DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“POLYMORPHIC FORMS OF MOLNUPIRAVIR AND ITS PREPARATION THEREOF”

LAURUS LABS LIMITED, an Indian Company, of DS-1, IKP knowledge park, Genome Valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri district, Hyderabad-500 078, Telangana, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION

The present invention relates to polymorphic forms of molnupiravir, processes for its preparation and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION

Molnupiravir (MK-4482 and EIDD-2801) is an experimental antiviral drug which is orally active and was developed for the treatment of influenza. It is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine, and exerts its antiviral action through introduction of copying errors during viral RNA replication. Activity has also been demonstrated against corona viruses including SARS, MERS and SARS-CoV-2. Molnupiravir is chemically known as [(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl-2-methylpropanoate and has the following structure:

Molnupiravir

Molnupiravir was developed at Emory University and was then acquired by Ridgeback Bio-therapeutics, who later partnered with Merck & Co. to develop the drug further for treatment of SARS-CoV-2 and presently FDA issued emergency use authorization for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in certain adults who are at high-risk for progression to severe COVID-19 as oral capsule under the brand name Lagevrio®.

PCT application Number: 2019/113462 (“the ‘462 publication”) disclosed different N4-hydroxy cytidine and its derivatives, including molnupiravir and its processes for the preparation from Uridine and the final molnupiravir was recrystallized from a mixture of Isopropyl alcohol and methyl tert-butyl ether.

David R. Snead et al. disclosed a process for preparation of molnupiravir from Cytidine in ChemRxiv, Pages 1-3, 2020 and ChemRxiv, Pages 1-2, 2020-Part -2. The final molnupiravir was purified by column chromatography from a mixture of methanol: methylene chloride and from a mixture of methanol: chloroform respectively.

Timothy F. Jamison et al. disclosed a process for preparation of molnupiravir from Cytidine by enzymatic method in ACS Omega 2021, 6, 15, 10396–10402 and the final molnupiravir was recrystallized from water.

Chinese Patent application number 112608357 (“the ‘357 publication”) disclosed a process for preparation of molnupiravir and the final molnupiravir was recrystallized from isopropanol and n-heptane.

Chinese Patent application number 112552288 (“the ‘288 publication”) disclosed a process for preparation of molnupiravir from Cytidine and the final molnupiravir was recrystallized from Isopropyl alcohol and methyl tert-butyl ether.

Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, differential scanning calorimetry (DSC), thermogram substantially (TGA) and infrared spectrometry (IR). Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

It is also important to discover polymorphic forms of molnupiravir, which may provide an opportunity to improve the performance characteristics of a pharmaceutical product. The discovery of crystalline polymorphic forms and solvates of a pharmaceutically useful compound, like molnupiravir, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Hence the main object of the present invention is to provide polymorphic forms of molnupiravir and its process.

SUMMARY OF THE INVENTION

The present invention encompasses polymorphic forms of molnupiravir, process for their preparation and pharmaceutical composition thereof.

In accordance with one embodiment, the present invention provides polymorphic forms of molnupiravir and some of which are in the form of solvates, co-crystals, anhydrous or hydrates.

In accordance with another embodiment, the present invention provides polymorphic forms of molnupiravir; which are designated herein as molnupiravir Form-A, molnupiravir Form-B and molnupiravir Form-I.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-A.

In accordance with another embodiment, molnupiravir polymorphic Form-A of the present invention is an ethanol solvate.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-A characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-A characterized by a powder X-ray diffraction (PXRD) pattern peaks at about:3.2, 6.5, 7.8, 8.8, 9.7, 10.2, 11.1, 12.2, 12.4, 13.0, 13.3, 14.2, 14.9, 15.7, 16.3, 16.7, 17.0, 17.2, 17.8, 18.2, 18.4, 19.3, 19.9, 20.3, 20.7, 20.8, 21.4, 21.7, 22.3, 22.9, 23.0, 23.4, 24.1, 24.4, 24.5, 25.1, 25.5, 26.5, 26.8, 27.3, 28.0, 28.6, 28.9, 29.7, 29.9, 30.1, 30.5, 31.3, 31.6, 32.1, 32.4, 32.9, 33.2, 33.3, 33.5, 34.4 and 34.9 ±0.2° 2?.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-A characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2.
In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-A characterized by a thermogravimetric analysis (TGA) substantially in accordance with Figure 3.

In accordance with another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-A, comprising:
a) dissolving or suspending molnupiravir in ethanol at a temperature of about ambient to reflux,
b) stirring the step a) solution or suspension at about 45°C to 55°C,
c) cooling the step b) solution or suspension to below 50°C, and
d) isolating the molnupiravir polymorphic Form-A.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-B.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-B characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 4.

In accordance with another embodiment, the present invention provides Molnupiravir polymorphic Form-B characterized by a powder X-ray diffraction (PXRD) pattern peaks at about: 3.4, 6.7, 10.2, 11.2, 13.3, 14.3, 16.8, 17.7, 18.3, 20.0, 20.4, 20.6, 21.0, 21.3, 22.3, 23.4, 24.3, 24.5, 25.5, 27.2, 28.8, 30.1, 31.0, 31.4, 31.9, 32.5, 33.0, 33.9 and 35.1±0.2° 2?.

In accordance with another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-B, comprising:
a) dissolving or suspending molnupiravir in ethanol at a temperature of about ambient to reflux under anhydrous conditions,
b) cooling the step a) solution or suspension to below 35°C under anhydrous conditions, and
c) isolating the molnupiravir polymorphic Form-B.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-I.
In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-I characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 5.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-I characterized by a powder X-ray diffraction (PXRD) pattern peaks at about: 3.3, 6.5, 9.8, 13.1, 16.3, 16.4, 17.0, 17.2, 18.1, 18.9, 19.4, 19.9, 20.3, 20.6, 21.2, 21.4, 21.9, 22.6, 23.4, 24.0, 24.3, 25.7, 26.4, 27.5, 28.1, 28.4, 28.9, 30.1, 30.9, 31.6, 33.8, 34.4 and 35.1 ±0.2° 2?.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-I characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 6.

In accordance with another embodiment, the present invention provides molnupiravir polymorphic Form-I characterized by a thermogravimetric analysis (TGA) substantially in accordance with Figure 7.

In accordance with another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-I, comprising:
a) dissolving or suspending molnupiravir in a suitable solvent at a temperature of about ambient to reflux,
b) cooling the step a) solution or suspension to below 35°C, and
c) isolating the molnupiravir polymorphic Form-I.

In accordance with another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-I, comprising:
a) dissolving or suspending molnupiravir in a suitable solvent at a temperature of about ambient to reflux,
b) cooling the step a) solution or suspension to below 35°C, and
c) isolating the molnupiravir polymorphic Form-I; wherein the suitable solvent is selected from the group consisting of alcohols, esters, ethers, ketones, nitriles, aliphatic or cyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, water and mixtures thereof.

In another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-I, comprising: subjected to heating molnupiravir polymorphic Form-A at about 70°C to about 90°C.

In another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-I, comprising: exposing molnupiravir polymorphic Form-A under atmosphere air or humid air at an ambient temperature.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising polymorphic forms of molnupiravir prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of molnupiravir polymorphic Form-A.

Figure 2 is the characteristic DSC thermogram of molnupiravir polymorphic Form-A.

Figure 3 is the characteristic TGA of molnupiravir polymorphic Form-A.

Figure 4 is the characteristic powder X-ray diffraction (PXRD) pattern of molnupiravir polymorphic Form-B.

Figure 5 is the characteristic powder X-ray diffraction (PXRD) pattern of molnupiravir polymorphic Form-I.

Figure 6 is the characteristic DSC thermogram of molnupiravir polymorphic Form-I.

Figure 7 is the characteristic TGA of molnupiravir polymorphic Form-I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses polymorphic forms, co-crystals, solvates and hydrates of molnupiravir, process for their preparation and pharmaceutical composition thereof.

The polymorphic forms of molnupiravir obtained by the process of the present invention are characterized by X-ray powder diffraction (XRPD) pattern, differential scanning calorimetric (DSC) and/orthermo gravimetric analysis (TGA).

The X-Ray powder diffraction data reported herein may be analyzed using PAN anlytical X’per3pro X-ray powder Diffractometer equipped with a Cu-anode ([?] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°2?; step size=0.01°; and Time per step=50 sec.

Alternatively the X-Ray powder diffraction data reported herein may be analyzed using Rigaku Miniflex 600 Benchtop Powder X-ray diffractometer equipped with a Cu-anode ([?] =1.54 Angstrom), X-ray source operated at 40kV, 15 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-40° 2?; step (deg) =0.02°; and Speed (deg/min) =10.

The differential scanning calorimetric data reported herein is analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.

Thermogravimetric analysis (TGA) data in the present invention was acquired using TA instruments TGA Q500 thermogravimetric analyzer with universal Analysis 2000 software using the following conditions; Heating rate: 10°C/min; Temperature range: 28±2°C - 250°C; Nitrogen flow: 60mL/minute.

As used herein in this specification, unless otherwise specified, molnupiravir, which is used as a starting material is known in the art and can be prepared by the process known in art, for example molnupiravir may be synthesized as disclosed in PCT application Number: 2019/113462. The starting molnupiravir may be in any form such as crude obtained directly from the reaction mass either as in an oily mass or as a semi solid or other forms of molnupiravir, including solid forms described herein for the present invention.

In one embodiment, the present invention provides polymorphic forms of molnupiravir; which are designated herein as molnupiravir Form-A, molnupiravir Form-B and molnupiravir Form-I.

In another embodiment, the present invention provides molnupiravir polymorphic Form-A.

In another embodiment, molnupiravir polymorphic Form-A of the present invention is an ethanol solvate.

In another embodiment, the present invention provides molnupiravir polymorphic Form-A characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In another embodiment, the present invention provides molnupiravir polymorphic Form-A characterized by a powder X-ray diffraction (PXRD) pattern peaks at about: 3.2, 6.5, 7.8, 8.8, 9.7, 10.2, 11.1, 12.2, 12.4, 13.0, 13.3, 14.2, 14.9, 15.7, 16.3, 16.7, 17.0, 17.2, 17.8, 18.2, 18.4, 19.3, 19.9, 20.3, 20.7, 20.8, 21.4, 21.7, 22.3, 22.9, 23.0, 23.4, 24.1, 24.4, 24.5, 25.1, 25.5, 26.5, 26.8, 27.3, 28.0, 28.6, 28.9, 29.7, 29.9, 30.1, 30.5, 31.3, 31.6, 32.1, 32.4, 32.9, 33.2, 33.3, 33.5, 34.4 and 34.9 ±0.2° 2?.

In another embodiment, the present invention provides molnupiravir polymorphic Form-A characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 2.

In another embodiment, the present invention provides molnupiravir polymorphic Form-A characterized by a thermogravimetric analysis (TGA) substantially in accordance with Figure 3.

In another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-A, comprising:
a) dissolving or suspending molnupiravir in ethanol at a temperature of about ambient to reflux,
b) stirring the step a) solution or suspension at about 45°C to 55°C,
c) cooling the step b) solution or suspension to below 45°C, and
d) isolating the molnupiravir polymorphic Form-A.

The step a) of the forgoing process involves dissolving or suspending molnupiravir in ethanol at a temperature of about ambient to reflux; preferably at about 25°C to about 35°C.

The step a) reaction mixture further heated to about reflux temperature to either partial or complete dissolution of the starting material, preferably heated to about 45°C to about 80°C for complete dissolution of the starting material. Optionally the step a) reaction may be filtered to remove any extraneous matter present in the step a) solution andstirring the step a) solution or suspension at about 45°C to 55°C for sufficient period of time; preferably at about 50°C for 1 hr to about 4 hrs.

Then the step c) of the aforementioned process involves, cooling the resultant reaction mass to below 45°C under The cooling step may be either gradual cooling of the solution temperature or rapid cooling, whichever is applicable. The step c) temperature may be cooled down to less than 35°C preferably if required less than 20°C and to less than 0°C. Then the precipitated molnupiravir Form-A may be recovered by any conventional process techniques that not limited to decantation, filtration and etc. The resultant product may be further dried at ambient temperature for sufficient period of time.

The drying of the wet material may be carried out in general drying conditions known in the art at a suitable temperature either under atmospheric pressure or under reduced pressure. Suitably drying step may be carried out at a temperature of up to about 40°C either in a step wise temperature increase manner or to direct single step temperature increase manner.

In another embodiment, the present invention provides molnupiravir polymorphic Form-B.

In another embodiment, the present invention provides molnupiravir polymorphic Form-B characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 4.

In another embodiment, the present invention provides Molnupiravir polymorphic Form-B characterized by a powder X-ray diffraction (PXRD) pattern peaks at about: 3.4, 6.7, 10.2, 11.2, 13.3, 14.3, 16.8, 17.7, 18.3, 20.0, 20.4, 20.6, 21.0, 21.3, 22.3, 23.4, 24.3, 24.5, 25.5, 27.2, 28.8, 30.1, 31.0, 31.4, 31.9, 32.5, 33.0, 33.9 and 35.1±0.2° 2?.

In another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-B, comprising:
a) dissolving or suspending molnupiravir in ethanol at a temperature of about ambient to reflux under anhydrous conditions,
b) cooling the step a) solution or suspension to below 35°C under anhydrous conditions, and
c) isolating the molnupiravir polymorphic Form-B.

The step a) of the forgoing process involves dissolving or suspending molnupiravir in ethanol at a temperature of about ambient to reflux under anhydrous conditions; preferably at about 25°C to about 35°C.

The step a) reaction mixture may be further heated to about reflux temperature to either partial or complete dissolution of the starting material, preferably heated to about 45°C to about 80°C for complete dissolution of the starting material. Optionally the step a) reaction may be filtered to remove any extraneous matter present in the step a) solution.

Then the step b) of the aforementioned process involves, cooling the resultant reaction mass to below 35°C under anhydrous conditions. The cooling step may be either gradual cooling of the solution temperature or rapid cooling, whichever is applicable. The step b) temperature may be cooled down to less than 35°C preferably if required less than 20°C and to less than 0°C. Then the precipitated molnupiravir Form-B may be recovered by any conventional process techniques that not limited to decantation, filtration and etc. The resultant product may be further dried at ambient temperature for sufficient period of time.

The drying of the wet material may be carried out in general drying conditions known in the art at a suitable temperature either under atmospheric pressure or under reduced pressure. Suitably drying step may be carried out at a temperature of up to about 75°C either in a step wise temperature increase manner or to direct single step temperature increase manner.

In another embodiment, the present invention provides molnupiravir polymorphic Form-I.

In another embodiment, the present invention provides molnupiravir polymorphic Form-I characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 5.

In another embodiment, the present invention provides molnupiravir polymorphic Form-I characterized by a powder X-ray diffraction (PXRD) pattern peaks at about: 3.3, 6.5, 9.8, 13.1, 16.3, 16.4, 17.0, 17.2, 18.1, 18.9, 19.4, 19.9, 20.3, 20.6, 21.2, 21.4, 21.9, 22.6, 23.4, 24.0, 24.3, 25.7, 26.4, 27.5, 28.1, 28.4, 28.9, 30.1, 30.9, 31.6, 33.8, 34.4 and 35.1 ±0.2° 2?.

In another embodiment, the present invention provides molnupiravir polymorphic Form-I characterized by a differential scanning calorimetry (DSC) substantially in accordance with Figure 6.

In another embodiment, the present invention provides molnupiravir polymorphic Form-I characterized by a thermogravimetric analysis (TGA) substantially in accordance with Figure 7.

In another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-I, comprising:
a) dissolving or suspending molnupiravir in a suitable solvent at a temperature of about ambient to reflux,
b) cooling the step a) solution or suspension to below 35°C, and
c) isolating the molnupiravir polymorphic Form-I.

The step a) of the forgoing process involves dissolving or suspending molnupiravir in a suitable solvent at a temperature of about ambient to reflux; preferably at about 25°C to about 35°C.

The suitable solvent used in aforementioned step a) is selected from the group consisting of but not limited to alcohols, esters,ethers, ketones, nitriles, aliphatic or cyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, water and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, isopropyl alcohol, butanol, n-butanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; aliphatic or cyclic hydrocarbons include, but are not limited to hexane, heptane, propane, butane, pentane, octane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; water and mixture thereof; preferably methanol, ethanol, isopropyl alcohol, n-butanol,ethyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, acetonitrile, cyclohexane, methylene chloride, toluene, tetrahydrofuran, diisopropyl ether; and water; and mixture thereof.

The step a) reaction mixture may be further heated to about reflux temperature to either partial or complete dissolution of the starting material, preferably heated to about 45°C to about 100°C for complete dissolution of the starting material. Optionally the step a) reaction may be filtered to remove any extraneous matter present in the step a) solution.

Then the step b) of the aforementioned process involves, cooling the resultant reaction mass to below 35°C. The cooling step may be either gradual cooling of the solution temperature or rapid cooling, whichever is applicable. The step b) temperature may be cooled down to less than 35°C preferably if required less than 20°C and to less than 0°C. Then the precipitated molnupiravir Form-I may be recovered by any conventional process techniques that not limited to decantation, filtration and etc.

The resultant product may be further dried at a suitable temperature for sufficient period of time. The drying of the wet material may be carried out in general drying conditions known in the art at a suitable temperature either under atmospheric pressure or under reduced pressure. Suitably drying step may be carried out at a temperature of up to about 95°C either in a step wise temperature increase manner or to direct single step temperature increase manner; preferably drying is carried out at a temperature of about 40°C to about 70°C.

In another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-I, comprising: subjected to heating molnupiravir polymorphic Form-A at about 70°C to about 90°Cfor about 1 to 12 hours; preferably at about 80°C to about 85°C for about 2 to 8 hours; more preferably the drying step may be carried out under vacuum.

In another embodiment, the present invention provides a process for preparation of molnupiravir polymorphic Form-I, comprising: exposing molnupiravir polymorphic Form-A under atmosphere air or humid air at an ambient temperature; preferably at 20-25°C.

In another embodiment, the present invention provides a pharmaceutical composition comprising polymorphic forms of molnupiravir prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.
EXAMPLE-1:

Preparation of molnupiravir Form A

Molnupiravir (500 gm) and ethanol (2250 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 70-75°C to get clear solution. Reaction mass was filtered and washed with hot ethanol (250 mL). Filtrate was charged in to a round bottom flask and heated to 70-75°C and stirred for 15 min at same temperature. Reaction mass was cooled to 50°C and stirred for 2 hrs at same temperature. Reaction mass was further cooled to 30°C and stirred for 1 hr at same temperature. Reaction mass was further cooled to 0-5°C and stirred for 1 hr at same temperature. Precipitated solid was filtered and washed with chilled ethanol (250 mL), suck dried the solid for 40 min and dried the wet material under vacuum at 30-35°C for about 2 hrs to obtain the title compound. Wt: 495 gm. The PXRD is set forth in Figure-1; DSC is set forth in Figure-2 and TGA is set forth in Figure-3.

EXAMPLE-2:

Preparation of molnupiravir Form B

Molnupiravir (120 gm) and ethanol (540 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 70-75°C u/N2 atmosphere to get clear solution. Reaction mass was filtered and washed with hot ethanol (50 mL). Filtrate was transferred in to a round bottom flask u/N2 atmosphere and concentrated under vacuum at below 45°C up to ~300-360 ml reaction mass remains in the flask. Reaction mass was allowed to cool to 20-25°C u/N2 atmosphere and allowed to stirred for 1hr at same temperature. Precipitated solid was filtered and washed with ethanol (50 mL), suck dried the solid for 60 min and dried the wet material on rota evaporator at 30-35°C for about 4 hrs and then dried at 60-65°C for about 8 hrs to obtain the title compound. Wt: 117 gm. The PXRD is set forth in Figure-4.

EXAMPLE-3:

Preparation of molnupiravir Form I

Molnupiravir (100 gm) and ethanol (450 mL) were added in to a round bottom flask at 20-25°C, heated the reaction mass to 70-75°C to get clear solution. Reaction mass was filtered and washed with hot ethanol (50 mL). Filtrate was transferred in to a round bottom flask and concentrated under vacuum at below 45°C up to ~250-300 ml reaction mass remains in the flask. Reaction mass was allowed to cool to 20-25°C and allowed to stirred for 1hr at same temperature. Precipitated solid was filtered and washed wet cake with 10% aq ethanol (45 ml ethanol +5 ml water), suck dried the solid for 60 min and dried the wet material on rota evaporator at 30-35°C for about 4 hrs. The material was further dried on rota evaporator for 4hrs at 40-45°C to obtain the title compound. Wt: 98 gm; HPLC Purity: Greater than 99.5% & triol impurity: less than 0.5%. The PXRD is set forth in Figure-5; DSC is set forth in Figure-6 and TGA is set forth in Figure-7.

EXAMPLE-4:

Preparation of molnupiravir Form I

Molnupiravir Form-B prepared according to example 2 (5 gm) and 10% aqueous ethanol (15 mL) in to a round bottom flask at 20-25°C and stir for 30 min at same temperature. Reaction mass was filtered and suck dried for 30 min. Washed the wet cake with 10% aqueous ethanol (2.5 mL), suck dried the solid for 60 min and dried the wet material on rota evaporator at 30-35°C for about 4 hrs. The material was further dried on rota evaporator for 4hrs at 40-45°C to obtain the title compound. Wt: 2.8 gm.

EXAMPLE-5:

Preparation of molnupiravir Form I

Molnupiravir Form-A prepared according to example 1 (10 gm) taken in a petri dish and exposure on R.H (60%) at 20-25°C for 24 hrs to obtain the title compound. Wt: 8.2 gm.

EXAMPLE-6:

Preparation of molnupiravir Form I

Molnupiravir Form-A prepared according to example 1 (11.7 gm) was dried under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4hrs at 80-85°C to obtain the title compound. Wt: 9 gm.
EXAMPLE-7:

Preparation of molnupiravir Form I

Molnupiravir (7.0 gm) and methanol (14 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 55-60°C and stirred for 30 min at same temperature. Reaction mass was filtered and wash with hot methanol (7 mL). Then the filtrate was gradually cool to 25-30°C and stirred for 1 hr at same temperature and followed by 1 hr at 0-5°C. Precipitated solid was filtered and washed with chilled methanol (3.5 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. . The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 3.4 gm.

EXAMPLE-8:

Preparation of molnupiravir Form I

Molnupiravir (7.0 gm) and Isopropyl alcohol (35 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 75-80°C and stirred for 30 min at same temperature. Reaction mass was filtered and was wash with hot Isopropyl alcohol (7 mL). Then the filtrate was heated to 75-80°C and stirred for 20 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C and followed by 1 hr at 0-5°C. Precipitated solid was filtered and washed with chilled Isopropyl alcohol (3.5 mL), suck dried the solid for 30 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. . The material was further dried under vacuum for 4 hrs at 50-55°C to obtain the title compound. Wt: 6.3 gm.

EXAMPLE-9:

Preparation of molnupiravir Form I

Molnupiravir (7 gm) and acetone (70 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 50-55°C and stirred for 30 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C and followed by 1 hr at 0-5°C. Precipitated solid was filtered and washed with chilled acetone (3.5 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. . The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 4.3 gm.

EXAMPLE-10:

Preparation of molnupiravir Form I

Molnupiravir (7 gm) and acetonitrile (35 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 75-80°C and stirred for 30 min at same temperature. Reaction mass was filtered and was wash with hot acetonitrile (7 mL). Then the filtrate mass was heated to 75-80°C and stirred for 20 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C and followed by 1 hr at 0-5°C. Precipitated solid was filtered and washed with chilled acetonitrile (3.5 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. . The material was further dried under vacuum for 4 hrs at 50-55°C to obtain the title compound. Wt: 6.2 gm.

EXAMPLE-11:

Preparation of molnupiravir Form I

Molnupiravir (7 gm) and n-butanol (35 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 80-85°C and stir for 30 min at same temperature. Reaction mass was filtered through micron filter and was wash with hot n-butanol (7 mL). Then the filtrate was heated to 80-85°C and stirred for 20 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C and followed by 1 hr at 0-5°C. Precipitated solid was filtered and washed with n-butanol (3.5 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. . The material was further dried under vacuum for 4 hrs at 50-55°C to obtain the title compound. Wt: 6.3 gm.

EXAMPLE-12:

Preparation of molnupiravir Form I

Molnupiravir (10 gm) and ethyl acetate (50 mL) were added in to a round bottom flask at 25-30°C and allowed to stir for 4 hr at same temperature. Precipitated solid was filtered and washed wet cake with chilled ethyl acetate (10 mL), suck dried the solid for 40 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 8 gm.

EXAMPLE-13:

Stability of molnupiravir Form-I

Molnupiravir Form–I (5 gm) and 10% aqueous ethanol (15 mL) were added in to a round bottom flask at 25-30°C and allowed to stir for 24 hr at same temperature. Filtered the reaction mass and washed wet cake with 10% aqueous ethanol (2.5 mL), suck dried the solid for 60 min and dried the wet material on rota evaporator at 30-35°C for about 4 hrs. The material was further dried on rota evaporator for 4 hrs at 40-45°C to obtain the title compound as molnupiravir Form -I. Wt: 4.8 gm.

EXAMPLE-14:

Preparation of molnupiravir Form-I

Molnupiravir (30 gm) and cyclohexane (150 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 70-75°C and stirred for 30 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C. Precipitated solid was filtered and washed with cyclohexane (15 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 29.2 gm; PXRD: Fig 1; DSC: Fig 2; and TGA: Fig 3.

EXAMPLE-15:

Preparation of molnupiravir Form-I

Molnupiravir (30 gm) and methylene chloride (150 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 40-45°C and stirred for 30 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C. Precipitated solid was filtered and washed with methylene chloride (15 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 29.5 gm.

EXAMPLE-16:

Preparation of molnupiravir Form-I

Molnupiravir (30 gm) and methyl isobutyl ketone (150 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 70-75°C and stirred for 30 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C. Precipitated solid was filtered and washed with methyl isobutyl ketone (15 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 29.3 gm.

EXAMPLE-17:

Preparation of molnupiravir Form-I

Molnupiravir (30 gm) and toluene (150 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 70-75°C and stirred for 30 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C. Precipitated solid was filtered and washed with toluene (15 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 29.4 gm.

EXAMPLE-18:

Preparation of molnupiravir Form-I

Molnupiravir (30 gm) and diisopropyl ether (150 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 70-75°C and stir for 30 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C. Precipitated solid was filtered and washed with diisopropyl ether (15 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 29.6 gm.

EXAMPLE-19:

Preparation of molnupiravir Form-I

Molnupiravir (30 gm) and isopropyl acetate (150 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 70-75°C and stirred for 30 min at same temperature. Reaction mass was gradually cool and stirred for 1 hr at 25-30°C. Precipitated solid was filtered and washed with isopropyl acetate (15 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 29.5 gm.

EXAMPLE-20:

Preparation of molnupiravir Form-I

Molnupiravir (30 gm) and tetrahydrofuran (150 mL) were added in to a round bottom flask at 25-30°C and stirred for 10 min at same temperature. Reaction mass temperature was heated to 70-75°C and stirred for 30 min at same temperature. Reaction mass was filtered through micron filter and was wash with hot tetrahydrofuran (15 mL). Then the filtrate was gradually cool and stirred for 1 hr at 25-30°C. Precipitated solid was filtered and washed with tetrahydrofuran (15 mL), suck dried the solid for 60 min and dried the wet material under vacuum at 30-35°C for about 2 hrs. The material was further dried under vacuum for 4 hrs at 40-45°C to obtain the title compound. Wt: 28.2 gm.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:We claim:

1. Molnupiravir polymorphic form-A, characterized by X-Ray diffraction (XRD) having one or more peaks selected from the group consisting of:3.2, 6.5, 7.8, 8.8, 9.7, 10.2, 11.1, 12.2, 12.4, 13.0, 13.3, 14.2, 14.9, 15.7, 16.3, 16.7, 17.0, 17.2, 17.8, 18.2, 18.4, 19.3, 19.9, 20.3, 20.7, 20.8, 21.4, 21.7, 22.3, 22.9, 23.0, 23.4, 24.1, 24.4, 24.5, 25.1, 25.5, 26.5, 26.8, 27.3, 28.0, 28.6, 28.9, 29.7, 29.9, 30.1, 30.5, 31.3, 31.6, 32.1, 32.4, 32.9, 33.2, 33.3, 33.5, 34.4 and 34.9 ±0.2° 2?.

2. A process for preparation of molnupiravir polymorphic Form-A, comprising:
a) dissolving or suspending molnupiravir in ethanol at a temperature of about ambient to reflux,
b) stirring the step a) solution or suspension at about 45°C to 55°C,
c) cooling the step b) solution or suspension to below 50°C, and
d) isolating the molnupiravir polymorphic Form-A.

3. Molnupiravir polymorphic form-B, characterized by X-Ray diffraction (XRD) having one or more peaks selected from the group consisting of:3.4, 6.7, 10.2, 11.2, 13.3, 14.3, 16.8, 17.7, 18.3, 20.0, 20.4, 20.6, 21.0, 21.3, 22.3, 23.4, 24.3, 24.5, 25.5, 27.2, 28.8, 30.1, 31.0, 31.4, 31.9, 32.5, 33.0, 33.9 and 35.1±0.2° 2?.

4. A process for preparation of molnupiravir polymorphic Form-B, comprising:
a) dissolving or suspending molnupiravir in ethanol at a temperature of about ambient to reflux under anhydrous conditions,
b) cooling the step a) solution or suspension to below 35°C under anhydrous conditions, and
c) isolating the molnupiravir polymorphic Form-B.

5. Molnupiravir polymorphic form-I, characterized by X-Ray diffraction (XRD) having one or more peaks selected from the group consisting of:3.3, 6.5, 9.8, 13.1, 16.3, 16.4, 17.0, 17.2, 18.1, 18.9, 19.4, 19.9, 20.3, 20.6, 21.2, 21.4, 21.9, 22.6, 23.4, 24.0, 24.3, 25.7, 26.4, 27.5, 28.1, 28.4, 28.9, 30.1, 30.9, 31.6, 33.8, 34.4 and 35.1 ±0.2° 2?.

6. A process for preparation of molnupiravir polymorphic Form-I, comprising:
a) dissolving or suspending molnupiravir in a suitable solvent at a temperature of about ambient to reflux,
b) cooling the step a) solution or suspension to below 35°C, and
c) isolating the molnupiravir polymorphic Form-I.

7. The process as claimed in claim 6, wherein the suitable solvent is selected from the group consisting methanol, ethanol, isopropyl alcohol, butanol, n-butanol, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, acetone, methyl isobutyl ketone, methyl ethyl ketone,acetonitrile, propionitrile,hexane, heptane, propane, butane, pentane, octane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane, methylene chloride, ethylene chloride, chloroform, toluene, xylene, water and mixture thereof.

8. The process as claimed in claim 6, wherein the step a) is carried out at a temperature of about 45°C to about 85°C.

9. A process for preparation of molnupiravir polymorphic Form-I, comprising: subjected to heating molnupiravir polymorphic Form-A at about 70°C to about 90°C.

10. A process for preparation of molnupiravir polymorphic Form-I, comprising: exposing molnupiravir polymorphic Form-A under atmosphere air or humid air at an ambient temperature.