DESC:CROSS-REFERENCE TO RELATED APPLICATIONS:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN202141007616 filed on Feb 23, 2021.
FIELD OF THE INVENTION:
The present invention relates to crystalline forms of Roxadustat and process for their preparation thereof.
BACKGROUND OF THE INVENTION:
Roxadustat is chemically known as [(4-hydroxy-1-methy1-7-phenoxy-isoquinoline-3-carbony1)-amino]-acetic acid and is represented by Formula 1. Roxadustat is for the treatment of anemia in patients with chronic kidney disease (CKD). It is in Phase III clinical development in US.

Formula I

Roxadustat was first disclosed in US patent 7323475B2.
US patent 8883823 disclosed crystalline Form A, Form B, Form C & Form D, crystalline sodium salt, crystalline L-arginine salt, crystalline L-lysine salt, crystalline ethanolamine salt, crystalline diethanolamine salt, crystalline tromethamine salt and their preparations thereof.

US patent 9206134B2 disclosed crystalline Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII.

IN201641016266 patent application disclosed an amorphous solid dispersion comprising Roxadustat and a pharmaceutically acceptable carrier and its process thereof.

IN201741028591 patent application disclosed Crystalline Roxadustat Form-d and Form-?.
IN201641043301 patent application disclosed Crystalline Roxadustat Form-a.

CN109369525A patent publication disclosed Crystal form of ARZ-A, ARZ-B, ARZ-E, ARZ-F, ARZ-G, ARZ-H, ARZ-J, ARZ-K, ARZ-C, ARZ-D, ARZ-I and Crystal form ARZ-L

The inventors of the present disclosure have developed new crystalline forms of Roxadustat.
SUMMARY OF THE INVENTION:
The main aspect of the present invention provides novel crystalline forms of Roxadustat designated as Form M1, Form M2, Form M3, Form M4 and Form M5 with their preparation process thereof.
In one aspect, the present invention provides crystalline form of Roxadustat designated as form M1 having 2 theta peaks as shown in figure 1
In yet another aspect, the present invention provides crystalline form of Roxadustat designated as form M2 having 2 theta peaks as shown in figure 2.
In another aspect, the present invention provides a process for the preparation of crystalline Roxadustat Form M1 or Form M2 comprising the steps of:
a) dissolving Roxadustat in an organic solvent at reflux temperature,
b) optionally adding seeds,
c) adding anti-solvent, and
e) isolating crystalline Roxadustat Form M1 or Form M2.
In yet another aspect, the present invention provides crystalline Roxadustat form M3 shown in Figure 3.
In yet another aspect, the present invention provides a process for the preparation of crystalline Roxadustat Form M3 comprising the steps of:
a) drying Roxadustat Form M1 or Form M2 at 40-50oC, and
b) isolating crystalline Roxadustat Form M3.
In yet another aspect, the present invention provides crystalline Roxadustat form M4 having 2 theta peaks as shown in figure 4.
In yet another aspect, the present invention provides a process for the preparation of crystalline Roxadustat Form M4 comprising the steps of:

a) drying Roxadustat Form M1 or Form M2 at 80-90°C, and
b) isolating crystalline Roxadustat Form M4.
In yet another aspect, the present invention provides crystalline Roxadustat form M5 having 2 theta peaks as shown in figure 5.
In yet another aspect, the present invention provides a process for the preparation of crystalline Roxadustat Form M5 comprising the steps of:
a) drying Roxadustat Form M1 or Form M2 at 150-160°C, and
b) isolating crystalline Roxadustat Form M5.

Brief description of the figures:

Figure 1: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat form M1.
Figure 2: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat form M2.
Figure 3: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat form M3.
Figure 4: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat form M4.
Figure 5: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat form M5.

DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to novel crystalline forms of Roxadustat designated as Form M1, Form M2, Form M3, Form M4 and Form M5 and with their preparation process thereof.
In one embodiment, the present invention relates to crystalline form of Roxadustat designated as Form M1 having 2 theta peaks as shown in figure 1.

In another embodiment, the present invention relates to crystalline form of Roxadustat designated as form M2 having 2 theta peaks as shown in figure 2.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat Form M1 or Form M2 comprising the steps of:
a) dissolving Roxadustat in an organic solvent at elevated temperature,
b) optionally adding seeds,
c) adding anti-solvent, and
e) isolating crystalline Roxadustat Form M1 or Form M2.
According to the present invention, Roxadustat may be dissolved in an organic solvent such as ethanol at a temperature of about 65-75°C followed by cooling the solution and adding anti solvent such as water. The resultant solid may be dried to obtain crystalline Roxadustat Form M1.
According to the present invention, Roxadustat may be dissolved in an organic solvent such as methanol at a temperature of about 60-70°C followed by cooling the solution and adding anti solvent such as water. The resultant solid may be dried to obtain crystalline Roxadustat Form M2.
According to the present invention, Roxadustat may be dissolved in an organic solvent such as ethanol at temperature of about 80±5°C followed by cooling the solution to about 55±5°C and added with Roxadustat seeds. Raising the temperature to about 80±5°C obtains clear solution which may be cooled to 60±5°C and added antisolvent such as water followed by addition of second lot of seeds at 60±5°C. The resultant mixture may initially cooled to about 25±2°C followed by further cooling to about 0±3°C and maintained for about 20 hours to obtain a solid which may be dried to obtain crystalline Roxadustat Form M1.
According to the present invention, Roxadustat may be dissolved in an organic solvent such as acetonitrile at temperature of about 80±5°C and added with Roxadustat seeds. The reaction mixture may be added water and maintained at about 80±5°C for half an hour followed by addition of second lot of seeds at 80±5°C. The resultant mixture may initially cooled to about 25±2°C followed by further cooling to about 0±3°C and maintained for about 48 hours to obtain a solid which may be dried to obtain crystalline Roxadustat Form M1.
According to the present invention, Roxadustat may be dissolved in an organic solvent such as acetone at temperature of about 50±5°C and added with Roxadustat seeds. The reaction mixture may be added water and maintained at about 50±5°C for half an hour followed by addition of second lot of seeds. The resultant mixture may initially cooled to about 25±2°C followed by further cooling to about 0±3°C and maintained for about 48 hours to obtain a solid which may be dried to obtain crystalline Roxadustat Form M1.
In yet another embodiment, the present invention relates to crystalline Roxadustat form M3 having 2 theta peaks as shown in Figure 3
In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat Form M3 comprising the steps of:
a) drying Roxadustat Form M1 or Form M2 at 40-50oC, and
b) isolating crystalline Roxadustat Form M3.
According to the present invention, Roxadustat Form-M1 or Form M2 may be dried under vacuum at about 40-50°C for about 30 min to obtain crystalline Roxadustat Form M3.
In yet another embodiment, the present invention relates to crystalline Roxadustat form M4 having 2 theta peaks as shown in figure 4
In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat Form M4 comprising the steps of:
a) drying Roxadustat Form M1 or Form M2 at 80-90°C, and
b) isolating crystalline Roxadustat Form M4.
According to the present invention, Roxadustat Form-M1 or Form M2 may be dried under vacuum at about 80-90°C for 30 min to obtain crystalline Roxadustat Form M4.
In yet another embodiment, the present invention relates to crystalline Roxadustat form M5 having 2 theta peaks as shown in figure 5.
In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat Form M5 comprising the steps of:
a) drying Roxadustat Form M1 or Form M2 at 150-160°C, and
b) isolating crystalline Roxadustat Form M5.
According to the present invention, Roxadustat Form-M1 or Form M2 may be heated at about 150-160°C on variable temperature powder X-ray diffraction stage for 30min to obtain crystalline Roxadustat Form M5.
In yet another embodiment, the present invention relates to a pharmaceutical composition comprising any of the crystalline Roxadustat forms selected from Form M1, Form M2, Form M3, Form M4 or Form M5 and a pharmaceutically acceptable excipient.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in anyway.

EXAMPLES:
Example 1: Process for the preparation of Roxadustat Form M1
In a glass vial, dissolved Roxadustat (20mg) in Ethanol (2.4mL) at 70-75°C. The obtained clear solution was cooled to 30°C and added water (2.4 mL). The reaction mass was maintained under shaking for 40h with 200 RPM at 30°C. The solid obtained was analyzed by PXRD and identified as novel crystalline form of Roxadustat Form M1.

Example-2: Process for the preparation of Roxadustat Form M1
In a RBF, dissolve Roxadustat (50mg) in Ethanol (6mL) at 85±5°C then cool to 55±5°C and added Roxadustat seeds (2mg). The obtained hazy solution was dissolved at 80±5°C and maintained for 15min. The clear solution was cooled to 60±5°C, added water (0.75mL) and stir at 60±5°C for 15min. Then added second lot of seeds (2mg) obtained

as per example 1 at 60±5°C then cooled to 25±2°C and further cooled to 0±3°C and stirred for 20h. The solid obtained was analyzed by PXRD and identified as novel crystalline form of Roxadustat Form M1.

Example-3: Process for the preparation of Roxadustat Form M1
In a RBF, dissolve Roxadustat (50mg) in Acetonitrile (6mL) at 80±5°C, added Roxadustat seeds (2mg) obtained as per example 1 and stir for 15min. Then added water (1mL) and stir for 15min at 80±5°C. To the clear solution then added second lot of Roxadustat seeds (2mg) obtained as per example 1 at 80±5°C and slowly cooled to 25±2°C in 60min. Further cooled to 0±3°C and stirred for 48h. The solid obtained was analyzed by PXRD and identified as novel crystalline form of Roxadustat Form M1.

Example-4: Process for the preparation of Roxadustat Form M1
In a RBF, dissolve Roxadustat (50mg) in Acetone (6mL) at 50±5°C then added Roxadustat seeds (2mg) obtained as per example-1 and stir for 15min at 50±5°C. Added water (1mL) and stir for 15min at 50±5°C. To the clear solution then added second lot of Roxadustat seeds (2mg) obtained as per example 1 cooled to 25±2°C. Further cooled to 0±3°C and stir for 48h. The solid obtained was analyzed by PXRD and identified as novel crystalline form of Roxadustat Form M1.

Example 5: Process for the preparation of Roxadustat Form M2
In a glass vial, dissolved Roxadustat (20mg) in Methanol (2.6mL) at 60-65°C. The obtained clear solution was cooled to 30°C and added water (2.4mL). The reaction mass was maintained under shaking for 40h with 200 RPM at 30°C. The solid obtained was analyzed by PXRD and identified as novel crystalline form of Roxadustat Form M2.

Example 6: Process for the preparation of Roxadustat Form M3
Roxadustat (50mg) Form-M1 or Form M2 was dried under vacuum at 40-50°C for 30min. The resulting solid was identified as crystalline Roxadustat Form M3.

Example 7: Process for the preparation of Roxadustat Form M4
Roxadustat (50mg) Form-M1 or Form M2 was dried under vacuum at 80-90°C for 30min. The resulting solid was identified as crystalline Roxadustat Form M4.

Example 8: Process for the preparation of Roxadustat Form M5
Roxadustat Form-M1 or Form M2 was heated at 150-160°C on variable temperature powder X-ray diffraction stage for 30min and the resulting solid was identified as crystalline Roxadustat Form M5.
,CLAIMS:We claim:
1. Crystalline Roxadustat Form M1 characterized by X-ray powder diffraction pattern having peaks at 8.4, 16.2, 22.5, 22.8 and 27.2 ±0.2° 2?.
2. Crystalline Roxadustat Form M2 characterized by X-ray powder diffraction pattern having peaks at 2.8, 8.3, 16.1, 21.4 and 22.7 ±0.2° 2?.
3. Crystalline Roxadustat Form M3 characterized by X-ray powder diffraction pattern having peaks at 2.8, 8.2, 16.0 and 22.6 ±0.2° 2?.
4. Crystalline Roxadustat Form M4 characterized by X-ray powder diffraction pattern having peaks at 2.9, 8.3 and 16.1±0.2° 2?.
5. Crystalline Roxadustat Form M5 characterized by X-ray powder diffraction pattern having peaks at 2.8, 8.2±0.2° 2?.
6. The process for preparation of crystalline Roxadustat Form M1 and Form M2 as claimed in claim 1 and claim 2, comprising the steps of;
a) dissolving Roxadustat in an organic solvent at elevated temperature,
b) optionally adding seeds,
c) adding anti-solvent, and
e) isolating crystalline Roxadustat Form M1 or Form M2.
wherein the organic solvent is selected from alcohols such as methanol, ethanol, isopropanol, ketones such as acetone or acetonitrile or mixtures thereof.
7. The process for preparation of crystalline Roxadustat Form M3 as claimed in claim 3, comprising the steps of:
a) drying Roxadustat Form M1 or Form M2 at 40-50oC, and
b) isolating crystalline Roxadustat Form M3.
8. The process for preparation of crystalline Roxadustat Form M4 as defined in claim 6, comprising the steps of:
a) drying Roxadustat Form M1 or Form M2 at 80-90°C, and
b) isolating crystalline Roxadustat Form M4.
9. The process for preparation of crystalline Roxadustat Form M5 as defined in claim 8, comprising the steps of:
a) drying Roxadustat Form M1 or Form M2 at 150-160°C, and
b) isolating crystalline Roxadustat Form M5.

10. A pharmaceutical composition comprising Crystalline Roxadustat Form M1 or Crystalline Roxadustat Form M2 or Crystalline Roxadustat Form M3 or Crystalline Roxadustat Form M4 or Crystalline Roxadustat Form M5 or mixtures thereof and a pharmaceutically acceptable carrier.