DESC:CROSS-REFERENCE TO RELATED APPLICATION:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN202041035152 filed on Aug 14, 2020.
FIELD OF THE INVENTION
The present invention relates to Co-crystal of Favipiravir with 4-Hydroxybenzoic acid and its preparation thereof.
DESCRIPTION OF THE RELATED ART
Favipiravir, sold under the brand names Avigan, Abigan and FabiFlu, is an antiviral medication used to treat influenza. It was developed and manufactured by Toyama Chemical (Fujifilm group) and was approved for medical use in Japan in 2014 for the treatment of Influenza. It is also being studied to treat a number of other viral infections including Covid 19. It is represented by formula 1 shown below:

Formula 1
Favipiravir was disclosed in U.S Patent 6787544 B2 which is hereby incorporated by reference.
The inventors of the present invention have developed Co-crystal of Favipiravir with 4-Hydroxybenzoic acid having improved stability thus suitable for formulation development.
SUMMARY OF THE INVENTION.
The main object of the present invention provides Co-crystal of Favipiravir with 4-Hydroxybenzoic acid and its preparation thereof.
In one aspect, the Co-crystal of Favipiravir with 4-Hydroxybenzoic acid formed by the present process is in the molar ratio of 1:1.
In yet another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is designated as Form M1.
In another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by powder X-ray diffraction pattern having peaks at, 15.52, 17.18, 25.23, 28.20 or 28.61 ± 0.2° degrees 2?.
Yet in another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by powder X-ray diffraction pattern having further peaks at 6.23, 12.04, 12.46, 13.20, 14.93, 15.52, 16.28, 17.57, 18.74, 19.49, 20.06, 20.79, 22.10, 22.49, 23.37, 23.79, 24.21, 24.48, 25.23, 25.85, 26.56, 28.20, 28.61, 29.35, 29.87, 30.36 ± 0.2° degrees 2?.
Yet in another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by powder X-ray diffraction pattern shown in Figure 1 as per example 1.
Yet in another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by powder X-ray diffraction pattern shown in Figure 2 as per example 2.
Yet in another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by differential scanning calorimetric (DSC) thermogram having endothermic peak at about 167.13°C, as per example 1.
Yet in another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by differential scanning calorimetric (DSC) thermogram having endothermic peaks at about 167.59°C, as per example 2.
Yet in another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is prepared comprising the steps of:
a) adding Favipiravir, 4-Hydroxybenzoic acid to a solvent,
b) heating the contents,
c) removing the solvent,
d) adding solvent, and
e) Isolating 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.

Yet in another aspect, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is prepared comprising the steps of:
a) adding Favipiravir, 4-Hydroxybenzoic acid to a solvent,
b) Isolating 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.

Brief description of the figures:
Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of Favipiravir 4-Hydroxybenzoic acid (1:1) Co-crystal, as per example 1.
Figure 2 depicts an X-Ray Powder Diffraction (XRPD) pattern of Favipiravir 4-Hydroxybenzoic acid (1:1) Co-crystal, as per example 2.
Figure 3 depicts DSC thermogram of Favipiravir 4-Hydroxybenzoic acid (1:1) Co-crystal as per example 1.
Figure 4 depicts DSC thermogram of Favipiravir 4-Hydroxybenzoic acid (1:1) Co-crystal as per example 2.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to Co-crystal of Favipiravir 4-Hydroxybenzoic acid and its preparation thereof.
In one embodiment, the Co-crystal of Favipiravir with 4-Hydroxybenzoic acid formed by the present process is in the molar ratio of 1:1.
In another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is designated as Form M1.
In yet another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by powder X-ray diffraction pattern having peaks at15.52, 17.18, 25.23, 28.20 or 28.61 ± 0.2° degrees 2?. Yet in another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by powder X-ray diffraction pattern having further peaks at 6.23, 12.04, 12.46, 13.20, 14.93, 15.52, 16.28, 17.57, 18.74, 19.49, 20.06, 20.79, 22.10, 22.49, 23.37, 23.79, 24.21, 24.48, 25.23, 25.85, 26.56, 28.20, 28.61, 29.35, 29.87, 30.36 ± 0.2° degrees 2?.
Yet in another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by powder X-ray diffraction pattern shown in Figure 1 as per example 1.
Yet in another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by powder X-ray diffraction pattern shown in Figure 2 as per example 2.
Yet in another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by differential scanning calorimetric (DSC) thermogram having endothermic peak at about 167.13°C, as per example 1.
Yet in another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is characterized by differential scanning calorimetric (DSC) thermogram having endothermic peaks at about 167.59°C, as per example 2.
Yet in another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is prepared comprising the steps of:
f) adding Favipiravir, 4-Hydroxybenzoic acid to a solvent,
g) heating the contents,
h) removing the solvent,
i) adding solvent, and
j) Isolating 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
According to the present invention, Favipiravir and 4-Hydroxybenzoic acid may be taken in an organic solvent selected from alcohols such as methanol, ethanol or isopropanol or mixtures thereof and the reaction contents may be heated to about 50-75°C and stirred for 15-30min. The obtained clear solution may be distilled completely under vacuum and resultant mass may be cooled to 25-30°C followed by addition of an organic solvent preferably an alcoholic solvent such as ethanol and maintain the reaction mass at room temperature for about 16 to 18 hours. The resultant solid may be filtered and dried under vacuum to obtain 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
Yet in another embodiment, the Co-crystal of Favipiravir 4-Hydroxybenzoic acid is prepared comprising the steps of:
c) adding Favipiravir, 4-Hydroxybenzoic acid to a solvent,
d) Isolating 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
According to the present invention, Favipiravir and 4-Hydroxybenzoic acid may be taken in an organic solvent selected from alcohols such as methanol, ethanol or isopropanol or mixtures and the reaction mixture may be maintained at room temperature for about 16 to 18 hours. The resultant solid may be filtered and dried under vacuum to obtain 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
Yet in another embodiment, the present invention relates to a pharmaceutical composition comprising of 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid and a pharmaceutically acceptable salt.
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 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
In a RBF, charged Favipiravir (0.3g), 4-Hydroxybenzoic acid (0.52g) and Ethanol (6mL) at 25±5°C. Heated the contents to 60-65°C and stirred for 15-30min at 60-65°C. The obtained clear solution was distilled completely under vacuum at 60-65°C. The reaction mass was cooled to 25-30°C, charged ethanol (3mL) and maintained under stirring at 25±5°C for 16h. The product obtained was filtered and dried under vacuum for 4h at 35?C. The solid obtained was identified as 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
Yield: 0.45g
Example 2: Process for the preparation of 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
In a RBF, charged Favipiravir (0.5g), 4-Hydroxybenzoic acid (0.88g) and Ethanol (5mL) at 25±5°C. Stirred the reaction mass for 16h at 25±5°C. The product obtained was filtered, washed with ethanol (0.5mL) and dried under vacuum for 16h at 35?C. The solid obtained was identified as 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
Yield: 0.73g
,CLAIMS:1. A Co-crystal of Favipiravir with 4-Hydroxybenzoic acid.
2. The Co-crystal as claimed in claim 1, wherein the molar ratio of Favipiravir and 4-Hydroxybenzoic acid is 1:1.
3. The Co-crystal as claimed in claim 1, is characterized by having a powder X-ray
diffractogram comprising reflections at 2-theta angles of 15.52, 17.18, 25.23,
28.20 or 28.61 ± 0.2° degrees 2?.
4. The Co-crystal as claimed in claim 3, as shown in Figure-1
5. The Co-crystal as claimed in claim 1, is prepared comprising the steps of
a) adding Favipiravir, 4-Hydroxybenzoic acid to a solvent,
b) heating the contents,
c) removing the solvent,
d) adding solvent, and
e) isolating 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.
6. The process as claimed in claim 5, wherein the solvent is selected from alcohols such as methanol, ethanol or isopropanol or mixtures thereof followed by addition of an organic solvent preferably an alcoholic solvent such as ethanol.
7. The Co-crystal as claimed in claim 1, is prepared comprising the steps of
a) adding Favipiravir, 4-Hydroxybenzoic acid to a solvent,
b) isolating 1:1 Co-crystal of Favipiravir 4-Hydroxybenzoic acid.

8. The process as claimed in claim 7, wherein the solvent selected from alcohols such as methanol, ethanol or isopropanol or mixtures thereof.
9. The Co-crystal of Favipiravir with 4-Hydroxybenzoic acid as claimed in claim 1, is characterized by differential scanning calorimetric (DSC) thermogram having endothermic peaks at about 167.13°C or 167.59°C.
10. A pharmaceutical composition comprising the Co-crystal of Favipiravir with 4-Hydroxybenzoic acid as defined in any one of claims and at least one pharmaceutically acceptable excipient.