Cocrystal of daprodustat

Abstract

To provide a cocrystal of daprodustat, a process for preparation thereof, and a pharmaceutical composition.SOLUTION: The present invention provides a cocrystal comprising a) daprodustat and b) a cocrystal-forming compound selected from the group consisting of pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butylamide, and L-arginine.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides co-crystals of daprodustat with pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, and L-arginine. The present invention also relates to processes for the preparation of the co-crystals of daprodustat in good yield and high purity suitable for industrial scale, pharmaceutical compositions containing them, and their use in therapy. [Background technology]

[0002] N-[(1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine (I), or its tautomer, N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidyl)carbonyl]-glycine (II), known as daprodustat, is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved by the FDA under the trade name Jesduvroq in film-coated tablets of 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg indicated for the treatment of anemia due to chronic kidney disease in adults undergoing dialysis for at least 4 months. [ka]

[0003] International Patent Publication No. 2007 / 150011 discloses daprodustat and its preparation in Example 18. International Patent Publication No. 2019 / 052133 discloses solid forms of daprodustat designated CS1 and CS9. International Patent Publication No. 2020 / 102302 discloses crystalline forms of daprodustat designated Form 3 and Form 4. International Patent Publication No. 2024 / 022998 discloses solvates of daprodustat with daprodustat-free acid, and pharmaceutically acceptable metal salts of daprodustat, such as sodium designated N2 or potassium designated K2.

[0004] Notwithstanding the above, there is a need to develop a solid formulation of daprodustat with good solubility that can be easily produced on an industrial scale with less energy and cost in order to improve bioavailability. Summary of the Invention

[0005] Daprodustat is a poorly soluble drug, and as a poorly soluble drug, it is important to increase the solubility to improve the bioavailability of the drug, thereby improving its efficacy and safety.

[0006] In this regard, the present inventors have tested the preparation of co-crystals of daprodustat with several co-crystal formers, such as 4-acetamidobenzoic acid, L-arginine, biotin, caffeine, citric acid, D-glucuronic acid, L-glutamine, hippuric acid, L-histidine, menthol, nicotinic acid, orotic acid, picolinamide, pyridoxine, L-pyroglutamic acid, saccharin, tartaric acid, 2,3,5,6-tetramethylpyrazine, theophylline, and butyramide, using cooling crystallization in acetone, acetonitrile, ethyl acetate, and isopropanol. However, after several attempts, crystalline co-crystals were only obtained with pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, and L-arginine as co-crystal formers.

[0007] Thus, the present invention refers to cocrystals of daprodustat with either pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, or L-arginine, particularly cocrystals comprising daprodustat and pyridoxine. Advantageously, these cocrystals of daprodustat have improved properties, such as solubility, hygroscopicity, and stability, as well as manufacturing properties (compaction, flowability, filterability, etc.), thereby providing advantages in the development of pharmaceutical products containing daprodustat.

[0008] A first aspect of the present invention is a) daprodustat, and b) a co-crystal former selected from the group consisting of pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, and L-arginine The present invention relates to a cocrystal comprising:

[0009] In particular, the present invention relates to a co-crystal comprising daprodustat and pyridoxine, preferably designated Form P3, having an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 6.1°±0.2°, 14.2°±0.2°, and 25.8°±0.2, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0010] A second aspect of the present invention provides a process for preparing a co-crystal of daprodustat as defined herein.

[0011] A further aspect of the present invention relates to a pharmaceutical composition comprising a co-crystal of daprodustat as defined herein and one or more pharmaceutically acceptable carriers or excipients.

[0012] A further embodiment refers to a cocrystal of daprodustat as defined herein, preferably a cocrystal of daprodustat with pyridoxine, referred to as the crystalline P3 form, for use in therapy, particularly for the treatment of renal anemia. This embodiment may also be formulated as a method of treating renal anemia, comprising administering a cocrystal of daprodustat as defined herein and one or more pharmaceutically acceptable carriers or excipients to a subject, including a human, in need thereof.

[0013] The use of a co-crystal of daprodustat as defined herein for the manufacture of a pharmaceutical composition for the treatment of renal anemia also forms part of the present invention.

[0014] definition When describing the compounds and methods of the present invention, the following terms have the following meanings unless otherwise specified.

[0015] The term "about" refers to a statistically meaningful range of values. Such a range may fall within the experimental error inherent in the standard methods used to measure and / or determine a given value or range. In one embodiment, the range is within ±5% of the stated value. In another embodiment, the range is within ±1% of the stated value. In yet another embodiment, the range is within ±0.5% of the stated value.

[0016] The term "solvate" refers to a crystalline form of a molecule that further contains solvent molecules incorporated within the crystalline structure. When the solvent incorporated into the crystal is water, it is called a hydrate. The solvent molecules in a solvate may exist in an ordered and / or disordered arrangement. A solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. A solvate may exhibit polymorphism.

[0017] As used herein, the term "cocrystal," also known as a "crystalline molecular complex," refers to a crystalline solid composed of two or more distinct chemical species in the same crystal lattice in a defined stoichiometric ratio, which possesses distinct physical, crystallographic, and spectroscopic properties when compared to the individual chemical species. The cocrystals of the present invention comprise daprodustat (a compound of formula (I) or (II)) and a cocrystal-forming compound selected from the group consisting of pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, and L-arginine. The cocrystal may be in the form of a hydrate or solvate.

[0018] Cocrystals are distinct from "salts," which contain charge-balanced species. The species that make up a cocrystal are usually neutral and are generally held together by weak, freely reversible non-covalent interactions. These weak interactions are defined as neither ionic nor covalent interactions, and include hydrogen bonding, van der Waals forces, pp interactions, and halogen bonding interactions. Cocrystals can generally be distinguished from salts by the lack of proton transfer between the species.

[0019] The term "traditional isolation techniques" or "purification," as used herein, refers to processes that remove extraneous elements from a product, thereby resulting in a purified product. The term "industrial purification" refers to purification that can be carried out on an industrial scale, such as solvent extraction, filtration, slurring, washing, phase separation, distillation, centrifugation, or crystallization.

[0020] The term "crystallization" refers to any method known to those skilled in the art, such as crystallization from a single solvent or combination of solvents by dissolving the compound, optionally at elevated temperature, precipitating the compound by cooling the solution or removing the solvent from the solution, or both. It also includes methods such as dissolving the compound in a solvent, precipitating it by adding an "antisolvent" (i.e., a solvent in which the desired compound has low solubility or is insoluble and which can be used to precipitate such a compound by adding it to a solution in which the compound is dissolved).

[0021] As used herein, the term "solvent" refers to water or an organic molecule that can at least partially dissolve another substance (i.e., a solute). A solvent can be a liquid at room temperature. Suitable solvents include, but are not limited to, hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene; toluene, o-xylene, m-xylene, and p-xylene (C6-C8); 14 ) Aromatic hydrocarbon solvents; halogenated (C1-C) such as 1,2-dichloroethane, dichloromethane, and chloroform 12) hydrocarbon solvents; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethyl malonate; ketone solvents such as acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, and 3-pentanone; (C1-C2) solvents such as diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane 12 ) Ether solvents; (C1-C6) such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, and m-cresol. 12 ) an alcohol solvent; a nitrile solvent such as acetonitrile; nitrobenzene; N,N-dimethylformamide; N,N-dimethylacetamide; N-methyl-2-pyrrolidone; or dimethyl carbonate. In some embodiments, the solvent may be formed by a combination of two or more solvents.

[0022] The term "room temperature" in the context of the present invention refers to a temperature between 15°C and 30°C, preferably between 20°C and 25°C.

[0023] As used herein, the term "solvent extraction" refers to a process of separating components of a mixture by using a solvent that has a greater affinity for one component and is therefore capable of separating said one component from at least a second component that is less miscible with said solvent than said one component.

[0024] The term "filtration" refers to the act of removing solid particles above a predetermined size from a feed containing a mixture of solid particles and liquid. The term filtrate refers to the mixture that has fewer solid particles removed by the filtration process. It will be understood that the mixture may contain solid particles smaller than a predetermined particle size. The term filter cake refers to the residual solid material remaining on the feed side of a filtration element.

[0025] The term "evaporation" refers to the change in state of a solvent from a liquid to a gas and the removal of the gas from the reactor. Various solvents may be evaporated during the processes disclosed herein. As known to those skilled in the art, each solvent may have a different evaporation time and / or temperature.

[0026] The term "distillation" refers to the process of separating component substances from a liquid mixture by selective evaporation and condensation. This may result in essentially complete separation (nearly pure components), or it may be a partial separation that increases the concentration of selected components of the mixture. In either case, the process exploits differences in the volatility of the components of the mixture.

[0027] As used herein, "slurry processing" refers to any process that uses a solvent to wash, suspend or disperse a crude solid product.

[0028] The term "phase separated" refers to a solution or mixture that has at least two physically distinct regions.

[0029] An embodiment of the present invention is illustrated by the following drawings. [Brief explanation of the drawings]

[0030] [Figure 1] FIG. 1 provides a representative X-ray powder diffraction (XRPD) pattern of the co-crystalline P3 form of daprodustat with pyridoxine. [Figure 2] FIG. 2 provides differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) plots of the cocrystalline P3 form of daprodustat with pyridoxine. [Figure 3] FIG. 3 provides a representative 1H-RMN plot of the co-crystalline P3 form of daprodustat with pyridoxine. [Figure 4] FIG. 4 provides a representative infrared absorption spectrum (IR) of the co-crystalline P3 form of daprodustat with pyridoxine. [Figure 5] FIG. 5 provides representative DVS analysis-derived adsorption and desorption isotherms of the P3 form of the co-crystal of daprodustat with pyridoxine, showing the change in weight (%) of the co-crystal as a function of relative humidity (RH). [Figure 6] FIG. 6 provides a representative X-ray powder diffraction (XRPD) pattern of the co-crystalline P1 form of daprodustat with pyridoxine. [Figure 7] FIG. 7 provides a representative X-ray powder diffraction (XRPD) pattern of the co-crystalline P2 form of daprodustat with pyridoxine. [Figure 8] FIG. 8 provides a representative X-ray powder diffraction (XRPD) pattern of the co-crystalline P4 form of daprodustat with pyridoxine. [Figure 9] FIG. 9 provides a representative X-ray powder diffraction (XRPD) pattern of the co-crystalline P5 form of daprodustat with pyridoxine. [Figure 10] FIG. 10 provides a representative X-ray powder diffraction (XRPD) pattern of the co-crystalline T1 form of daprodustat with 2,3,5,6-tetramethylpyrazine. DETAILED DESCRIPTION OF THE INVENTION

[0031] All crystalline forms that provide X-ray powder diffraction patterns substantially identical to those disclosed in the accompanying drawings are within the scope of the present invention. The ability to ascertain the substantial identity of X-ray powder diffraction patterns is within the skill of one in the art.

[0032] In a first aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: a) daprodustat, and b) a co-crystal former selected from the group consisting of pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, and L-arginine The present invention relates to a cocrystal comprising:

[0033] As mentioned above, daprodustat refers to both N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine (I) and its tautomer, N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidyl)carbonyl]-glycine (II). Preferably, daprodustat refers to N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine (I).

[0034] In certain embodiments, the molar ratio of daprodustat to co-crystal former, as defined above, is 1:3 to 3:1, preferably 1:2 to 2:1, and more preferably about 1:1. In certain embodiments, the molar ratio of daprodustat to co-crystal former in the co-crystal is about 2:1. In a preferred embodiment, the molar ratio of daprodustat free acid to co-crystal former in the co-crystal is about 1:1.

[0035] In certain embodiments, the present invention relates to a co-crystal of daprodustat with pyridoxine.

[0036] In one embodiment, the molar ratio of daprodustat to pyridoxine in the cocrystal is 1:3 to 3:1, preferably 1:2 to 2:1, and more preferably about 1:1.

[0037] In one embodiment, the molar ratio of daprodustat to pyridoxine in the co-crystalline P3 form is about 1:1.

[0038] In one embodiment, the present invention relates to a co-crystal of daprodustat and pyridoxine, designated Co-crystal P3 Form, having an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 6.1°±0.2°, 14.2°±0.2°, and 25.8°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0039] In one embodiment, the co-crystalline P3 form further comprises peaks at 2θ values ​​of 4.7°±0.2°, 5.4°±0.2°, and 9.5°±0.2° as measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0040] In one embodiment, cocrystal P3 is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 XRPD peaks at approximately the following locations: 4.7, 5.4, 6.1, 9.5, 14.2, 14.9, 16.8, 17.1, 21.0, 25.8±0.2 degrees two-theta measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0041] In one embodiment, the co-crystal is characterized by an XRPD pattern that matches the pattern presented in Figure 1. In one embodiment, co-crystal P3 is characterized by an XRPD pattern having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match peaks in the representative co-crystal P3 pattern provided in Table 1.

[0042] [Table 1]

[0043] In certain embodiments, cocrystal P3 is characterized by thermal analysis. A representative DSC plot of cocrystal P3 is shown in Figure 2. In certain embodiments, cocrystal P3 is characterized by a DSC plot containing an endothermic event with an onset temperature of about 173-175°C, preferably about 173.8°C.

[0044] A representative TGA plot of cocrystal P3 is also shown in Figure 2. In certain embodiments, cocrystal P3 is characterized by a TGA plot comprising a mass loss of about 0.7% below 70°C. In certain embodiments, cocrystal P3 is anhydrous.

[0045] In certain embodiments, the cocrystal P3 has a proton nuclear magnetic resonance (NMR) spectrum shown in FIG. 1 Characterized by H-NMR.

[0046] In certain embodiments, the cocrystal P3 is characterized by an infrared absorption spectrum (FTIR) having the spectrum shown in FIG. 4, with the following wavenumbers (cm -1 ): 693, 728, 762, 791, 836, 893, 914, 960, 1001, 1015, 1033, 1096, 1131, 1175, 1235, 1266, 1284, 1309, 1340, 1407, 1443, 1457, 1478, 1522, 1541, 1560, 1586, 1654, 1684, 1716, 2852, 2875, 2924, 2980. -1 ) may contain an error of ±0.5% depending on the measuring device, measuring conditions, etc., but such an error level is within the allowable range in the present invention.

[0047] In certain embodiments, cocrystal P3 is characterized by vapor sorption / desorption analysis. A representative DVS of cocrystal P3 is shown in FIG. 5. In certain embodiments, the XRPD pattern of cocrystal P3 is substantially unchanged after vapor sorption / desorption analysis. In certain embodiments, cocrystal P3 is stable to humidity. In certain embodiments, cocrystal P3 is not hygroscopic according to the European Pharmacopoeia 6.0 (5.11).

[0048] In certain embodiments, cocrystal P3 is characterized by its stability profile: In certain embodiments, the cocrystal P3 material is stable, e.g., its XRPD pattern remains substantially unchanged upon exposure to high temperatures, high humidity, one or more solvents, and / or upon crushing, milling, or pressing.

[0049] In certain embodiments, co-crystal P3 remains unchanged in its morphology for at least one month in a dry environment at room temperature, 40° C., and 60° C. In certain embodiments, daprodustat co-crystal P3 remains unchanged in its morphology for at least one week under accelerated conditions at 40° C. and 75% RH (relative humidity).

[0050] In certain embodiments, the present invention relates to a co-crystal of daprodustat and pyridoxine, designated Co-crystal Form P1, having an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 5.1°±0.2°, 6.8°±0.2°, and 9.4°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0051] In one embodiment, the molar ratio of daprodustat to pyridoxine in the co-crystal P1 form is about 1:1.

[0052] In one embodiment, co-crystal P1 is characterized by an XRPD pattern that matches the pattern presented in Figure 6. In one embodiment, co-crystal P1 is characterized by an XRPD pattern having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match peaks in the XRPD pattern of representative co-crystal P1 provided in Table 2.

[0053] [Table 2]

[0054] In certain embodiments, the present invention relates to a co-crystal of daprodustat and pyridoxine, designated Co-crystal Form P2, having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 6.4°±0.2°, 6.8°±0.2°, and 9.5°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0055] In one embodiment, the molar ratio of daprodustat to pyridoxine in the co-crystalline P2 form is about 1:1.

[0056] In one embodiment, cocrystal P2 is characterized by an XRPD pattern that matches the pattern shown in Figure 7. In one embodiment, cocrystal P2 is characterized by an XRPD pattern having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match peaks in the XRPD pattern of representative cocrystal P2 provided in Table 3.

[0057] [Table 3]

[0058] In certain embodiments, the present invention relates to a co-crystal of daprodustat and pyridoxine, designated Co-crystal Form P4, having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 5.4°±0.2°, 7.9°±0.2°, and 14.9°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0059] In one embodiment, the molar ratio of daprodustat to pyridoxine in the co-crystalline P4 form is about 3:1.

[0060] In one embodiment, the co-crystal P4 form is characterized by an XRPD pattern that matches the pattern presented in Figure 8. In one embodiment, the co-crystal P4 form is characterized by an XRPD pattern having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match peaks of a representative co-crystal P4 pattern provided in Table 4.

[0061] [Table 4]

[0062] In certain embodiments, the present invention relates to a co-crystal of daprodustat and pyridoxine, designated Co-crystal Form P5, having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 5.4°±0.2°, 8.1°±0.2°, and 10.1°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0063] In one embodiment, the molar ratio of daprodustat to pyridoxine in the co-crystalline P5 form is about 3:1.

[0064] In one embodiment, the co-crystal P5 form is characterized by an XRPD pattern that matches the pattern presented in Figure 9. In one embodiment, the co-crystal P5 form is characterized by an XRPD pattern having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks that match those of a representative co-crystal P5 pattern provided in Table 5.

[0065] [Table 5]

[0066] In certain embodiments, the present invention relates to a co-crystal of daprodustat with 2,3,5,6-tetramethylpyrazine.

[0067] In one embodiment, the molar ratio of daprodustat to 2,3,5,6-tetramethylpyrazine in the co-crystal is 1:3 to 3:1, preferably 1:2 to 2:1, and more preferably about 1:1.

[0068] In certain embodiments, the present invention relates to a co-crystal of 2,3,5,6-tetramethylpyrazine and daprodustat, designated the co-crystal T1 form, having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 6.5°±0.2°, 7.8°±0.2°, and 14.5°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

[0069] In one embodiment, the co-crystal T1 form is characterized by an XRPD pattern that matches the pattern presented in Figure 10. In one embodiment, the co-crystal T1 is characterized by an XRPD pattern that features an XRPD pattern having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks that match peaks of a representative co-crystal T1 pattern provided in Table 6.

[0070] [Table 6]

[0071] In a second aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: i. contacting daprodustat and a co-crystal former selected from the group consisting of pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, and L-arginine, optionally in the presence of a solvent; ii. Isolating the co-crystal The present invention relates to a process for the preparation of a co-crystal as defined in the first aspect, comprising:

[0072] In one embodiment, the molar ratio of daprodustat to the co-crystal former is 1:3 to 3:1. Preferably, the molar ratio of daprodustat to the co-crystal former is 2:1 to 1:2. More preferably, the molar ratio of daprodustat to the co-crystal former is about 1:1.

[0073] In another particular embodiment, the co-crystal former used is in an amount ranging from about 0.25 to 5.0 equivalents, preferably 0.25 to 3.0 equivalents, relative to an equivalent of daprodustat.

[0074] In one embodiment, a solvent is present and is a hydrocarbon solvent such as n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene; (C6-C8) solvents such as toluene, o-xylene, m-xylene, and p-xylene; 14 ) Aromatic hydrocarbon solvents; halogenated (C1-C) such as 1,2-dichloroethane, dichloromethane, and chloroform 12 ) hydrocarbon solvents; ketone solvents such as acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, and 3-pentanone; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, and ethyl malonate; (C1-C2) solvents such as diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane 12 ) Ether solvents; (C1-C6) such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, and m-cresol. 12) alcohol solvents; nitrile solvents such as acetonitrile; nitrobenzene; N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); N-methyl-2-pyrrolidone, dimethyl carbonate, and combinations thereof.

[0075] In one embodiment, a solvent is present and is selected from the group consisting of ketone solvents such as acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone, preferably acetone; nitrile solvents such as acetonitrile, dimethyl carbonate, ester solvents such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, preferably (C1-C2) solvents such as ethyl acetate, methanol, ethanol, isopropanol, etc. 12 ) alcohol solvents, and combinations thereof.

[0076] In certain embodiments, the daprodustat used in step i) can be a solvate, hydrate, anhydrous, crystalline, or amorphous form thereof. Preferably, the daprodustat is in a crystalline form, and even more preferably, the daprodustat used in step i) is in anhydrous form. In certain embodiments, the daprodustat solvate used in step i) can be a diethyl ether solvate prepared by Method 1 in Experiment 18 of WO 2007 / 150011. In certain embodiments, the daprodustat solvate is a methyl tert-butyl ether solvate, dioxane solvate, tetrahydrofuran solvate, methanol solvate, ethanol solvate, isopropanol solvate, tert-butanol solvate, dimethylformamide (DMF) solvate, or dimethyl sulfoxide (DMSO) solvate, as disclosed in WO 2024 / 022998.

[0077] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: i. contacting daprodustat with pyridoxine, optionally in the presence of a solvent; ii. Isolating the co-crystal The present invention provides a process for the preparation of a co-crystal comprising daprodustat and pyridoxine as defined in the first aspect, comprising:

[0078] In one embodiment, the molar ratio of daprodustat to pyridoxine co-crystal formers is about 1:1.

[0079] In another particular embodiment, pyridoxine is used in an amount ranging from 0.9 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents, more preferably 1.0 to 2.0 equivalents relative to an equivalent of daprodustat.

[0080] In certain embodiments, the present invention provides a process for the preparation of daprodustat and pyridoxine, comprising the steps of: i. contacting daprodustat with pyridoxine in the presence of a solvent selected from a ketone solvent, such as acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone, preferably acetone; and a nitrile solvent, such as acetonitrile, and combinations thereof; ii. Isolating the co-crystal The present invention provides a process for the preparation of co-crystalline Form P3 as defined in the first aspect, comprising:

[0081] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: i. contacting daprodustat with pyridoxine in the presence of acetone or acetonitrile; ii. Isolating the co-crystal The present invention provides a process for the preparation of co-crystalline Form P3 as defined in the first aspect, comprising:

[0082] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: i. contacting daprodustat with pyridoxine in the presence of an ester solvent such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, preferably ethyl acetate, or dimethyl carbonate; ii. Isolating the co-crystal The present invention provides a process for the preparation of co-crystal Form P1 defined in the first aspect, comprising:

[0083] In a particular embodiment, the present invention provides a method for producing a phenolic solvent (C1-C6) such as: i. methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc. 12 ) contacting daprodustat with pyridoxine in the presence of an alcohol solvent, preferably isopropanol; ii. Isolating the co-crystal The present invention provides a process for the preparation of co-crystal Form P2 defined in the first aspect, comprising:

[0084] In certain embodiments, the present invention provides a process for the preparation of co-crystal form P4 as defined in the first aspect, comprising slurrying co-crystal P3 as defined in the first aspect in water and isolating co-crystal P4.

[0085] In certain embodiments, the present invention provides a process for the preparation of co-crystal form P5 as defined in the first aspect, comprising drying co-crystal P4 as defined in the first aspect under vacuum and isolating co-crystal P5.

[0086] In certain embodiments, the process for the preparation of cocrystal P5 comprises drying cocrystal P4 under vacuum (about 12 mbar = 1200 Pa) at a temperature between room temperature and 75°C, preferably at about 60°C, for at least 6 hours, preferably at least 12 hours, and isolating cocrystal P5.

[0087] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: i. contacting daprodustat with 2,3,5,6-tetramethylpyrazine, optionally in the presence of a solvent; ii. Isolating the co-crystal The present invention provides a process for the preparation of a co-crystal comprising daprodustat and 2,3,5,6-tetramethylpyrazine as defined in the first aspect, preferably referred to as Form T1, comprising:

[0088] In one embodiment, the molar ratio of daprodustat to 2,3,5,6-tetramethylpyrazine co-crystal formers is about 1:3, preferably about 1:2, and more preferably about 1:1.5.

[0089] In one embodiment, a solvent for preparing the co-crystalline Form T1 is present and is a solvent selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, and the like (C1-C 12 ) an alcohol solvent, preferably selected from the group consisting of methanol, ethanol, isopropanol, and combinations thereof.

[0090] The present invention is further illustrated by the following examples, which are not to be construed in any way as limiting the scope of the invention as defined in the claims, and in which, unless otherwise indicated, all percentages are by weight and temperatures are in degrees Celsius.

[0091] General method X-ray powder diffraction (PXRD) Sample preparation: Approximately 20 mg of unmanipulated sample was prepared in a standard sample holder using two polyacetate foils. Data acquisition: Powder diffraction patterns were obtained on a Bruker D8 Advance series 2θ / theta powder diffraction system using CuKα1 radiation in transmission geometry. The system is equipped with a VÅNTEC-1 single-photon counting PSD, a germanium monochromator, a 90-position autochanger sample stage, a fixed divergence slit, and a radial solar. Programs used: Data collection with DIFFRAC plus XRD Commander V.2.5.1 and evaluation with HighScore Plus V.4.9. Measurement conditions: Samples were measured at room temperature in the range 4° to 40° 2θ using an angle step of 0.049° and a time per step of 2787 s, with a measurement time of 0.5 hours.

[0092] Those skilled in the art will understand that powder X-ray diffraction patterns can be obtained with measurement errors that depend on the measurement conditions used. It is generally known that the intensities of X-ray diffraction patterns can vary depending on the measurement conditions used, and that relative intensity values ​​can vary, for example, by ±30%. It is further understood that relative intensities may also vary depending on experimental conditions, and therefore the exact order of magnitude of the intensities should not be considered. Furthermore, the measurement error of the diffraction angle for a conventional X-ray diffraction pattern is typically about ±0.2 degrees 2θ, and this degree of measurement error should be considered relative to the diffraction angle described above. Therefore, it should be understood that the crystalline form of the present invention is not limited to a crystalline form that provides an X-ray diffraction pattern that is exactly the same as the X-ray diffraction pattern depicted in the accompanying figures.

[0093] Differential scanning calorimetry (DSC) Sample preparation: Approximately 1-4 mg of sample was weighed (using an MX5 Mettler Toledo microbalance) into a 40 μL aluminum crucible with a pinhole lid. Data acquisition: DSC analyses were recorded on a Mettler Toledo DSC822e calorimeter. Program used: Data collection and evaluation with the software STARe. Measurement conditions: The sample was heated from 30 to 300°C at 10°C / min under dry nitrogen (flow rate: 50 mL / min).

[0094] Thermogravimetric analysis (TGA) Sample preparation: Approximately 1-4 mg of sample was weighed (using an MX5 Mettler Toledo microbalance) into a 40 μL aluminum crucible with a pinhole lid. Data acquisition: Thermogravimetric analyses were recorded on a Mettler Toledo TGA / DSC 3+ balance type XP1. Program used: Data collection and evaluation with the software STARe. Measurement conditions: The sample was heated from 30 to 300°C at 10°C / min under dry nitrogen (flow rate: 10 mL / min).

[0095] Proton Nuclear Magnetic Resonance (1H-NMR) Sample preparation: Approximately 2–5 mg of sample was dissolved in 0.7 mL of deuterated solvent (dimethyl sulfoxide-d6). Data Acquisition: Proton nuclear magnetic resonance analyses were recorded on a Bruker 300 NMR spectrometer equipped with a z-gradient 5 mm BBO (Broadband Observe) probe containing ATM and an automatic autosampler. Measurement conditions: Samples were analyzed at room temperature.

[0096] Fourier transform infrared spectroscopy (FTIR) FTIR spectra were recorded using an Agilent Technologies Cary 630 FTIR spectrometer equipped with an Agilent Diamond single reflection ATR system, a mid-infrared light source as the excitation source, and a DTGS detector. -1 ~650cm -1 In the range of 4cm -1 32 scans were acquired at a resolution of .

[0097] Dynamic Vapor Sorption Analysis (DVS) Sample preparation: Approximately 5-10 mg of sample was weighed into an open 150 μL platinum crucible (using an MX5 Mettler Toledo microbalance). Data acquisition: Experiments were performed on a Mettler Toledo TGA / DSC 1LF instrument equipped with an LF SDTA FRS2 sensor and connected to a Modular Humidity Generator MHG 32. Data acquisition and evaluation were performed with STARe software. Measurement conditions: Samples were analyzed following a humidity cycle at 25° C. for 60 minutes from 5% RH up to 90% RH and then decreasing to 5% RH in 10% steps (RH: relative humidity).

[0098] Example Example 1: Preparation of the co-crystal P3 form of daprodustat and pyridoxine Daprodustat (250 mg, 0.64 mmol) and pyridoxine (107.5 mg, 0.64 mmol, 1 equiv.) were dissolved in acetonitrile (25 mL) by reflux. Once dissolved, the solution was slowly cooled to room temperature. The resulting suspension was stirred at room temperature for 1 hour. The resulting solid was then filtered, washed with acetonitrile (2 mL), and dried under vacuum at 50°C for 2 hours to provide daprodustat / pyridoxine cocrystal P3 form (300 mg, 84% yield).

[0099] PXRD (Figure 1): Crystalline. Co-crystalline P3 form. DSC (Figure 2): Endothermic peak with onset at 174°C (-72 J / g). TGA (Figure 2): 0.7% weight loss below 70°C. Weight loss due to decomposition started at 180°C. 1 H-NMR (Figure 3): No displacement of NMR signals. Daprodustat / pyridoxine ratio: 1:1. FTIR: v (cm -1 ,Figure 4):693, 728, 762, 791, 836, 893, 914, 960, 1001, 1015, 1033, 1096, 1131, 1175, 1235, 1266, 1284, 1309, 1340, 1407, 1443, 1457, 1478, 1522, 1541, 1560, 1586, 1654, 1684, 1716, 2852, 2875, 2924, 2980. DVS (Figure 5): Weight gain of 0.59% from 10 to 80% RH. No changes were observed in the PXRD before and after the DVS cycle.

[0100] Example 2: Preparation of Daprodustat and Pyridoxine Cocrystal P1 Form Daprodustat (100 mg) and pyridoxine (1 equivalent, 43 mg) were dissolved in ethyl acetate (5 mL) by reflux. Once dissolved, the solution was slowly cooled to room temperature and stirred for 1 hour. The resulting solid was filtered, washed with ethyl acetate (1 mL), dried under vacuum at 45°C (43% yield), and analyzed by PXRD. PXRD (Figure 6): crystalline. Crystalline P1 form.

[0101] Example 3: Preparation of the co-crystal P2 form of daprodustat and pyridoxine Daprodustat (100 mg) and pyridoxine (1 equivalent, 43 mg) were dissolved in isopropanol (3 mL) by reflux. Once dissolved, the solution was It was cooled slowly to room temperature and stirred for 1 hour. The resulting solid was filtered, washed with isopropanol (1 mL) and dried under vacuum at 45° C. (50% yield). PXRD (Figure 7): Crystalline. Co-crystalline P2 form.

[0102] Example 4: Preparation of Daprodustat and Pyridoxine Cocrystal Form P4 A sample of the co-crystalline P3 form (obtained in Example 1) was suspended in water (30 mg in 1 mL) and slurried at room temperature for 30 minutes, after which the solid was isolated by filtration and analyzed by PXRD without further drying. PXRD (Figure 8): Crystalline. Co-crystalline P4 form.

[0103] Example 5: Preparation of Daprodustat and Pyridoxine Cocrystal Form P5 The solid obtained in Example 4 (P4 form) was dried under vacuum at 60° C. overnight to give , provided the P5 form. PXRD (Figure 9): Crystalline. Co-crystalline P5 form. DSC: Endothermic peaks with onset at 72°C (-2 J / g), 166°C (-19 J / g) and 216°C (-30 J / g). TGA: 1.4% weight loss below 70°C. Weight loss due to decomposition started at 165°C. 1 H-NMR: No displacement of NMR signals. Daprodustat / pyridoxine ratio: 1:3.

[0104] Example 6: Preparation of the co-crystalline T1 form of daprodustat and 2,3,5,6-tetramethylpyrazine Daprodustat (20 mg) and 2,3,5,6-tetramethylpyrazine (1.5 equivalents, 10.4 mg) were dissolved in isopropanol (0.6 mL) by reflux. Once dissolved, the solution was slowly cooled to room temperature. The mother liquor was decanted, and the solid was dried under vacuum at 45°C. PXRD (Figure 10): Crystalline. Co-crystalline T1 form.

[0105] Example 7: Temperature Stability Test Samples of cocrystal P3 were stored in closed and open vials at different temperatures (T), e.g., 40° C. and 60° C. After some time, the solids were isolated and analyzed by XRPD analysis. The results are summarized in Table 7.

[0106] [Table 7]

[0107] Example 8: Preparation of co-crystals of daprodustat and butyramide Daprodustat (20 mg) and butyramide (1 equivalent, 4.4 mg) were dissolved in isopropanol (0.6 mL) by reflux. Once dissolved, the solution was slowly cooled to room temperature and stirred for 1 hour. The mother liquor was decanted and the solid was dried under vacuum at 45°C. PXRD: Crystalline. Cocrystal B1 form.

[0108] Example 9: Preparation of co-crystals of daprodustat and picolinamide Daprodustat (20 mg) and picolinamide (1 equivalent, 6.2 mg) were dissolved in isopropanol (0.6 mL) by reflux. Once dissolved, the solution was slowly cooled to room temperature and stirred for 1 hour. The mother liquor was decanted, and the solid was dried under vacuum at 45°C. PXRD: Crystalline. Cocrystal PC1 form.

[0109] Example 10: Synthesis of co-crystals of daprodustat and L-arginine Daprodustat (20 mg) and L-arginine (1 equivalent, 8.9 mg) were suspended in ethyl acetate (1 mL) by reflux. Once dissolved, the solution was slowly cooled to room temperature and stirred for 1 hour. The resulting solid was filtered, washed with isopropanol, and dried under vacuum at 45°C. PXRD: Crystalline. Cocrystal A1 form.

Claims

1. a) daprodustat, and b) a co-crystal former selected from the group consisting of pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, and L-arginine A cocrystal comprising:

2. 2. The co-crystal of claim 1, wherein the co-crystal former is pyridoxine.

3. 3. The co-crystal of claim 2, wherein the molar ratio of daprodustat to pyridoxine in the co-crystal is 1:3 to 3:1, preferably 1:2 to 2:1, more preferably about 1:

1.

4. 4. The co-crystal of claim 2 or 3, designated as the P3 form and having an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 6.1°±0.2°, 14.2°±0.2°, and 25.8°±0.2, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

5. 5. The co-crystal of claim 4, wherein the X-ray powder diffraction pattern of the crystalline P3 form further comprises peaks at 2θ values ​​of 4.7°±0.2°, 5.4°±0.2°, and 9.5°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

6. 6. The co-crystal of any one of claims 4 and 5, wherein the co-crystal P3 Form has a differential scanning calorimetry thermogram using a heating rate of 10°C min 1 and a nitrogen purge gas, comprising an endothermic peak with an onset at about 173-175°C.

7. 4. The co-crystalline form of daprodustat of claim 2, wherein the co-crystal is designated as Form P1 and has an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 5.1°±0.2°, 6.8°±0.2°, and 9.4°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

8. 4. The co-crystal of claim 2, wherein the co-crystal is designated as Form P2 and has an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 6.4°±0.2°, 6.8°±0.2°, and 9.5°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

9. 4. The co-crystal of claim 2, wherein the co-crystal is designated as Form P4 and has an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 5.4°±0.2°, 7.9°±0.2°, and 14.9°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

10. 4. The co-crystal of claim 2, wherein the co-crystal is designated as Form P5 and has an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 5.4°±0.2°, 8.1°±0.2°, and 10.1°±0.2°, measured with copper Kα radiation having an X-ray wavelength of 1.5406 Å at room temperature.

11. 2. The co-crystal of claim 1, wherein the co-crystal former is 2,3,5,6-tetramethylpyrazine.

12. 12. The co-crystal of claim 11, wherein the molar ratio of daprodustat to 2,3,5,6-tetramethylpyrazine in the co-crystal is from 1:3 to 3:1, preferably from 1:2 to 2:1, more preferably about 1:1.

5.

13. 13. The co-crystal of claim 12, wherein the co-crystal is designated as the T1 form and has an X-ray powder diffraction pattern comprising peaks at 2θ values ​​of 6.5°±0.2°, 7.8°±0.2°, and 14.5°±0.2°, measured at room temperature with copper Kα radiation having an X-ray wavelength of 1.5406 Å.

14. i. contacting daprodustat with a co-crystal former selected from the group consisting of pyridoxine, 2,3,5,6-tetramethylpyrazine, picolinamide, butyramide, and L-arginine, optionally in the presence of a solvent; ii. Isolating the co-crystal 14. A process for the preparation of a co-crystal as defined in claims 1 to 13, comprising:

15. The solvent is present and is selected from hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, and the like; (C ) solvents such as toluene, o-xylene, m-xylene, and p-xylene; ６ -C １４ ) aromatic hydrocarbon solvents; halogenated (C) solvents such as 1,2-dichloroethane, dichloromethane, and chloroform １ -C １２ ) hydrocarbon solvents; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, and ethyl malonate; (C) solvents such as diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane; １ -C １２ ) ether solvents; (C) such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, and m-cresol; １ -C １２ 15. The process of claim 14, wherein the solvent is selected from the group consisting of: alcohol solvents; nitrile solvents such as acetonitrile; nitrobenzene, N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); N-methyl-2-pyrrolidone, dimethyl carbonate, and combinations thereof.

16. 16. The process of claim 14 or 15, wherein the solvent is present and is selected from the group consisting of acetone, acetonitrile, dimethyl carbonate, ethanol, ethyl acetate, isopropanol, and combinations thereof.

17. 14. A pharmaceutical composition comprising a co-crystal as defined in any one of claims 1 to 13 together with one or more pharmaceutically acceptable carriers or excipients.

18. 18. A co-crystal as defined in any one of claims 1 to 13, or a pharmaceutical composition as defined in claim 17, for use in the treatment of renal anemia.

Images