Related Application:

This application claims the benefit of priority of our Indian patent applications number 202041057493 filed on 31 ^st December 2020 and 202141000396 filed on 05 ^th January 2021 which are incorporated herein by reference.

Field of the invention:

The present invention relates to amorphous form of N-{(2S)-l-[3-(3-chloro-4- cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl) -lH-pyrazole-3-carboxamide of formula- 1, having specific surface area (SSA) in a range from about 0.1 to 10 m ² /g and process for preparation of amorphous form of formula- 1.

Background of the invention:

Darolutamide is chemically known as N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH- pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl)-lH-pyrazole-3-c arboxamide of formula- 1.

Darolutamide was developed by Orion Corporation and Bayer Health Care. It is an anti-androgen medication which is used in the treatment of prostate cancer in men. It was approved by USFDA in July 2019, approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration.

US8975254 B2 discloses N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazol-l-yl] propan-2-yl}-5-(l-hydroxyethyl)-lH-pyrazole-3-carboxamide and process for its preparation.

US 11168058 B2 discloses crystalline particles of N-{(2S)-l-[3-(3-chloro-4- cyanophenyl)-lH-pyrazol-l-yl]propan-2-yl}-5-(l-hydroxyethyl) -lH-pyrazole-3-carboxamide having a specific surface area (SSA) in a range from about 8 to 16 m ² /g.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms 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.

Due to its low solubility and high permeability, Darolutamide can be put into class II of the Biopharmaceutical Classification System (BCS). When administering such low soluble substances orally, the dissolution rate is the limiting factor during drug absorption. Enhancement of bioavailability of poorly soluble drugs is routinely attempted by micronization. Micronization, i.e. reduction of particle size to the range of only few micrometers, typically increases the dissolution rate of the poorly soluble drug through increased specific surface area (SSA).

Micronized particles, however, often suffer from poor flow and dispersion properties causing drawbacks in subsequent pharmaceutical processing. Micronization of crystalline forms could introduce impurities in to drug substance and can induce polymorphic changes, cause degradation, and impact bulk density. Hence, there is still a need for improving its dissolution rate and bioavailability. Hence, the object of the present invention is to provide amorphous Darolutamide which is having powder properties allowing straightforward pharmaceutical processing, high dissolution rate and consequently improved bioavailability. Another object of the present invention is to provide particles of Darolutamide with lower sticking tendency during processing and better flow properties.

Brief description of the invention:

The present invention provides amorphous form of Darolutamide of formula- 1, having specific surface area (SSA) in a range from about 0.1 to about 10 m ² /g and process for the preparation of such form.

The present invention also provides crystalline form of Darolutamide of formula- 1, having specific surface area (SSA) in a range from about 17 to about 40 m ² /g and process for the preparation of such form.

Brief description of the Drawings:

Figure-1: Illustrates the PXRD pattern of amorphous Darolutamide. Figure-2: Illustrates the PXRD pattern of crystalline Darolutamide.

Detailed description of the Invention:

As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, di chloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2 -methoxyethanol, 1,2-ethoxy ethanol, diethylene glycol, 1,2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.

The term “enantiopure” as used herein means that a compound has an enantiomeric excess of at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99%.

The term “enantiopure” as used herein means that an enantiomer is present in a purity of at least 99% enantiomeric excess, preferably in a purity of 99.5-100% enantiomeric excess. In the first embodiment, the present invention provides a process for the preparation of amorphous form of Darolutamide of formula- 1, which comprises: a) providing a solution of Darolutamide in a solvent, b) isolating amorphous form of Darolutamide of formula- 1.

In the process of first embodiment, the solvent used in step-a) is selected from alcohol solvent, chloro solvent and /or mixture thereof.

In the process of first embodiment, providing a solution of Darolutamide is carried out by suspending or dissolving Darolutamide in a solvent.

In the process of first embodiment, providing a solution of Darolutamide is optionally by heating the mixture to a suitable temperature ranging from ambient temperature to reflux temperature of the solvent used. Optionally, the solution is filtered to make it particle free.

In the process of first embodiment, isolating amorphous form of Darolutamide is carried out by employing any of the techniques, but not limited to decantation, spray drying, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of first embodiment, the resulting amorphous form of Darolutamide can be dried by techniques such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying is 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 is carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In the process of first embodiment, the present invention provides amorphous form of Darolutamide having specific surface area (SSA) of about 0.1 to about 10 m ² /g.

In the process of first embodiment, the present invention provides amorphous form of Darolutamide, which is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure- 1.

In the process of first embodiment, the present invention provides amorphous form of Darolutamide prepared according to the present invention is having purity of about 99.9%; preferably about 99.95%; more preferably about 99.97% as measured by HPLC.

In the second embodiment, the present invention provides amorphous form of Darolutamide having specific surface area (SSA) in the range from about 0.1 to about 100 m ² /g or from about 0.1 to about 50 m ² /g or from about 0.1 to about 10 m ² /g or from about 0.1 to about 5 m ² /g or from about 0.1 to about 4 m ² /g or from about 0.1 to about 3 m ² /g.

In the third embodiment, the present invention provides amorphous form of Darolutamide having specific surface area (SSA) in the range from about 0.5 to about 100 m ² /g or from about 0.5 to about 50 m ² /g or from about 0.5 to about 10 m ² /g or from about 0.5 to about 5 m ² /g or from about 0.5 to about 4 m ² /g or from about 0.5 to about 3 m ² /g.

In the fourth embodiment, the present invention provides amorphous form of Darolutamide having volume median diameter (Dv50) between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 0.5-25 pm. Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1- 50 pm, in particular between 1-50 pm.

In the fifth embodiment, the present invention provides Darolutamide having specific surface area (SSA) in the range from about 0.5 to about 100 m ² /g or from about 0.5 to about 50 m ² /g or from about 0.5 to about 10 m ² /g or from about 0.5 to about 5 m ² /g or from about 0.5 to about 4 m ² /g or from about 0.5 to about 3 m ² /g.

In the sixth embodiment, the present invention provides Darolutamide having volume median diameter (Dv50) between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 0.5-25 pm. Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 1-50 pm.

In the seventh embodiment, the present invention provides a pharmaceutical composition comprising amorphous form of Darolutamide compound of formula- 1 and one or more pharmaceutically acceptable excipients.

In the eighth embodiment, the present invention provides a process for the preparation of Crystalline form of Darolutamide of formula- 1, which comprises: a) providing a solution of Darolutamide in a solvent, b) isolating crystalline form of Darolutamide of formula- 1.

In the process of eighth embodiment, the solvent used in step-a) is selected from alcohol solvent, ester solvent, water and /or mixture thereof.

In the process of eighth embodiment, providing a solution of Darolutamide is carried out by suspending or dissolving Darolutamide in a solvent.

In the process of eighth embodiment, providing a solution of Darolutamide is optionally by heating the mixture to a suitable temperature ranging from ambient temperature to reflux temperature of the solvent used. Optionally, the solution is filtered to make it particle free.

In the process of eighth embodiment, isolating Crystalline form of Darolutamide is carried out by employing any of the techniques, but not limited to decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, cooling the mixture to solidify followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

In the process of eighth embodiment, the resulting Crystalline form of Darolutamide can be dried by techniques such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying is 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 is carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In the process of eighth embodiment, the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 17 to about 40 m ² /g, which is characterized by its Specific surface area (SSA) Method of Analysis.

In the process of eighth embodiment, the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 0.5 to about 7 m ² /g, which is obtained by micronization techniques such as ball milling, roller milling and hammer milling, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

In the process of eighth embodiment, the present invention provides Crystalline form of Darolutamide, which is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-2.

In the process of eighth embodiment, the present invention provides Crystalline form of Darolutamide prepared according to the present invention is having purity of about 99.9%; preferably about 99.95%; more preferably about 99.97% as measured by HPLC.

In the ninth embodiment, the present invention provides Crystalline form of Darolutamide having specific surface area (SSA) of about 0.5 m ² /g or 1 m ² /g or 2 m ² /g or 3 m ² /g or 4 m ² /g or 5 m ² /g or 6 m ² /g or 7 m ² /g or in the range from about 17 to about 100 m ² /g or from about 17 to about 50 m ² /g or from about 17 to about 40 m ² /g or from about 17 to about 30 m ² /g or from about 25 to about 35 m ² /g. In the tenth embodiment, the present invention provides crystalline form of Darolutamide having volume median diameter (Dv50) between 0.1-100 pm, preferably between 0.1-75 pm, more preferably between 0.1-50 pm, in particular between 1-25 pm.

In the eleventh embodiment, the present invention provides Crystalline form of Darolutamide having volume median diameter Dv90 is between 0.1-1000 pm, preferably between 0.1-100 pm, more preferably between 0.1-50 pm, in particular between 50-100 pm.

In the twelfth embodiment, the present invention provides a pharmaceutical composition comprising Crystalline form of Darolutamide prepared according to the present invention and one or more pharmaceutically acceptable excipients and/or earners.

The excipient can be selected from one or more described in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.

As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The starting material of Darolutamide used in the present invention can be prepared from any of the processes known in the art.

Darolutamide produced by the present invention can be micronized or milled using conventional techniques to get the desired particle size and surface area to achieve desired solubility profile to suit to pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

Specific surface area (SSA) Method of Analysis:

Specific surface area (SSA) of Crystalline form of Darolutamide can be analyzed using three -point nitrogen adsorption technique based on the Brunauer, Emmett and Teller (BET) theory using TriStar 3000 automated gas adsorption analyzer, (Micromeritics, Inc.). The samples were dried for 16 hours in 25°C. The volumetric method was applied at the relative pressure range 0.05 to 0.3 P/P _o .

P-XRD Method of Analysis:

PXRD analysis of compound of formula- 1 was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Kα radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. PSD method of Analysis:

Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example- 1: Preparation of Darolutamide.

Methanol (500 ml) was added to (S)-5-acetyl-N-(l-(3-(3-chloro-4-cyanophenyl)-lH- pyrazol-l-yl)propan-2-yl)-lH-pyrazole-3 -carboxamide (100 g) at 25-30°C. Cooled the mixture to 15-20°C. Sodium borohydride (9.51 g) was added to the mixture at 15-20°C and stirred for 45 minutes. Raised the temperature of the mixture to 25-30°C and stirred for 90 minutes. Water (1000 ml) was slowly added to the mixture at 25-30°C and stirred for 6 hours. Filtered the solid, washed with water and dried to get the title compound. Yield: 90.0 g; Purity by HPLC: 98.58% and MR: 178-183°C.

Example-2: Preparation of crystalline form-I of Darolutamide.

A mixture of ethyl acetate (18 Lt) and water (3 Lt) were added to Darolutamide (1.5 kg) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 75-80°C and stirred for 1 hour. Cooled the mixture to 65-70°C. The mixture was treated with carbon in ethyl acetate. Filtered the mixture through hyflow bed and washed with ethyl acetate. Observed solid filtered and dried. To the obtained solid, ethyl acetate (18 Lt) and water (3.0 Lt) were added at 25-30°C. Raised the temperature of the mixture to 75-80°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 10 hours. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 1.2 kg.

Example-3: Preparation of amorphous Darolutamide

A mixture of methanol (32.5 Lt) and dichloromethane (32.5 Lt) were added to crystalline form-I of Darolutamide (2.60 kg) at 25-30°C and stirred for 30 minutes. Filtered the mixture for particle free and washed with methanol and dichloromethane. The obtained particle free solution was spray dried at below mentioned parameters Inlet temperature: 70-75°C; Outlet temperature: 65-70°C; Feed rate: 10 ml/min; Atomizer Nozzle tip diameter: 1.2 mm; Aspirator flow rate: 80%; Nitrogen pressure: 2.5 kg The obtained solid was collected from the spray dryer and dried under vacuum to get the title compound. Yield: 2.05 kg; Specific surface area (SSA): 1.43 m2/g.

The PXRD pattern of the obtained compound was shown in figure- 1.

Example-4: Preparation of Darolutamide

Methanol (1000 ml) was added to (S)-5-acetyl-N-(l-(3-(3-chloro-4-cyanophenyl)-lH- pyrazol-l-yl)propan-2-yl)-lH-pyrazole-3-carboxamide (100 g) at 25-30°C. Cooled the mixture to 15-20°C. Sodium borohydride (11.41 g) was slowly added to the mixture at 15- 20°C and stirred for 45 minutes. Raised the temperature of the mixture to 25-30°C and stirred for 90 minutes. Cooled the mixture to 10-15°C and slowly added the mixture to water (2500 ml) at 25-30°C. Treated with aqueous acetic acid at 25-30°C and stirred for 3 hours. Filtered the solid, washed with water and dried. Obtained solid added to water (1500 ml) at 25-30°C. Heated the mixture at 50-55°C and stirred for 60 minutes. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the solid and dried. Obtained solid was added to the mixture of methanol (720 ml) and ethyl acetate (360 ml) at 25-30°C. Heated the mixture to 60-65°C and treated with carbon powder. Cooled the mixture to 25-30°C and water (1200 ml) was added to the mixture. Stirred the mixture for 4 hours at 25-30°C. Filtered the solid and washed with methanol water mixture. Dried to get the title compound.

Yield: 71.0 g; Purity by HPLC: 99.85%

Example-5: Preparation of amorphous Darolutamide

A mixture of methanol (1875 ml) and dichloro methane (1875 ml) were added to Darolutamide (150 g) at 25-30°C and stirred for 30 minutes. Filtered the mixture for particle free and washed with methanol and dichloromethane. The obtained particle free solution was spray dried at below mentioned parameters

Inlet temperature: 65-70°C; Outlet temperature: 50-55°C; Feed rate: 10 ml/min; Atomizer Nozzle tip diameter: 1.0 mm; Aspirator flow rate: 70%; Nitrogen pressure: 2.0 kg

The obtained solid was collected from the spray dryer and dried under vacuum to get the title compound.

Yield: 108g; Purity by HPLC: 99.88%

Specific surface area (SSA): 0.939 m ² /g.

Particle size distribution (PSD): (Dv50): 10.38 pm; (Dv90): 19.26 pm

Example-6: Preparation of amorphous Darolutamide

Methanol (875 ml) was added to Darolutamide (25 g) at 25-30°C. Heated the mixture to 45-50°C and stirred for 10 minutes. Filtered the mixture for particle free and washed with methanol. The obtained particle free solution was spray dried at below mentioned parameters. Inlet temperature: 70-75°C; Outlet temperature: 50-55°C; Feed rate: 10 ml/min; Atomizer Nozzle tip diameter: 1.0 mm; Aspirator flow rate: 70%; Nitrogen pressure: 2.0 kg

The obtained solid was collected from the spray dryer and dried under vacuum to get the title compound.

Yield: 15g; Specific surface area (SSA): 0.988 m ² /g.

Particle size distribution (PSD): (Dv50): 12.27 pm; (Dv90): 23.80 pm

Example-7: Preparation of amorphous Darolutamide

A mixture of methanol (875 ml) and dichloromethane (12.5 ml) were added to Darolutamide (25 g) at 25-30°C. Heated the mixture to 45-50°C and stirred for 10 minutes. Filtered the mixture for particle free and washed with methanol. The obtained particle free solution was spray dried at below mentioned parameters.

Inlet temperature: 70-75°C; Outlet temperature: 50-55°C; Feed rate: 10 ml/min; Atomizer Nozzle tip diameter: 1.0 mm; Aspirator flow rate: 70%; Nitrogen pressure: 2.0 kg

The obtained solid was collected from the spray dryer and dried under vacuum to get the title compound. Yield: 15g;

Particle size distribution (PSD): (Dv50): 8.06 pm; (Dv90): 15.11 pm

Example-8: Preparation of crystalline Darolutamide

A mixture of ethyl acetate (18 liter) and water (3 liter) were added to Darolutamide (1.5 kg) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 75- 80°C and stirred for 1 hour. Cooled the mixture to 65-70°C. The mixture was treated with carbon in ethyl acetate. Filtered the mixture through hyflow bed and washed with ethyl acetate. Mixture/filterate stirred for 10 hours at 25-30°C. Filtered the solid, washed with ethylacetate and dried to get solid. To the obtained solid, ethyl acetate (18 liter) and water (3.0 liter) were added at 25-30°C. Raised the temperature of the mixture to 75-80°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 10 hours. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 1.2 kg.

Specific surface area (SSA): 29.56 m ² /g.

Particle size distribution (PSD): (Dv50): 11.63 pm; (Dv90): 76.18 pm

The PXRD pattern of the obtained compound was shown in figure-2.

Example-9: Preparation of crystalline Darolutamide

Methanol (6.6 litre) was added to Darolutamide (550 gm) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 65-70°C and stirred for 1 hour. The mixture was treated with carbon at 65-70°C. Filtered the mixture through hyflow bed and washed with methanol. Mixture/filtrate cooled to 25-30°C and seeded with crystalline Darolutamide, stirred for 3 hours at 25-30°C. Mixture cooled to 0-5°C and stirred for 6 hours.

Filtered the solid, washed with methanol and dried to get the title compound.

Yield: 502 gm.

Specific surface area (SSA): 20.11 m ² /g. Particle size distribution (PSD): (Dv50): 15.01 pm; (Dv90): 62.65 pm

The PXRD pattern of the obtained compound was shown in figure-2.