DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF DAROLUTAMIDE AND SOLID STATE FORMS THEREOF

FIELD OF THE INVENTION
The present invention relates to process for the preparation of Darolutamide and intermediates thereof. The present application relates to solid state forms of Darolutamide, process for the preparation thereof and pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
The drug compound having the adopted name Darolutamide, has a chemical name N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide, and is represented by the structure of formula I.

Formula I
Darolutamide is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC).
Darolutamide, its synthetic process and its pharmaceutical compositions are described in US patent No. 8,975,254; its solid state form is described in US patent No. 10,010,530.
Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Darolutamide.
SUMMARY OF THE INVENTION
In one aspect the present application provides amorphous form of Darolutamide.
In another aspect the present application provides a process for preparation of
amorphous form of Darolutamide, comprising:
a) providing Darolutamide in one or more of suitable solvents;
b) isolating amorphous form of Darolutamide.
In another aspect the present application provides amorphous form of Darolutamide, characterized by a PXRD pattern as represented by figure 1.
In another aspect the present application provides pharmaceutical compositions comprising amorphous form of Darolutamide described in this application and one or more pharmaceutically acceptable excipient.
In another aspect the present application provides amorphous solid dispersion of Darolutamide.
In another embodiment, the present application provides a process for preparation of amorphous solid dispersion of Darolutamide, comprising:
a) providing Darolutamide and a pharmaceutically acceptable excipient in one or more of suitable solvents;
b) isolating amorphous solid dispersion of Darolutamide.
In another aspect the present application provides crystalline Form DT1 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 11.59, 15.83, 20.62, 21.28 and 22.8 ± 0.2° 2?.
In another aspect the present application provides crystalline Form DT2 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 9.22, 13.85, 15.29, 15.97, 20.45 and 26.4 ± 0.2° 2?.
In another aspect the present application provides crystalline Form DT3 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 11.71, 15,11, 15.76, 20.31 and 26.80 ± 0.2° 2?.
In another aspect the present application provides pharmaceutical compositions comprising crystalline forms DT1, DT2 or DT3 of Darolutamide described in this application and one or more pharmaceutically acceptable excipient.
In another embodiment, the present invention provides a process for the preparation of Darolutamide intermediate of Formula II,

Formula II
comprising:
a) reacting a compound of Formula III

Formula III
with a compound of Formula IV

Formula IV
wherein Lg is a leaving group and Pg is a protecting group and the reaction is carried out in presence of a base and a phase transfer catalyst to obtain compound of Formula V

Formula V
b) converting compound of formula V to Darolutamide intermediate of Formula II.
In another embodiment, the present invention relates to use of Darolutamide intermediate of Formula II prepared according to the methods disclosed herein in the preparation of Darolutamide.
BRIEF DESCRIPTION OF DRAWINGS
Figure-1 is powder X-ray diffraction (PXRD) pattern of amorphous form prepared according to example 1.
Figure-2 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Darolutamide with Copovidone according to example 2.
Figure-3 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Darolutamide with PVP K-90 according to example 3.
Figure-4 is powder X-ray diffraction (PXRD) pattern of crystalline Form DT1 of Darolutamide according to example 4.
Figure-5 is powder X-ray diffraction (PXRD) pattern of crystalline Form DT2 of Darolutamide according to example 5.
Figure-6 is powder X-ray diffraction (PXRD) pattern of crystalline Form DT3 of Darolutamide according to example 6.
DETAILED DESCRITPION OF THE INVENTION
In one aspect the present application provides amorphous form of Darolutamide.
In another aspect the present application provides a process for preparation of
amorphous form of Darolutamide, comprising:
a) providing Darolutamide in one or more of suitable solvents;
b) isolating amorphous form of Darolutamide.
In another aspect the present application provides amorphous form of Darolutamide, characterized by a PXRD pattern as represented by figure 1.
In another aspect the present application provides pharmaceutical compositions comprising amorphous form of Darolutamide described in this application and one or more pharmaceutically acceptable excipient.
In another aspect the present application provides amorphous solid dispersion of Darolutamide.
In another embodiment, the present application provides a process for preparation of amorphous solid dispersion of Darolutamide, comprising:
a) providing Darolutamide and a pharmaceutically acceptable excipient in one or more of suitable solvents;
b) isolating amorphous solid dispersion of Darolutamide.
In another aspect the present application provides amorphous solid dispersion of Darolutamide with Copovidone.
In another aspect the present application provides amorphous solid dispersion of Darolutamide with PVP K-90.
In another embodiment, at least one pharmaceutically acceptable excipient may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; 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, or any other excipient at any aspect of present invention. A thorough discussion of pharmaceutically acceptable excipients is presented in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing Company) and Remington: The Science and Practice of Pharmacy (21st ed., Lippincott Williams & Wilkins), which are hereby incorporated by reference.
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.
In another aspect the present application provides crystalline Form DT1 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 11.59, 15.83, 20.62, 21.28 and 22.8 ± 0.2° 2?.
In another aspect the present application provides crystalline Form DT1 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 8.97, 16.99, 17.98, 18.80 and 25.61 ± 0.2° 2?.
In another aspect the present application provides crystalline Form DT1 of Darolutamide, characterized by a PXRD pattern as represented by figure 4.
In another embodiment, the present application provides a process for preparation of crystalline Form DT1 of Darolutamide, comprising:
a) providing Darolutamide in one or more of suitable solvents;
b) optionally, adding one or more of suitable anti-solvents;
c) isolating crystalline Form DT1 of Darolutamide.
In another aspect the present application provides crystalline Form DT2 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 9.22, 13.85, 15.29, 15.97, 20.45 and 26.4 ± 0.2° 2?.
In another aspect the present application provides crystalline Form DT2 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 11.97,15.97, 18.95 and 29.00 ± 0.2° 2?.
In another aspect the present application provides crystalline Form DT2 of Darolutamide, characterized by a PXRD pattern as represented by figure 5.
In another embodiment, the present application provides a process for preparation of crystalline Form DT2 of Darolutamide, comprising:
a) providing Darolutamide in one or more of suitable solvents;
b) optionally, adding one or more of suitable anti-solvents;
c) isolating crystalline Form DT2 of Darolutamide.
In another aspect the present application provides crystalline Form DT3 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 11.71, 15,11, 15.76, 20.31 and 26.80 ± 0.2° 2?.
In another aspect the present application provides crystalline Form DT3 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 8.91, 13.44, 18.88, 22.52 and 28.62 ± 0.2° 2?.
In another aspect the present application provides crystalline Form DT3 of Darolutamide, characterized by a PXRD pattern as represented by figure 6.
In another embodiment, the present application provides a process for preparation of crystalline Form DT3 of Darolutamide, comprising:
a) providing Darolutamide in one or more of suitable solvents;
b) optionally, adding one or more of suitable anti-solvents;
c) isolating crystalline Form DT3 of Darolutamide.
In another aspect the present application provides pharmaceutical compositions comprising crystalline forms DT1, DT2 or DT3 of Darolutamide described in this application and one or more pharmaceutically acceptable excipient.
In another embodiment, the present invention provides a process for the preparation of Darolutamide intermediate of Formula II,

Formula II
comprising:
a) reacting a compound of Formula III

Formula III
with a compound of Formula IV

Formula IV
wherein Lg is a leaving group and Pg is a protecting group and the reaction is carried out in presence of a base and a phase transfer catalyst to obtain compound of Formula V

Formula V
b) converting compound of formula V to Darolutamide intermediate of Formula II.
In another embodiment, the present invention provides a process for the preparation of Darolutamide intermediate of Formula II,

Formula II
comprising:
a) reacting a compound of Formula III

Formula III
with a compound of Formula IV-a

Formula IV-a
wherein the reaction is carried out in presence of a base and a phase transfer catalyst to obtain compound of Formula V-a

Formula V-a
b) converting compound of formula V-a to Darolutamide intermediate of Formula II.
The step a) may be carried out in the presence of a suitable base. In a preferred embodiment the reaction is carried out in the presence of potassium carbonate. The reaction may be carried out in the presence of a suitable phase transfer catalyst. In a preferred embodiment the reaction is carried out in the presence of tetrabutylammonium iodide. The step (b) may be carried out according to procedures known in prior art or as described in the present application.
Inventors of the present invention have identified that reaction of compound of formula III with compound of formula IV progresses well in presence of a phase transfer catalyst. The inventors also observed either incomplete reaction or hardly any reaction with organic bases such as 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).
In another embodiment, the present invention relates to use of Darolutamide intermediate of Formula II prepared according to the methods disclosed herein in the preparation of Darolutamide.
The suitable leaving group- Lg may be selected from the group consisting of chloride, bromide, iodide, tosylate, triflate, mesylate, methosulfate, fluorosulfonate, brosylate, nosylate or the like.
The suitable protecting group- Pg may be selected from the group consisting of acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, phenylacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as phenylsulfonyl, benzenesulfonyl, 4-nitrobenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyl-oxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyloxycarbonyl, 2,4-dimethoxy-benzyloxycarbonyl, 4-methoxybenzyl-oxycarbonyl, 2-nitro-4,5-dimethoxy-benzyloxycarbonyl, 3,4,5-trimethoxybenzyl-oxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5-di-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, di-isopropylmethoxycarbonyl, isopropyl-oxycarbonyl, ethoxycarbonyl, methoxy-carbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyl-oxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl (trityl), p-methoxybenzyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl or the like. Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999).
The phase transfer catalyst may be selected from the group consisting of tricaprylylmethylammonium chloride, methyl tributyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, triethyl benzyl ammonium chloride, tetrabutyl phosphonium bromide, tetrabutyl phosphonium chloride, tetraoctylphosphonium bromide or the like.
The suitable base at any stage of the process of the present invention may be selected from alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like; alkali metal fluorides, such as, for example, cesium fluoride or the like; metal alkoxides, such as, for example, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide or the like; organometallic base, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide (LTMP) or the like.
The suitable ‘organic solvent’ or "solvent" or “anti-solvent” at any stage of the process of the present invention may be selected from the group consisting of alcohols, such as methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl alcohol, octanol, 1,2-propanediol, S-(+)-1,2-propanediol and ethylene glycol; ethers, such as diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate and t-butyl acetate; ketones, such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; nitriles, such as acetonitrile; hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane and tetraline; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl 2-pyrrolidone, dimethylsulfoxide, pyridine, phenol, DMA, carbon disulphide, acetic acid, propionic acid and the like; water; or mixtures thereof.
Suitable temperatures for the reaction at any stage of the process of the present invention may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures.
Suitable times at any stage of the process of the present invention may be from about 30 minutes to about 10 hours, or longer.
The removal of solvent at any stage of the process of the present invention may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The compounds at any stage of the process of the present invention may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
In another embodiment, amorphous form of Darolutamide, amorphous solid dispersion of Darolutamide and crystalline form DT1, DT2, DT3 of Darolutamide of the present invention are stable under thermal, humid and stress conditions.
In another embodiment, amorphous form of Darolutamide, amorphous solid dispersion of Darolutamide and crystalline form DT1, DT2, DT3 of Darolutamide of the present invention or the pharmaceutical compositions thereof, comprises Darolutamide with a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In an embodiment, Darolutamide of present invention has average particle size of particles between 1 to 100 µm, less than 90 µm, less than 80 µm, less than 60 µm, less than 50 µm, less than 40 µm, less than 30 µm, less than 20 µm, less than 10 µm, less than 5 µm or any other suitable particle sizes. In another embodiment, Darolutamide of present invention may have particle size distribution: D10 of particles smaller than 20 µm, smaller than 15 µm, smaller than 10 µm, or smaller than 5 µm; D50 of particles smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm; D90 of particles smaller than 200 µm, smaller than 175 µm, smaller than 150 µm, smaller than 140 µm, smaller than 130 µm, smaller than 120 µm, smaller than 110 µm, smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm.
Particle size distributions of Darolutamide particles may be measured using any techniques known in the art. For example, particle size distributions of Darolutamide particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred herein, the term “D10” in the context of the present invention is 10% of the particles by volume are smaller than the D10 value and 90% particles by volume are larger than the D10 value. “D50” in the context of the present invention is 50% of the particles by volume are smaller than the D50 value and 50% particles by volume are larger than the D50 value. “D90” in the context of the present invention is 90% of the particles by volume are smaller than the D90 value and 10% particles by volume are larger than the D90 value.
In an embodiment, Darolutamide of present invention can be micronized or milled using conventional techniques to get the desired particle size 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. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The starting material Darolutamide may be obtained according to any method known in the art.
The compound of this application can be characterized by X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. X-ray diffraction was measured using PANalytical X-ray diffractometer, Model: Empyrean. System description: CuK-Alpha 1 wavelength= 1.54060, voltage 45 kV, current 40 mA, divergence slit = 1/4°; Sample stage=Reflection-spinner. Revolution time [s]: 1.000; Scan type: Pre-set time; Detector – Pixcel; Measurement parameters: Start Position [°2Th.]: 3.0066; End Position [°2Th.]: 39.9916; Step Size [°2Th.]: 0.0130; Scan Step time [s]: 1.000.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
Example-1: Preparation of amorphous form of Darolutamide.
Darolutamide (2 g) was dissolved in methanol (20 V) at 50-60 °C. The solution was subjected to dry distillation over rotavapour under vacuum at 50-60 °C. Obtained dried material was checked for PXRD. The PXRD pattern is shown in Figure 1.
Example-2: Preparation of amorphous solid dispersion of Darolutamide with Copovidone (1: 0.25 w/w).
Darolutamide and of Copovidone in a ratio of 1: 0.25 were dissolved in Methanol (20 V) at 50-60 °C. The solution was subjected to dry distillation over rotavapour under vacuum at 50-60 °C., isolated material was collected and checked for PXRD. The PXRD pattern is shown in Figure 2.
Example-3: Preparation of amorphous solid dispersion of Darolutamide with PVP K-90 (1: 0.25 w/w).
Darolutamide and of PVPK-90 in a ratio of 1: 0.25 were dissolved in Methanol (20 V) at 50-60 °C. The solution was subjected to dry distillation over rotavapour under vacuum at 50-60 °C., isolated material was collected and checked for PXRD. The PXRD pattern is shown in Figure 3.
Example-4: Preparation of crystalline Form DT1 of Darolutamide
Darolutamide amorphous form (0.8 g) was dissolved in THF (8 mL) at 25-30°C. This clear solution slowly charged to the pre-cooled n-heptane (80 mL) which is maintained at -10°C. The resulting reaction mass was stirred about 4-5 hours at -5 to -10 °C. The material was filtered under vacuum and dried in VTD at 40°C about 4-5 hours to obtain crystalline Form DT1 of Darolutamide. The PXRD pattern is shown in Figure 4.
Example-5: Preparation of crystalline Form DT2 of Darolutamide
Darolutamide amorphous form (0.8 g) was dissolved in Acetone (8 mL) at 25-30 °C. This clear solution slowly charged to the pre-cooled n-heptane (56 mL) which is maintained at -10°C. The resulting reaction mass was stirred about 3-4 hours at -5 to -10 °C. The material was filtered under vacuum and dried in VTD at 40°C about 3-4 hours to obtain crystalline Form DT2 of Darolutamide. The PXRD pattern is shown in Figure 5.
Example-6: Preparation of crystalline Form DT3 of Darolutamide
Darolutamide amorphous form (0.8 g) was dissolved in propionic acid (2 mL) at 30-35 °C. This clear solution slowly charged to the pre-cooled n-heptane (40 mL) which is maintained at -10°C. The resulting reaction mass was stirred about 3-4 hours at -5 to -10 °C. The material was filtered under vacuum and dried in VTD at 60°C about 10-12 hours to obtain crystalline Form DT3 of Darolutamide. The PXRD pattern is shown in Figure 6.
Example-7: Preparation of Darolutamide intermediate of formula (II)

Formula II
Step-a: Preparation of formula IV-a

Formula IV-a
Triethylamine (15 mL) was added to a solution of Boc-L-Alaninol (10 g) and DCM (100 mL), cooled to 0-5 °C. Methanesulfonyl chloride (6.6 g) was added in to the reaction mixture slowly over a period of 15 min at 0-5 °C. The temperature of the reaction mixture was raised to 25-35 °C. The reaction mass was stirred for 2-3 h at 25-35 °C. Upon completion of reaction, the reaction mixture was quenched with water. DCM (50 mL) was charged into the reaction mixture at 25-35 °C. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under vacuum below 40 °C to obtain the crude product (15 g). Hexane (70 mL) was charged into the above crude compound at 25-35 °C. The reaction mass was stirred for 2 h at 25-35 °C and filtered. The wet cake was washed with hexanes (10 mL) and dried under vacuum at 40-45 °C for 3 h to obtain compound of formula IV-a as a white colored solid (13 g).
Step-b: Preparation of formula V-a

Formula V-a
Tetrabutylammonium iodide (0.9 g) and K2CO3 (3.38 g) were charged under nitrogen atmosphere in to a solution of compound of Formula III (1.0 g) and compound of formula IV-a (2.48 g) in DMF (30 mL) at 25-35 °C. The reaction mixture obtained was heated to 85-95 °C and stirred at the same temperature for 10 h. Upon completion of reaction, the reaction mixture was cooled to 25-35 °C. Water (100 mL) was charged in to the above reaction mixture, which was then stirred for 3-4 h at 25-35 °C and filtered. The wet cake was washed with water (5 mL) and dried under vacuum at 25-35 °C for 4-6 h to obtain compound of formula V-a as an off-white colored solid (1.4 g).
Step-C: Preparation of Darolutamide intermediate of formula II

Formula II
Ethanolic HCl (5.0 ml) was added to compound of formula V-a (0.5 g) at 25-35 °C and the reaction mixture was stirred for 24 h at the same temperature. Upon completion of reaction, the reaction mixture was cooled to 10-15 °C, stirred for 30 min at the same temperature and filtered. The wet cake was washed with ethanol (0.5 mL) and dried under vacuum for 2-3 h at 25-35 °C to obtain the Darolutamide intermediate of formula II as an off white colored solid (0.23 g).

,CLAIMS:We Claim:
1. Amorphous solid dispersions comprising Darolutamide and one or more pharmaceutically acceptable excipient.
2. A process for preparation of amorphous solid dispersion of Darolutamide, comprising:
a) providing Darolutamide and a pharmaceutically acceptable excipient in one or more of suitable solvents;
b) isolating amorphous solid dispersion of Darolutamide.
3. A process for preparation of amorphous form of Darolutamide, comprising:
a) providing Darolutamide in one or more of suitable solvents;
b) isolating amorphous form of Darolutamide.
4. A process for preparation of crystalline form of Darolutamide, comprising:
a) providing Darolutamide in one or more of suitable solvents;
b) optionally, adding one or more of suitable anti-solvents;
c) isolating crystalline of Darolutamide.
Wherein, crystalline form is selected from:
crystalline from DT1, characterized by a PXRD pattern comprising peaks at about 11.59, 15.83, 20.62, 21.28 and 22.8 ± 0.2° 2? or Figure 4;
crystalline Form DT2 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 9.22, 13.85, 15.29, 15.97, 20.45 and 26.4 ± 0.2° 2? or Figure 5;
crystalline Form DT3 of Darolutamide, characterized by a PXRD pattern comprising peaks at about 11.71, 15,11, 15.76, 20.31 and 26.80 ± 0.2° 2? or Figure 6.
5. A process for the preparation of Darolutamide intermediate of Formula II,

Formula II
comprising:
a) reacting a compound of Formula III

Formula III
with a compound of Formula IV

Formula IV
wherein Lg is a leaving group and Pg is a protecting group and the reaction is carried out in presence of a base and a phase transfer catalyst to obtain compound of Formula V

Formula V
b) converting compound of formula V to Darolutamide intermediate of Formula II.
6. A process for preparation of Darolutamide comprising converting intermediate Formula II as prepared according to claim 5), to Darolutamide.
7. A pharmaceutical composition comprising solid forms of Darolutamide as claimed in any of claims 1-6, and one or more pharmaceutically acceptable excipient.