DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

CO-CRYSTAL OF ROXADUSTAT

INTRODUCTION

The present invention provides co-crystal of Roxadustat and its process for the preparation.

BACKGROUND

Roxadustat (I) or FG-4592 is chemically known as [(4-Hydroxy-1-methyl-7-phenoxy-iso quinoline-3-carbonyl)-amino]-acetic acid. It is an oral small molecule inhibitor of HIF prolyl hydroxylases, or HIF-PHs, in Phase 3 clinical development for treating and preventing disorders associated with HIF, including anemia in chronic kidney disease, or CKD, ischemia, and hypoxia.
(I)
The US patent number 7323475 B2, Example D-81 (e), by referring Example D-78 (d), discloses a process for preparation followed by isolation of roxadustat by concentration of organic phases (EtOAc/Methanol) under vacuum.
The US patent number 8883823 B2 discloses crystalline Forms of roxadustat and their processes for the preparation. The crystalline forms are designated as Form A, Form B (hemihydrate), Form C (hexafluropropan-2-ol solvate) and Form D (DMSO: Water solvate). It further discloses various salts of roxadustat and amorphous form roxadustat.
The US patent number 9206134 B2 discloses various crystalline Forms of roxadustat and their processes for the preparation. The crystalline forms are designated as Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII.
Different forms of Active pharmaceutical ingredients (API) in pharmaceutical compositions can be prepared. For example, API may be prepared in amorphous form, crystalline forms, solvate or hydrate and salt form. This variation in solid forms may be significant and may result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties. Accordingly, variation of the crystalline state of roxadustat is one way in which physical properties of the roxadustat can be modulated. It has now been found that new co-crystalline forms of roxadustat can be obtained which improve the properties of roxadustat as compared to such roxadustat in a non-co-crystalline state.

SUMMARY OF THE INVENTION
In the first aspect, the present invention provides a co-crystal of roxadustat comprising; roxadustat and a co-crystal former.
In the second aspect, the present invention provides a co-crystal of roxadustat comprising roxadustat and caffeine.
In the third aspect, the present invention provides a co-crystal of roxadustat comprising roxadustat and caffeine wherein the co-crystal is characterized by power X-ray diffraction position at 8.90, 10.06, 14.90, 18.10, 20.23, 21.10, 25.03 and 26.70 ±0.2 2?°. The co-crystal of roxadustat with caffeine is further characterized by PXRD peaks at 11.89, 21.50, 24.53 and 26.00 ±0.2 2?°.
In the fourth aspect, the present invention provides a process for preparation of co-crystal of roxadustat, comprising;
i) grinding or contacting in solution the roxadustat with the co-crystal former;
ii) optionally drying; and
iii) isolating co-crystals formed thereby.

BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 illustrates the powder X-ray diffraction ("PXRD") pattern of co-crystal of roxadustat with caffeine.

DETAILED DESCRIPTION
In the first aspect, the present invention provides a co-crystal of roxadustat comprising; roxadustat and co-crystal former.
The term “co-crystal” as used herein means a crystalline material comprises two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point and heats of fusion. The co-crystals of the present invention comprises a co-crystal former hydrogen bonded to roxadustat. The additional molecule may be hydrogen bonded to the roxadustat or bound ionically or covalently to roxadustat. The roxadustat and the co-crystal former may have other non-covalent interactions, including p-stacking and van der Waals interactions.
Roxadustat input material may be in the form of salts, solvates, hydrates, crystalline or amorphous forms known in the literatures.
The co-crystal former is selected from caffeine, adenine, thymine, saccharine and the like.
The ratio of roxadustat to co-crystal former may be stoichiometric or non-stoichiometric according to the present invention. The ratio of roxadustat:co-crystal former is about 1:1 or 1:2 or 2:1 or 1:3 or 3:1.
In the second aspect, the present invention provides a co-crystal of roxadustat comprising roxadustat and caffeine.
The ratio of roxadustat to caffeine may be stoichiometric or non-stoichiometric according to the present invention. The ratio of roxadustat:caffeine is about 1:1 or 1:2 or 2:1 or 1:3 or 3:1.
In the third aspect, the present invention provides a co-crystal of roxadustat comprising roxadustat and caffeine wherein the co-crystal is characterized by power X-ray diffraction (PXRD) peaks at 8.90, 10.06, 14.90, 18.10, 20.23, 21.10, 25.03 and 26.70 ±0.2 2?°. The co-crystal of roxadustat with caffeine is further characterized by PXRD peaks at 11.89, 21.50, 24.53 and 26.00 ±0.2 2?°.
In the fourth aspect, the present invention provides a process for preparation of co-crystal of roxadustat, comprising;
i) grinding or contacting in solution the roxadustat with the co-crystal former;
ii) optionally drying; and
iii) isolating co-crystals formed thereby.
The grinding process comprises dry grinding or wet grinding of roxadustat with co-crystal former. In dry grinding process, roxadustat and the co-crystal former grind in a mortar, a grinder or a mill to obtain a co-crystal. Grinding in a mortar involves physical grinding of roxadustat and co-crystal. In wet grinding process, roxadustat and the co-crystal former grind in mortar, a grinder or a mill with the solvent or mixture of solvents followed by drying to obtain the co-crystal. The solvent for wet grinding process includes but are not limited to: aprotic solvents such as ethers which includes tetrahydrofuran, 1,4-dioxane and the like; halogenated hydrocarbon which includes dichloromethane, trichloromethane and the like;
The amount of solvent used for wet grinding is in the range of up to about 40% by weight (w/w). For example, a weight percent of less than or equal to about 1, 2, 3, 4, 5 10, 15, 20, 25, 30 and 35 may be used.
Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like.
Co-crystal may be formed by contacting the roxadustat with the co-crystal former in solution. The process comprises a) dissolving roxadustat and the co-crystal former in a suitable solvent; b) cooling the solution and c) isolation of the co-crystal formed.
In the process according to the invention, contacting roxadustat with the co-crystal former involves either solubilizing roxadustat and adding co-crystal former, or solubilizing co-crystal former and adding roxadustat to it.
Suitable solvents which can be used for preparing the solution include but are not limited to aprotic solvents such as ethers which includes tetrahydrofuran, 1,4-dioxane and the like; halogenated hydrocarbon which includes dichloromethane, trichloromethane and the like;
The dissolution temperatures can range from about 20 to 120° C. depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution is obtained.
For isolation to occur, the reaction mass may be maintained further at temperatures lower than the dissolution temperatures such as for example below about 10° C. to about 25° C., for a period of time as required for a more complete isolation of the product. The exact cooling temperature and time required for complete crystallization can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
Optionally isolation may be initiated or enhanced by methods such as cooling, seeding, partial removal of the solvent from the solution, using anti-solvent or a combination thereof.
The method by which the solid material is recovered from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as filtration by gravity or by suction, decantation, centrifugation, and the like.
Optionally, the obtained product is further dried. Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like.
Co-crystal may be formed from the slurry by contacting the roxadustat with the co-crystal former in solvent. The process comprises a) contacting roxadustat and the co-crystal former in a suitable solvent; and b) drying the slurry.
Suitable solvents which can be used for preparing the solution include but are not limited to aprotic solvents such as ethers which includes tetrahydrofuran, 1,4-dioxane and the like; halogenated hydrocarbon which includes dichloromethane, trichloromethane and the like;
The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration. The pharmaceutical composition of the present invention may comprise the solid dispersion, and any possible carrier and excipient.

Examples
Example-1: Preparation of co-crystal of roxadustat with caffeine
100 mg of roxadustat and 55.1 mg of caffeine were taken in a mortar and mixed physically using spatula at room temperature. 2 ml of acetonitrile was added and ground for 3 minutes using pestle. 2 ml of tetrahydrofuran (THF) was added and ground for 3 minutes using pestle to obtain the title co-crystal.

Example-2: Preparation of co-crystal of roxadustat with caffeine
200 mg of roxadustat and 110.2 mg of caffeine were taken in a mortar and mixed physically using spatula at room temperature. 10 ml of tetrahydrofuran (THF) was added to the mixture to obtain the slurry. The slurry was dried under vacuum at room temperature to obtain the title co-crystal.

Example-3: Preparation of co-crystal of roxadustat with caffeine
100 mg of roxadustat and 55.1 mg of caffeine were taken in a mortar and mixed physically using spatula at room temperature. 2 ml of tetrahydrofuran (THF) was added and ground for 3 minutes using pestle followed by dried under vacuum at room temperature to obtain the title co-crystal.
,CLAIMS:WE CLAIM:

1) A co-crystal of Roxadustat comprising Roxadustat and co-crystal former.
2) The co-crystal of Roxadustat according to claim 1, wherein co-crystal former is selected from caffeine, adenine, thymine, saccharine or the like.
3) A co-crystal of Roxadustat comprising Roxadustat and caffeine.
4) A co-crystal of Roxadustat comprising Roxadustat and caffeine wherein the co-crystal is characterized by power X-ray diffraction (PXRD) peaks at 8.90, 10.06, 14.90, 18.10, 20.23, 21.10, 25.03 and 26.70 ±0.2 2?°.
5) A co-crystal of Roxadustat comprising Roxadustat and caffeine substantially as shown in Figure-1.
6) A process for preparation of co-crystal of Roxadustat, comprising;
i) grinding or contacting in solution the Roxadustat with the co-crystal former;
ii) optionally drying; and
iii) isolating co-crystals formed thereby.