DESC:
FIELD OF THE INVENTION
Present invention provides novel polymorphic forms of Fezolinetant compound of Formula I and their process of preparation.

BACKGROUND OF THE INVENTION
Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause and is approved and marketed as VEOZAHTM.

Polymorphism, the occurrence of different crystalline forms, is a property of some molecules. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern and infrared absorption fingerprint. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

There always remains a need to provide the new polymorphic forms of Fezolinetant and processes for making the new polymorphic forms.

The present invention provides new polymorphic forms of Fezolinetant which can be used in the pharmaceutical composition.
The present invention provides stable amorphous Fezolinetant and amorphous solid dispersion of Fezolinetant having high stability and physical integrity, e.g. during storage, handling, packaging and the like.

OBJECT OF THE INVENTION
Main object of the present invention is to provide a stable amorphous form of Fezolinetant and an amorphous solid dispersion of Fezolinetant.

Another object of the present invention is to provide a process for the preparation of stable amorphous form of Fezolinetant and amorphous solid dispersion of Fezolinetant.

Yet another object of the present invention provides novel crystalline forms of Fezolinetant and their preparation.

Yet another object of the preparation invention is to provide different salts of Fezolinetant and its use in the preparation of Fezolinetant.

SUMMARY OF THE INVENTION
Main aspect of the present invention provides a stable amorphous form of Fezolinetant.

Another aspect of the present invention is to provide a process for the preparation of stable amorphous form of Fezolinetant.

Another aspect of the present invention provides an amorphous solid dispersion of Fezolinetant.

Another aspect of the present invention is to provide a process for the preparation of amorphous solid dispersion of Fezolinetant.

Yet another aspect of the present invention provides novel crystalline forms, MK-1 & MK-2 of Fezolinetant and their preparation.

Yet another aspect of the preparation invention is to provide different salts of Fezolinetant and its use in the preparation of Fezolinetant.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Represents the X-Ray Powder Diffraction (XRPD) pattern of the crystalline form MK-1 of Fezolinetant of the present invention.
Figure 2: Represents the X-Ray Powder Diffraction (XRPD) pattern of the crystalline form MK-2 of Fezolinetant of the present invention.
Figure 3: Represents the X-Ray Powder Diffraction (XRPD) pattern of the amorphous form of Fezolinetant of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The term “suitable solvent” as used in the context of the present invention, is selected from the group comprising of, but not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, water and mixture thereof.

In an embodiment, the present invention provides a stable amorphous form of Fezolinetant.

In an embodiment, the present invention provides a stable amorphous form of Fezolinetant, which can be identified by one or more analytical methods.

In another embodiment, the present invention provides a stable amorphous form of Fezolinetant characterized by an X-ray powder diffraction pattern as depicted in Figure 3.

In an embodiment, present invention provides a process for the preparation of stable amorphous form of Fezolinetant.

In an embodiment, the present invention provides a process for the preparation of a stable amorphous form of Fezolinetant, comprising:
a) providing a solution of Fezolinetant in a solvent or mixture of solvents;
b) removing the solvent from the solution obtained in step a), and
b) isolating a stable amorphous form of Fezolinetant.

In another embodiment, providing a solution of Fezolinetant in a solvent or mixture of solvents includes:
i) solutions obtained from reaction mixtures in the final stage of processes for preparing the Fezolinetant or
ii) dissolving Fezolinetant in a suitable solvent or mixture of solvents.

Suitable solvents that may be used in step a) include, but are not limited to, polar solvents such as but not limited to alcohol solvents; ketone solvents; halogenated hydrocarbon solvents; ether solvents; ester solvents; nitrile solvents; polar aprotic solvents; water; or mixtures thereof, preferably methanol and water.

Step c) involves the isolation of a stable amorphous form of Fezolinetant from the solution of step b). The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.

In embodiments of step c) the stable amorphous form obtained from step b) may be optionally dried. Drying may be suitably carried out in a tray dryer, vacuum oven, Büchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100° C., less than about 50° C., less than about 40° C., or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 5 minutes to 24 hours or longer.

In another embodiment, the present invention provides a process for the preparation of amorphous form of Fezolinetant, comprising the steps of:
a) milling/grinding Fezolinetant under suitable milling conditions; and
b) isolating the amorphous form of Fezolinetant.

In another embodiment, the present invention provides a process for the preparation of a stable amorphous form of Fezolinetant, comprising the steps of:
a) providing a solution of Fezolinetant in one or more solvent;
b) lyophilizing or spray drying the solution obtained in step a); and
c) isolating the stable amorphous form of Fezolinetant.

In another embodiment, the present invention provides a process for the preparation of a stable amorphous form of Fezolinetant, comprising the steps of:
a) providing a solution of Fezolinetant in one or more solvent;
b) adding suitable pharmaceutically acceptable acid to obtain pharmaceutically acceptable salt of Fezolinetant;
c) adding suitable base to the solution of step b); and
d) isolating the stable amorphous form of Fezolinetant.

In another embodiment, the solvent use for the preparation of a stable amorphous form of Fezolinetant are selected from methanol, ethanol, acetone, dichloromethane, water or mixture thereof.

Yet another embodiment of the preparation invention is to provide different salts of Fezolinetant and its use in the preparation of Fezolinetant.

In another embodiment, the present invention provides a process for the preparation of pharmaceutically acceptable salt of Fezolinetant, comprising the steps of:
a) providing a solution of Fezolinetant in one or more solvent;
b) adding suitable pharmaceutically acceptable acid; and
c) isolating the pharmaceutically acceptable salt of Fezolinetant.

In another embodiment, the solvent use for the preparation of salt of Fezolinetant are selected from methanol, ethanol, acetone, dichloromethane, water or mixture thereof.

In another embodiment, the pharmaceutically acceptable acid used in the present invention are selected from hydrochloric acid, sulphuric acid, acetic acid, oxalic acid, formic acid and tartaric acid.

In another embodiment, the suitable base used in the present invention are selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, ammonia, sodium carbonate and sodium bicarbonate.

As used herein, the term “stable amorphous Fezolinetant” includes amorphous Fezolinetant that does not convert to any other solid form when stored at a temperature of up to about 40° C. and at a relative humidity of about 25% to about 75% for about three months or more.

In general, the stable amorphous form of Fezolinetant is substantially free from residual solvents. The term “substantially free” means residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example, but not limited to less than 0.5%, particularly less than 0.3% or more particularly less than 0.2%.

In another embodiment, the present invention provides a stable amorphous form of Fezolinetant, wherein said Fezolinetant is stable after exposure to 40 °C/75% RH for a period of six months or 25°C /60% RH., for a period of at least 12 months.
The amorphous form maintains good physical and chemical stability under the accelerated conditions (40±2°C, humidity 75%±5%).

In an embodiment, the experimental results of stability test of stable amorphous form of Fezolinetant are shown in Table below:
Time 25±2°C/60±5% RH 40±2°C/75±5% RH
HPLC purity (%) HPLC purity (%)
Initial 99.90 99.90
1st month 99.82 99.80
3rd month 99.81 99.89
6th month 99.89 99.86
12th month 99.81 99.83

In a further embodiment, the stable amorphous form of Fezolinetant has a purity of at least about 98% by area percentage of HPLC, preferably at least 99% by area percentage of HPLC, more preferably at least 99.5% by area percentage of HPLC, most preferably at least 99.90% by area percentage of HPLC.

In another embodiment, the present invention provides an amorphous solid dispersion of Fezolinetant.

In an embodiment, the present invention provides solid dispersion of amorphous Fezolinetant together with one or more pharmaceutically acceptable carriers.

In an embodiment, present invention provides a process for the preparation of amorphous solid dispersion of Fezolinetant.

In an embodiment, the amorphous solid dispersion of Fezolinetant and at least one pharmaceutically acceptable carrier according to the present invention has a ratio of at least one pharmaceutically acceptable carrier to the Fezolinetant at least about 1:2 to about 2:1 (w/w).

In an embodiment, the amorphous solid dispersion of Fezolinetant and at least one pharmaceutically acceptable carrier according to the present invention has a ratio of at least one pharmaceutically acceptable carrier to the Fezolinetant at least about 1:5 to about 5:1 (w/w).

In an embodiment, the present invention provides a process for preparing a solid dispersion of amorphous Fezolinetant together with one or more pharmaceutically acceptable carriers, comprising:
a) providing a solution or suspension of Fezolinetant in combination with one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents;
b) removing the solvent from the solution or suspension obtained in step a) or combining the solution obtained in step a), with an anti-solvent, and
c) isolating solid dispersion of amorphous Fezolinetant together with one or more pharmaceutically acceptable carrier.

Step a) involves providing a solution or suspension of Fezolinetant in combination with one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents.

In another embodiment, step a) may involve forming a solution of Fezolinetant together with one or more pharmaceutically acceptable carriers. In another embodiment, a carrier is one which enhances stability of the amorphous solid upon removal of the solvent.

Providing the solution in step a) includes:
i) solutions obtained from reaction mixtures in the final stage of processes for preparing the Fezolinetant, if desired, after addition of one or more pharmaceutically acceptable carriers; or
ii) dissolution of Fezolinetant in a suitable solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.

In an embodiment, the present invention provides a process for preparing a solid dispersion of amorphous Fezolinetant together with one or more pharmaceutically acceptable carriers, comprising:
a) blending Fezolinetant and at least one carrier/excipient selected from copovidone, povidone, PVP, poly (1-vinylpyrrolidone-co-vinyl acetate) (PVP-Co-VA), polyvinyl acetate, methyl cellulose, hypromellose acetate succinate, polyethylene oxide, and polyethylene glycol;
b) heating the blend of step a) to form a molten slurry;
c) extruding the slurry of step b); and
d) milling the extrudates of step c) to obtain amorphous solid dispersion of Fezolinetant.

In an embodiment, the present invention provides a process for preparing solid dispersion of amorphous Fezolinetant together with one or more pharmaceutically acceptable carriers, comprising:
a) providing a solution or suspension of Fezolinetant in combination with amorphous silica and one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents;
b) spraying the mixture of step a) on a suitable substrate in a fluidized bed processor or top spray granulator;
c) drying the mass till desired loss on drying (LOD) is achieved.

Pharmaceutically acceptable carriers/ excipients that may be used for the preparation of solid dispersions of Fezolinetant of the present invention include, but are not limited to: gelatines, ovalbumin, soybean proteins, gums, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, cellulose derivative including microcrystalline cellulose, silicified microcrystalline cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxy ethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hypromellose acetate succinate (HPMC AS), hypromellose phthalate, polymers of carboxymethyl celluloses, polycarbophil, polyethylene glycol (PEG), propylene glycol derivatives, polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, copovidone, povidone, polyvinyl pyrrolidone (PVP, povidone), polyvinylpyrrolidones (homopolymers or copolymers), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), sugars, lactose, fructose, polyvinyl alcohols, polyhydric alcohol, sorbitol, mannitol, maltitol, xylitol, saccharose, Isomalt, maltodextrin, dextrins, lactitol, cyclodextrins such as a-cyclodextrins, ß-cyclodextrins, ?-cyclodextrins and hydroxyl-propyl-ß-cyclodextrins, sodium carboxymethylcellulose, sodium alginate, xantham gum, caavageenan, locust bean gum (ceratonia), chitosan, guar gum, cross-linked high amylase starch, and cross-linked polyacrylic acid (carbopol) or the like; or organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

Suitable carrier that may be used in step a) include, but are not limited to, copovidone, povidone, PVP, poly (1-vinylpyrrolidone-co-vinyl acetate) (PVP-Co-VA), polyvinyl acetate, methyl cellulose, hypromellose acetate succinate, polyethylene oxide, polyethylene glycol or mixture thereof.

When the solution or suspension of Fezolinetant is prepared together with a pharmaceutically acceptable carrier, the order of charging different materials to the solution is not critical for obtaining the desired solid dispersion. A specific order may be preferred with respect to the equipment being used and will be easily determined by a person skilled in the art. Fezolinetant may be completely soluble in the solvent or they may form a suspension. In embodiments, Fezolinetant and the pharmaceutically acceptable carrier may be separately dissolved either in the same solvent or in different solvents, and then combined to form a mixture.

Suitable solvents that may be used in step a) include, but are not limited to, alcohol solvents; ketone solvents; halogenated hydrocarbon solvents; ester solvents; nitrile solvents; polar aprotic solvents; water; or mixtures thereof.

In another embodiment, Suitable antioxidants include butylated hydroxytoluene (BHT), butyl hydroxy anisole (BHA), DL-a-tocopherol, propyl gallate, ascorbyl palmitate, malonic acid, fumaric acid and the like may additionally add to amorphous fezolinetant or amorphous solid dispersion of fezolinetant to stabilize.

Suitable substrate used in the fluid bed process or the top spray granulation process includes one or more of pharmaceutically acceptable carriers.

Suitable substrate used in the fluid bed process or the top spray granulation process is one or more of silicified microcrystalline cellulose, polyethylene glycol or polyethylene oxide (PEO) or mixture thereof.

In another embodiment, isolation may also be affected by combining the solution of step a) with a suitable anti-solvent optionally comprising one or more pharmaceutically acceptable carriers. Adding the solution obtained in step a) to the anti-solvent, or adding an anti-solvent to the solution obtained in step a), to affect the crystallization process are both within the scope of the present invention. Optionally, the addition may be carried out after concentrating the solution obtained in step a). Suitable anti-solvents that may be used include, but are not limited to: water; aliphatic or alicyclic hydrocarbon solvents; aromatic hydrocarbon solvents; ether solvents; or mixtures thereof.

In embodiments of step c) involves isolation of solid dispersion of amorphous Fezolinetant together with one or more pharmaceutically acceptable carriers from the solution of step a).

The compound obtained from step c) may be collected using techniques such as by scraping, or by shaking the container, or filtration, or adding solvent for making slurry followed by filtration, or other techniques specific to the equipment used. The product thus isolated may be optionally further dried to afford an amorphous form of Fezolinetant together with a pharmaceutically acceptable excipient. Drying may be suitably carried out in a tray dryer, vacuum oven, Büchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100° C., less than about 60° C., less than about 40° C., or any
other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

The solid dispersions differ from physical mixtures of amorphous Fezolinetant and one or more pharmaceutically acceptable carriers, so that individual particles of the components cannot be distinguished using techniques such as optical microscopy. In instances, the solid dispersions contain the components on a molecular level, such as in the nature of solid solutions.

The dissolution temperatures may range from 0° C. to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of Fezolinetant is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.

Optionally, the solution obtained above may be filtered to remove any insoluble particles. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

In an embodiment, suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a Büchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), atmospheric distillation, vacuum distillation, and the like, or any other suitable technique.

The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100° C., less than about 60° C., less than about 40° C., less than about 20° C., less than about 0° C., less than about -20° C., less than about -40° C., less than about -60° C., less than about -80° C., or any other suitable temperatures.

Freeze drying (lyophilization) may be carried out by freezing a solution of Fezolinetant at low temperatures and reducing the pressure as required for removing the solvent from the frozen solution of Fezolinetant. Temperatures that may be required to freeze the solution, depending on the solvent chosen to make the solution of Fezolinetant, may range from about -80° C. to about 0° C., or up to about 20° C. Temperatures that may be required to remove the solvent from the frozen solution may be less than about 20° C., less than about 0° C., less than about -20° C., less than about -40° C., less than about -60° C., less than about -80° C., or any other suitable temperatures.

Another embodiment of the present invention provides novel crystalline forms of Fezolinetant and their preparation.

In another embodiment, the present invention provides a crystalline form of Fezolinetant represented as crystalline form MK-1, which can be identified by one or more analytical methods.

In another embodiment, the present invention provides a crystalline form MK-1 of Fezolinetant, characterized by an X-ray powder diffraction spectrum (XRPD) with characteristic peaks at 2? angle values of 11.9, 16.6, 18.4, 20.0, 22.3, and 25.2°±0.2°.

In another embodiment, the present invention provides a crystalline form MK-1 of Fezolinetant, further characterized by its X-Ray Powder Diffraction (XRPD) pattern comprises peaks (2? values) at least five peaks at about 9.2, 9.9, 11.9, 16.6, 18.4, 19.6, 20.0, 22.3, 25.2, 27.3, 27.6 and 28.7±0.2° and/or one or more additional peaks selected from 13.3, 14.6, 15.6, 19.0, 21.4, 21.7, 24.0 and 30.7±0.2°2?.

In another embodiment, the present invention provides a crystalline form MK-1 of Fezolinetant characterized by an X-ray powder diffraction pattern as depicted in Figure 1.
In another embodiment, the present invention provides a crystalline form MK-1 of Fezolinetant characterized by thermogravimetric analysis (TGA) that exhibits weight loss of less than about 0.5% upon heating from about 30 to about 110° C.

In another embodiment, the crystalline form MK-1 of Fezolinetant is characterized by differential scanning calorimetry (DSC) showing an endotherm onset at about 171°C and an endotherm peak at about 173 °C.

In an embodiment, the present invention provides a process for the preparation of a novel crystalline form MK-1 of Fezolinetant, comprising:
a) providing a solution of Fezolinetant in one or more solvents;
b) heating the reaction mixture;
c) cooling the reaction mixture; and
d) isolating the crystalline form MK-1 of Fezolinetant.

In an embodiment, the present invention provides a process for the preparation of a novel crystalline form MK-1 of Fezolinetant, comprising:
a) providing a solution of Fezolinetant in one or more solvents; and
b) isolating the crystalline form of Fezolinetant.

In an embodiment, the present invention provides a process for the preparation of a novel crystalline form MK-1 of Fezolinetant, comprising:
a) providing a solution of Fezolinetant in one or more solvents; and
b) adding suitable amount of anti-solvent to the solution of Fezolinetant at suitable temperature to obtain crystalline form of Fezolinetant.

In an embodiment, the present invention provides a process for the preparation of a novel crystalline form MK-1 of Fezolinetant, comprising:
a) providing a solution of Fezolinetant in one or more solvents;
b) adding suitable pharmaceutically acceptable acid to obtain pharmaceutically acceptable salt of Fezolinetant;
c) adding suitable base to the solution of step b); and
d) isolating the crystalline form of Fezolinetant.

In another embodiment, the solvent use for the preparation of crystalline Form MK-1 of Fezolinetant are selected from methanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, methyl acetate, water or mixture thereof.

In another embodiment, the present invention provides a crystalline form of Fezolinetant represented as crystalline form MK-2, which can be identified by one or more analytical methods.

In another embodiment, the present invention provides a crystalline form MK-2 of Fezolinetant, characterized by an X-ray powder diffraction spectrum (XRPD) with characteristic peaks at 2? angle values of 4.8, 8.7, 12.0, 14.3, 19.2, and 20.7 ±0.2°.

In another embodiment, the present invention provides a crystalline form MK-2 of Fezolinetant, characterized by an X-ray powder diffraction spectrum (XRPD) with characteristic at least five peaks at 2? angle values 4.8, 8.7, 9.5, 12.0, 14.3, 15.3, 16.1, 16.4, 19.2, and 20.7 ±0.2°.

In another embodiment, the present invention provides a crystalline form MK-2 of Fezolinetant characterized by an X-ray powder diffraction pattern as depicted in Figure 2.

In another embodiment, the present invention provides a crystalline form MK-2 of Fezolinetant characterized by thermogravimetric analysis (TGA) that exhibits weight loss of less than about 0.5% upon heating from about 30 to about 110° C.

In another embodiment, the crystalline form MK-2 of Fezolinetant is characterized by differential scanning calorimetry (DSC) showing an endotherm onset at about 210°C and an endotherm peak at about 212 °C.

In an embodiment, the present invention provides a process for the preparation of a novel crystalline form MK-2 of Fezolinetant, comprising:
c) providing a solution of Fezolinetant in one or more solvents; and
d) isolating the crystalline form of Fezolinetant.

In an embodiment, the present invention provides a process for the preparation of a novel crystalline form MK-2 of Fezolinetant, comprising:
c) providing a solution of Fezolinetant in one or more solvents; and
d) adding suitable amount of anti-solvent to the solution of Fezolinetant at suitable temperature to obtain crystalline form of Fezolinetant.

In an embodiment, the present invention provides a process for the preparation of a novel crystalline form (MK-2) of Fezolinetant, comprising:
a) providing a solution of Fezolinetant in a mixture of solvents;
b) heating the reaction mixture;
c) cooling the reaction mixture; and
d) isolating the crystalline form MK-2 of Fezolinetant.

In another embodiment, the solvent use for the preparation of crystalline Form MK-2 of Fezolinetant are selected from methanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, methyl acetate, hexane, heptane, cyclohexane, water or mixture thereof.

In an embodiment, the experimental results of stability test of Form MK-1 & MK-2 of Fezolinetant are shown in Table below:
Time 25±2°C/60±5% RH 40±2°C/75±5% RH
HPLC purity (%)
Form MK-1 HPLC purity (%)
Form MK-2 HPLC purity (%)
Form MK-1 HPLC purity (%)
Form MK-2
Initial 99.91 99.90 99.91 99.90
1st month 99.84 99.89 99.82 99.81
3rd month 99.86 99.90 99.89 99.85
6th month 99.89 99.89 99.86 99.86
12th month 99.83 99.85 99.84 99.84

In an embodiment, the residue solvent content in stable amorphous, Form MK-1 & MK-2 of Fezolinetant are given in the table below:
Residual Solvent Example 7 (Amorphous) Example 8
(Form MK-1) Example 9
(Form MK-2)
Methanol 500 ppm ND ND
Ethanol ND ND ND
Methylene dichloride ND ND ND
Ethyl acetate 366 ppm 442 ppm 381 ppm
Hexane ND ND ND
Tetrahydrofuran ND ND ND

In another embodiment, the present invention provides Fezolinetant having a chiral purity of greater than 99%, preferably at least 99.5%, or more preferably at least 99.9%.

In another embodiment, the present invention provides Fezolinetant having less than 0.1 % of any impurity as measured by HPLC.

In another embodiment, Fezolinetant as prepared by the process of the present invention is characterized by particle size distribution wherein, d90 is 0.1µm to 500µm, preferably d90 is 50 µm.

In an embodiment, the stable amorphous Fezolinetant may be micronized or sieved to achieve the better particle size distribution in order to make suitable Formulation.

In a further embodiment, the present invention further provides a composition comprising Fezolinetant of Formula I obtained by the process of the present invention along with at least one pharmaceutically acceptable excipient thereof.

In a further embodiment, the present invention provides a solid comprising Fezolinetant with a purity more than 99% and preferably more than 99.9%.

EXAMPLES
Example 1: Preparation of amorphous Fezolinetant
Fezolinetant (3.0 grams) was dissolved in a mixture of ethanol (80 mL) and water (40 mL) at room temperature (RT). Carbon was added to the mixture and filtered the solution. Solvent was removed spray drying. Obtained solid was analyzed by XRPD. Amorphous form of Fezolinetant was obtained. Yield: 2.9g, Purity: 99.87% by HPLC.

Example 2: Preparation of amorphous solid dispersion of Fezolinetant with poly (1-vinylpyrrolidone-co-vinyl acetate) (PVP-Co-VA)
A mixture of Fezolinetant (1.2 g) and poly (1-vinylpyrrolidone-co-vinyl acetate) (PVP-Co-VA) (2.4 g) was dissolved in methanol (30 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get the title compound. Yield: 3.6g.

Example 3: Preparation of amorphous solid dispersion of Fezolinetant with povidone
Blend Fezolinetant (1 g) and povidone (0.2 g) to form a mixture. The mixture was heated to get molten slurry. Extruded the obtained molten slurry followed by milling to obtain the title compound. Yield: 1.2g.

Example 4: Preparation of amorphous solid dispersion of Fezolinetant with silica
A mixture of Fezolinetant (1.2 g), silica (1.2 g) and poly vinyl acetate (1.2 g) were dissolved in acetone (30 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get the title compound. Yield: 3.6g.

Example 5: Preparation of amorphous Fezolinetant
Fezolinetant (3.0 g) was dissolved in a mixture of dichloromethane (80 mL) and water (40 mL) at room temperature (RT). Adjust the pH of reaction mass to below 3 with hydrochloric acid. Separate the layer and washed the aqueous layer with dichloromethane (30.0 ml). To the aqueous layer adjust pH more than 8 with 1N sodium hydroxide (30.0 ml). Charge dichloromethane (30.0 ml) at room temperature (RT) and separate the layer. Carbon was added to the dichloromethane layer and filtered the solution. Solvent was removed by spray drying to obtain amorphous Fezolinetant. Yield: 2.8g, Purity: 99.90% by HPLC.

Example 6: Preparation of amorphous Fezolinetant
Fezolinetant (3.0 g) was dissolved in water (40 mL) at room temperature (RT). Adjust the pH of reaction mass to below 3 with hydrochloric acid. Again, adjust the pH more than 8 with 1N sodium hydroxide (30.0 mL). Stirred the reaction mass at room temperature (RT). Filter the reaction mass and washed with water. Wet material dried under vacuum to get amorphous Fezolinetant. Yield: 2.9 g, Purity: 99.89% by HPLC.

Example 7: Preparation of amorphous Fezolinetant
Fezolinetant (1.0 g) was dissolved in methanol (15 ml) and water (5 mL) at room temperature (RT). Filtered the solution through micron filter. Freeze the solution at -60ºC and then Lyophilized for 10-12 hours to get amorphous Fezolinetant. Yield: 0.95 g, Purity: 99.90% by HPLC.

Example 8: Preparation of crystalline form MK-1 of Fezolinetant
Fezolinetant (10.0 g) and ethylacetate [100 ml] heated to reflux temperature. Filtered the solution through micron filter. Then gradually cooled the clear solution to room temperature. Solid crystals filtered, washed with ethyl acetate and dried in VTD under vacuum at 50ºC temperature to get crystalline form MK-1 of Fezolinetant. Yield: 8.95 g, Purity: 99.91% by HPLC.

Example 9: Preparation of crystalline form MK-2 of Fezolinetant
Fezolinetant (10.0 g), ethyl acetate [100 ml] and hexane [50 ml] heated to reflux temperature till dissolution. Filtered the solution through micron filter. Then clear solution is concentrated under vacuum at rota vapour temperature 45ºC to get solid material. Solid material is dried in VTD under vacuum at 50ºC temperature to get crystalline form MK-2 of Fezolinetant. Yield: 8.1 g, Purity: 99.90% by HPLC.
,CLAIMS:WE CLAIM:
1. A process for the preparation of stable amorphous form of Fezolinetant, comprising the steps of:
a) providing a solution of Fezolinetant in a solvent or mixture of solvents;
b) removing the solvent from the solution obtained in step a); and
c) isolating a stable amorphous form of Fezolinetant.

2. A process for the preparation of stable amorphous form of Fezolinetant, comprising the steps of:
a) providing a solution of Fezolinetant in one or more solvent;
b) adding suitable pharmaceutically acceptable acid to obtain pharmaceutically acceptable salt of Fezolinetant;
c) adding suitable base to the solution of step b); and
d) isolating the stable amorphous form of Fezolinetant.

3. The process as claimed in claim 2, wherein the pharmaceutically acceptable acid is selected from hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, formic acid, and tartaric acid and suitable base is selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, ammonia, sodium carbonate and, sodium bicarbonate.

4. A process for the preparation of amorphous solid dispersion of Fezolinetant, comprising Fezolinetant, and one or more pharmaceutically acceptable carriers, the process comprising:
a) providing a solution or suspension of Fezolinetant in combination with one or more pharmaceutically acceptable carriers in a solvent or mixture of solvents;
b) removing the solvent from the solution or suspension obtained in step a) or combining the solution obtained in step a), with an anti-solvent; and
c) isolating amorphous solid dispersion of Fezolinetant together with one or more pharmaceutically acceptable carrier.

5. A process for the preparation of stable amorphous solid dispersion of Fezolinetant, comprising Fezolinetant, and one or more pharmaceutically acceptable carriers, the process comprising:
a) blending Fezolinetant and at least one carrier/excipient;
b) heating the blend of step a) to form a molten slurry;
c) extruding the slurry of step b); and
d) milling the extrudates of step c) to obtain amorphous solid dispersion of Fezolinetant.

6. The process as claimed in claim 4 or 5, wherein carrier/excipient selected from copovidone, povidone, PVP, poly (1-vinylpyrrolidone-co-vinyl acetate) (PVP-Co-VA), polyvinyl acetate, methyl cellulose, hypromellose acetate succinate, polyethylene oxide, and polyethylene glycol.

7. A crystalline form of Fezolinetant of formula I, wherein,
i) crystalline form MK-1 of Fezolinetant characterized by X ray powder diffraction spectrum (XRPD) comprising one or more peaks selected from 9.2, 9.9, 11.9, 16.6, 18.4, 19.6, 20.0, 22.3, 25.2, 27.3, 27.6 and 28.7±0.2° (at 2? angle), or as depicted in Figure 1;
or
ii) crystalline form MK-2 of Fezolinetant characterized by X ray powder diffraction spectrum (XRPD) comprising one or more peaks selected from 4.8, 8.7, 9.5, 12.0, 14.3, 15.3, 16.1, 16.4, 19.2, and 20.7 ±0.2° (at 2? angle), or as depicted in Figure 2;

8. The crystalline form as claimed in claim 7, wherein form MK-1 is prepared by a process, comprising the steps of:
a) providing a solution of Fezolinetant in a solvent;
b) heating the reaction mixture;
c) cooling the reaction mixture; and
d) isolating the crystalline form MK-1 of Fezolinetant.

9. The crystalline form as claimed in claim 7, wherein form MK-2 is prepared by a process, comprising the steps of:
a) providing a solution of Fezolinetant in a mixture of solvents;
b) heating the reaction mixture;
c) cooling the reaction mixture; and
d) isolating the crystalline form MK-2 of Fezolinetant.

10. The process according to any of the preceding claims, wherein, the amorphous, crystalline form MK-1 and crystalline form MK-2 of Fezolinetant are substantially free from other polymorphic forms and having purity greater than 99.9%.

Dated 14th Day of August, 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer