DESC:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULES 2003
(SECTION 10 AND RULE 13)

COMPLETE SPECIFICATION

“HIGHLY PURE CRYSTALLINE FORM 1 OF 6-FLUORO-3-HYDROXYPYRAZINE-2-CARBOXAMIDE”

SYMED LABS LIMITED
An Indian Company having its Office at
8-2-293/174/3, Beside B.N. Reddy Colony,
Road No. 14, Banjara Hills,
Hyderabad-500 034,
Telangana, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES AND ASSERTAINS THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

CROSS REFERENCE TO RELATED APPLICATION
This patent application claims the benefit of priority to Indian Provisional Patent Application No. 202041026478, filed on June 23, 2020, which is incorporated herein by
reference in their entirety.

FIELD OF THE INVENTION
The present invention relates to a stable and highly pure crystalline Form 1 of 6-fluoro-3-hydroxypyrazine-2-carboxamide. The present invention further relates to a novel, consistently reproducible and commercially viable process for the production of highly pure crystalline Form 1 of 6-fluoro-3-hydroxypyrazine-2-carboxamide.

BACKGROUND OF THE INVENTION
U.S. Patent No. 6,787,544 discloses a variety of Nitrogen-containing heterocyclic carboxamide derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds have antiviral activity against various viruses, especially influenza viruses. Among them, Favipiravir, chemically named 6-Fluoro-3-hydroxypyrazine-2-carboxamide, is a most promising antiviral agent exhibiting a preventive effect and a therapeutic effect against various viruses, especially influenza. Favipiravir is represented by the following structural formula 1:

Favipiravir was approved by the Japanese Pharmaceuticals and Medical Device Agency (PMDA) for use in Japan for the treatment of novel or re-emerging pandemic influenza virus infections (limited to cases in which other influenza antiviral drugs are ineffective or not sufficiently effective) and it is sold under the trade name AVIGAN®. It is orally administered as tablets containing 200mg of Favipiravir.
The recent studies suggest that Favipiravir also has efficacy against infection with the new corona virus (COVID-19) in view of its characteristic mechanism of action. Favipiravir is a selective inhibitor of the RNA polymerase involved in viral replication. Animal studies showed that it’s effective against influenza as well as West Nile virus, yellow fever, foot-and-mouth disease. Favipiravir (Avigan) is approved in Japan and China for influenza and is investigational for use in COVID-19. Phase III clinical trials are ongoing in Japan for the treatment of COVID-19.
Various processes for the preparation of Favipiravir, and its intermediates, and pharmaceutically acceptable salts, are disclosed in U.S. Patent Nos. US 6,787,544; US 8,168,789; US 8,586,741; and US 8,901,302.
U.S. Patent No. 6,787,544 (hereinafter referred to as the ‘544 patent) describes the synthesis of Favipiravir in an analogous manner. The synthesis of Favipiravir is depicted in below scheme-1:

According to the synthesis process described in the US’544 patent, Favipiravir is prepared by the following reaction steps: a) methyl 6-bromo-3-amino-2-pyrazinecarboxylate is reacted with sodium nitrite in the presence of concentrated sulphuric acid and methanol to produce methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate; b) methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate is reacted with benzophenone-imine in the presence of tris(dibenzylideneacetone) dipalladium, (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and a base sodium t-butoxide and toluene as solvent to produce methyl 6-amino-3-methoxy-2-pyrazinecarboxylate; c) methyl 6-amino-3-methoxy-2-pyrazinecarboxylate is reacted with gaseous ammonia in the presence of solvent methanol to produce 6-amino-3-methoxy-2-pyrazinecarboxamide; d) 6-amino-3-methoxy-2-pyrazinecarboxamide is reacted with sodium nitrite in the presence of solvent 70% hydrogen fluoride in pyridine to produce 6-fluoro-3-methoxy-2-pyrazinecarboxamide; and e) 6-fluoro-3-methoxy-2-pyrazine carboxamide is reacted with trimethylsilylchloride in the presence of sodium iodide and acetonitrile as solvent to produce Favipiravir.
The PMDA Product Report dated March 4, 2014 discloses that Favipiravir is known to exhibit polymorphism and two crystalline forms (designated as Form A and Form B) are so far known. The PMDA Report discloses that the Favipiravir drug substance is not hygroscopic at 25°C/51% to 93%RH. The melting point is 187°C to 193°C, and the dissociation constant (pKa) is 5.1 due to hydroxyl group of Favipiravir. The stability study does not show any change in crystal form over time; and a change from Form A to Form B is unlikely. However, the PMDA Product Report does not disclose any characterization data (XRPD and/or IR) of the said crystalline forms (Form A and Form B) of Favipiravir.
Various crystalline forms of sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, and its meglumine salt are apparently disclosed in U.S. Patent Nos. US 9,096,547 and US 9,090,571 (assigned to Toyama Chemical Industry Co., Ltd.).
U.S. Patent No. 9,096,547 (hereinafter referred to as the US’547 patent), assigned to Toyama Chemical Industry Co., Ltd, discloses three crystalline forms of sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide namely Hydrate, Dihydrate and Anhydrous Forms.
According to the US’547 patent, the crystalline hydrate form of sodium salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (Favipiravir sodium salt) is characterized by an XRPD pattern having 2-theta peaks at 9.4, 13.6, 14.2, 14.7, 17.8, 18.8, 23.4, 28.0, 28.6, 33.0 and 34.3 ± 0.2 degrees; the crystalline dihydrate form of Favipiravir sodium salt is characterized by an XRPD pattern having 2-theta peaks at 10.0, 20.1, 29.2, 30.3, 31.1, and 36.2 ± 0.2 degrees; and the crystalline anhydrous form of Favipiravir sodium salt is characterized by an XRPD pattern having 2-theta peaks at 13.7, 15.6, 27.5, 29.6, 31.6 and 35.2 ± 0.2 degrees. However, the US’547 patent does not disclose any polymorphic forms of Favipiravir.
U.S. Patent No. 9,090,571 (hereinafter referred to as the US’571 patent), assigned to Toyama Chemical Industry Co., Ltd, discloses two crystalline forms and an amorphous form of meglumine salt of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (Favipiravir meglumine salt) namely monohydrate, anhydrous and amorphous Forms.
According to the US’571 patent, the crystalline monohydrate form of Favipiravir meglumine salt is characterized by an XRPD pattern having 2-theta peaks at 10.8, 12.4, 16.2, 16.5, 18.7, 18.9, 19.7, 20.7, 21.7, 22.0, 23.2 14.7, and 23.6 ± 0.2 degrees and the crystalline anhydrous form of Favipiravir meglumine salt is characterized by an XRPD pattern having 2-theta peaks at 10.2, 11.3, 13.0, 15.9, 17.0, 18.7, 19.7 20.5, 22.0, 24.2, 26.4 and 28.1 ± 0.2 degrees. However, the US’571 patent does not disclose any polymorphic forms of Favipiravir.
CN102977039B (hereinafter referred to as the CN’039 publication) discloses an alpha crystalline form of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (Favipiravir) and characterizes the crystalline form by X-ray crystallographic analysis, with approximate crystal parameters as follows: Crystallographic system: its unit cell parameters are a=9.1106(8)A, b=14.7619 (14) A, c=4.6910 (4) A, a=90°, ß=90°, ?=90°, the spatial structure is layered, and the molecules are connected by hydrogen bonds. The alpha crystalline form of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is further characterized by an XRPD pattern having 2-theta peaks at 11.8-11.9°, 20.2-20.3°, 22.8-22.9° and 27.8-27.9°± 0.2 degrees; and an infrared (IR) absorption spectrum in potassium bromide having the characteristic absorption bands at 1264-1266 cm-1, 1397-1399 cm-1, 1437- 1441 cm-1, 1670-1673cm-1, 3224-3227cm-1 and 3347-3356 cm-1. According to the CN’039 patent, alpha crystalline form of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide is prepared by adding solvent to 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, the mixture is heated to refluxed for one hour, naturally cooled to crystallize, the separated solid is filtered and dried under vacuum at 55-65°C for 6-8 hours. The solvent is selected from the group consisting of methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, and ethyl acetate.
A need still remains for a stable and highly pure crystalline form of Favipiravir, and consistently reproducible and industrially advantageous processes for the preparation thereof.

SUMMARY OF THE INVENTION
In one aspect, provided herein is a stable and highly pure crystalline Form 1 of Favipiravir characterized by an X-ray powder diffraction (XPRD) pattern having peaks expressed as 2-theta angle positions at about 18.36 and 21.16 ± 0.2 degrees substantially in accordance with Figure 1 and/or Figure 4.
In one embodiment, the X-ray powder diffraction (XPRD) pattern crystalline Form 1 of Favipiravir is having additional 2-theta peaks at about 12.07, 19.91, 20.46, 22.99, 24.17, 26.29, 26.80, 27.33 and 28.02 ± 0.2 degrees substantially in accordance with Figure 1 and/or Figure 4.
In another embodiment, the crystalline Form 1 of Favipiravir is further characterized by an infra red (FT-IR) spectrum having main bands at about 3416, 3363, 3279, 3232, 1674, 1602, 1563, 1470, 1438, 1397, 1329, 1265, 1184, 1113, 1063, 971, 929, 819, 788 and 714 cm-1 ± 5 cm-1 substantially in accordance with Figure 2 and/or Figure 5.
In another embodiment, the crystalline Form 1 of Favipiravir is further characterized by a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 181.7°C and a sharp endotherm peak at about 186.4°C substantially in accordance with Figure 3 and/or Figure 6.
The crystalline Form 1 of Favipiravir is consistently reproducible does not have the tendency to convert to other forms and found to be thermally more stable.
In one embodiment, the crystalline Form 1 of Favipiravir obtained by the processes disclosed herein is essentially free from other crystalline forms of Favipiravir detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The term “crystalline Form 1 of Favipiravir essentially free of other crystalline forms” means that no other polymorphic forms of Favipiravir can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Favipiravir” is intended to mean the polymorphic forms of Favipiravir other than crystalline Form 1.
In another aspect, provided also herein is a simple, cost effective and consistently reproducible process for the preparation of highly pure crystalline Form 1 of Favipiravir essentially free of other crystalline forms.
The highly pure crystalline Form 1 of Favipiravir obtained by the process disclosed herein has a purity of greater than about 99%, specifically greater than about 99.5%, and most specifically greater than about 99.9% as measured by HPLC. For example, the purity of the highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein is about 99% to about 99.99% as measured by HPLC.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20°C to about 35°C. For example, “room temperature” can refer to a temperature of about 25°C to about 30°C.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form 1 of Favipiravir as disclosed herein, and one or more pharmaceutically acceptable excipients.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form 1 of Favipiravir made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form 1 of Favipiravir disclosed herein, with one or more pharmaceutically acceptable excipients.
In another aspect, the highly pure crystalline Form 1 of Favipiravir made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 1 micron to about 110 microns, and most specifically about 4 microns to about 90 microns.
Unless otherwise specified, the term “crude Favipiravir” refers to any form of Favipiravir having purity less than 99.3% as measured by HPLC.
Unless otherwise specified, the term “pure Favipiravir” refers to any form of Favipiravir having purity greater than 99.3% as measured by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form 1 of Favipiravir.
Figure 2 is a characteristic infra-red (IR) spectrum of crystalline Form 1 of Favipiravir.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of
crystalline Form 1 of Favipiravir.
Figure 4 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form 1 of Favipiravir.
Figure 5 is a characteristic infra-red (IR) spectrum of crystalline Form 1 of Favipiravir.
Figure 6 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form 1 of Favipiravir.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a stable and highly pure crystalline Form 1 of Favipiravir characterized by an X-ray powder diffraction (XRPD) pattern having peaks expressed as 2-theta angle positions at about 18.36 and 21.16 ± 0.2 degrees substantially in accordance with Figure 1 and/or Figure 4.
In one embodiment, the X-ray powder diffraction (XRPD) pattern crystalline Form 1 of Favipiravir is having additional 2-theta peaks at about 12.07, 19.91, 20.46, 22.99, 24.17, 26.29, 26.80, 27.33 and 28.02 ± 0.2 degrees substantially in accordance with Figure 1 and/or Figure 4.
In another embodiment, the crystalline Form 1 of Favipiravir is further characterized by an infra red (FT-IR) spectrum having main bands at about 3416, 3363, 3279, 3232, 1674, 1602, 1563, 1470, 1438, 1397, 1329, 1265, 1184, 1113, 1063, 971, 929, 819, 788 and 714 cm-1 ± 5 cm-1 substantially in accordance with Figure 2 and/or Figure 5.
In another embodiment, the crystalline Form 1 of Favipiravir is further characterized by a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 181.7°C and a sharp endotherm peak at about 186.4°C substantially in accordance with Figure 3 and/or Figure 6.
According to another aspect, there is provided a process for the preparation of stable and highly pure crystalline Form 1 of Favipiravir, comprising:
a) providing a suspension of Favipiravir (crude or pure) in an aromatic hydrocarbon solvent at the reflux temperature of the solvent used;
b) stirring the suspension formed in step-(a) at the reflux temperature of the solvent used to obtain a hot slurry;
c) cooling the hot slurry obtained in step-(b) to below about 55°C;
d) recovering the highly pure crystalline Form 1 of Favipiravir formed in step-(c); and
e) optionally repeating the process steps (a) to (d) to improve the purity of the resulting crystalline Form 1 of Favipiravir obtained in step-(d).
In one embodiment, the aromatic hydrocarbon solvent used in step-(a) is selected from the group consisting of toluene, xylene, and mixtures thereof. A most specific aromatic hydrocarbon solvent used in step-(a) is toluene.
Usually, the amount of solvent employed in step-(a) is about 8 volumes to about 12 volumes, and most specifically about 10 volumes, with respect to the quantity of Favipiravir taken as starting material.
In one embodiment, the stirring in step-(b) is carried out for at least 10 minutes, specifically for about 30 minutes to 5 hours, and most specifically for about 1 hour to about 3 hours.
In another embodiment, the hot slurry in step-(c) is cooled while stirring at a temperature of about 0°C to about 55°C for at least 10 minutes and more specifically at a temperature of about 30°C to about 50°C for about 15 minutes to about 2 hours.
The recovering in step-(d) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
According to another aspect, there is provided a purification process for the preparation of highly pure crystalline form of Favipiravir, comprising:
a) providing a solution of Favipiravir in a solvent at a temperature of above 35ºC, wherein the solvent is selected from the group consisting of water, an alcohol, a ketone, an ester, a halogenated hydrocarbon, a polar aprotic solvent, and mixtures thereof;
b) optionally, subjecting the solution obtained in step-(a) to carbon treatment to obtain a filtrate;
c) isolating highly pure crystalline form of Favipiravir from the solution formed in step-(a) or step-(b) by cooling, seeding, partial removal of the solvent from the solution, or by admixing the solution with an anti-solvent, or a combination thereof; and
d) collecting the highly pure crystalline form of Favipiravir obtained in step-(c).
In one embodiment, the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. The term “solvent” as used herein also includes the mixture of solvents.
Step-(a) of providing a solution of Favipiravir includes dissolving an impure Favipiravir in the solvent used in step-(a), or obtaining an existing solution from a previous processing step.
In another embodiment, the Favipiravir is dissolved in the solvent used in step-(a) at a temperature of about 40°C to the reflux temperature of the solvent used, and specifically at reflux temperature of the solvent used. After complete dissolution of Favipiravir, the resulting solution is stirred at a temperature of about 40°C to the reflux temperature of the solvent used for at least 5 minutes, and specifically for about 10 minutes to about 1 hour.
In another embodiment, the solution in step-(a) is also prepared by suspending Favipiravir in the solvent used in step-(a) at room temperature, followed by heating the suspension at a temperature of about 40°C to the reflux temperature to form a clear solution, specifically at the reflux temperature of the solvent used. After complete dissolution of Favipiravir, the resulting solution is stirred at reflux temperature for at least 5 minutes, and specifically for about 10 minutes to about 1 hour.
The carbon treatment in step-(b) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Favipiravir by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In one embodiment, the isolation in step-(c) is accomplished by cooling the solution while stirring at a temperature of below 35°C for at least 5 minutes; more specifically at a temperature of about 0°C to about 30°C for about 10 minutes to about 10 hours, and most specifically at a temperature of about 15°C to about 30°C for about 30 minutes to about 5 hours.
In another embodiment, the isolation in step-(c) is also accomplished by combining the solution with an anti-solvent. As used herein, the term “anti-solvent” means a solvent which when added to an existing solution of a substance reduces the solubility of the substance.
The anti-solvent used in step-(c) is selected from the group consisting of water, an ether, an ester, a hydrocarbon solvent, and mixtures thereof. Specifically, the anti-solvent is selected from the group consisting of water, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof.
The admixing in step-(c) may be done in any order, for example, the anti-solvent may be added to the solution, or alternatively, the solution may be added to the anti- solvent. When the hot solution is added to the anti-solvent, the temperature difference causes the fast crystallization. The addition may be carried out drop wise or in one volume. The addition is preferably carried out while stirring at a temperature of about 35ºC to about 80ºC for at least 5 minutes, and more preferably at a temperature of about 40ºC to about 75ºC from about 10 minutes to about 5 hours. After completion of the addition process, the admixture may preferably be cooled at a temperature of below 35ºC, and more preferably at a temperature of about 0ºC to about 30ºC.
The collection of the highly pure crystalline form of Favipiravir in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
Unless otherwise specified, the crude Favipiravir as used herein above as starting material can be obtained, for example, by the process described in the U.S. Patent Nos. US 6,787,544; US 8,168,789; US 8,586,741; and US 8,901,302; and Chinese Patent Application Nos. CN106478528A and CN105732523A; and Scientific Articles: 113th Electronic Conference on Synthetic Organic Chemistry; Chemical Papers, 2017, 71(11), 2153-2158; Drug Discoveries & Therapeutics. 2014; 8(3):117-120; and Chemical Papers 2019 Volume73 (5), 1043-1051.
The highly pure crystalline Form 1 of Favipiravir obtained by the process disclosed herein has a purity of greater than about 99%, specifically greater than about 99.5%, and most specifically greater than about 99.9% as measured by HPLC. For example, the purity of the highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein is about 99% to about 99.99% as measured by HPLC.
Unless otherwise specified, the highly pure crystalline Form 1 of Favipiravir obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 100°C, and specifically at about 50°C to about 90°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 30 minutes to about 30 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed dryer, spin flash dryer, flash dryer, and the like.
Further encompassed herein is the use of the highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.
In one embodiment, the highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 1 microns to about 110 microns, and most specifically about 4 microns to about 90 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form 1 of Favipiravir obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, parenteral, or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, suspensions, powders, and the like.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr.The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 250°C.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = Kromasil C18, (250 × 4.6) mm, 5 µm; Detector wavelength = 325 nm; Flow Rate = 0.8 ml/minute; Injection volume = 10 µL; Oven temperature = 45°C; Run time = 50 minutes; Diluent = Acetonitrile and water in the ratio of 10:90, (v/v); Elution = Gradient; and Sample Concentration: 1.0 mg/ml.
Mobile Phase-A: Buffer
Mobile Phase-B: Methanol
The following example is given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLE
Preparation of pure crystalline Form 1 of Favipiravir
Toluene (70 ml) was added to crude Favipiravir (7 g) at 25-30ºC and the resulting suspension was heated to reflux temperature (110-115ºC), followed by stirring the suspension for 1 hour at reflux temperature to obtain a hot slurry. The resulting hot slurry was cooled to 50oC and then filtered the material and washed with toluene (2 x 14 ml). The resulting material was dried at 60-65ºC for 1 to 2 hours to produce 6.7 g of a pale yellow solid (Purity by HPLC: 99.36%). Toluene (67 ml) was added to the resulting pale yellow solid at 25-30ºC, and the resulting suspension was heated to reflux temperature (110ºC-115ºC) to form a suspension, followed by stirring the solution for 1 hour to 2 hours at reflux temperature to obtain a hot slurry. The resulting hot slurry was cooled to 50oC, filtered the solid and then washed the material with toluene (2 x 7 ml). The resulting material was dried at 60-65ºC for 1 to 2 hours to produce 6 g of pure crystalline Form 1 of Favipiravir as pale yellow solid (Purity by HPLC: 99.75%).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethyl cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
,CLAIMS:We Claim:
1. A stable and highly pure crystalline Form 1 of Favipiravir characterized by an X-ray powder diffraction (XRPD) pattern having peaks expressed as 2-theta angle positions at about 18.36 and 21.16 ± 0.2 degrees substantially in accordance with Figure 1 and/or Figure 4.
2. The highly pure crystalline Form 1 of Favipiravir as claimed in claim 1, which is further characterized by: (i) an X-ray powder diffraction (XPRD) pattern comprising one or more additional 2-theta peaks at about 12.07, 19.91, 20.46, 22.99, 24.17, 26.29, 26.80, 27.33 and 28.02 ± 0.2 degrees substantially in accordance with Figure 1 and/or Figure 4; (ii) an infra red (FT-IR) spectrum having main bands at about 3416, 3363, 3279, 3232, 1674, 1602, 1563, 1470, 1438, 1397, 1329, 1265, 1184, 1113, 1063, 971, 929, 819, 788 and 714 cm-1 ± 5 cm-1 substantially in accordance with Figure 2 and/or Figure 5; and (iii) a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 181.7°C and a sharp endotherm peak at about 186.4°C substantially in accordance with Figure 3 and/or Figure 6.
3. A process for the preparation of stable and highly pure crystalline Form 1 of Favipiravir, comprising:
a) providing a suspension of Favipiravir (crude or pure) in an aromatic hydrocarbon solvent at the reflux temperature of the solvent used;
b) stirring the suspension formed in step-(a) at the reflux temperature of the solvent used to obtain a hot slurry;
c) cooling the hot slurry obtained in step-(b) to below about 55°C;
d) recovering the highly pure crystalline Form 1 of Favipiravir formed in step-(c); and
e) optionally repeating the process steps (a) to (d) to improve the purity of the resulting crystalline Form 1 of Favipiravir obtained in step-(d).

4. The process as claimed in claim 3, wherein the aromatic hydrocarbon solvent used in step-(a) is selected from the group consisting of toluene, xylene, and mixtures thereof; wherein the amount of solvent employed in step-(a) is about 8 volumes to about 12 volumes with respect to the quantity of Favipiravir taken as starting material; wherein the stirring the suspension in step-(b) is carried out for at least 10 minutes; wherein the hot slurry in step-(c) is cooled while stirring at a temperature of about 0°C to about 55°C for at least 10 minutes; and wherein the recovering in step-(d) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
5. The process as claimed in claim 4, wherein the aromatic hydrocarbon solvent used in step-(a) is toluene; wherein the amount of solvent employed in step-(a) is about 10 volumes with respect to the quantity of Favipiravir taken as starting material; wherein the stirring in step-(b) is carried out for about 30 minutes to about 5 hours; and wherein the hot slurry in step-(c) is cooled while stirring at a temperature of about 30°C to about 50°C for about 15 minutes to about 2 hours.
6. A pharmaceutical composition comprising the stable and highly pure crystalline Form 1 of Favipiravir obtained by the process as claimed in claim 3, and one or more pharmaceutically acceptable excipients.
7. A pharmaceutical composition comprising the stable and highly pure crystalline Form 1 of Favipiravir as claimed in claims 1 and 2, and one or more pharmaceutically acceptable excipients.
8. The pharmaceutical composition as claimed in claim 7, wherein the pharmaceutically acceptable excipient is selected from the group consisting of buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants.