperazine eutectic

[0174] Example 1

[0175] 150 mg of crude Vadadostat (solid form not specified) was added to 5 ml of acetone solvent. After stirring at room temperature to obtain a clear solution, 97.12 mg of piperazine hexahydrate was slowly added. The mixture was stirred for half an hour, precipitating a white solid. The precipitate was filtered and dried under vacuum at 50°C for 24 hours, yielding approximately 150 mg of white solid. Its X-ray powder diffraction pattern was determined to be similar to... Figure 1 Basically the same, its DSC and TGA spectra are similar to Figure 2 Basically the same.

[0176] Preparation of Vadadustat-Isoniazid Cocrystal Form I

[0177] Example 2

[0178] 150 mg of crude Vadedustat (solid form not specified) was added to 5 ml of acetone solvent. After stirring at room temperature to obtain a clear solution, 68.57 mg of isoniazid was slowly added, precipitating a white solid. The precipitate was filtered and dried under vacuum at 50°C for 24 hours, yielding approximately 140 mg of white solid. Its X-ray powder diffraction pattern was determined to be similar to... Figure 3 Basically the same, its DSC and TGA spectra are similar to Figure 4 Basically the same.

[0179] Preparation of Vadadustat-Isoniazid Co-crystal Form II

[0180] Example 3

[0181] 150 mg of crude Vadadostat (solid form not specified) was added to 5 ml of ethyl acetate solvent. The solution was heated to 50 °C and stirred until a clear solution was obtained. Then, 68.57 mg of isoniazid was slowly added. The solution was cooled to room temperature and stirred for one day, precipitating a white solid. The precipitate was filtered and dried under vacuum at 50 °C for 24 hours, yielding approximately 140 mg of white solid. Its X-ray powder diffraction pattern was determined to be similar to... Figure 5 Basically the same, its DSC and TGA spectra are similar to Figure 6 Basically the same.

[0182] Preparation of Vadadustat-Isoniazid Co-crystal Form III

[0183] Example 4

[0184] 820 mg of crude Vadadostat-isocyanate eutectic form II was added to 20 ml of pure water and stirred for 24 h. The mixture was then filtered and dried under vacuum at 50 °C for 24 h to obtain approximately 390 mg of a white solid. Its X-ray powder diffraction pattern was determined to be similar to... Figure 7 Basically the same, its DSC and TGA spectra are similar to Figure 8 Basically the same.

[0185] Preparation of Vadadustat-p-toluenesulfonate

[0186] Example 5

[0187] 150 mg of crude Vadedustat (solid form not specified) was added to 5 ml of acetone solvent. After stirring at room temperature to obtain a clear solution, 95 mg of p-toluenesulfonic acid monohydrate was slowly added. The mixture was stirred for half an hour, precipitating a white solid. The precipitate was filtered and dried under vacuum at 50°C for 24 hours, yielding approximately 140 mg of white solid. Its X-ray powder diffraction pattern was determined to be similar to... Figure 9 Basically the same, its DSC and TGA spectra are similar to Figure 10 Basically the same.

[0188] Preparation of Vadadustat-Camphorsulfonate

[0189] Example 6

[0190] 150 mg of crude Vadedustat (solid form not specified) was added to 5 ml of acetone solvent. After stirring at room temperature to obtain a clear solution, 116 mg of camphor sulfonic acid was slowly added. The mixture was stirred for half an hour, precipitating a white solid. The precipitate was filtered and dried under vacuum at 50°C for 24 hours, yielding approximately 140 mg of white solid. Its X-ray powder diffraction pattern was determined to be similar to... Figure 11 Basically the same, its DSC and TGA spectra are similar to Figure 12 Basically the same.

[0191] Example 7 Solubility Test

[0192] Following the solubility test guidelines in the current Chinese Pharmacopoeia, an experiment was designed to measure the solubility of seven crystalline forms of vardurostat in pure water at 37°C. The results are shown in Table 1. The results indicate that the solubility of the four cocrystals is significantly higher than that of vardurostat crystal form A. Among them, the vardurostat-piperazine cocrystal has the highest solubility, being 54 times that of vardurostat crystal form A. The solubilities of vardurostat-isoniazid cocrystal forms I, II, and III are 3.3, 4.4, and 2.9 times that of vardurostat, respectively.

[0193] Table 1: Solubility data of 7 crystal forms of vardrusstat (37℃, water)

[0194] sample Solubility (calculated as vardustal, mg / ml) Vardurost A 0.0271 Vardustat-piperazine crystal form 1.4504 Vardustat-Isoniazid eutectic crystal form I 0.0901 Vardustat-Isoniazid eutectic crystal form II 0.1192 Vardustat-Isoniazid eutectic crystal form III 0.0802 vardurostat-p-toluenesulfonic acid 0.0016 Vardustat-camphorsulfonic acid 0.0017

[0195] Example 8 Stability Study

[0196] According to the guidelines for drug formulation stability testing, experiments were conducted on the influencing factors of vardurostat's crystal form, including high temperature test, high humidity test and strong light irradiation test, to investigate the conditions affecting the stability of its crystal form, as shown in Table 2 below.

[0197] High temperature test: Take an appropriate amount of crystal form sample, spread it flat in a weighing bottle, and place it in a constant temperature and humidity chamber at 60℃±5℃ and RH 75±5%. Then, take about 100mg of the above sample at 0, 5 and 15 days respectively, and test its crystal form by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

[0198] High humidity test: Take an appropriate amount of crystal sample, spread it flat in a weighing bottle, and place it in a constant temperature and humidity chamber at 25℃ and RH 92.5±5%. Then, take about 100mg of the above sample at 0, 5 and 15 days respectively, and test its crystal form by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

[0199] Irradiation test: Take an appropriate amount of crystal form sample and spread it evenly in a weighing bottle. Place it in a constant temperature and humidity chamber (25℃, RH 60%±5%) under visible light 4500Lux±500Lux (VIS) and ultraviolet light 1.7W*h / m2 (UV). Then, take about 100mg of the above sample at 0, 5 and 15 days respectively, and test its crystal form by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

[0200] Table 2: Stability data of six crystal forms of vardrusstat under influencing factors

[0201]

[0202] Conclusion: Powder X-ray diffraction (XRPD) results of four eutectic samples (vardulstat-piperazine eutectic, vardulstat-isoniazid crystal form I, vardulstat-isoniazid crystal form II, and vardulstat-isoniazid crystal form III) after 15 days of exposure to three influencing factors—high temperature, high humidity, and light—showed no crystal transformation under these conditions, indicating good stability. The XRD pattern of vardulstat-camphor sulfonate changed after 15 days of exposure to high humidity, revealing a small amount of camphor sulfonic acid.

[0203] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A valdustat-piperazine eutectic crystal form, the X-ray powder diffraction pattern of which is essentially as shown in Figure 1; the molar ratio of valdustat to piperazine is 1:1; thermogravimetric analysis shows that the crystal form exhibits weight loss of 1.0%-15.0% at 200℃-270℃; the differential scanning calorimetry curve of the crystal form shows an endothermic peak at 200℃-260℃; the preparation method of the crystal form includes: Vardulopestat was dissolved in acetone, and then piperazine hexahydrate was added to the solution. The mixture was stirred, filtered, and dried to constant weight to obtain the vardulopestat-piperazine eutectic crystal form. The concentration of vardulopestat after complete dissolution in acetone was 5 mg / ml-300 mg / ml.

2. A composition comprising: The valdustat-piperazine co-crystal form and pharmaceutically acceptable excipients or carriers as described in claim 1; wherein, by weight, the crystalline form is at least 90% of valdustat, or the crystalline form does not exceed 0.5%-5% of valdustat.

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