AMORPHOUS 4-(3-(4-CYANO-3-(TRIFLUOROMETHYL)PHENYL)-5,5-DIMETHYL-4-OXO-2-THIOXOIMIDAZOLIDIN-l-YL)-2-FLUORO-N-

METHYLBENZAMIDE

FIELD OF THE INVENTION

The present invention relates to amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2-fluoro-N-methylbenzamide (I) and process for preparation thereof.

The invention further relates to pharmaceutical compositions comprising amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide having anti-cancer activity.

INTRODUCTION

Particular aspects of the present application relate to amorphous 4-(3-(4-cyano-3- (trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide or Enzalutamide and its process for preparation. The invention of the present application further relates to pharmaceutical compositions comprising amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fiuoro-N-methylbenzamide having anti-cancer activity.

Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received Docetaxel. It was approved by USFDA in August of 2012 and is marketed under the trade name XTANDI™. Early preclinical studies suggest that Enzalutamide also inhibits breast cancer cell growth. It is chemically mentioned in the USFDA label as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl] -5,5 -dimethyl-4-oxo-2-sulfanylideneimidazolidin-1 -yl} -2-fluoro-N-methylbenzamide (I).

Enzalutamide is a white crystalline non-hygroscopic solid which is practically insoluble in water.

Sawyers et al in US7709517 provided the first disclosure of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide (also known as Enzalutamide). This patent also describes the process for preparing 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide.

Further Thompson et al in WO2011/106570 Al also disclose processes for the preparation of Enzalutamide by following reaction schemes:

As described earlier that Enzalutamide is reported to exist as white crystalline non- hygroscopic solid. Further to this, only polymorphism details known for 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide is in US7709517, where it is mentioned as a colorless crystal.

Polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles. Peculiar phenomenon of polymorphism is well known in solid materials, wherein existence of different physical forms including shape, size and arrangement of molecules in the physical state or polymorphs of same compound are known to exist in the natural and other conditions. It is known to provide distinct physical properties, which often results in substantial differences in bioavailability, stability, and other differences between production lots of formulated pharmaceutical products. Since polymorphic forms can vary in their chemical and physical properties, regulatory authorities often require that efforts be made to identify all possible polymorphic forms, e.g., hydrate or anhydrate, crystalline or amorphous, solvated or un-solvated forms, etc. of the drug substances. However in the phenomenon of Polymorphism, the existence, and possible numbers, of polymorphic forms for a given compound may not be predicted. In addition, there are no "standard" procedures that can be applied/ utilized to prepare different polymorphic forms of a substance. Moreover, it is often uncertain for a chemical entity-whether any polymorphism phenomenon exists in the molecule or not.

Exploring new forms of pharmaceutically active / useful compounds such as 4-(3-(4-cyano-3 -(trifluoromethyl) phenyl)-5,5 -dimethyl-4-oxo-2-thioxoimidazolidin-1 -yi)-2-fluoro-N-methylbenzamide may thus provide an opportunity to improve the drug performance characteristics of such products.

Hence, inventors of the present application report- new stable and usable form of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide and processes for their preparation, which may be industrially amenableand usable for preparing their pharmaceutical compositions. The present invention provides an amorphous 4-(3 -(4-cyano-3 -(trifluoromethyl) phenyl)-5,5 -dimethyl-4-oxo-2-\ thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide and process for preparation thereof.

SUMMARY OF INVENTION

Particular aspects of the present specification relate to the amorphous 4-(3-(4-cyano-3- (trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2-fluoro-N- methylbenzamide and process for preparation thereof.

In one aspect according to the present invention, it provides an amorphous 4-(3-(4- cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2-fluoro-N- methylbenzamide or Enzalutamide (I):

In another aspect, the present invention provides a process for preparation of amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide characterized by XRPD pattern as per Fig-1 and DSC pattern as per Fig-2 comprising the steps of-

a) Providing a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fiuoro-ALmethylbenzamide in an organic solvent;

b) Heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;

c) Optionally filtering the reaction mixture;

d) Drying the solution of step b) or c);

e) Optionally repeating the steps a) to d);

f) Isolating the amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2-fluoro-N-methylbenzamide.

In another aspect, amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide obtained by the process of the present invention is having HPLC purity greater than 99 %.

In a further aspect, the present invention also relates to a composition comprising amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, of which at least 95% by total weight of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide in the composition, is the amorphous form. Such composition is substantially free of any other forms of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide.

In a further aspect, the present application also relates to a pharmaceutical composition comprising amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide of the present application and at least one or more pharmaceutically acceptable excipients.

Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide amorphous form.

Fig. 2 is an example of a Differential Scanning Calorimetry ("DSC") curve of 4-(3-(4-cyano-3-(trifluoromemyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide amorphous form.

DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention relate to amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2-fluoro-N-methylbenzamide and a process for preparation thereof.

In one embodiment of the present application, it provides amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide or Enzalutamide (I):

Substantially pure amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 1 indicating a solid form that lacks the long-range order (a characteristic of crystal) and having no pattern or structure.

The amorphous 4-(3-(4-cyano-3-(trifiuoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide produced by the inventors of the present application is characterized by -

1. XRPD pattern similar to as shown in FIG. 1

2. DSC isotherm similar to as shown in FIG. 2 or comprising at least one exothermic peak ranging between 125 to 150 °C and at least one endothermic peak ranging between 190 to 210 °C.

In another embodiment of the present application, it provides a process for preparation of amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, comprising the steps of-

a) Providing a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-A/-methylbenzamide in an organic solvent;

b) Heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;

c) Optionally filtering the reaction mixture;

d) Drying the solution of step b) or c);

e) Optionally repeating the steps a) to d);

f) Isolating the amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2-fluoro-N-methylbenzamide.

The individual steps of the process according to the present invention for preparing amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide are detailed separately herein below.

Step a) comprises providing a solution of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide in an organic solvent; 4-(3-(4-cyano-3-(trifiuoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide is dissolved in an organic solvent. Organic solvent may be selected from C1-C2 alcohols for eg. Methanol and ethanol or halohydrocarbon solvent for eg. dichloromethane, dichloroethane and the like.

In one particular embodiment methanol is used as an organic solvent to prepare solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-ox8-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide. The amount of solvent methanol (in mL) used in this step ranges from 20-50 times (v/w) w.r.t. weight (in g) of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide taken for this reaction. In one particular embodiment, of the present application, for 1 gm of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, 40 mL methanol was used to finally obtain the amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, by following the complete process of the present invention.

In another specific embodiment, when halohydrocarbon solvent is used to prepare solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide in this step, the amorphous end product obtained by following the complete process of the present invention, has at least more than 90% amorphous nature.

Step b) comprises heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;

Reaction mixture prepared in step a) is heated to a temperature ranging between 40 °C and the boiling point of the organic solvent used, to provide a clear solution. In one particular embodiment of the present application, wherein methanol was used as a solvent, temperature employed for the current step was 50-55 °C. After the clear solution is obtained, the reaction mass is maintained at the same raised temperature for ajtime duration of 20 mins to 1 hr.

Step c) comprises optionally filtering the reaction mixture;

The solution obtained from step b) is filtered at the same raised temperature wherein clear solution was achieved. Any conventional process for filtration may be employed to perform the current step. In one particular embodiment of the current application, filtration was performed by using micron filter paper. Filtration is performed to get impurities levels controlled in the clear solution stage.

Step d) comprises drying the solution of step b) or c);

The filtrate obtained from filtration in above step is subjected to drying to reduce the solvent content of the reaction mass. Drying may be performed by any conventional process not limited to spray drying or distillation to remove the solvent. If distillation is chosen as the mode of drying, it may be carried out at temperature ranging between 40 °C and the boiling point of the organic solvent used. Drying may optionally be performed under reduced pressure conditions. In one particular embodiment of the current application, drying was performed under vacuum, wherein vacuum strength was slowly increased from 100 mm Hg to 650 mm Hg-

Step e) which is optional comprises repeating the steps a) to d)

The optional step e) which comprises repeating the steps a) to d) i.e. re-dissolving the residue obtained on drying in step d) in organic solvent, heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used, optionally filtering the reaction mixture and again subjecting the filtrate to drying to yield a residue, is performed if required, to achieve the purity of greater than 99 % (area %) by HPLC along with equilibration to impurity profile compliance. In view of maintaining the equilibrium to the impurity profile compliance, the process may require in-process quality checks to avoid unnecessary repetitions of the same process step.

Step f) comprises isolating the amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-mcthylbenzamide.

The material obtained from step d) or e) is dried at a temperature ranging between 50-60 °C or above. The drying process may be performed under reduced pressure conditions. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed for time ranging from 20 mins to 4 hrs depending upon the physical attributes of the end product obtained i.e. amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide.

Process of isolating amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-mcthylbenzamide may further comprise processes but not limited to conventional processes including scrapping and if required filtering from slurry which may be carried out at room temperature for the suitable durations to retain the amorphous form characteristics.

Any 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide material i.e. its crystalline form or any of its less stable form or impure form obtained from any source or by any of the processes known in the prior art may be utilized to result directly inio the amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide of the present invention, by using the process mentioned in this application.

The process related impurities that appear in the impurity profile of the 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide may be substantially removed by the process of the present invention resulting in the formation of amorphous form of high purity.

The merit of the process according to the present invention resides in that - product isolated after drying is directly obtained as amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide. Said material is found devoid of any crystal lattice and is adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its morphology and physicochcmical characteristics. Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-ox(v2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide obtained according to the process of the present invention results in the final API purity by HPLC of more than 99 % w/w, with moisture content of not more than 1.5%.

The amorphous 4-(3 -(4-cyano-3 -(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of analytical data for the amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide obtained in the examples are set forth in the Figs. 1-2.

In a further embodiment according to this specification, the invention also relates to a composition containing amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbcnzamide, of which at least 95% by total weight of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide in the composition, is the amorphous form. In yet another embodiment of the invention, the composition may be substantially free of any other forms of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimcthyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide.

The amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimcthyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, while retaining the amorphous nature of the premix.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleatc, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-mcthylbenzamide according to the present application include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystallinc cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellosc sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stcarate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions of amorphous 4-(3-(4-cyano-3-(trifluoromcthyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-mcthylbcnzamidc of the present application may also comprise to include the pharmaceutically acceptable carriers used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

EXAMPLES

Examplc-01: Process for preparation of amorphous 4-(3-(4-cyano-3-(trifluoromcthyl)phenyl)-5,5-dimcthyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbcnzamidc 0.5 gin 4-(3-(4-cyano-3-(trifluoromcthyl)phcnyl)-5,5-dimcthyl-4-oxo-2-thioxoimidazolidin-l-y[)-2-lluoro-N-methylbcnzamidc was charged to a 100 mL RBF. 15 ml methanol was added to the reaction mass and heating was performed to about 50 °C to get clear solution. Temperature of- 50 °C was maintained for 30 mins after getting clear solution. At the same raised temperature, the solution was filtered through micron filter paper. The filtrate was then charged to the rotavapour flask and distillation was performed at about 50 °C under vacuum. Vacuum was applied slowly from 100mm/Hg and increased to 650mm/Hg. After complete distillation of solvent, material was dried under vacuum at 50°C for 30 mins at high RPM. further 15 mL methanol was charged to the residue obtained in rotavapour flask. The solution was then heated to 50 °C to get clear solution without applying vacuum. After getting clear solution, reaction mass was maintained at temperature of 50 °C for 30 mins. Then again distillation was performed at 50 °C under vacuum. As earlier, vacuum was applied slowly from 100mm/IIg and increased to 650mm/Hg. The material obtained after distillation was then dried under vacuum at 50 °C for 2 hrs to afford amorphous 4-(3-(4-cyano-3-(trilluoromethyl)phcnyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbcnzamide having the XRPD diffractogram and DSC isotherm as shown in Figs. 1 and 2 rcsp.

Yield: 0.36 gm; HPLC purity: 99.07 %; Moisture Content 0.81% (by KF) Example-02: Process for preparation of amorphous 4-(3-(4-cyano-3-(tnfluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-mcthylbenzamidc 1 g 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-mcthylbcnzamidc was charged to 100 ml RI3F having 40 ml methanol. The temperature was raised to about 55 °C till a clear solution was attained. Temperature of 55°C was maintained for 30 mins after getting clear solution. At the same raised temperature, the solution was filtered through micron filter paper. The filtrate was then charged to the rotavapour flask and distillation was performed under vacuum at about 55 °C. Vacuum was applied slowly from 100mm/Hg and increased to 650mm/Hg. After complete distillation of solvent, material obtained was dried under vacuum at 60°C for 30 min at high RPM. Further 40 mL methanol was charged to the residue obtained in rotavapour flask. Without applying vacuum the solution was again heated to about 55°C to get clear solution. After getting clear solution, it was maintained at about 55 °C for 30 mins. Then again distillation was performed under vacuum at 55 °C. Vacuum was applied slowly from 100mm/Hg and increased to 650mm/IIg. The material obtained after distillation was dried under vacuum at 60 °C for 3 hrs to afford amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin~l-yl)-241uoro-N-methylbenzamide having the XRPD difiractogram and DSC isotherm as shown in Figs. 1 and 2 resp.

Yield: 0.94 gra, ITPLC purity: 99.07 %

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

Claims:

1) Amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phcnyl)-5,5-dimethyl-4-oxo-2- thioxoimida/olidin-1 -yl)-2-fluoro-./V-methylbenzamide (I).

2) Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimemyl-4-oxo-2-thioxoimidazoIidin-l-yI)-2-fluoro-A^-mcthylbenzamide, according to claim-1, characterized by DSC isotherm comprising at least one exothermic peak ranging between 125 to 150 °C and at least one endothermic peak ranging between 190 to 210 °C.

3) Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phcnyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-7V-methylbenzamide, according to claim-1, characterized by XRPD similar to Fig -1 and DSC similar to Fig-2.

4) A process for the preparation of amorphous 4-(3-(4-cyano-3-(trifluoromcthyl) phenyl)-5,5-dimcthyl- 4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-A/-methyl benzamide, comprising the steps of:

a) Providing a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-7^-methylbenzamide in an organic solvent;

b) Heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;

c) Optionally filtering the reaction mixture;

d) Drying the solution of step b) or c);

c) Optionally repeating the steps a) to d);

f) Isolating the amorphous 4-(3-(4-cyano-3-(trifluoromcthyl) phenyl)-5,5-dimethyl-4-oxo-2-t'hioxoimida/.olidin-l-yl)-2-'fluoro-N-methylbenzamide.

5) A process for the preparation of amorphous 4-(3-(4-cyano-3-(trifluoromcthyl) phenyl)-5,5-dimcthyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-/V-methyl benzamide according to claim-4, wherein organic solvent in step a) is selected from C1-C2 alcohol and halohydrocarbon solvent.

6) A process for the preparation of amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimcthyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methyl benzamide, according to cIaim-5, wherein C1-C2 alcohol is methanol or cthanol and is used in quantity ranging between 20-50 times (v/w) w.r.t. weight of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yI)-2-fluoro-Af-mcthylbenzamide.

7) A process for the preparation of amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-A'-methylbenzamidc, according to claim-4, wherein in step b) the reaction mixture is heated to a temperature ranging between 45-60 °C.

8) A process for the preparation of amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-7^-methylbcnzamide, according to claim-4, wherein in step d) drying is carried out by distillation under reduced pressure conditions.

9) Amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-A/-methylbcnzamide having HPLC purity greater than 99 %.

10) A pharmaceutical composition comprising amorphous 4-(3-(4-cyano-3-(trifluoromcthyl) phenyl)-5,5-dimcthyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-A^-methylbcnzamide according to any of the preceding claims, and at least one or more pharmaceutically acceptable excipients.