DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“CO-CRYSTALS OF ROXADUSTAT AND PROCESS THEREOF”

Glenmark Life Sciences Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.
PRIORITY
This application claims the benefit to Indian Provisional Application No. 201921053500, filed on 23 December, 2019, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION
The present invention relates to co-crystals of roxadustat and process for the preparation.

BACKGROUND OF THE INVENTION
Roxadustat, an orally available inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) developed by FibroGen, AstraZeneca and Astellas, was launched in China and Japan in 2019 for the treatment of anemia caused by chronic kidney disease (CKD). The product is in phase III clinical trials in US.
The chemical name of roxadustat is N-[(4-hydroxy-1-methyl-7-phenoxyisoquinolin-3-yl) carbonyl]glycine, depicted by compound of formula I,

Formula I
As per the regulatory classification of pharmaceutical co-crystals guidance for industry, co-crystals are crystalline materials composed of two or more different molecules, typically active pharmaceutical ingredient (API) and co-crystal formers (coformers), in the same crystal lattice.
Pharmaceutical co-crystals have provided opportunities for engineering solid-state forms beyond conventional solid-state forms of an API, such as salts and polymorphs.
The present invention provides a co-crystal of roxadustat with gentisic acid and process thereof.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a co-crystal of roxadustat with gentisic acid characterized by powder X-ray diffraction (XRPD) peaks at 5.5, 7.4, 18.5, 22.2 and 23.1 ±0.2o 2?.
In one embodiment, the present invention provides a process for the preparation of co-crystal of roxadustat with gentisic acid, comprising:
(a) dissolving roxadustat and gentisic acid in a solvent;
(b) heating the solution obtained in step a) to a temperature of about 40°C to 110°C;
(c) optionally filtering;
(d) cooling the solution of step b) or step c) to a temperature of about -5°C to about 35°C; and
(e) vigorously stirring for about 12 hours to about 24 hours; and
(f) isolating co-crystal of roxadustat with gentisic acid.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of 1:1 co-crystal of roxadustat with gentisic acid.
Figure 2 is a DSC thermogram of 1:1 co-crystal of roxadustat with gentisic acid.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a co-crystal of roxadustat with gentisic acid.
In one embodiment, the present invention provides a co-crystal of roxadustat with gentisic acid, characterized by powder X-ray diffraction (XRPD) as shown in figure 1, having characteristics peaks at 5.5, 7.4, 18.5, 22.2 and 23.1 ±0.2o 2?.
In one embodiment, the co-crystal of roxadustat with gentisic acid is characterized by differential scanning calorimeter (DSC) as shown in figure 2, having endothermic peak at about 186 ± 4oC.
In one embodiment, the present invention provides co-crystal of roxadustat with gentisic acid wherein the ratio of roxadustat:gentisic acid is about 1:1, 1:2 or 1:3.
In one embodiment, the present invention provides co-crystal of roxadustat with gentisic acid wherein the ratio of roxadustat:gentisic acid is about 1:1.
In one embodiment, the present invention provides a process for the preparation of co-crystal of roxadustat with gentisic acid, comprising:
(a) dissolving roxadustat and gentisic acid in a solvent;
(b) heating the solution obtained in step a) to a temperature of about 40°C to 110°C;
(c) optionally filtering;
(d) cooling the solution of step b) or step c) to a temperature of about -5°C to about 35°C; and
(e) vigorously stirring for about 12 hours to about 24 hours; and
(f) Isolating co-crystal of roxadustat with gentisic acid.
In one embodiment, the solvent used in step a) may be selected from C1-C6 aliphatic carboxylic acid.
In one embodiment, C1-C6 aliphatic carboxylic acid may be selected from the group consisting of formic acid, acetic acid, propanoic acid, butanoic acid and the like.
In one embodiment, solution obtained in step a) may be heated to a temperature of about 40oC to about 110oC.
In one embodiment, solution obtained in step a) may be heated to a temperature of about 60oC to about 80oC.
In one embodiment, stirring in step e) may be carried out for about 12 hours to about 18 hours.
In one embodiment, the present invention provides pharmaceutical composition comprising co-crystal of roxadustat.
In one embodiment, the present invention provides pharmaceutical composition comprising co-crystal of roxadustat with gentisic acid.
X-ray powder diffraction profiles were obtained using an X-ray diffractometer (Philips
X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module
programmable divergence slit and anti-scatter Slit (Offset 0.00°); target, Cu; filter, Ni;
detector, X’Celerator; Scanning Mode; Active length (2?) = 2.122°; generator 45KV;
tube current 40mAmp. The samples were scanned in the full 2? range of 2-50° with a
15 “time-per-step” optimized to 50 sec.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages

EXAMPLES
Example 1: Preparation of Roxadustat (I)
3-isoquinolinecarboxylic acid-4-hydroxy-1-methyl-7-phenoxy methyl ester (10gm) and glycine (7.28gm) was charged in methanol. The reaction mixture was stirred for about 6 hours to about 8 hours at about 110oC to about 115°C. After completion of reaction, reaction mixture was cooled to about 25oC to about 30oC, filtered, washed with methanol and dried under vacuum to give Roxadustat disodium salt (13.1gm). The solid was dissolved in water and washed with ethyl acetate. Aqueous layer was treated with activated carbon and pH was adjusted to about 4.50 to about 5.0 using acetic acid. The solid was filtered, washed with water and air dried.

Example 2: Purification of Roxadustat (I)
Roxadustat was charged in acetone and stirred for about 1 hour to about 2 hour at the temperature of about 50oC to about 55oC. The reaction mixture was cooled to about 0oC to about 5oC, filtered, washed with acetone and dried under vacuum to obtain Roxadustat (I).

Example 3: Preparation of co-crystal of Roxadustat with gentisic acid
Roxadustat, the compound of formula I (10gm), gentisic acid (4.37gm) were dissolved in formic acid (160ml) and stirred at about 70oC to about 75°C for about 30 minutes to about 45 minutes, to obtain clear solution. The solution was filtered and washed with formic acid. The solution was gradually cooled to room temperature, co-crystal was obtained by vigorous mixing for about 15 hours to about 18 hours. The slurry was filtered and dried. Yield: 7.0 gm.

XRD peaks of co-crystal of Roxadustat with gentisic acid
Pos. [°2?] d-spacing [Å] Rel. Int. [%] Pos. [°2?] d-spacing [Å] Rel. Int. [%]
5.5 16.1 8.4 23.1) 3.8 16.0
7.4 11.9 100.00 24.1 3.7 3.7
12.9 6.9 9.4 25.0 3.6 10.0
13.7 6.5 9.2 25.7 3.5 3.1
14.9 5.9 1.9 26.5 3.4 9.5
15.5 5.7 7.8 28.1 3.2 11.6
16.3 5.4 11.59 28.8 3.1 13.2
16.6 5.3 5.6 30.3 2.9 2.6
16.9 5.2 3.8 31.3 2.9 4.6
17.7 5.0 7.3 32.6 2.7 1.0
18.5 4.8 24.3 35.1 2.6 1.9
19.5 4.6 1.4 37.8 2.4 1.8
22.3 4.0 20.4 23.1 3.8 16.0
,CLAIMS:We Claim:
1. A co-crystal of roxadustat with gentisic acid.
2. The co-crystal of roxadustat with gentisic acid as claimed in claim 1, characterized by powder X-ray diffraction (XRPD) peaks at 5.5, 7.4, 18.5, 22.2 and 23.1 ±0.2o 2?.
3. The co-crystal as claimed in claim 1, characterized by differential scanning calorimeter (DSC) having endothermic peak at about 186 ± 4oC.
4. The co-crystal of roxadustat with gentisic acid as claimed in claim 1, wherein the ratio of roxadustat:gentisic acid is about 1:1, 1:2 or 1:3.
5. A process for the preparation of co-crystal of roxadustat with gentisic acid, comprising:
(a) dissolving roxadustat and gentisic acid in a solvent;
(b) heating the solution obtained in step a) to a temperature of about 40°C to 110°C;
(c) optionally filtering;
(d) cooling the solution of step b) or step c) to a temperature of about -5°C to about 35°C; and
(e) vigorously stirring for about 12 hours to about 24 hours; and
(f) isolating co-crystal of roxadustat with gentisic acid.
6. The process as claimed in claim 5, wherein solvent used in step a) is selected from C1-C6 aliphatic carboxylic acid such as formic acid, acetic acid, propanoic acid, butanoic acid.

Dated this 18th day of December, 2020

(Signed)____________________

DR. VARSHA SADEKAR
GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED