Polymorphs of darolutamide

Abstract

The present invention discloses novel polymorphs of Darolutamide Form C1, Form C2 and Form C3, processes for their preparation and pharmaceutical 10 compositions thereof.

Description

[0001] POLYMORPHS OF DAROLUTAMIDE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel polymorphs of Darolutamide Form Cl, Form C2 and Form C3, processes for their preparation and pharmaceutical compositions thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Darolutamide chemically known as N-{(2S)-l-[3-(3-chloro-4-cyanophenyl)-lH-pyrazol- 1 -yl]propan-2-yl } -5-(l -hydroxy ethyl)- lH-pyrazole-3 -carboxamide is a androgen receptor inhibitor used in the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC). It is sold under the brand name Nubeqa. Darolutamide has the following chemical structure;

[0006]

[0007] Structure-I

[0008] Prostate cancer is the most common form of cancer among males. Prostate cancer is a type of cancer that occurs when cells in the prostate gland grow out of control. Deaths from prostate cancer are second highest after deaths from lung cancer. The rate of prostate cancer is higher in North America, Europe, Australia, and New Zealand. This rate increases year by year in each country.

[0009] Darolutamide is an androgen receptor (AR) inhibitor. The actions of androgens on androgen receptors (AR) potentiate the growth and survival of prostate cancer cells. Darolutamide competitively inhibits androgens from binding to their receptors, inhibiting AR nuclear translocation, as well as AR-mediatedtranscription. The result of these processes is a decrease in prostate cancer cell proliferation and tumor size. Darolutamide is a nonsteroidal androgen receptor antagonist for the treatment of castrate-resistant, non-metastatic prostate cancer (nmCRPC). This condition occurs in most patients with advanced prostate cancer who have been treated with androgen receptor antagonists.

[0010] The compound Darolutamide and its preparation have been disclosed in WO 2011051540 Al.

[0011] A crystalline Form I of Darolutamide, crystalline Form I’ and crystalline Form I” of its diastereomer and method of their preparation are disclosed in WO 2016120530 Al.

[0012] Alternative process for the preparation of crystalline Form I of Darolutamide is disclosed in CN 107602471 B.

[0013] The discovery of new polymorphs is well recognized to potentially lead to improved properties for pharmaceutical substance including enhanced dissolution, enhanced stability, and enhanced solubility.

[0014] It is found that, in the present invention, different forms of Darolutamide have improved physical and pharmacological activity and further provides the process of preparation thereof. This remains the object of the invention.

[0015] OBJECTIVE OF THE INVENTION

[0016] In accordance with the above, the primary objective of the present invention is to provide novel polymorphs of Darolutamide.

[0017] The other objective of the present invention is to provide processes for the preparation of polymorphs of Darolutamide.Another objective of the present invention is to provide a pharmaceutical composition comprising novel polymorphs of Darolutamide and pharmaceutically acceptable carrier, diluent or excipients.

[0018] Yet another objective of the present invention is to use pharmaceutical composition as defined above for the treatment of prostate cancer.

[0019] SUMMARY OF THE INVENTION

[0020] In an aspect, the present invention provides Darolutamide polymorph Form Cl.

[0021] In another aspect, the present invention provides Darolutamide Form Cl characterized by X-ray powder diffraction pattern (XRPD), Differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA) as depicted in Fig. 1, Fig.

[0022] 2 and Fig. 3 respectively.

[0023] In an aspect, the present invention provides Darolutamide polymorph Form C2.

[0024] In another aspect, the present invention provides Darolutamide polymorph Form C2 characterized by X-ray powder diffraction pattern (XRPD), Differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA) as depicted in Fig. 4, Fig. 5 and Fig. 6 respectively.

[0025] In yet another aspect, the present invention provides Darolutamide polymorph Form C3.

[0026] In another aspect, the present invention provides Darolutamide polymorph Form C3 characterized by X-ray powder diffraction pattern (XRPD), Differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA) as depicted in Fig. 7, Fig. 8 and Fig. 9 respectively.In another aspect, the present invention provides a process for preparation of Darolutamide Form Cl, Form C2 and Form C3.

[0027] In yet another aspect, the present invention provides the pharmaceutical composition defined hereinabove for prostate cancer.

[0028] In yet another aspect, the present invention provides the use of pharmaceutical composition as defined above for the treatment of prostate cancer.

[0029] DESCRIPTION OF FIGURES

[0030] Figure 1 shows X-ray powder diffraction spectrum (XRPD) of Darolutamide Polymorph Form Cl according to example 1.

[0031] Figure 2 shows Differential scanning calorimetry (DSC) of Darolutamide Polymorph Form Cl according to example 1.

[0032] Figure 3 shows Thermogravimetric analysis (TGA) of Darolutamide Polymorph Form Cl according to example 1.

[0033] Figure 4 shows X-ray powder diffraction spectrum (XRPD) of Darolutamide Polymorph Form C2 according to example 2.

[0034] Figure 5 shows Differential scanning calorimetry (DSC) of Darolutamide Polymorph Form C2 according to example 2.

[0035] Figure 6 shows Thermogravimetric analysis (TGA) of Darolutamide Polymorph Form C2 according to example 2.Figure 7 shows X-ray powder diffraction spectrum (XRPD) of Darolutamide Polymorph Form C2 according to example 3.

[0036] Figure 8 shows: X-ray powder diffraction spectrum (XRPD) of Darolutamide Polymorph Form C3 according to example 5.

[0037] Figure 9 shows Differential scanning calorimetry (DSC) of Darolutamide Polymorph Form C3 according to example 5.

[0038] Figure 10 shows Thermogravimetric analysis (TGA) of Darolutamide Polymorph Form C3 according to example 5.

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040] The present invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects therefore maybe fully understood and appreciated.

[0041] Polymorphs are solid materials that can exist in different crystallographic structures with varying crystal lattice arrangement. Polymorphism causes differences in physical properties with different molecular arrangements. During drug development, altering the physical form of polymorphs can achieve favorable physicochemical properties of compound, such as bioavailability, solubility, dissolution, and chemical stability.

[0042] As used herein, the term "PXRD" refers to powder X-ray diffraction, the term "DSC" refers to Differential scanning calorimetry, the term "TGA" refers to thermogravimetric analysis.

[0043] In an embodiment, the present application relates to Darolutamide polymorph Form Cl.

[0044] In another embodiment, the present invention discloses Darolutamide polymorph Form Cl characterized by X-ray powder diffraction pattern (XRPD) with peaks at9.06, 10.99, 16.41, 18.32, 19.04, 20.19, 23.42 and 27.52 ± 0.2°20 as depicted in Fig i.

[0045] In an embodiment, the DSC thermogram for the Darolutamide polymorph Form Cl shows an endothermic peak with an onset temperature at 166.80°C and a peak maximum at about 174.49 °C as represented in Fig 2.

[0046] In an embodiment, the TGA data of the Darolutamide Form Cl shows a weight loss of approximately 0.819 % at temperature about 150 °C as represented in Fig 3.

[0047] In an embodiment, the present invention discloses Darolutamide Form C2.

[0048] In another embodiment, the present invention discloses Darolutamide polymorph Form C2 characterized by X-ray powder diffraction pattern (XRPD) with peak at 7.69, 9.06, 11.02, 13.14, 16.6, 22.05, 27.40 and 28.8 ± 0.2°20 as represented in Figure 4.

[0049] In another embodiment, the DSC thermogram for the Darolutamide polymorph Form C2 shows an endothermic peak with an onset temperature at 165.04°C and a peak maximum at about 170.92 °C as represented in Fig 5.

[0050] In another embodiment, TGA data of the Darolutamide polymorph Form C2 shows a weight loss of approximately 0.229 % at temperature about 150 °C as represented in Fig 6.

[0051] In an embodiment, the present invention discloses Darolutamide Form C3.

[0052] In another embodiment, the present invention discloses Darolutamide polymorph Form C3 characterized by X-ray powder diffraction pattern (XRPD) with peaks at 9.3, 11.96, 13.97, 15.07, 15.79, 19.48, 23.43 and 26.85 ± 0.2°20 as represented in Fig 7.

[0053] In another embodiment, the DSC thermogram for the Darolutamide polymorph Form C3 shows a first endothermic peak with an onset temperature at 100.78°C and a peak maximum at about 113.22 °C, second endothermic peak with an onset temperature at 117.93°C and a peak maximum at about 119.20°C, Thirdendothermic peak with an onset temperature at 176.69°C and peak maximum at about 180.63°C as represented in Fig 8.

[0054] In an embodiment, , the TGA data of the Darolutamide polymorph Form C3 shows a weight loss of approximately 13.043 % at temperature about 150 °C as represented in Fig 9.

[0055] In an embodiment, the present invention discloses processes for preparation of Darolutamide polymorph Form Cl, Darolutamide polymorph Form C2 and Darolutamide polymorph Form C3.

[0056] In another embodiment, the present invention discloses a process for preparation of Darolutamide polymorph Form Cl or Form C2 or Form C3 comprising;

[0057] a. Dissolving Darolutamide or Darolutamide polymorph in a suitable solvent or a mixture of solvents at a suitable temperature;

[0058] b. Filtering the solution of step (a) to remove any undissolved particulate matter to obtain clear solution;

[0059] c. Adding one or more suitable antisolvent at a suitable temperature to the above solution and stirring at specific period of time;

[0060] d. Isolating resulting solid of Darolutamide;

[0061] e. Drying the isolated resulting material of Darolutamide;

[0062] f. Heating the resulting material of Darolutamide at specific temperature at specific time; and

[0063] g. Cooling to specific temperature resulting into desired form of Darolutamide.

[0064] The starting material can be obtained by any method known in the art, such as the one described in the WO 2011051540 Al which is incorporated herein by reference.

[0065] Darolutamide or Darolutamide polymorph is dissolved in suitable solvent at a suitable temperature of about 40°C to 80°C, preferably about 40°C to 60°C and about 50°C to 70°C.The reaction is carried out in suitable solvent, which is preferred, from the group comprising of ethers, esters, ketones, hydrocarbons, alcohols, acids, nitriles, amines, amides, water and the like, either alone or in mixtures thereof.

[0066] Crystallization is carried out by using an antisolvent which is selected from the group comprising of acids, alcohols, ethers, esters, ketones, amines, amide, hydrocarbons and the like, either alone or in mixtures thereof.

[0067] The Antisolvent is added at temperature which ranges from - 25°C to 30°C, preferably about -10°C to 15°C.

[0068] The reaction mixture is stirred for about 1 minute to 4 hours, more preferably about 30 minutes to 3 hours.

[0069] After stirring, the resulting solid is isolated by the known method.

[0070] The resulting solid is dried at a temperature ranging from 25°C to 65°C, more preferably about 35°C to 55°C for about specific time ranging 1 minute to 3 hours, more preferably 30 minutes to 3 hours.

[0071] This resulting material is further heated at a specific temperature ranging from 50°C to 110°C, more preferably at 50°C to 100°C for specific time ranging from 1 minute to 4 hours, more preferably 30 minutes to 3 hours.

[0072] Optionally, the material is further heated at a specific temperature ranging from 60°C to 120°C and kept at a specific temperature ranging from 60°C to 120°C, more preferably at 70°C to 110°C for specific time ranging from 1 minute to 2 hours, more preferably for 30 minutes to 1 hour.

[0073] The cooling is done at specific temperature ranging from 10°C to 40°C, more preferably at 15°C to 35°C to get desired polymorph of Darolutamide.In another embodiment, the present invention discloses a process for preparation of Darolutamide polymorph Form Cl or Form C2 or Form C3 comprising;

[0074] a. Dissolving Darolutamide in a suitable solvent or a mixture of solvents at a suitable temperature;

[0075] b. Filtering the solution of step (a) to remove any undissolved particulate matter to obtain clear solution;

[0076] c. Cooling the clear solution obtained in step (b) to a suitable temperature and stirring the above mixture at specific period of time;

[0077] d. Filtering and drying at a specific temperature at specific time to obtain crude product;

[0078] e. Dissolving the crude product obtained in step (d) in a suitable solvent at specific temperature and stirring the suspension for a specific period of time; and

[0079] f. Filtering and drying at a specific temperature and specific time resulting into desired form of Darolutamide.

[0080] Darolutamide is dissolved in suitable solvent or a mixture of solvent at a temperature of about 20°C to 105°C, preferably about 40°C to 85°C, more preferably about 50°C to 75°C.

[0081] Suitable solvent is used to carry reaction, which is preferred, from the group comprising of ethers, esters, ketones, hydrocarbons, alcohols, acids, nitriles, amines, amides, water and the like, either alone or in mixtures thereof.

[0082] The reaction mixture is cooled at a specific temperature ranging from -15°C to 20°C, more preferably at -10°C to 15°C and then stirred for about specific time ranging from 30 minutes to 6 hours, more preferably about 1 hour to 5 hours.

[0083] After stirring, resulting solid is filtered and dried at specific temperature ranging from 15°C to 75°C, more preferably about 25°C to 65°C for specific time rangingfrom 30 minutes to 7 hours, more preferably about 1 hour to 6 hours to get crude Darolutamide.

[0084] Crude Darolutamide is dissolved in suitable solvent or a mixture of solvent which is selected from ether, ester, alcohol, acid, amide, amines, hydrocarbon and the like, either alone or in mixtures thereof at specific temperature ranging from -15°C to 20°C, more preferably at -10°C to 15°C and stirred for specific time ranging from 1 minute to 4 hours, more preferably 30 minutes to 3 hours.

[0085] Resulting solid is then filtered and dried under at a temperature ranging from 25°C to 65°C, more preferably about 35°C to 55°C for specific time ranging from 1 hour to 7 hours, more preferably for about 2 hours to 6 hours.

[0086] In another embodiment, the present invention discloses a process for preparation of Darolutamide polymorph Form Cl or Form C2 or Form C3 comprising;

[0087] a. Dissolving Darolutamide or Darolutamide polymorph in a suitable solvent or a mixture of solvents;

[0088] b. Filtering the solution of step (a) to remove any undissolved particulate matter to obtain clear solution;

[0089] c. Adding one or more suitable antisolvents at a suitable temperature to the above solution and stirring the solution for a specific period of time; d. Isolating the resulted solid of Darolutamide; and

[0090] e. Drying the isolated crystalline form of Darolutamide.

[0091] Darolutamide or Darolutamide polymorph is dissolved in suitable solvent at a temperature of about 20°C to 100°C, preferably about 30°C to 90°C, more preferably about 40°C to 80°C,

[0092] The reaction is carried out in a suitable solvent, which is preferred, from the group comprising of ethers, esters, ketones, hydrocarbons, alcohols, acids, nitriles, amines, amides, water and the like, either alone or in mixtures thereof.Crystallization is carried out by using Antisolvent which is selected from the group comprising of alcohols, acid, ethers, esters, ketones, amines, amide, hydrocarbons and the like, either alone or in mixtures thereof.

[0093] Antisolvent is added at temperature which ranges from - 25°C to 30°C, preferably about -10°C to 20°C.

[0094] The reaction mixture is stirred for about 1 minute to 6 hours, more preferably about 30 minutes to 5 hours.

[0095] After stirring, the resulting solid is isolated by the known method.

[0096] The resulting solid is dried at a temperature ranging from 25°C to 65°C, more preferably about 35°C to 55°C for about 1 hour to 7 hours.

[0097] In another embodiment, the present invention discloses a process for preparation of Darolutamide polymorph Form Clor Form C2 or Form C3 comprising;

[0098] a. Dissolving Darolutamide in a suitable solvent or a mixture of solvents at a suitable temperature;

[0099] b. Filtering the solution of step (a) to remove any undissolved particulate matter to obtain clear solution;

[0100] c. seeding the above clear solution with freshly prepared Darolutamide Form C2 seed crystals in solvent or mixture of solvents and stirring the solution for a specific period of time;

[0101] d. Filtering and drying at a specific temperature at specific time;

[0102] e. Heating at specific temperature at specific time to obtain dried product; f. Dissolving the dried product obtained in step (e) in one or more suitable solvent at specific temperatures and stirring for a specific period of time; and

[0103] g. Filtering and drying at a specific temperature and specific time resulting into desired form of Darolutamide.Darolutamide is dissolved in suitable solvent or a mixture of solvent at a temperature of about 40°C to 80°C, preferably about 50°C to 70°C.

[0104] Suitable solvent is used to carry reaction, which is preferred, from the group comprising of ethers, esters, ketones, hydrocarbons, alcohols, acids, nitriles, amines, amides, water and the like, either alone or in mixtures thereof.

[0105] Crystallization is carried out by using Antisolvents which is selected from the group comprising of alcohols, acid, ethers, esters, ketones, amines, amide, hydrocarbons, water and the like, either alone or in mixtures thereof.

[0106] Antisolvent is added at temperature which ranges from 0°C to 30°C, preferably about 10°C to 30°C and then stirred for about specific time ranging from 30 minutes to 15 hours, more preferably about 5 hours to 12 hours.

[0107] After stirring, resulting solid is filtered and dried at specific temperature ranging from 15°C to 75°C, more preferably about 20°C to 40 °C for specific time ranging from 30 minutes to 7 hours, more preferably about 2 hours to 6 hours and further heating at specific temperature ranging from 20°C to 80°C, more preferably about 35°C to 65 °C for specific time ranging from 30 minutes to 7 hours, more preferably about 2 hours to 6 hours to obtain dried product.

[0108] Dried product is dissolved in suitable solvent or a mixture of solvent which is selected from ether, ester, alcohol, acid, amide, amines, hydrocarbon and the like, either alone or in mixtures thereof at specific temperature ranging from -15°C to 20°C, more preferably at -10°C to 15°C and stirred for specific time ranging from 1 minute to 4 hours, more preferably 30 minutes to 3 hours.

[0109] Resulting solid is then filtered and dried under at a temperature ranging from 30°C to 70°C, more preferably about 40°C to 60°C for specific time ranging from 5 hour to 15 hours, more preferably for about 7 hours to 12 hours.In an embodiment, the present invention discloses the process for preparing Darolutamide Form C2 comprising;

[0110] a) dissolving Darolutamide in a solvent or mixture of solvents at a temperature of 50-65°C;

[0111] b) filtering to remove any undissolved particulate matter to obtain clear solution;

[0112] c) cooling the solution to 0-5° with stirring;

[0113] d) filtering and drying to obtain crude Darolutamide;

[0114] e) dissolving crude Darolutamide of step d) in pre-chilled solvent at 0-5°C and stirring;

[0115] f) filtering and drying to obtain Darolutamide Form C2.

[0116] In another embodiment, the present invention relates to a process for preparing Darolutamide Form C2 comprising;

[0117] a) dissolving Darolutamide in a solvent or mixture of solvents at a temperature of 50-65°C;

[0118] b) filtering to remove any undissolved particulate matter to obtain clear solution;

[0119] c) adding one or more pre-cooled antisolvent at 0-5°C with stirring; d) filtering, washing and drying initially at a temperature of 35-45°C; e) heating to 50-60°C for 1-2 hours followed by cooling to room temperature to obtain Darolutamide Form C2.

[0120] In yet another embodiment, the process for preparing Darolutamide Form C2 comprising;

[0121] a) dissolving Darolutamide in a solvent or mixture of solvents at a temperature of 50-65°C;

[0122] b) filtering to remove any undissolved particulate matter to obtain clear solution;

[0123] c) Seeding the above clear solution with freshly prepared Darolutamide Form C2 seed crystals in solvent or mixture of solvents;d) Filtering, washing and drying at a temperature of 35-45°C followed by heating at 50-60°C to obtain dried solid;

[0124] e) Adding the above dried solid to the pre-chilled solvent or solvent mixture, stirring, filtering and drying to obtain Darolutamide Form C2.

[0125] The solvent for the process of preparation of Darolutamide Form C2 is selected from water, (un) substituted C1-C3 alcohols, formic acid, aq. Ammonia, ethyl acetate, alone or mixture thereof.

[0126] The anti-solvnet the solvent for the process of preparation of Darolutamide Form C2 is selected from aliphatic hydrocarbons such as n-hexane or n-heptane; ethers alone or mixtures thereof.

[0127] The present Darolutamide polymorphs have distinctive advantageous properties such as polymorphic purity, solubility, bioavailability, dissolution rate, stability with respect to polymorphic conversion, low content of residual solvent and such other properties useful in formulating the pharmaceutical compositions.

[0128] In an embodiment, Darolutamide Form C2 is stable up to a period of six months under storage conditions of 2-8°C with total impurities NMT 0.50 as shown in table 1.

[0129] The present invention comprises 1) a pharmaceutical composition comprising any one, or combination of Darolutamide Polymorph Forms Cl, C2 or C3 described above and at least one pharmaceutically acceptable excipient; and 2) the use of any one, or combination, of the above described Darolutamide Polymorph Forms Cl, C2 or C3 in the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition can be useful for the treatment or prevention of cancer.

[0130] The pharmaceutical composition can be prepared by a process comprising combining any one, or combination of the above described DarolutamidePolymorph Forms Cl, C2 or C3; with at least one pharmaceutically acceptable excipient.

[0131] Any one, or combination, of the above mentioned Darolutamide Polymorph Forms Cl, C2 or C3 particularly in a pharmaceutical composition and dosage form, can be used to treat or prevent cancer in a mammal such as a human, comprising administering a treatment effective amount of the one, or combination, of the Darolutamide Polymorph Forms Cl, C2 or C3 in the mammal.

[0132] The invention will now be further described by the following examples, which are illustrative rather than limiting.

[0133] EXAMPLES:

[0134] Example 1: Process for preparation of Darolutamide Form Cl

[0135] 8.0 g of amorphous Darolutamide was dissolved in 120 ml (15 volumes) of acetone at 50-55°C, and the resulting solution was filtered to remove any undissolved particulate matter. The resulted clear solution was added to 250 ml (30 volumes) of pre-cooled n-heptane at 0-5°C and stirred for 1-2 hours. The resulted solid was isolated via filtration, washed with 16 ml (2 volumes) of n-heptane, and initially dried at 45°C in an Air Tray Dryer (ATD) for 1 hour. A 2.0 g portion of this material was then heated to 80°C over 30-60 minutes and maintained at 80°C for 30 minutes, followed by further heating to 90°C with a maintenance period of 30 minutes at that temperature. Finally, the material was cooled to room temperature to obtain Darolutamide Form Cl.

[0136] Yield: 1.5 gm.

[0137] Example 2: Process for the preparation of Darolutamide Form C22.0 g of Darolutamide was dissolved in a solvent mixture comprising 20 ml (10 volumes) of trifluoroethanol and 2 ml (1.0 volume) of water by heating to 60-65°C. The resulting solution was filtered to remove any particles or undissolved particulate matter, and the clear solution was transferred into a clean roundbottom flask. The solution was then cooled to 0-5°C and stirred for 3-4 hours. The obtained solid was isolated by filtration, washed with 4 ml (2 volumes) of water, and dried in an Air Tray Dryer (ATD) at 45°C for 3-4 hours to obtain 2.0 g of crude Darolutamide.

[0138] This crude material (2.0 g) was subsequently suspended in 20 ml (10 volumes) of pre-chilled methanol at 0-5°C and stirred for 1-2 hours. The resulted solid was filtered, washed with 2 ml (1 volume) of chilled methanol, and suck-dried under vacuum. The material was further dried in an ATD at 45°C for 4 hours to obtain Darolutamide Form C2.

[0139] Yield: 1.3 gm.

[0140] Example 3: Process for the preparation of Darolutamide Form C2

[0141] 10.0 g of Darolutamide was dissolved in 20.0 ml (2.0 volumes) of formic acid at 60-65°C. The solution was filtered to remove any undissolved particulate matter to obtain a particle-free clear solution. Separately, a mixture of 200.0 ml (20 volumes) of water and 60.0 ml (6.0 volumes) of aqueous ammonia (Aq. NH3) was prepared, to which 2.0 g of Darolutamide Form C2 seed crystals were added. The particle-free clear solution was then added to this mixture at 20-30°C and stirred for 10 hours. The resulting solid was isolated by filtration and washed with 20.0 ml (2 volumes) of water. The obtained wet material was initially dried at 30°C in a Vacuum Tray Dryer (VTD) for 4 hours, followed by heating at 50-55°C for an additional 4 hours.

[0142] The resulting dried material was then charged into 10 volumes of pre-chilled ethyl acetate and stirred for 1 hour. Subsequently, 10 volumes of n-heptane were added to the suspension, and stirring was continued for 1 hour. The solid was filtered and dried under vacuum at 50°C for 10 hours to obtain Darolutamide Form C2.Yield: 7.5 gm.

[0143] Example 4: Process for the preparation of Darolutamide Form C2

[0144] 2.0 g of Darolutamide was dissolved in 40.0 ml (20.0 volumes) of ethanol at 60-65°C. The solution was filtered to remove any undissolved particulate matter to obtain a particle-free clear solution. This clear solution was then added to 100.0 ml (50 volumes) of pre-cooled n-heptane maintained at 0-5°C and stirred for 1-2 hours. The resulting solid was isolated by filtration and washed with 4.0 ml (2 volumes) of n-heptane. The obtained wet material was initially dried at 40°C in an Air Tray Dryer (ATD) for 1 hour, then further heated to 50-55°C and maintained at this temperature for 1-2 hours. The material was subsequently cooled to room temperature to obtain Darolutamide Form C2.

[0145] Yield: 1.5 gm.

[0146] Example 5: Process for the preparation of Darolutamide Form C3

[0147] 2.0 g of Darolutamide was dissolved in a solvent mixture of 20 ml (10 volumes) of acetone and 10 ml (5.0 volumes) of acetic acid by heating to 60-65°C. The resulting solution was filtered to remove any particles or undissolved particulate matter to obtain a clear solution. This clear solution was then added slowly to 100 ml (50 volumes) of pre-chilled tertiary butyl methyl ether (MTBE) maintained at 0-5°C and stirred for 4 hours to facilitate precipitation. The resulted solid was isolated by filtration and washed with 4 ml (2 volumes) of tertiary butyl methyl ether. The obtained wet material was dried in an Air Tray Dryer (ATD) at 45°C for 3-4 hours to obtain Darolutamide Form C3.

[0148] Yield: 1.3 gm.

[0149] Example 6: Long Term Stability data:

[0150] Table 1

[0151]

[0152] Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.

Claims

1. We claim:

1. A Darolutamide Form C2, characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 29 angle values: 7.69, 9.06, 11.02, 13.14, 16.6 and 22.05±0.2°.

2. The Form C2 as claimed in Claim 1, characterized by an X-ray powder diffraction pattern comprising diffraction peaks having the following 29 angle values: 27.40±0.2° and 28.8±0.2°.

3. The Form C2 as claimed in claim 1 or 2, characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak with an onset temperature at 165.04°C and a peak maximum at about 170.92 °C.

4. The Form C2 as claimed in claim 1 or 2, characterized by TGA with a weight loss of approximately 0.229 % at temperature about 150 °C.

5. A Darolutamide Form Cl characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 29 angle values: 9.06, 10.99, 16.41, 18.32 and 23.42±0.2°.

6. The Form Cl as claimed in Claim 5, characterized by an X-ray powder diffraction pattern comprising diffraction peaks having the following 29 angle values: 19.04±0.2°, 20.19±0.2° and 27.52±0.2°.

7. The Form Cl as claimed in claim 5 or 6, characterized by a differential scanning calorimetry (DSC) curve comprising an endothermic peak with an onset temperature at 166.80°C and a peak maximum at about 174.

498. The crystalline Form Cl as claimed in claim 5 or 6, characterized by TGA with a weight loss of approximately 0.819 % at temperature about 150 °C.

9. A Darolutamide Form C3, characterized by an X-ray powder diffraction pattern comprising diffraction peaks at 29 angle values: 9.3, 11.96, 13.97, 15.07, 15.79, 19.48 and 26.85±0.2°.

10. The Form C3 as claimed in Claim 9, characterized by an X-ray powder diffraction pattern comprising diffraction peaks having the following 29 angle values: 23.43±0.2°.

11. The Form C3 as claimed in claim 9 or 10, characterized by a differential scanning calorimetry (DSC) curve comprising a first endothermic peak with an onset temperature at 100.78°C and a peak maximum at about 113.22 °C, second endothermic peak with an onset temperature at 117.93°C and a peak maximum at about 119.20°C, Third endothermic peak with an onset temperature at 176.69°C and peak maximum at about 180.63°C.

12. The Form C3 as claimed in claim 9 or 10, characterized by TGA with a weight loss of approximately 13.043 % at temperature about 150 °C.

13. A process for preparing Darolutamide Form Cl or Form C2 or Form C3 as claimed in any one of the preceding claims 1 to 12, comprising:a) dissolving Darolutamide or Darolutamide polymorph in a suitable solvent or a mixture of solvents at a suitable temperature;b) filtering the solution of step (a) to remove any undissolved particulate matter to obtain clear solution;c) adding one or more suitable antisolvent at a suitable temperature to the above solution and stirring at specific period of time;d) isolating resulting solid of Darolutamide;e) drying the isolated resulting material of Darolutamide;f) heating the resulting material of Darolutamide at specific temperature at specific time; andg) cooling to specific temperature.

14. A process for preparing Darolutamide Form Cl or Form C2 or Form C3 as claimed in any one of the preceding claims 1 to 12, comprising:a) dissolving Darolutamide in a suitable solvent or a mixture of solvents at a suitable temperature;b) filtering the solution of step (a) to remove any undissolved particulate matter to obtain clear solution;c) cooling the clear solution obtained in step (b) to a suitable temperature and stirring the above mixture at specific period of time;d) filtering and drying at a specific temperature at specific time to obtain crude product;e) dissolving the crude product obtained in step (d) in a suitable solvent at specific temperature and stirring the suspension for a specific period of time; andf) filtering and drying at a specific temperature and specific time resulting into desired form of Darolutamide.

15. A process for preparing Darolutamide Form Cl or Form C2 or Form C3 as claimed in any one of the preceding claims 1 to 12, comprising:a) dissolving Darolutamide or Darolutamide polymorph in a suitable solvent or a mixture of solvents;b) filtering the solution of step (a) to remove any undissolved particulate matter to obtain clear solution;c) adding one or more suitable antisolvents at a suitable temperature to the above solution and stirring the solution for a specific period of time;d) isolating the resulted solid of Darolutamide; ande) drying the isolated crystalline form of Darolutamide.

16. A process for preparing Darolutamide Form Cl or Form C2 or Form C3 as claimed in any one of the preceding claims 1 to 12, comprising:a) dissolving Darolutamide in a suitable solvent or a mixture of solvents at a suitable temperature;b) filtering the solution of step (a) to remove any undissolved particulate matter to obtain clear solution;c) seeding the above clear solution with freshly prepared Darolutamide Form C2 seed crystals in solvent or mixture of solvents and stirring the solution for a specific period of time;d) filtering and drying at a specific temperature at specific time;e) heating at specific temperature at specific time to obtain dried product; f) dissolving the dried product obtained in step (e) in one or more suitable solvent at specific temperatures and stirring for a specific period of time; andg) filtering and drying at a specific temperature and specific time resulting into desired form of Darolutamide.

17. The process as claimed in claims 13 to 16, wherein the suitable solvent is selected from ethers, esters, ketones, hydrocarbons, alcohols, acids, nitriles, amines, amides, water and the like, either alone or in mixtures thereof.

18. The process as claimed in claims 13 to 16, wherein the suitable anti- solvents is selected from the group consisting of acids, alcohols, ethers, esters, ketones, amines, amide, hydrocarbons and the like alone or in combination thereof.

19. A process for preparing Darolutamide Form C2 as claimed in claim 14 comprising;a) dissolving Darolutamide in a solvent or mixture of solvents at a temperature of 50-65°C;b) filtering to remove any undissolved particulate matter to obtain clear solution;c) cooling the solution to 0-5° with stirring;d) filtering and drying to obtain crude Darolutamide;e) dissolving crude Darolutamide of step d) in pre-chilled solvent at 0- 5°C and stirring;f) filtering and drying to obtain Darolutamide Form C2.

20. A process for preparing Darolutamide Form C2 as claimed in claim 15 comprising;a) dissolving Darolutamide in a solvent or mixture of solvents at a temperature of 50-65°C;b) filtering to remove any undissolved particulate matter to obtain clear solution;c) adding one or more pre-cooled antisolvent at 0-5°C with stirring; d) filtering, washing and drying initially at a temperature of 35-45°C; e) heating to 50-60°C for 1-2 hours followed by cooling to room temperature to obtain Darolutamide Form C2.

21. A process for preparing Darolutamide Form C2 as claimed in claim 16 comprising;a) dissolving Darolutamide in a solvent or mixture of solvents at a temperature of 50-65°C;b) filtering to remove any undissolved particulate matter to obtain clear solution;c) seeding the above clear solution with freshly prepared Darolutamide Form C2 seed crystals in solvent or mixture of solvents;d) filtering, washing and drying at a temperature of 35-45°C followed by heating at 50-60°C to obtain dried solid;e) adding the above dried solid to the pre-chilled solvent or solvent mixture, stirring, filtering and drying to obtain Darolutamide Form C2.

22. The process as claimed in any one of the claims 19-21, wherein the solvent for the process is selected from water, (un) substituted C1-C3 alcohols, formic acid, aq. Ammonia, ethyl acetate, alone or mixture thereof.

23. The process as claimed in any one of the claims 19-21, wherein the solvent for the process is selected from aliphatic hydrocarbons such as n-hexane or n-heptane; ethers alone or mixtures thereof.

24. A pharmaceutical composition comprising the Darolutamide Form Cl or Form C2 or Form C3 prepared by the process as claimed in any one of the claims 1 to 23 together with acceptable excipients.

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