A co-crystal of an acid and a method of making the same

Abstract

The application mainly provides a co-crystal of an acid and a preparation method thereof, and belongs to the technical field of medicines. The co-crystal has good stability and solubility and can be applied to pharmaceutical preparations.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and relates to an acid eutectic and a preparation method thereof. Background Art

[0002] Daprodustat (CAS No. 960539-70-2) is a novel, orally active hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) inhibitor. Stabilizing HIF through HIF-PHD inhibition may improve ischemic conditions such as peripheral arterial disease (PAD). Daprodustat stimulates endogenous EPO synthesis and effectively induces erythropoiesis. It has been approved for marketing in Japan.

[0003] The August 2020 revised edition (2nd edition) of Japan's Summary of Pharmaceuticals (Medical Products Instructions) discloses that Daprodustat has a melting point of about 244°C and a solubility in water of 0.074 mg / ml, which is almost insoluble. The compound of Daprodustat is disclosed in patent application WO2007150011, its two crystal forms are disclosed in patent application WO2019052133, and its four crystal forms are disclosed in WO2020102302. Although the prior art has disclosed a variety of crystal forms, these crystal forms have the typical characteristics of low water solubility. The structure of Daprodustat is shown below:

[0004]

[0005] Because the crystal form and solid form of drugs have an important impact on the preparation of drugs, the preparation, storage, application, dissolution, and bioavailability of drug preparations, different crystal forms may differ in many aspects, which may lead to obvious differences in the efficacy, safety and application of drug preparations or easily fail to meet quality requirements. Improving the solubility of drugs, especially improving the solubility of poorly soluble drugs, and obtaining crystal forms, salt forms, or co-crystal forms with better solubility properties are effective ways to solve the low solubility of poorly soluble drugs. The obtained crystal form with high solubility properties will be beneficial to the development of drug preparations. Therefore, it is necessary to study the crystal form and solid form of drugs in order to obtain crystal forms with better solubility properties. Summary of the Invention

[0006] Definition of terms

[0007] The present invention is intended to cover all alternatives, modifications, and equivalents, which are included within the scope of the present invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including but not limited to defined terms, term usage, described techniques, etc.), this application shall prevail.

[0008] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0009] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0010] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0011] The term "include" or "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0012] The term "substantially as shown" refers to a substantially pure "crystalline form" whose X-ray powder diffraction pattern comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks appearing in the given X-ray powder diffraction pattern. As the content of a crystalline form in a sample gradually decreases, some diffraction peaks attributable to that crystalline form in its X-ray powder diffraction pattern may become less frequent due to the sensitivity of the instrument.

[0013] The term "relative intensity" refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak in a group of diffraction peaks belonging to a certain crystal form, when the intensity of the first strongest peak is defined as 100%.

[0014] In the context of the present invention, the 2θ (also known as 2theta or diffraction peak) values ​​in the X-ray powder diffraction pattern are all in degrees (°).

[0015] When referring to a spectrum and / or data therein, the term "diffraction peak" refers to a feature that one skilled in the art would not attribute to background noise.

[0016] The X-ray powder diffraction peak, the measurement of 2θ or diffraction peak of the X-ray powder diffraction pattern has experimental errors. The measurement of 2θ or diffraction peak of the X-ray powder diffraction pattern may vary slightly between one machine and another and between one sample and another. The error of 2θ is ±0.2°, so the value of 2θ or diffraction peak cannot be regarded as absolute.

[0017] The differential scanning calorimetry (DSC) curve has experimental errors. The position and peak value of the endothermic peak may differ slightly between one machine and another, and between one sample and another. The numerical value of the experimental error or difference may be 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.

[0018] Thermogravimetric analysis (TGA) curves are subject to experimental error. Endothermic curves or weight loss rates may vary slightly between machines and samples. The experimental error or difference may be less than or equal to 0.004%, 0.003%, 0.002%, or 0.001%. Therefore, the TGA curves or weight loss rates described above should not be considered absolute. When the TGA curve for a sample shows a weight loss of less than 0.5% within a certain temperature range, it is considered to have no significant weight loss within that temperature range.

[0019] In the context of the present invention, all numerical values ​​disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The numerical value of each numerical value may vary by + / -1%, + / -2%, + / -3%, + / -4%, or + / -5%, etc., based on the disclosed value. When "about" is used to describe the 2θ value (also known as 2theta or diffraction peak) of an X-ray powder diffraction peak, "about" means that the 2θ value may vary by + / -0.2 units, + / -0.1 units, or + / -0.05 units.

[0020] "Room temperature" refers to a temperature between about 20°C and 35°C, or about 23°C and 28°C, or about 25°C.

[0021] The term "good solvent" can be a single solvent or a mixed solvent, and means that the solubility of the sample in the single solvent or the mixed solvent is greater than 1g / L, or greater than 2g / L, or greater than 3g / L, or greater than 4g / L, or greater than 5g / L, or greater than 6g / L, or greater than 7g / L, or greater than 8g / L, or greater than 9g / L, or greater than 10g / L, or greater than 15g / L, or greater than 20g / L, or greater than 30g / L, or greater than 40g / L, or greater than 50g / L, or greater than 60g / L, or greater than 70g / L, or greater than 80g / L, or greater than 100g / L. In some embodiments, the solubility of the sample in the good solvent is greater than that in the antisolvent; in some embodiments, the difference in solubility of the sample in the good solvent and the antisolvent is approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%; in some embodiments, the solubility of the sample in the good solvent is greater than that in the antisolvent, and is greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. Detailed Description of the Invention

[0023] On the one hand, the inventors have developed a co-crystal formed by Daprodustat and an amino compound, wherein the amino compound is isoniazid, isonicotine, propionamide, urea or 3-aminopyridine.

[0024] The co-crystal of Daprodustat and isoniazid provided by the present invention has an X-ray powder diffraction pattern with diffraction peaks at 2θ (unit: degree, °, error ±0.2°) of 5.5, 8.1, 16.5 and 20.7 degrees.

[0025] In some embodiments, the X-ray powder diffraction pattern of the co-crystal of daprodustat and isoniazid has diffraction peaks at 2θ of 5.5, 8.1, 10.3, 12.4, 14.5, 16.5, 17.4, 19.3, 20.7, 22.2, 24.1, 24.8, 26.4, 27.0 and 27.7 degrees.

[0026] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the co-crystal of Daprodustat and isoniazid is as follows: Figure 1 shown.

[0027] The co-crystal of Daprodustat and isoniazid also has the following characteristics: its differential scanning calorimetry (DSC) curve has endothermic peaks in the three temperature ranges of 100°C-150°C, 150°C-190°C, and 190°C-210°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and isoniazid has endothermic peaks in the three temperature ranges of 135°C-145°C, 175°C-185°C, and 195°C-205°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and isoniazid has endothermic peaks in the three temperature ranges of 137°C-143°C, 178°C-183°C, and 197°C-203°C, with peak top values ​​of 140.6°C, 180.7°C, and 199.1°C, respectively. In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and isoniazid is as follows: Figure 2 shown.

[0028] The thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and isoniazid shows no obvious weight loss below 150°C.

[0029] In some embodiments, the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and isoniazid is as follows: Figure 3 shown.

[0030] The aforementioned co-crystal of Daprodustat and isoniazid has a molar ratio of Daprodustat to isoniazid of 2:1.

[0031] According to experimental studies, it was found that the co-crystal of Daprodustat and isoniazid is a stable crystal form that is stable under high temperature, high humidity or light conditions and does not undergo crystal transformation. Moreover, the co-crystal of Daprodustat and isoniazid is a crystal form with good solubility properties and has good solubility in various media. Compared with known crystal forms, it is more conducive to the preparation of pharmaceutical preparations and more competitive.

[0032] The co-crystal of Daprodustat and isonicotine provided by the present invention has an X-ray powder diffraction pattern with diffraction peaks at 2θ (unit: degree, °, error ±0.2°) of 6.5, 6.9, 7.3, 9.4, 16.5, 19.7, 21.2 and 21.5 degrees.

[0033] In some embodiments, the X-ray powder diffraction pattern of the co-crystal of daprodustat and isonicotine has diffraction peaks at 2θ of 6.5, 6.9, 7.3, 9.4, 15.1, 16.5, 17.5, 19.7, 20.6, 21.2, 21.5, 22.0, 23.0, 24.9, 26.6 and 26.9 degrees.

[0034] In some embodiments, the X-ray powder diffraction pattern of the co-crystal of daprodustat and isonicotine has diffraction peaks at 2θ of 6.5, 6.9, 7.3, 9.4, 15.1, 16.5, 17.5, 18.9, 19.7, 20.6, 21.2, 21.5, 22.0, 23.0, 23.8, 24.2, 24.4, 24.9, 26.6 and 26.9 degrees.

[0035] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the co-crystal of Daprodustat and isonicotine is as follows: Figure 4 shown.

[0036] The co-crystal of daprodustat and isonicotine further has the following characteristics: its differential scanning calorimetry (DSC) curve has endothermic peaks in the temperature ranges of 125°C-160°C and 190°C-210°C, respectively. In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of daprodustat and isonicotine has endothermic peaks in the temperature ranges of 145°C-155°C and 200°C-205°C, respectively, with peak temperatures of the endothermic peaks being 150.6°C and 203.3°C, respectively.

[0037] In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and isonicotine is as follows: Figure 5 shown.

[0038] The thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and isonicotine shows no obvious weight loss in the range of 30°C-150°C.

[0039] In some embodiments, the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and isonicotine is as follows: Figure 6 shown.

[0040] In the aforementioned co-crystal of Daprodustat and isonicotine, the molar ratio of Daprodustat to isonicotine is 2:1.

[0041] Stability studies of influencing factors revealed that the co-crystal of daprodustat and isonicotine is a stable crystalline form, stable under high temperature, high humidity, or light conditions, and does not undergo crystal transformation. Performance studies of the co-crystal of daprodustat and isonicotine suggest that the co-crystal is less hygroscopic and has higher solubility in water than known crystalline forms.

[0042] The co-crystal of Daprodustat and propionamide provided by the present invention has an X-ray powder diffraction pattern with diffraction peaks at 2θ (unit: degree, °, error ±0.2°) of 6.4, 7.2, 7.5, 19.1 and 20.8 degrees.

[0043] In some embodiments, the X-ray powder diffraction pattern of the co-crystal of daprodustat and propionamide has diffraction peaks at 2θ of 6.4, 7.2, 7.5, 15.3, 15.7, 16.7, 18.7, 191, 19.6, 19.8, 20.1, 20.8, 22.8, 25.5 and 26.2 degrees.

[0044] In some embodiments, the X-ray powder diffraction pattern of the co-crystal of daprodustat and propionamide has diffraction peaks at 2θ of 6.4, 7.2, 7.5, 12.9, 15.3, 15.7, 16.3, 16.7, 17.2, 18.7, 191, 19.6, 19.8, 20.1, 20.8, 22.8, 23.2, 24.7, 25.5, 26.2, 27.9 and 28.9 degrees.

[0045] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the co-crystal of Daprodustat and propionamide is as follows: Figure 7 shown.

[0046] The co-crystal of Daprodustat and propionamide also has the following characteristics: its differential scanning calorimetry (DSC) curve has endothermic peaks in the temperature ranges of 190°C-210°C and 225°C-250°C, respectively. In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and propionamide has endothermic peaks in the temperature ranges of 195°C-205°C and 235°C-245°C, respectively, with peak temperatures of the endothermic peaks being 201.6°C and 241.5°C, respectively.

[0047] In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and propionamide is as follows: Figure 8 shown.

[0048] The thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and propionamide showed no obvious weight loss at 30°C-120°C.

[0049] In some embodiments, the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and propionamide is as follows: Figure 9 shown.

[0050] In the aforementioned co-crystal of Daprodustat and propionamide, the molar ratio of Daprodustat to propionamide is 2:1.

[0051] Based on stability testing of influencing factors, it was found that the co-crystal of daprodustat and propionamide is a stable crystalline form that is stable under high temperature, high humidity, or light conditions and does not undergo crystal transformation. Based on the performance research results of the co-crystal of daprodustat and propionamide, it is believed that the co-crystal of daprodustat and propionamide is less hygroscopic and has a higher solubility than known crystalline forms.

[0052] The co-crystal of Daprodustat and urea provided by the present invention has an X-ray powder diffraction pattern with diffraction peaks at 2θ (unit: degree, °, error ±0.2°) of 6.4, 7.5, 15.4, 19.3, 19.9, 20.9, and 22.9 degrees.

[0053] In some embodiments, the X-ray powder diffraction pattern of the co-crystal of Daprodustat and urea has diffraction peaks at 2θ of 6.4, 7.5, 15.4, 16.7, 18.7, 18.9, 19.3, 19.9, 20.9, 22.5, 22.9, 24.9, and 28.0 degrees.

[0054] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the co-crystal of Daprodustat and urea is as follows: Figure 10 shown.

[0055] The co-crystal of Daprodustat and urea also has the following characteristics: its differential scanning calorimetry (DSC) curve has an endothermic peak in the temperature range of 175°C-225°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and urea has an endothermic peak in the temperature range of 210°C-220°C, and the peak temperature of the endothermic peak is 215.7°C.

[0056] In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and urea is as follows: Figure 11 shown.

[0057] The thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and urea showed no obvious weight loss below 170°C.

[0058] In some embodiments, the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and urea is as follows: Figure 12 shown.

[0059] In the aforementioned co-crystal of Daprodustat and urea, the molar ratio of Daprodustat to urea is 2:1.

[0060] Stability testing of influencing factors revealed that the co-crystal of daprodustat and urea is a stable crystalline form, stable under high temperature, high humidity, or light conditions, and does not undergo phase transitions. Performance studies of the co-crystal of daprodustat and urea suggest that it is less hygroscopic and more water-soluble than known crystalline forms.

[0061] The co-crystal of Daprodustat and 3-aminopyridine provided by the present invention has an X-ray powder diffraction pattern with diffraction peaks at 2θ (unit: degree, °, error ±0.2) of 5.6, 8.0, 16.3, 16.7, 20.7, 24.2, 24.6, 26.5 and 27.4 degrees.

[0062] In some embodiments, the X-ray powder diffraction pattern of the co-crystal of Daprodustat and 3-aminopyridine has diffraction peaks at 2θ of 5.6, 8.0, 16.3, 16.7, 20.7, 24.2, 24.6, 26.5 and 27.4 degrees, and the relative intensities of these diffraction peaks are not less than 15%.

[0063] In some embodiments, the X-ray powder diffraction pattern of the co-crystal of daprodustat and 3-aminopyridine has diffraction peaks at 2θ of 5.6, 8.0, 10.3, 12.2, 14.5, 14.8, 15.9, 16.3, 16.7, 17.0, 17.6, 18.0, 18.6, 19.1, 20.7, 21.1, 22.3, 24.2, 24.6, 26.5 and 27.4 degrees.

[0064] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the co-crystal of Daprodustat and 3-aminopyridine is as follows: Figure 13 shown.

[0065] The co-crystal of daprodustat and 3-aminopyridine also has the following characteristics: its differential scanning calorimetry (DSC) curve has an endothermic peak in the temperature range of 180°C-210°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of daprodustat and 3-aminopyridine has an endothermic peak in the temperature range of 195°C-200°C, and the peak temperature of the endothermic peak is 198.8°C.

[0066] In some embodiments, the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and 3-aminopyridine is as follows: Figure 14 shown.

[0067] The thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and 3-aminopyridine shows no obvious weight loss in the temperature range of 50° C.-150° C.

[0068] In some embodiments, the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and 3-aminopyridine is as follows: Figure 15 shown.

[0069] In the aforementioned co-crystal of Daprodustat and 3-aminopyridine, the molar ratio of Daprodustat to 3-aminopyridine is 2:1.

[0070] Based on stability testing of influencing factors, it was found that the co-crystal of daprodustat and 3-aminopyridine is a stable crystalline form that is stable under high temperature, high humidity, or light conditions and does not undergo crystal transformation. Based on the performance test results of the co-crystal of daprodustat and 3-aminopyridine, compared to known crystalline forms, the co-crystal of daprodustat and 3-aminopyridine is believed to be less hygroscopic and has relatively high solubility in various media.

[0071] In another aspect, the present invention provides a method for preparing the aforementioned co-crystal of Daprodustat and an amino compound.

[0072] A method for preparing the aforementioned co-crystal of Daprodustat and an amino compound comprises: suspending Daprodustat and the amino compound in a solvent and stirring, then filtering, drying and removing the solvent to obtain the co-crystal; wherein the amino compound is isoniazid, isonicotine, propionamide, urea or 3-aminopyridine.

[0073] In the method, the molar ratio of Daprodustat to the amino compound is 1:0.5-1:2.0.

[0074] In the method, the solvent is a ketone solvent, an ester solvent, or a combination thereof.

[0075] In the method, the mass volume ratio of Daprodustat to the solvent is 4.0 mg:1 ml-80.0 mg:1 ml.

[0076] The ketone solvent is selected from at least one of acetone and butanone. In some embodiments, the ketone solvent is acetone, which is more conducive to operation and obtaining the eutectic.

[0077] The ester solvent is selected from at least one of methyl formate, ethyl formate, butyl formate, methyl acetate, ethyl acetate and isopropyl acetate. In some embodiments, the ester solvent is ethyl acetate, which is more conducive to operation and obtaining the cocrystal.

[0078] The temperature of the suspension stirring is 20°C-35°C.

[0079] The suspension stirring time is 4h-72h. In some embodiments, the suspension stirring time is 4h-24h.

[0080] In another aspect, the present invention provides a base addition salt of daprodustat, wherein the base is piperazine or tromethamine, and wherein the molar ratio of daprodustat to the base is 1:1.

[0081] The salts are the salt of Daprodustat with piperazine and the salt of Daprodustat with tromethamine.

[0082] A salt of daprodustat and piperazine is referred to as piperazine salt of daprodustat, wherein the molar ratio of daprodustat to piperazine is 1:1.

[0083] The piperazine salt of Daprodustat has an X-ray powder diffraction pattern with diffraction peaks at 2θ (unit: degree, error ±0.2) of 5.0, 6.9, 8.3, 12.7, 16.5, 18.5, 19.8, 23.4 and 25.4 degrees.

[0084] In some embodiments, the piperazine salt of Daprodustat has an X-ray powder diffraction pattern with diffraction peaks at 2θ of 5.0, 5.6, 6.9, 8.3, 8.7, 11.1, 12.7, 16.0, 16.5, 16.7, 18.5, 19.1, 19.8, 20.3, 21.3, 23.4, 24.9 and 25.4 degrees.

[0085] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the piperazine salt of Daprodustat is as follows: Figure 16 shown.

[0086] The piperazine salt of Daprodustat also has the following characteristics: its differential scanning calorimetry (DSC) curve has endothermic peaks in the temperature ranges of 200°C-230°C and 230°C-250°C, respectively. In some embodiments, the differential scanning calorimetry (DSC) curve of the piperazine salt of Daprodustat has endothermic peaks in the temperature ranges of 220°C-230°C and 235°C-245°C, respectively, with the peak temperatures of the endothermic peaks being 225.2°C and 240.9°C, respectively.

[0087] In some embodiments, the differential scanning calorimetry (DSC) curve of the piperazine salt of Daprodustat is as follows: Figure 17 shown.

[0088] The thermogravimetric analysis (TGA) curve of the piperazine salt of Daprodustat shows no obvious weight loss in the temperature range of 70°C-170°C.

[0089] In some embodiments, the thermogravimetric analysis (TGA) curve of the piperazine salt of Daprodustat is as follows: Figure 18 shown.

[0090] Based on stability testing of influencing factors, it was found that the piperazine salt of daprodustat is a stable crystalline form that is stable under high temperature, high humidity, or light conditions and does not undergo crystalline form transformation. Based on the performance research results of the piperazine salt of daprodustat, it is believed that the piperazine salt of daprodustat has a higher solubility than known crystalline forms.

[0091] A salt of daprodustat and tromethamine, referred to as tromethamine salt of daprodustat, wherein the molar ratio of daprodustat to tromethamine is 1:1.

[0092] The tromethamine salt of Daprodustat has an X-ray powder diffraction pattern with diffraction peaks at 2θ (unit: degree, error ±0.2) of 4.2, 6.7, 9.7, 14.1, 15.8, 16.3, 16.8, 18.2, 20.4, 21.0, 24.4, 25.9 and 26.7 degrees.

[0093] In some embodiments, the X-ray powder diffraction pattern of the tromethamine salt of Daprodustat has diffraction peaks at 2θ of 4.2, 6.7, 9.7, 10.5, 12.3, 14.1, 15.8, 16.3, 16.8, 18.2, 20.4, 21.0, 21.4, 21.7, 22.5, 23.6, 24.4, 25.9, 26.2, 26.7, 27.1, 29.4 and 31.7 degrees.

[0094] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the tromethamine salt of Daprodustat is as follows: Figure 19 shown.

[0095] The tromethamine salt of Daprodustat also has the following characteristics: its differential scanning calorimetry (DSC) curve has endothermic peaks in the temperature ranges of 75°C-125°C and 200°C-250°C, respectively. In some embodiments, the differential scanning calorimetry (DSC) curve of the tromethamine salt of Daprodustat has endothermic peaks in the temperature ranges of 120°C-130°C and 210°C-220°C, respectively, with peak endothermic peak temperatures of 124.5°C and 218.6°C, respectively.

[0096] In some embodiments, the differential scanning calorimetry (DSC) curve of the tromethamine salt of Daprodustat is as follows: Figure 20 shown.

[0097] The thermogravimetric analysis (TGA) curve of the tromethamine salt of Daprodustat shows a weight loss of 3.0% to 3.5% in the range of 30° C. to 150° C. In some embodiments, the thermogravimetric analysis (TGA) curve of the tromethamine salt of Daprodustat shows a weight loss of 3.2% in the range of 30° C. to 150° C.

[0098] In some embodiments, the thermogravimetric analysis (TGA) curve of the tromethamine salt of Daprodustat is as follows: Figure 21 shown.

[0099] Based on stability testing of influencing factors, it was found that the tromethamine salt of Daprodustat is a stable crystalline form that is stable under high temperature, high humidity, or light conditions and does not undergo crystal transformation. Based on the performance research results of the tromethamine salt of Daprodustat, it is believed that the tromethamine salt of Daprodustat is a crystalline form with better water solubility than known crystalline forms.

[0100] On the other hand, the present invention also provides a method for preparing the piperazine salt of Daprodustat and the tromethamine salt of Daprodustat.

[0101] A method for preparing the piperazine salt of Daprodustat or the tromethamine salt of Daprodustat comprises: suspending and stirring Daprodustat and piperazine or tromethamine in a solvent, then filtering, drying and removing the solvent to obtain the piperazine salt of Daprodustat or the tromethamine salt of Daprodustat.

[0102] In the method, the molar ratio of Daprodustat to piperazine or tromethamine is 1:0.5-1:2.0.

[0103] In the method, the solvent is a ketone solvent, an ester solvent, or a combination thereof.

[0104] In the method, the mass volume ratio of Daprodustat to the solvent is 4.0 mg:1 ml-80.0 mg:1 ml.

[0105] The ketone solvent is selected from at least one of acetone and butanone. In some embodiments, the ketone solvent is acetone, which is more conducive to operation and obtaining the eutectic.

[0106] The ester solvent is selected from at least one of methyl formate, ethyl formate, butyl formate, methyl acetate, ethyl acetate and isopropyl acetate. In some embodiments, the ester solvent is ethyl acetate, which is more conducive to operation and obtaining the cocrystal.

[0107] The temperature of the suspension stirring is 20°C-35°C.

[0108] The suspension stirring time is 4h-72h. In some embodiments, the suspension stirring time is 4h-24h.

[0109] The co-crystal and salt of the present invention have good stability, are convenient for storage, transfer and operation in production process, and can be prepared into pharmaceutical compositions with pharmaceutically acceptable carriers.

[0110] The co-crystals of daprodustat and isoniazid and the co-crystals of daprodustat and 3-aminopyridine have relatively good properties in terms of dissolution and fluidity, are convenient for storage, transfer, and operation in the production process, and are suitable for preparation into pharmaceutical compositions with pharmaceutically acceptable carriers.

[0111] In another aspect, the present invention also provides a composition.

[0112] A composition comprising: at least one selected from the aforementioned co-crystal and salt crystal forms and a pharmaceutically acceptable excipient.

[0113] In some embodiments, in the composition, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 80% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 85% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 90% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 95% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 97% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, in the composition, the amount of Daprodustat in the crystalline form of the co-crystal or salt is at least 99% of the total weight of Daprodustat in the composition, calculated based on the weight of Daprodustat.

[0114] In some embodiments, in the composition, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 10% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 5% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 1% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 0.5% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat. In some embodiments, the amount of Daprodustat in the crystalline form of the cocrystal or salt is at least 5%-10% of the total weight of Daprodustat in the composition, calculated by mass of Daprodustat.

[0115] In some embodiments, the amount of Daprodustat in the cocrystal or salt form in the composition is at most 10% by weight of the total Daprodustat in the composition, calculated by weight of Daprodustat. In some embodiments, the amount of Daprodustat in the cocrystal or salt form in the composition is at most 6%, or at most 5%, or at most 3%, or at most 1%, or at most 0.5% by weight of the total Daprodustat in the composition, calculated by weight of Daprodustat.

[0116] In some embodiments, the crystalline form of the co-crystal or salt in the composition is at least 0.05%-95%, 0.1%-95%, 1%-95%, 5%-95%, or 1%-50% of the total mass of the composition, calculated by weight. In some embodiments, the crystalline form of the co-crystal or salt in the composition is at least 0.5%-5% of the total mass of the composition, calculated by weight. In some embodiments, the crystalline form of the co-crystal or salt in the composition is at least 5%-10% of the total mass of the composition, calculated by weight.

[0117] In some embodiments, a composition comprises the aforementioned co-crystal of Daprodustat and isoniazid and a pharmaceutically acceptable excipient.

[0118] In some embodiments, a composition comprises the aforementioned co-crystal of Daprodustat and 3-aminopyridine and a pharmaceutically acceptable excipient.

[0119] The pharmaceutically acceptable excipients may include diluents, disintegrants, binders, or lubricants.

[0120] The various co-crystals or salt crystal forms can be used to prepare drugs for treating or improving ischemic diseases.

[0121] The composition can be used to prepare medicine for treating or improving ischemic diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0122] Figure 1 shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat and isoniazid;

[0123] Figure 2 shows the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and isoniazid;

[0124] Figure 3 Figure 4 shows the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and isoniazid.

[0125] Figure 4shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat and isonicotine;

[0126] Figure 5 shows the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and isonicotine;

[0127] Figure 6 Thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and isonicotine

[0128] Figure 7 shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat and propionamide;

[0129] Figure 8 shows the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and propionamide;

[0130] Figure 9 Shown is the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and propionamide.

[0131] Figure 10 shows an X-ray powder diffraction pattern (XRPD) of a co-crystal of Daprodustat and urea;

[0132] Figure 11 shows the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and urea;

[0133] Figure 12 Figure 4 shows the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and urea.

[0134] Figure 13 Figure 5 shows the X-ray powder diffraction pattern (XRPD) of the co-crystal of Daprodustat and 3-aminopyridine.

[0135] Figure 14 shows the differential scanning calorimetry (DSC) curve of the co-crystal of Daprodustat and 3-aminopyridine;

[0136] Figure 15 Figure 4 shows the thermogravimetric analysis (TGA) curve of the co-crystal of Daprodustat and 3-aminopyridine.

[0137] Figure 16 shows the X-ray powder diffraction pattern (XRPD) of the piperazine salt of Daprodustat;

[0138] Figure 17 shows the differential scanning calorimetry (DSC) curve of the piperazine salt of Daprodustat;

[0139] Figure 18 Shown is the thermogravimetric analysis curve (TGA) of the piperazine salt of Daprodustat.

[0140] Figure 19 shows the X-ray powder diffraction pattern (XRPD) of the tromethamine salt of Daprodustat;

[0141] Figure 20 shows the differential scanning calorimetry (DSC) curve of the tromethamine salt of Daprodustat;

[0142] Figure 21 Shown is the thermogravimetric analysis curve (TGA) of the tromethamine salt of Daprodustat.

[0143] In the above drawings, 2Theta (°) represents 2θ (degrees), Temperature (°C) represents temperature (°C), Heat Flow (W / g) represents heat flow (watts / gram), J / g represents joules / gram, and Weight represents weight. DETAILED DESCRIPTION

[0144] In order 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 further illustrate the present invention in detail.

[0145] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0146] In the present invention, mg means milligram, mL means milliliter; rpm means revolutions per minute; when referring to time, h means hour, d means day; and RH means relative humidity.

[0147] In the present invention, unless otherwise specified, room temperature refers to ambient temperature, which is 15°C-40°C, or 20°C-30°C, or 22°C-28°C.

[0148] Instrument parameters

[0149] Unless otherwise specified in the parameters, all analyses below were performed at room temperature.

[0150] X-ray powder diffraction (XRPD) studies

[0151] X-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero-background sample holder and a transflective sample stage. The radiation sources used were (Cu, kα, 1.540598; 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage was set at 45KV and the current was set at 40mA. The beam divergence of the X-rays, that is, the effective size of the X-ray confinement on the sample, was 6.6mm. A θ-θ continuous scanning mode was used to obtain an effective 2θ range of 3° to 60°. Take an appropriate amount of sample and place it under ambient conditions (about 18℃-32℃) on the circular groove of the zero background sample holder, gently press it with a clean glass slide to obtain a flat surface, and fix the zero background sample holder. The sample was scanned at a step size of 0.0167° to generate a traditional XRPD pattern in the 2θ±0.2° range of 3 to 60°. The software used for data collection was Data Collector, and the data were analyzed and displayed using Data Viewer and HighScore Plus.

[0152] Differential Scanning Calorimetry (DSC)

[0153] DSC measurements were performed on a TA Instruments™ model Q2000 using a sealed pan setup. Samples (approximately 1-3 mg) were weighed into aluminum pans, sealed with a Tzero seal, and recorded to the nearest hundredth of a milligram. The sample was then transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL / min. Data were collected between 30°C and 300°C at a heating rate of 10°C / min. Plots were plotted with the endothermic peak downward, and data were analyzed and displayed using a TA Universal Analysis.

[0154] Thermogravimetric analysis (TGA)

[0155] TGA data were collected on a TA Instruments Q500. The instrument temperature was calibrated using certified nickel. Typically, 8-12 mg of sample was loaded into a pre-weighed platinum crucible and heated from 30°C to 300°C at 10°C / min. A nitrogen purge of 60 mL / min was maintained over the sample. In the TGA graphs, the abscissa represents temperature (°C) and the ordinate represents weight loss (%).

[0156] In the following examples, the raw material Daprodustat used was tested, and its XRPD and DSC data were basically consistent with CS1 described in patent application WO2019052133.

[0157] Example 1-1

[0158] Daprodustat (78.7 mg) and isoniazid (27.4 mg) were added to a 5 ml EP tube, followed by 2.0 ml of acetone. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 69.1 mg of a cocrystal of Daprodustat and isoniazid. The results of X-ray powder diffraction, DSC, and TGA were determined by HPLC. Figure 1-Figure 3 .

[0159] Example 1-2

[0160] Daprodustat 39.3 mg and isoniazid 13.7 mg were added to a 5 ml EP tube, followed by 1.0 ml of ethyl acetate. The mixture was magnetically stirred at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 34.7 mg of the same cocrystal of Daprodustat and isoniazid.

[0161] Example 2-1

[0162] Daprodustat (78.7 mg) and isonicotine (24.4 mg) were added to a 5 ml EP tube, followed by 2.0 ml of acetone. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture was not completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 65.3 mg of a cocrystal of Daprodustat and isonicotine. The results of X-ray powder diffraction, DSC, and TGA were determined by HPLC. Figure 4-Figure 6 .

[0163] Example 2-2

[0164] Daprodustat 39.3 mg and isonicotine 12.2 mg were added to a 5 ml EP tube, followed by 1.0 ml of ethyl acetate. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 31.2 mg of the same cocrystal of Daprodustat and isonicotine.

[0165] Example 3-1

[0166] Daprodustat (78.7 mg) and propionamide (14.6 mg) were added to a 5 ml EP tube, followed by 2.0 ml of acetone. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 47.5 mg of a cocrystal of Daprodustat and propionamide. The results of X-ray powder diffraction, DSC, and TGA were determined by HPLC. Figure 7-Figure 9 .

[0167] Example 3-2

[0168] Daprodustat (39.3 mg) and propionamide (7.3 mg) were added to a 5 ml EP tube, followed by 1.0 ml of ethyl acetate. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 25.3 mg of the same cocrystal of Daprodustat and propionamide.

[0169] Example 4-1

[0170] Daprodustat (78.7 mg) and urea (12.0 mg) were added to a 5 ml EP tube, followed by 2.0 ml of acetone. The mixture was stirred at room temperature (25.0°C) at 200 rpm. If the mixture was not completely dissolved, the mixture was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 63.7 mg of a cocrystal of Daprodustat and urea. For detection, X-ray powder diffraction, DSC, and TGA results, see [see references for more information]. Figure 10-12 .

[0171] Example 4-2

[0172] Daprodustat (39.3 mg) and urea (6.0 mg) were added to a 5 ml EP tube, followed by 1.0 ml of ethyl acetate. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, the mixture was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 32.4 mg of the same cocrystal of Daprodustat and urea.

[0173] Example 5-1

[0174] Daprodustat (78.7 mg) and 3-aminopyridine (18.8 mg) were added to a 5 ml EP tube, followed by 2.0 ml of acetone. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 67.6 mg of a cocrystal of Daprodustat and 3-aminopyridine. For detection, X-ray powder diffraction, DSC, and TGA results, see [see References] Figure 13-15 .

[0175] Example 5-2

[0176] Daprodustat (39.3 mg) and 3-aminopyridine (9.4 mg) were added to a 5 ml EP tube, followed by the addition of 1.0 ml of ethyl acetate solvent. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, the mixture was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 31.8 mg of the same cocrystal of Daprodustat and 3-aminopyridine.

[0177] Example 6-1

[0178] Daprodustat (78.7 mg) and piperazine hexahydrate (38.8 mg) were added to a 5 ml EP tube, followed by 2.0 ml of acetone. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 71.5 mg of the piperazine salt of Daprodustat. For detection, X-ray powder diffraction, DSC, and TGA results, see [see References] Figure 16-Figure 18 ; NMR: 1 H NMR (400MHz, DMSO) δ10.08(t,J=5.1Hz,1H),4.66(t,J=11.8Hz,2H),3.84(d,J=5.2Hz,4H),2.31(q,J=12.2Hz,4H), 1.76(d,J=12.4Hz,4H), 1.61(d,J=11.7Hz,2H), 1.48(d,J=10.7Hz,4H), 1.25(q,J=12.8Hz,4H), 1.04-1.15(m,2H).

[0179] Example 6-2

[0180] Daprodustat (39.3 mg) and piperazine hexahydrate (19.4 mg) were added to a 5 ml EP tube, followed by 1.0 ml of ethyl acetate. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 33.4 mg of the piperazine salt of Daprodustat.

[0181] Example 7-1

[0182] Daprodustat (78.7 mg) and tromethamine (24.2 mg) were added to a 5 ml EP tube, followed by 2.0 ml of acetone. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture was not completely dissolved, the mixture was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 65.3 mg of tromethamine salt of Daprodustat. The results of X-ray powder diffraction, DSC, and TGA were determined by HPLC. Figures 19-21; NMR: 1 H NMR (400MHz, DMSO) δ10.06(s,1H),4.65(t,J=11.9Hz,2H),3.75(d,J=4.9Hz,2H),2.37–2.22(m,4H),1.76(d,J=12 .4Hz, 4H), 1.61 (d, J = 11.9Hz, 2H), 1.49 (d, J = 10.7Hz, 4H), 1.25 (q, J = 12.7Hz, 4H), 1.11 (dd, J = 25.5, 12.8Hz, 2H).

[0183] Example 7-2

[0184] To a 5 ml EP tube, 39.3 mg of Daprodustat and 12.1 mg of tromethamine were added, followed by 1.0 ml of ethyl acetate. The mixture was stirred magnetically at 200 rpm at room temperature (25.0°C). If the mixture could not be completely dissolved, it was suspended at room temperature for 24 h, filtered, and dried under vacuum at 50°C for 12 h to obtain 29.5 mg of the tromethamine salt of Daprodustat.

[0185] Example 8 Stability Test

[0186] According to the guidelines for drug substance stability testing, various crystal form samples were subjected to influencing factor experiments, including high temperature test, high humidity test and strong light irradiation test, to investigate the stability of each crystal form under different conditions. The specific experimental conditions are as follows:

[0187] Light test (UV+VIS): Take appropriate amount of samples and spread them flatly in weighing bottles, open them, and test them under visible light 4500Lux±500Lux (VIS) and ultraviolet light 1.7W*h / m 2 The samples were placed in a constant temperature and humidity chamber (25°C, RH 60%±5%) under UV (UV) conditions, and then about 10 mg of the above samples were taken at 5, 10, and 15 days, respectively, and the crystal form was analyzed by X-ray powder diffraction (XRPD);

[0188] High humidity test (25°C + 92.5% RH): Take an appropriate amount of sample and place it flat in a weighing bottle, open, and place it in a constant temperature and humidity chamber at 25°C and 92.5±5%. Then, take approximately 10 mg of sample after 5, 10, and 15 days, and analyze the crystal form by X-ray powder diffraction (XRPD).

[0189] High-Temperature Test (60°C + 75% RH): Appropriate amounts of samples were placed flat in weighing bottles, uncovered, and placed in a constant temperature and humidity chamber at 60°C ± 5°C and 75% ± 5% RH. Approximately 10 mg of samples were then collected after 5, 10, and 15 days, and the crystal forms were analyzed by X-ray powder diffraction (XRPD). The test results for each sample are shown in Table 1.

[0190] Table 1: Stability test results

[0191]

[0192] According to the results, all eutectics and salt crystal forms are relatively stable to high temperature, high humidity and light conditions.

[0193] Example 9: Stability in Water

[0194] To each 5 ml EP tube, 10.0 mg of the aforementioned cocrystal or salt and 2.0 ml of purified water were added. The temperature was set to 37.0°C and magnetic stirring was applied at 200 rpm. A large amount of solid did not dissolve. Maintaining the same temperature and magnetic stirring, the suspension was maintained for 2.0 and 12.0 hours, respectively. Samples were then filtered and tested for their crystal form. The test results for each sample are shown in Table 2.

[0195] Table 2: Stability in purified water at 37.0°C

[0196]

[0197] According to the above results, the various cocrystals and salts provided by the present invention can maintain stable existence in 37.0°C purified water for 12 hours, indicating that the cocrystals and salts are relatively stable under 37.0°C purified water conditions.

[0198] Example 10 Solubility Test

[0199] 1) Add a certain amount of sample to each 50ml round-bottom flask. Set the magnetic stirrer to 250rpm at a block temperature of 25.0°C. Then, use 200μL and 1000μL pipettes to add 25.0°C purified water. First, use the 1000μL pipette to add 1000μL at a time (when the solid is almost completely dissolved, switch to 200μL to add purified water). After adding, wait for half an hour until it is completely dissolved. Continue to add purified water until it is completely dissolved. Finally, calculate the total amount of purified water required to dissolve the sample solid and calculate the corresponding solubility. The results for each sample are shown in Table 3.

[0200] Table 3: Solubility in purified water at 25.0°C

[0201]

[0202] 2) Add a certain amount of sample to a 50ml round-bottom flask, set the magnetic stirring to 250rpm at a block temperature of 37.0°C, and then use 200μL and 1000μL pipettes to add different media at 37.0°C. First, use a 1000μL pipette to add 1000μL at a time (when the solid is almost completely dissolved, use 200μL to add the medium). After adding, stay for half an hour. If it is not dissolved, continue to add the medium until it is completely dissolved. Finally, count the total amount of medium required to dissolve the sample solid and calculate the corresponding solubility. See Table 4 for the results of each sample.

[0203] pH 1.2 medium: 87 ml of concentrated hydrochloric acid and 9.913 L of purified water are prepared to a volume of 10 L.

[0204] pH 4.5 medium: 29.9g sodium acetate trihydrate or 18.0g anhydrous sodium acetate, mixed with 18.5ml concentrated glacial acetic acid and 9.9815L purified water to a volume of 10L.

[0205] pH 6.8 medium: 68.05g of anhydrous potassium dihydrogen phosphate, 8.96g of sodium hydroxide and purified water are prepared to a volume of 10L.

[0206] Table 4: Solubility in different media at 37.0℃

[0207]

[0208] The above results indicate that in purified water at 25.0°C, the cocrystals of daprodustat with isoniazid, daprodustat with 3-aminopyridine, the piperazine salt of daprodustat, and the tromethamine salt of daprodustat exhibit superior solubility compared to daprodustat. At 37°C in various media, the cocrystal of daprodustat with isoniazid exhibits superior solubility compared to daprodustat at pH 6.8. Considering the characteristics of each crystalline form under multiple factors and conditions, the cocrystal of daprodustat with isoniazid is considered optimal and advantageous for pharmaceutical formulation preparation. The cocrystals of daprodustat with 3-aminopyridine, the piperazine salt of daprodustat, and the tromethamine salt of daprodustat are also relatively stable and exhibit solubility advantages under certain conditions. The tromethamine salt of daprodustat exhibits superior solubility compared to the piperazine salt of daprodustat at pH 6.8, making it advantageous for pharmaceutical formulation application.

[0209] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the present invention and appropriately modify the process parameters. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered to be encompassed by the present invention.

Claims

1. A co-crystal of daprodustat and isoniazid, wherein the molar ratio of daprodustat to isoniazid is 2:1, and the X-ray powder diffraction pattern of the co-crystal has diffraction peaks at 2θ of 5.5, 8.1, 16.5 and 20.7 degrees.

2. The eutectic according to claim 1, wherein The X-ray powder diffraction pattern of the co-crystal has diffraction peaks at 2θ of 5.5, 8.1, 10.3, 12.4, 14.5, 16.5, 17.4, 19.3, 20.7, 22.2, 24.1, 24.8, 26.4, 27.0 and 27.7 degrees.

3. The eutectic according to claim 1, wherein The differential scanning calorimetry curve of the co-crystal has endothermic peaks in three temperature ranges of 100°C-150°C, 150°C-190°C and 190°C-210°C respectively.

4. The eutectic according to claim 1, wherein The thermogravimetric analysis curve of the co-crystal shows no obvious weight loss below 150°C.

5. The eutectic according to claim 1, wherein The X-ray powder diffraction pattern of the co-crystal is shown in FIG1 .

6. A method for preparing the cocrystal according to any one of claims 1 to 5, comprising: Daprodustat and isoniazid are suspended and stirred in a solvent, then filtered and dried to remove the solvent to obtain the cocrystal; wherein the solvent is selected from at least one of acetone, butanone, methyl formate, ethyl formate, butyl formate, methyl acetate, ethyl acetate and isopropyl acetate, and the molar ratio of Daprodustat to isoniazid is 1:0.5-1:2.

0.

7. The method according to claim 6, wherein: The mass volume ratio of daprodustat to solvent is 4.0 mg:1 ml-80.0 mg:1 ml.

8. The method according to claim 6, wherein: The temperature of the suspension stirring is 20°C-35°C.

9. The method according to claim 6, wherein: The suspension stirring time is 4h-72h.

10. A composition comprising the co-crystal according to any one of claims 1 to 5, and further comprising a pharmaceutically acceptable carrier; wherein, The Daprodustat in the co-crystal is at least 80% by weight of the total Daprodustat in the composition, calculated based on the mass of Daprodustat.

11. The composition according to claim 10, wherein The Daprodustat in the co-crystal is at least 85% by weight of the total Daprodustat in the composition, calculated based on the mass of Daprodustat.

12. The composition according to claim 10, wherein The Daprodustat in the co-crystal is at least 90% by weight of the total Daprodustat in the composition, calculated based on the mass of Daprodustat.

13. The composition according to claim 10, wherein The Daprodustat in the co-crystal is at least 95% by weight of the total Daprodustat in the composition, calculated based on the mass of Daprodustat.

14. The composition according to claim 10, wherein The amount of Daprodustat in the co-crystal is at least 97% by weight of the total amount of Daprodustat in the composition, calculated based on the mass of Daprodustat.

15. The composition according to claim 10, wherein The Daprodustat in the co-crystal is at least 99% by weight of the total Daprodustat in the composition, calculated based on the mass of Daprodustat.

16. The composition according to claim 10, wherein the eutectic accounts for 0.05% to 95% of the total mass of the composition, calculated by mass ratio.

17. The composition according to claim 10, wherein the eutectic accounts for 1% to 50% of the total mass of the composition, calculated by mass ratio.

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