DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian provisional patent application no IN 201841030375 filed on Aug 13, 2018.

FIELD OF THE INVENTION:

The present disclosure relates to crystalline forms of Roxadustat Sodium and their preparation process thereof. The present invention further relates to process for the preparation of amorphous Roxadustat, Roxadustat morpholine salt and its preparation thereof.

BACKGROUND OF THE INVENTION:

Roxadustat, chemically named as [(4-hydroxy-1-methy1-7-phenoxy-isoquinoline-3-carbony1)-amino]-acetic acid is in Phase III clinical trials for the treatment of anemia in patients with chronic kidney disease (CKD). It is represented by formula I, shown below:

Formula I

Roxadustat was first disclosed in US7323475.

US patent 8883823 disclosed crystalline Form A, Form B, Form C & Form D [DMSO: water solvate], 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.

The inventors of the present disclosure have developed new crystalline forms of Roxadustat salts, in particular sodium and morpholine salts suitable for formulation development.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention is to provide crystalline forms of Roxadustat sodium designated as Form M1, Form M2, Form M3, Form M4 and Form M5 with their preparation process thereof. Further the present invention provides crystalline morpholine salt and its preparation thereof.

Another object of the present invention is to provide process for the preparation of amorphous Roxadustat.

In one aspect, the present invention provides crystalline form of Roxadustat sodium designated as form M1, characterized by powder X-ray diffraction pattern having peaks at 2.8, 5.6, 6.9, 7.6, 8.5, 9.3, 10.0, 10.4, 11.3, 12.5, 13.2, 13.5, 14.1, 14.6, 15.4,16.3, 17.1, 17.8, 18.4, 18.7, 19.1, 20.0, 21.3, 22.2, 22.5, 22.9, 23.3, 24.0, 24.4, 25.4, 25.7, 26.3, 26.7, 27.4, 28.1, 28.8, 30.2 and 31.7± 0.2° degrees 2?, shown in Figure 1.

In yet another aspect, the present invention provides a process for the preparation of crystalline Roxadustat sodium Form M1.

In yet another aspect, the present invention provides crystalline Roxadustat sodium form M2 characterized by powder X-ray diffraction pattern having peaks at 2.4, 2.9,5.8, 6.9, 8.0, 8.7, 9.8, 10.6, 11.6, 12.1, 13.2, 13.3, 14.1, 14.7, 15.9, 16.4, 17.6, 18.0, 19.2, 19.7, 20.5, 21.4, 22.9, 23.5, 25.3, 25.6, 26.8, 27.4, 28.1, 29.7, 32.5±0.2° degrees 2?, shown in Figure 2.

In yet another aspect, the present invention provides a process for the preparation of crystalline Roxadustat sodium Form M2.

In yet another aspect, the present invention provides crystalline Roxadustat sodium form M3 characterized by powder X-ray diffraction pattern having peaks at 2.7, 10.4, 24.6, 42.7,43.9 ± 0.2° degrees 2?, shown in Figure 3.

In yet another aspect, the present invention provides a process for the preparation of crystalline Roxadustat sodium Form M3.

In yet another aspect, the present invention provides crystalline Roxadustat sodium form M4 characterized by powder X-ray diffraction pattern having peaks at 2.7, 4.7, 5.4, 8.3, 10.3, 16.5, 22.1, 26.0 ±0.2° degrees 2?, shown in Figure 4.

In yet another aspect, the present invention provides a process for the preparation of crystalline Roxadustat sodium Form M4.

In yet another aspect, the present invention provides crystalline Roxadustat sodium form M5 characterized by powder X-ray diffraction pattern having peaks at 4.3, 6.6, 7.6, 9.1, 11.2, 11.7, 12.6, 13.9, 14.7, 17.0, 17.6, 19.3, 20.6, 21.3, 22.1, 24.0, 25.4, 25.9, 27.0, 27.9, 29.1, 30.4, 31.9, 42.7, 43.8, 45.7 ± 0.2° degrees 2?, shown in Figure 5.

In yet another aspect, the present invention provides a process for the preparation of crystalline Roxadustat sodium Form M5.

In yet another aspect, the present invention provides Roxadustat Morpholine salt.

In yet another aspect, the Roxadustat Morpholine salt is characterized by powder X-ray diffraction pattern having peaks at 5.3, 10.5, 11.9, 13.1, 15.5, 16.3, 17.0, 17.7 ,18.6, 19.0, 19.8, 20.3, 20.9, 21.5, 22.1, 22.6, 23.5, 24.1, 24.8, 25.8, 26.8, 27.1, 27.7, 28.5, 28.8, 30.1, 30.9, 31.6, 33.3, 33.9, 34.3, 36.4, 37.6, 38.6, ± 0.2° degrees 2?.

In yet another aspect, the present invention provides a process for the preparation of Roxadustat Morpholine salt comprising the steps of:
a) suspending Roxadustat in a solvent,
b) adding morpholine, and
c) isolating Roxadustat morpholine salt.

In yet another aspect, the present invention provides a process for the preparation of amorphous form of Roxadustat.
Brief description of the figures:

Figure 1: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat Sodium form M1.
Figure 2: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat Sodium form M2.
Figure 3: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat Sodium form M3.
Figure 4: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat Sodium form M4.
Figure 5: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat Sodium form M5.
Figure 6: shows a powder X-ray diffraction (PXRD) pattern of Roxadustat Morpholine salt.
Figure 7: shows a powder X-ray diffraction (PXRD) pattern of amorphous Roxadustat.

DETAIL DESCRIPTION OF THE INVENTION:

The present invention relates to crystalline forms of Roxadustat Sodium.

In one embodiment, the present invention relates to crystalline Roxadustat sodium designated as Form M1.

In yet another embodiment, the present invention relates to crystalline Roxadustat sodium form M1 characterized by powder X-ray diffraction pattern having peaks at 2.8, 5.6, 6.9, 7.6, 8.5, 9.3, 10.0, 10.4, 11.3, 12.5, 13.2, 13.5, 14.1, 14.6, 15.4,16.3, 17.1, 17.8, 18.4, 18.7, 19.1, 20.0, 21.3, 22.2, 22.5, 22.9, 23.3, 24.0, 24.4, 25.4, 25.7, 26.3, 26.7, 27.4, 28.1, 28.8, 30.2 and 31.7± 0.2° degrees 2?

In yet another embodiment, the crystalline Roxadustat sodium Form M1 may be characterized by the powder X-ray diffraction pattern as given in Figure 1.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat sodium Form M1 comprising the steps of:
a) suspending Roxadustat acid addition salt in an organic solvent,
b) adding base, and
c) isolating crystalline Roxadustat sodium Form M1 of.

According to the present invention, Roxadustat acid addition salt such as morpholine salt may be suspended in an alcoholic hydrochloride solvent such as methanolic hydrochloride followed by addition of a base such as Sodium bicarbonate, Sodium hydroxide, Sodium carbonate. The resultant solid may be filtered and dried to obtain crystalline Roxadustat sodium Form M1.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat sodium Form M1 comprising the steps of:
a) dissolving Roxadustat in a base,
b) cooling the reaction mass, and
c) isolating crystalline Roxadustat sodium Form M1.

According to the present invention, Roxadustat may be dissolved in an aqueous base such as Sodium bicarbonate, Sodium hydroxide, sodium bicarbonate at a temperature of about 25+5oC followed by cooling the solution to about 20+5oC. The suspension may be maintained for about 12 hours and the resultant solid may be filtered and dried to obtain crystalline Roxadustat sodium Form M1.

In yet another embodiment, the present invention relates to crystalline Roxadustat Sodium designated as Form M2.

In yet another embodiment, the present invention relates to crystalline Roxadustat sodium Form M2 characterized by powder X-ray diffraction pattern having peaks at 2.4, 2.9,5.8, 6.9, 8.0, 8.7, 9.8, 10.6, 11.6, 12.1, 13.2, 13.3, 14.1, 14.7, 15.9, 16.4, 17.6, 18.0, 19.2, 19.7, 20.5, 21.4, 22.9, 23.5, 25.3, 25.6, 26.8, 27.4, 28.1, 29.7 and 32.5±0.2° degrees 2?.

In yet another embodiment, the crystalline Roxadustat sodium Form M2 may be characterized by the powder X-ray diffraction pattern as given in Figure 2.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat sodium Form M2 comprising the steps of:
a) drying Roxadustat sodium Form M1 at 45-65oC,
b) cooling the reaction mixture to 15-35°C, and
c) isolating crystalline Roxadustat sodium Form M2.

According to the present invention, drying Roxadustat sodium Form M1 at a temperature of about 45-65oC for 2 hours followed by slow cooling to 15-35°C obtains crystalline Roxadustat sodium Form M2.

In yet another embodiment, the present invention relates to crystalline Roxadustat sodium designated as Form M3.

In yet another embodiment, the present invention relates to crystalline Roxadustat sodium Form M3 characterized by powder X-ray diffraction pattern having peaks at 2.7,10.4, 24.6, 42.7,43.9 ±0.2° degrees 2?

In yet another embodiment, the crystalline Roxadustat sodium Form M3 may be characterized by the powder X-ray diffraction pattern as given in Figure 3.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat sodium Form M3 comprising the steps of:
a) drying Roxadustat sodium Form M1 at 100-125oC,
b) cooling to reaction mixture to 10-35°C, and
c) isolating crystalline Roxadustat sodium Form M3.

According to the present invention, drying Roxadustat sodium Form M1 at a temperature of about 100-125oC for 4 to 5 hours followed by slow cooling to about 10-35°C obtains crystalline Roxadustat sodium Form M3.

In yet another embodiment, the present invention relates to crystalline Roxadustat Sodium designated as Form M4.

In yet another embodiment, the present invention relates to crystalline Roxadustat sodium form M4 characterized by powder X-ray diffraction pattern having peaks at 2.7, 4.7, 5.4, 8.3, 10.3, 16.5, 22.1, 26.0 ±0.2° degrees 2?.

In yet another embodiment, the crystalline Roxadustat sodium Form M4 may be characterized by the powder X-ray diffraction pattern as given in Figure 4.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat sodium Form M4 comprising the steps of:
a) drying Roxadustat sodium Form M1 at 80oC,
b) cooling the reaction mixture to 20-30°C, and
c) isolating crystalline Roxadustat sodium Form M4.

According to the present invention, drying Roxadustat sodium Form M1 at a temperature of about 70 - 80?C for about 4 hours followed by slow cooling to about 20-30°C obtains crystalline Roxadustat sodium Form M4.

In yet another embodiment, the present invention relates to crystalline Roxadustat sodium designated as Form M5.

In yet another embodiment, the present invention relates to crystalline Roxadustat sodium form M5 characterized by powder X-ray diffraction pattern having peaks at 4.3, 6.6, 7.6, 9.1, 11.2, 11.7, 12.6, 13.9, 14.7, 17.0, 17.6, 19.3, 20.6, 21.3, 22.1, 24.0, 25.4, 25.9, 27.0, 27.9, 29.1, 30.4, 31.9, 42.7, 43.8, 45.7 ± 0.2° degrees 2?.

In yet another embodiment, the crystalline Roxadustat sodium Form M5 may be characterized by the powder X-ray diffraction pattern as given in Figure 5.

In yet another embodiment, the present invention relates to a process for the preparation of crystalline Roxadustat sodium Form M5 by placing Roxadustat sodium Form M3 in a petri-dish and expose to 90% relative humidity for 72hours.

In yet another embodiment, the present invention relates to Roxadustat Morpholine salt.

In yet another embodiment, the Roxadustat Morpholine salt is characterized by powder X-ray diffraction pattern having peaks at 5.3, 10.5, 11.9, 13.1, 15.5, 16.3, 17.0, 17.7 ,18.6, 19.0, 19.8, 20.3, 20.9, 21.5, 22.1, 22.6, 23.5, 24.1, 24.8, 25.8, 26.8, 27.1, 27.7, 28.5, 28.8, 30.1, 30.9, 31.6, 33.3, 33.9, 34.3, 36.4, 37.6 and 38.6, ± 0.2° degrees 2?.

In yet another embodiment, the Roxadustat Morpholine salt may be characterized by the powder X-ray diffraction pattern as given in Figure 6.

In yet another embodiment, the present invention relates to a process for the preparation of Roxadustat Morpholine salt comprising the steps of:
a) suspending Roxadustat in a solvent,
b) adding morpholine, and
c) isolating Roxadustat morpholine salt.
According to the present invention, Roxadustat may be suspended in an organic solvent such as isobutyl acetate, Ethyl acetate, n-butyl acetate, isopropyl acetate, n-propyl acetate and added with morpholine at elevated temperature. The resultant reaction mixture may be slowly cooled to 25+5oC and the solid obtained may be filtered and dried to obtain Roxadustat morpholine salt.
According to the present invention, morpholine may be added at a temperature of about 80+5oC.
In yet another embodiment, the present invention relates to a process for the preparation of amorphous form of Roxadustat comprising the steps of:
a) dissolving Roxadustat in a mixture of solvents, and
b) isolating amorphous Roxadustat
According to the present invention, Roxadustat may be dissolved in a solvent or mixture of solvents selected from alcohols such as methanol, ethanol or ketones such as acetone, esters such as ethyl acetate and spray dried the solvent at a feed rate of 5ml/min and inlet temperature of about 75oC to obtain Roxadustat amorphous form.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in anyway.

EXPERIMENTAL PROCEDURE:

Example 1: Roxadustat was suspended (1.0g) in Isobutyl acetate (10mL) at 80±5°C. Slowly added Morpholine (10mL) at 80±5°C and stirred for 60min at 80±5°C. Reaction mass further cooled to 25±5°C and stirred for 12h at 25±5°C. The resulting reaction mass was filtered and suck-dried for 30min. The solid obtained was identified as crystalline Roxadustat Morpholine salt.

Example 2: Process for the preparation of Roxadustat sodium Form M1

Roxadustat Morpholine salt (0.2g) was suspended in Methanolic HCl (1ml) at 25±5°C and stirred for 1h at 25±5°C. Slowly added 10% sodium bicarbonate solution (1ml) and stirred for 12h at 25±5°C. The resulting reaction mass was filtered and suck-dried for 30min. The solid obtained was identified as crystalline Roxadustat sodium Form M1.

Example 3: Process for the preparation of Roxadustat sodium Form M1

Roxadustat (3g) was dissolved in 10% aqeous sodium bicarobonate solution (30ml) at 25±5°C and the resulting clear solution was stirred for 60min. at 25±5°C. Then the clear solution was cooled to 20±5°C and the suspension was stirred for 12h at 20±5°C. The reaction mass was filtered and suck-dried for 30min. The solid obtained was identified as crystalline Roxadustat sodium Form M1.

Example 4: Process for the preparation of Roxadustat sodium Form M2

Roxadustat sodium Form M1 (0.5g) was dried at 50-60°C for 2h and followed by slow cooling to 30?C. The resulting solid was identified as crystalline Roxadustat sodium Form M2.

Example 5: Process for the preparation of Roxadustat sodium Form M3

Roxadustat sodium Form M1 (0.5g) was dried at 110-120°C for 4h and followed by slow cooling to 30?C. The resulting solid was identified as crystalline Roxadustat sodium Form M3.

Example 6: Process for the preparation of Roxadustat sodium Form M4

Roxadustat sodium Form M1 (100mg) was dried at 80°C for 4h and slowly cooled to 20-30?C. The resulting solid was identified as crystalline Roxadustat crystalline sodium Form M4.

Example 7: Process for the preparation of Roxadustat sodium Form M5

Roxadustat sodium Form M3 (100mg) was placed in a petri-dish and exposed to 90% relative humidity for 72h. The product obtained was tested by PXRD analysis and identified as crystalline Roxadustat sodium Form M5.

Example 8: Process for the preparation of Roxadustat amorphous form

Roxadustat(2.0g) was dissolved in a mixture of methanol(30mL) and acetone(30mL) at 25±5°C. Filtered through hiflow to remove any undisslved particulates. The clear solution was cooled to 25-30°C, then subjected to spray-drying in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5ml/min and inlet temperature at 75°C with 100% aspiration to yield Roxadustat amorphous form.
,CLAIMS:1. Crystalline Roxadustat Sodium.
2. The crystalline Roxadustat sodium as claimed in claim 1, has powder X-ray diffraction pattern having peaks at 2.8, 5.6, 6.9, 7.6, 8.5, 9.3, 10.0, 10.4, 11.3, 12.5, 13.2, 13.5, 14.1, 14.6, 15.4,16.3, 17.1, 17.8, 18.4, 18.7, 19.1, 20.0, 21.3, 22.2, 22.5, 22.9, 23.3, 24.0, 24.4, 25.4, 25.7, 26.3, 26.7, 27.4, 28.1, 28.8, 30.2 and 31.7± 0.2° degrees 2?, designated as Form M1.

3. The crystalline Roxadustat sodium Form M1 as claimed in claim 2, is prepared comprising the steps of:
c) suspending Roxadustat acid addition salt in an organic solvent,
d) adding base, and
c) isolating crystalline Roxadustat sodium Form M1 of.
wherein the acid addition salt is morpholine salt, solvent is an alcoholic hydrochloride solvent such as methanolic hydrochloride and the base is selected from Sodium bicarbonate, Sodium hydroxide, Sodium carbonate.
Or
a) dissolving Roxadustat in a base,
b) cooling the reaction mass, and
c) isolating crystalline Roxadustat sodium Form M1.
wherein the base is selected from Sodium bicarbonate, Sodium hydroxide, sodium bicarbonate and the cooling temperature is 20+5oC.
4. The crystalline Roxadustat sodium as claimed in claim 1, has powder X-ray diffraction pattern having peaks at 2.4, 2.9,5.8, 6.9, 8.0, 8.7, 9.8, 10.6, 11.6, 12.1, 13.2, 13.3, 14.1, 14.7, 15.9, 16.4, 17.6, 18.0, 19.2, 19.7, 20.5, 21.4, 22.9, 23.5, 25.3, 25.6, 26.8, 27.4, 28.1, 29.7 and 32.5±0.2° degrees 2?, designated as Form M2.

5. The crystalline Roxadustat sodium Form M2 as claimed in claim 4, is prepared comprising the steps of:
d) drying Roxadustat sodium Form M1 at 45-65oC,
e) cooling the reaction mixture to 15-35°C, and
f) isolating crystalline Roxadustat sodium Form M2.

6. The crystalline Roxadustat sodium as claimed in claim 1, has powder X-ray diffraction pattern having peaks at 2.7,10.4, 24.6, 42.7,43.9 ±0.2° degrees 2?, designated as Form M3.

7. The crystalline Roxadustat sodium Form M3 as claimed in claim 6, is prepared comprising the steps of:
c) drying Roxadustat sodium Form M1 at 100-125oC,
d) cooling the reaction mixture to 10-35°C, and
c) isolating crystalline Roxadustat sodium Form M3.

8. The crystalline Roxadustat sodium as claimed in claim 1, has powder X-ray diffraction pattern having peaks at 2.7, 4.7, 5.4, 8.3, 10.3, 16.5, 22.1, 26.0 ±0.2° degrees 2?, designated as Form M4.

9. The crystalline Roxadustat sodium Form M4 as claimed in claim 8, is prepared comprising the steps of:
c) drying Roxadustat sodium Form M1 at 80oC,
d) cooling the reaction mixture to 20-30°C, and
e) isolating crystalline Roxadustat sodium Form M4.

10. The crystalline Roxadustat sodium as claimed in claim 1, has powder X-ray diffraction pattern having peaks at 4.3, 6.6, 7.6, 9.1, 11.2, 11.7, 12.6, 13.9, 14.7, 17.0, 17.6, 19.3, 20.6, 21.3, 22.1, 24.0, 25.4, 25.9, 27.0, 27.9, 29.1, 30.4, 31.9, 42.7, 43.8, 45.7 ± 0.2° degrees 2?, designated as Form M5.

11. Roxadustat Morpholine salt.

12. The Roxadustat Morpholine salt as claimed in claim 11 has powder X-ray diffraction pattern having peaks at 5.3, 10.5, 11.9, 13.1, 15.5, 16.3, 17.0, 17.7 ,18.6, 19.0, 19.8, 20.3, 20.9, 21.5, 22.1, 22.6, 23.5, 24.1, 24.8, 25.8, 26.8, 27.1, 27.7, 28.5, 28.8, 30.1, 30.9, 31.6, 33.3, 33.9, 34.3, 36.4, 37.6 and 38.6, ± 0.2° degrees 2?.

13. The Roxadustat Morpholine salt as claimed in claim 11, is prepared by a process comprising the steps of:
a) suspending Roxadustat in a solvent,
b) adding morpholine, and
c) isolating Roxadustat morpholine salt.
Wherein the organic solvent is selected from isobutyl acetate, Ethyl acetate, n-butyl acetate, isopropyl acetate, n-propyl acetate.

14. A process for the preparation of amorphous form of Roxadustat comprising the steps of:
c) dissolving Roxadustat in a mixture of solvents, and
d) isolating amorphous Roxadustat
wherein the solvent or mixture of solvents is selected from alcohols such as methanol, ethanol or ketones such as acetone, esters such as ethyl acetate and the isolation is by spray drying.