DESC:SOLID FORMS OF ROXADUSTAT AND THEIR PREPARATION

INTRODUCTION

The present invention provides crystalline forms of Roxadustat and its process for the preparation and pharmaceutical composition thereof.

BACKGROUND

Roxadustat (I) or FG-4592 is chemically known as [(4-Hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. It is an oral small molecule inhibitor of Hypoxia-Inducible Factor-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 solid state form i.e., co-crystals of Roxadustat can be obtained which may modify the properties of Roxadustat as compared to traditional solid forms such as salts, polymorphs, hydrates, solvates etc.

SUMMARY OF THE INVENTION
In the first aspect, the present invention provides a crystalline form SR1 of Roxadustat, characterized by a PXRD comprising the peaks at about 3.20, 6.28 and 19.05 ± 0.2° 2?. In an embodiment, the application provides a crystalline form SR1 of Roxadustat, characterized by a PXRD having additional peaks at about 13.52, 17.02, 18.62 and 26.72 ± 0.2° 2?.
In the second aspect, the present invention provides a process for preparation of crystalline Roxadustat form SR1, comprising;
a) providing a mixture of Roxadustat in water;
b) adding sodium hydroxide to the solution of step a);
c) acidifying the solution obtained from step b) with acid;
d) isolating crystalline Roxadustat form SR1.
In the third aspect, the present invention provides a crystalline form SR2 of Roxadustat, characterized by a PXRD comprising the peaks at about 4.98, 14.85 and 18.44 ± 0.2° 2?. In an embodiment, the application provides a crystalline form SR2 of Roxadustat, characterized by a PXRD having additional peak at about 20.86 ± 0.2° 2?.
In the fourth aspect, the present invention provides a process for preparation of crystalline Roxadustat form SR2, comprising;
a) providing a mixture of Roxadustat form SR1 in alcohol solvent;
b) isolating crystalline Roxadustat form SR2.
In the fifth aspect, the present invention provides a crystalline form SR3 of Roxadustat, characterized by a PXRD comprising the peaks at about 9.38, 9.66 and 10.50 ± 0.2° 2?. In an embodiment, the application provides a crystalline form SR3 of Roxadustat, characterized by a PXRD having additional peak at about 8.63 ± 0.2° 2?.
In the sixth aspect, the present invention provides a process for preparation of crystalline Roxadustat form SR3, comprising;
a) providing a solution of Roxadustat form SR1 in alcohol solvent at 5°C;
b) isolating crystalline Roxadustat form SR3.
In the seventh aspect, the present application provides a pharmaceutical composition comprising crystalline Form of Roxadustat selected from the group comprising form SR1, form SR2 and form SR3 or mixtures thereof together with at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction of crystalline Form SR1 of Roxadustat prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction of crystalline Form SR2 of Roxadustat prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction of crystalline Form SR3 of Roxadustat prepared by the method of Example-3.

DETAILED DESCRIPTION
In the first aspect, the present invention provides a crystalline form SR1 of Roxadustat, characterized by a PXRD comprising the peaks at about 3.20, 6.28 and 19.05 ± 0.2° 2?. In an embodiment, the application provides a crystalline form SR1 of Roxadustat, characterized by a PXRD having additional peaks at about 13.52, 17.02, 18.62 and 26.72 ± 0.2° 2?.

In an embodiment, the present application provides crystalline form SR1 of Roxadustat, characterized by a PXRD substantially as shown in figure 1.
In the second aspect, the present invention provides a process for preparation of crystalline Roxadustat form SR1, comprising;
a) providing a mixture of Roxadustat in water;
b) adding sodium hydroxide to the solution of step a);
c) acidifying the solution obtained from step b) with acid;
d) isolating crystalline Roxadustat form SR1.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Suitable acid used in step c) include, but are not limited to acetic acid, hydrochloric acid, hydrobromic acid, nitric acid, hydroiodic acid, sulfuric acid or the like.
The temperature at which the above steps may be carried out in between about 10 °C and about 100 °C, based on the solvent or mixture of solvent used in particular step.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
Starting material may be either in a crystalline or amorphous state or an alternate crystalline form of Roxadustat known in the art.
In the third aspect, the present invention provides a crystalline form SR2 of Roxadustat, characterized by a PXRD comprising the peaks at about 4.98, 14.85 and 18.44 ± 0.2° 2?. In an embodiment, the application provides a crystalline form SR2 of Roxadustat, characterized by a PXRD having additional peak at about 20.86 ± 0.2° 2?.
In an embodiment, the present application provides crystalline form SR2 of Roxadustat, characterized by a PXRD substantially as shown in figure 2.
In the fourth aspect, the present invention provides a process for preparation of crystalline form SR2 of Roxadustat, comprising;
a) providing a mixture of Roxadustat form SR1 in alcohol solvent;
b) isolating crystalline form SR2 of Roxadustat.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Suitable alcohol solvent used in step a) include, but are not limited to methanol, ethanol, isopropyl alcohol, n-butanol, 1-propanol or the like.
The temperature at which the above steps may be carried out in between about 10 °C and about 100 °C, based on the solvent or mixture of solvent used in particular step.
The isolation of step b) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
In the fifth aspect, the present invention provides a crystalline form SR3 of Roxadustat, characterized by a PXRD comprising the peaks at about 9.38, 9.66 and 10.50 ± 0.2° 2?. In an embodiment, the application provides a crystalline form SR3 of Roxadustat characterized by a PXRD having additional peak at about 8.63 ± 0.2° 2?.
In an embodiment, the present application provides crystalline form SR3 of Roxadustat, characterized by a PXRD substantially as shown in figure 2.
In the sixth aspect, the present invention provides a process for preparation of crystalline form SR3 of Roxadustat, comprising;
a) providing a mixture of Roxadustat form SR1 in alcohol solvent at 5°C;
b) isolating crystalline form SR3 of Roxadustat.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Suitable alcohol solvent used in step a) include, but are not limited to methanol, ethanol, isopropyl alcohol, n-butanol, 1-propanol or the like.
The temperature at which the above steps may be carried out in between about 10 °C and about 100 °C, based on the solvent or mixture of solvent used in particular step.
The isolation of step b) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
In the seventh aspect, the present application provides a pharmaceutical composition comprising crystalline Form of Roxadustat selected from the group comprising form SR1, form SR2 and form SR3 or mixtures thereof together with at least one pharmaceutically acceptable excipient.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example-1: Preparation of crystalline Roxadustat Form-SR1.
Roxadustat (7 g) was added to distilled water (240 mL) at 70 °C under stirring on a magnetic hot plate. Sodium hydroxide in water (1 M) was slowly added to the resultant suspension until complete dissolution. Acetic acid (1.1 M) was slowly added to the resultant suspension. The obtained suspension was filtered under vacuum for 1 hour. Collected the material and slightly ground it and kept for drying in vacuum tray drier at 45 °C for 1 hour to obtain the title compound.

Example-2: Preparation of crystalline Roxadustat Form-SR2.
Roxadustat Form-SR1 (0.6 g) was added to the methanol (15 mL) at room temperature under stirring and kept for slurry on magnetic plate for 12 hours. The obtained suspension was filtered under vacuum for 15 minutes to obtain the title compound.

Example-3: Preparation of crystalline Roxadustat Form-SR3.
Roxadustat Form-SR1 (2 g) was added to the methanol (30 mL) at 5°C under stirring and kept for stirring for 7 hours, followed by maintenance without out stirring at room temperature for 11 hours. The obtained suspension was further stirred at 5°C for 9 hours, followed by maintenance without stirring at room temperature for 65 hours. The suspension was further stirred for 4 hours at room temperature. The obtained suspension was filtered under vacuum for 30 minutes and kept for drying in vacuum tray drier at 45°C to obtain the title compound.
,CLAIMS:
1) A crystalline Roxadustat form SR1, characterized by X-ray powder diffraction pattern having peaks at about 3.20, 6.28 and 19.05 ± 0.2° 2?.
2) A process for preparation of crystalline Roxadustat form SR1, comprising;
a) providing a mixture of Roxadustat in water;
b) adding sodium hydroxide to the solution of step a);
c) acidifying the solution obtained from step b) with acid;
d) isolating crystalline Roxadustat form SR1.
3) A crystalline Roxadustat form SR2, characterized by X-ray powder diffraction pattern having peaks at about 4.98, 14.85 and 18.44 ± 0.2° 2?.
4) A process for preparation of crystalline Roxadustat form SR2, comprising:
a) providing a mixture of Roxadustat form SR1 in alcohol solvent;
b) isolating crystalline Roxadustat form SR2.
5) The process as claimed in claim 4, wherein alcohol solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol, 1-propanol or mixtures thereof.
6) A crystalline Roxadustat form SR3, characterized by X-ray powder diffraction pattern having peaks at about 9.38, 9.66 and 10.50 ± 0.2° 2?.
7) A process for preparation of crystalline Roxadustat form SR3, comprising;
a) providing a solution of Roxadustat form SR1 in alcohol solvent at 5°C;
b) isolating crystalline Roxadustat form SR3.
8) The process as claimed in claim 7, wherein alcohol solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol, 1-propanol or mixtures thereof.