WO2014167428A2 - Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-n-methylbenzamide - Google Patents

Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-n-methylbenzamide Download PDF

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WO2014167428A2
WO2014167428A2 PCT/IB2014/059443 IB2014059443W WO2014167428A2 WO 2014167428 A2 WO2014167428 A2 WO 2014167428A2 IB 2014059443 W IB2014059443 W IB 2014059443W WO 2014167428 A2 WO2014167428 A2 WO 2014167428A2
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trifluoromethyl
cyano
oxo
phenyl
dimethyl
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PCT/IB2014/059443
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French (fr)
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WO2014167428A3 (en
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Dr. RAFIUDDIN
Vinod Kumar Singh
Nagnnath KOKARE
Sanjay HIRPARA
Ashok Kumar ADDANKI
Pothuraju RAJU
Akshaykant CHATURVEDI
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Shilpa Medicare Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin

Definitions

  • the present invention relates to amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl-4-oxo-2-thio am (I)
  • the invention further relates to a solid dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier.
  • the amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide (I) and/or its solid dispersion of the present invention can be useful in the treatment of cancer.
  • 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, its solid dispersion with a pharmaceutically acceptable carrier and the process for preparation thereof.
  • 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 hioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide or its solid dispersion, useful in the treatment of cancer.
  • 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 XTA DITM. 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] -5,5dim
  • Enzalutamide is a white crystalline non-hygroscopic solid which is practically insoluble in water.
  • 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.
  • 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.
  • polymorphic forms e.g., hydrate or anhydrate, crystalline or amorphous, solvated or un- solvated forms, etc. of the drug substances.
  • the existence, and possible numbers, of polymorphic forms for a given compound may not be predicted.
  • Exploring new forms of pharmaceutically active / useful compounds such as 4-(3-(4- cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2 hioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide may thus provide an opportunity to improve the drug performance characteristics of such products.
  • inventors of the present application report- a novel 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 its preparation, which may be industrially amenable and usable for preparing the pharmaceutical compositions.
  • the present invention provides an amorphous form of 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.
  • the present invention further relates to a solid dispersion comprising 4-(3-(4-cyano-3- (trifluoromethyl) phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2-fluoro-N- methylbenzamide and at least one pharmaceutically acceptable carrier.
  • Particular aspects of the present specification relate to the amorphous 4-(3-(4-cyano-3- (trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide or its solid dispersion and the process for preparation thereof.
  • the present invention further relates to solid dispersion comprising 4- (3-(4-cyano-3-(trifluoromethyl) phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2- fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier.
  • 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 and/or its solid dispersion comprising the steps of- a) Providing a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-
  • Amorphous 4-(3-(4-cyano-3- (trifluoromethyl) phenyl) -5,5- dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide obtained according to the process of the present invention is characterized by XRPD pattern as per Fig-1 and DSC pattern as per Fig-2
  • 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 %.
  • the present invention also relates to a solid dispersion comprising 4- (3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2- fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier.
  • the present invention also relates to a solid dispersion comprising amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, and at least one pharmaceutically acceptable carrier.
  • Such solid dispersion 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.
  • 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-fluoro-N-methylbenzamide or its solid dispersion, useful in the treatment of cancer.
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of 4-(3-(4-cyano-3-
  • Fig. 2 is an example of a Differential Scanning Calorimetry ("DSC") curve of 4-(3-(4- cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide amorphous form.
  • DSC Differential Scanning Calorimetry
  • Fig. 3 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 solid dispersion as obtained in Example 3.
  • XRPD X-ray powder diffraction
  • Fig. 4 is an example of a Differential Scanning Calorimetry ("DSC") curve of 4-(3-(4- cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide solid dispersion as obtained in Example 3.
  • DSC Differential Scanning Calorimetry
  • embodiments of the present invention relate to amorphous 4-(3-(4- cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2-fluoro-N- methylbenzamide, and/or its solid dispersion and the process for preparation thereof.
  • 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.
  • 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 endo thermic peak ranging between 190 to 210 °C.
  • Another embodiment of the present application provides a solid pharmaceutical dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2- fluoro-N-methylbenzamide (I) with at least one pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers that may be used for the preparation of solid dispersions containing 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide (I) may be selected from pharmaceutically acceptable carriers such as polyvinylpyrrolidones (povidones for e.g.
  • plasdone-K plasdone k29/32, plasdone k 12, plasdone k 30, plasdone s-630, plasdone k25 or plasdone c-17
  • copolymers of N-vinylpyrrolidone gums, cellulose derivatives (for e.g.
  • Pharmaceutically acceptable carriers that may be used for the preparation of solid dispersions of the present invention may be of any viscosity or molecular weight.
  • 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- methyl benzamide and/or its solid dispersion, comprising the steps of- a) Providing a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-
  • 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;
  • Organic solvent may be selected from Ci-C 2 alcohols for e.g. methanol and ethanol or halohydrocarbon solvent for e.g. dichloromethane, dichloroethane and the like.
  • methanol is used as an organic solvent to prepare solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide.
  • the amount of solvent methanol (in mL) used in this step ranges from 20-70 times (v/w) w.r.t.
  • 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.
  • the reaction mixture obtained in step a) may be filtered before proceeding with heating of the reaction mixture.
  • temperature employed for the current step was 50-55 °C.
  • the reaction mass is optionally maintained at the same raised temperature for a time duration of 20 mins to 1 hr, based on the dissolution.
  • 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.
  • 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 solution obtained from step b) or c) 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. Method of distillation may be suitably chosen by the person having ordinary skill in the art. 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) in presence or absence of at least one pharmaceutically acceptable carrier;
  • 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.
  • the process may require in-process quality checks to avoid unnecessary repetitions of the same process step.
  • the reaction procedure of step e) may be performed in the presence of at least one pharmaceutically acceptable carrier as has been described herein this specification.
  • Pharmaceutically acceptable carrier is preferably selected from polyvinylpyrrolidones, cellulose derivatives, polyvinyl alcohols, polyhydroxy alcohols, gelatins, polyethylene glycols, polyethylene oxides, polyoxy ethylene derivatives, propylene glycol derivatives, cyclodextrins or a mixture thereof.
  • the pharmaceutically acceptable carrier used in this invention is selected from Plasdone-K or Hydroxy Propyl Methyl Cellulose (HPMC).
  • Pharmaceutically acceptable carrier is used in quantity ranging between 5-50 % (w/w) w.r.t. quantity of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl - 4 - oxo- 2- thioxoimidazolidin-l-yl) -2-fluoro-N-methylbenzamide, used initially in the reaction.
  • the solid dispersion described herein includes 4-(3-(4- cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl - 4 - oxo- 2-thioxoimidazolidin-l-yl) -2- fluoro-N-methylbenzamide and the pharmaceutically acceptable carrier, present in weight ratios ranging from about 50:50 to about 95:5.
  • Pharmaceutically acceptable carrier may also be used in this reaction in dissolved form, wherein solvent used for dissolution of the carrier is either the same or different solvent as compared to the solvent used in step a).
  • 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-methylbenzamide or its solid dispersion.
  • the material obtained from step d) or e) is dried at a temperature up to 60 °C.
  • 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.
  • Process of isolating amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide or its solid dispersion 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.
  • 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.
  • Amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-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%.
  • Solid dispersion forms of the present invention comprising of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl - 4 - oxo- 2-thioxoimidazolidin-l- yl) -2-fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier which is present in weight ratios ranging from about 50:50 to about 95:5, are adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in the morphology and physicochemical characteristics.
  • the solid dispersion form containing 5% Plasdone-K (w/w) retained its polymorphic form for about one week; the material containing 10% Plasdone-K (w/w) retained its polymorphic nature even up to 60 days.
  • the solid dispersion forms of the present invention not only enhance the stability of amorphous form of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl - 4 - oxo- 2- thioxoimidazolidin-l-yl) -2-fluoro-N-methylbenzamide but also provide suitably desired release profiles.
  • the amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide or its solid dispersion, as described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis.
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the invention also relates to composition containing 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.
  • the composition may be 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.
  • 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 also be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can also 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.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, 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.
  • compositions comprising amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide according to the present application
  • diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like
  • binders such as acacia, guar gum, tragacanth, gelatin, pregelatinized starch and the like
  • disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like
  • lubricants such as stearic acid, magnesium stearate, zinc stearate and the like;
  • compositions of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide 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.
  • Example-01 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 0.5 gm 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide 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.
  • Example-02 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
  • Example-03 Process for preparation of solid dispersion of 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide
  • Example-04 Process for preparation of solid dispersion of 4-(3-(4-cyano-3-
  • Example-05 Process for preparation of solid dispersion of 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide

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Abstract

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) (I) and process for preparation thereof. The invention further relates to a solid dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier. The amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (I) and/or its solid dispersion of the present invention can be useful in the treatment of cancer.

Description

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-thio am (I)
Figure imgf000002_0001
and process for preparation thereof.
The invention further relates to a solid dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier.
The amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide (I) and/or its solid dispersion of the present invention can be useful in the treatment of cancer.
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, its solid dispersion with a pharmaceutically acceptable carrier and the process for preparation thereof. 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 hioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide or its solid dispersion, useful in the treatment of cancer.
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 XTA DI™. 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] -5,5dim
methylbenzamide (I).
Figure imgf000003_0001
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 disclosed processes for the preparation of Enzalutamide by following reaction schemes:
Figure imgf000003_0002
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 hioxoimidazolidin-l-yl)-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- a novel 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 its preparation, which may be industrially amenable and usable for preparing the pharmaceutical compositions. The present invention provides an amorphous form of 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.
The present invention further relates to a solid dispersion comprising 4-(3-(4-cyano-3- (trifluoromethyl) phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2-fluoro-N- methylbenzamide and at least one pharmaceutically acceptable carrier.
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-l-yl)-2-fluoro-N- methylbenzamide or its solid dispersion and the process for preparation thereof.
In one aspect according to the present invention, it provides the amorphous 4-(3-(4- cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide or Enzalutamide (I):
Figure imgf000005_0001
(I)
In another aspect, the present invention further relates to solid dispersion comprising 4- (3-(4-cyano-3-(trifluoromethyl) phenyl)-5, 5-dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2- fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier.
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 and/or its solid dispersion 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-N-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) in presence or absence of at least one pharmaceutically acceptable carrier;
f) Isolating the amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide or its solid dispersion.
Amorphous 4-(3-(4-cyano-3- (trifluoromethyl) phenyl) -5,5- dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide obtained according to the process of the present invention is characterized by XRPD pattern as per Fig-1 and DSC pattern as per Fig-2
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 solid dispersion comprising 4- (3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2- fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier. In a still further aspect, the present invention also relates to a solid dispersion comprising amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, and at least one pharmaceutically acceptable carrier. Such solid dispersion 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.
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-fluoro-N-methylbenzamide or its solid dispersion, useful in the treatment of cancer.
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-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide amorphous form.
Fig. 3 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 solid dispersion as obtained in Example 3.
Fig. 4 is an example of a Differential Scanning Calorimetry ("DSC") curve of 4-(3-(4- cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide solid dispersion as obtained in Example 3.
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- l-yl)-2-fluoro-N- methylbenzamide, and/or its solid dispersion and the 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):
Figure imgf000007_0001
(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-(trifluoromethyl) 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 endo thermic peak ranging between 190 to 210 °C.
Another embodiment of the present application, provides a solid pharmaceutical dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2- fluoro-N-methylbenzamide (I) with at least one pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers that may be used for the preparation of solid dispersions containing 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide (I) may be selected from pharmaceutically acceptable carriers such as polyvinylpyrrolidones (povidones for e.g. plasdone-K, plasdone k29/32, plasdone k 12, plasdone k 30, plasdone s-630, plasdone k25 or plasdone c-17), copolymers of N-vinylpyrrolidone, gums, cellulose derivatives (for e.g. hydro xypropyl methylcelluloses-HPMC, hydroxyethyl cellulose-HEC, HydroxyPropylCellulose- HPC, MethylCellulose-MC, Low-substituted Hydroxy Propyl Cellulose-LHPC or Crystalline Micro Cellulose-CMC), cyclodextrins, gelatins, polyhydroxy alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, polyvinylalcohols, propylene glycol derivatives, or a mixture thereof. Pharmaceutically acceptable carriers that may be used for the preparation of solid dispersions of the present invention may be of any viscosity or molecular weight. 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- methyl benzamide and/or its solid dispersion, 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-N-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) in presence or absence of at least one pharmaceutically acceptable carrier;
f) Isolating the amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide or its solid dispersion.
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-methyl benzamide or its solid dispersion 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-(trifluoromethyl) 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 Ci-C2 alcohols for e.g. methanol and ethanol or halohydrocarbon solvent for e.g. 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-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide. The amount of solvent methanol (in mL) used in this step ranges from 20-70 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 used 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-methyl benzamide, 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. Optionally the reaction mixture obtained in step a) may be filtered before proceeding with heating of the reaction mixture. 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 optionally maintained at the same raised temperature for a time duration of 20 mins to 1 hr, based on the dissolution.
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 solution obtained from step b) or c) 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. Method of distillation may be suitably chosen by the person having ordinary skill in the art. 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) in presence or absence of at least one pharmaceutically acceptable carrier;
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.
Optionally the reaction procedure of step e) may be performed in the presence of at least one pharmaceutically acceptable carrier as has been described herein this specification. Pharmaceutically acceptable carrier is preferably selected from polyvinylpyrrolidones, cellulose derivatives, polyvinyl alcohols, polyhydroxy alcohols, gelatins, polyethylene glycols, polyethylene oxides, polyoxy ethylene derivatives, propylene glycol derivatives, cyclodextrins or a mixture thereof. In a specific embodiment, the pharmaceutically acceptable carrier used in this invention is selected from Plasdone-K or Hydroxy Propyl Methyl Cellulose (HPMC).
Pharmaceutically acceptable carrier is used in quantity ranging between 5-50 % (w/w) w.r.t. quantity of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl - 4 - oxo- 2- thioxoimidazolidin-l-yl) -2-fluoro-N-methylbenzamide, used initially in the reaction. In an embodiment of the present invention, the solid dispersion described herein includes 4-(3-(4- cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl - 4 - oxo- 2-thioxoimidazolidin-l-yl) -2- fluoro-N-methylbenzamide and the pharmaceutically acceptable carrier, present in weight ratios ranging from about 50:50 to about 95:5. Pharmaceutically acceptable carrier may also be used in this reaction in dissolved form, wherein solvent used for dissolution of the carrier is either the same or different solvent as compared to the solvent used in step a).
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-methylbenzamide or its solid dispersion. The material obtained from step d) or e) is dried at a temperature up to 60 °C. 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 or its stable solid dispersion.
Process of isolating amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide or its solid dispersion, 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 into the amorphous 4-(3-(4-cyano-3- (trifluoromethyl)phenyl) - 5,5 - dimethyl -4- oxo -2- thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide or its solid dispersion, as per 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. Amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-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%.
Pharmaceutically acceptable solid dispersion forms of the present invention, comprising of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl - 4 - oxo- 2-thioxoimidazolidin-l- yl) -2-fluoro-N-methylbenzamide and at least one pharmaceutically acceptable carrier which is present in weight ratios ranging from about 50:50 to about 95:5, are adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in the morphology and physicochemical characteristics. In a particular embodiment of the present application, though the solid dispersion form containing 5% Plasdone-K (w/w) retained its polymorphic form for about one week; the material containing 10% Plasdone-K (w/w) retained its polymorphic nature even up to 60 days.
The solid dispersion forms of the present invention not only enhance the stability of amorphous form of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl - 4 - oxo- 2- thioxoimidazolidin-l-yl) -2-fluoro-N-methylbenzamide but also provide suitably desired release profiles.
The amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide or its solid dispersion, as 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 and or its stable solid dispersion, 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 or its solid dispersion, obtained in the examples are set forth in the Figs. 1-4.
In a further embodiment according to this specification, the invention also relates to composition containing 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. 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-dimethyl-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 also 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 also 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.
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 oleate, 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-methylbenzamide according to the present application include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, 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.
As already described in detail, pharmaceutically acceptable excipients used in the compositions of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide 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
Example-01: 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 0.5 gm 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide 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 lOOmm/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 (Rotations per minute). 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 lOOmm/Hg 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-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2-fluoro-N- methylbenzamide having the XRPD diffractogram and DSC isotherm as shown in Figs. 1 and 2 resp.
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-(trifluoromethyl)phenyl)- 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide
1 g 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide was charged to 100 ml RBF 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 100 mm/Hg and increased to 650 mm/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 lOOmm/Hg and increased to 650mm/Hg. 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-t oxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide having the XRPD diffractogram and DSC isotherm similar to as shown in Figs. 1 and 2 resp.
Yield: 0.94 gm, HPLC purity: 99.07 %
Example-03: Process for preparation of solid dispersion of 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide
670 mg 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide was dissolved in 25 mL of methanol and filtered. The filtrate was charged in to 250 mL of single neck rotavapor flask. At high RPM, the solvent was distilled out by applying temperature of ~ 40 °C. Removal of solvent was carried out under reduced pressure conditions for time duration of about 30 mins. To the solid material obtained, 25 mL of methanol was added and again distillation of solvent by rotavapor was carried out, and a solid material was obtained. To this solid material, 67 mg Plasdone-K and 25 mL of methanol were added. The temperature of the reaction mixture was raised to about 55 °C which was maintained for ~ 1 hr. Then again, removal of solvent by distillation was performed under vacuum to afford solid dispersion of 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)- 5,5- dimethyl-4-oxo - 2- thioxo-imidazolidin -1-yl) -2- fluoro-N- methylbenzamide, having the XRPD diffractogram and DSC isotherm as shown in Figs. 3 and 4 resp.
HPLC purity: 98.90 %
Example-04: Process for preparation of solid dispersion of 4-(3-(4-cyano-3-
(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide
600 mg 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide was dissolved in 25 mL of methanol and filtered. The filtrate was charged in to 250 mL of single neck rotavapor flask. At high RPM, the solvent was distilled out by applying temperature of ~ 40 °C. Removal of solvent was carried out under reduced pressure conditions for time duration of about 30 mins. To the solid material obtained, 25 mL of methanol was added and again distillation of solvent by rotavapor was carried out, and a solid material was obtained. To this solid material, 120 mg Plasdone-K and 25 mL of methanol were added. The temperature of the reaction mixture was raised to about 55 °C which was maintained for ~ 1 hr. Then again, removal of solvent by distillation was performed under vacuum to afford solid dispersion of 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)- 5,5- dimethyl-4-oxo - 2- thioxo-imidazolidin -1-yl) -2- fluoro-N- methy lbenzamide .
Example-05: Process for preparation of solid dispersion of 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N- methylbenzamide
400 mg 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide was dissolved in 25 mL of methanol and filtered. The filtrate was charged in to 250 mL of single neck rotavapor flask. At high RPM, the solvent was distilled out by applying temperature of ~ 40 °C. Removal of solvent was carried out under reduced pressure conditions for time duration of about 30 mins. To the solid material obtained, 25 mL of methanol was added and again distillation of solvent by rotavapor was carried out, and a solid material was obtained. To this solid material, 200 mg Plasdone-K and 25 mL of methanol were added. The temperature of the reaction mixture was raised to about 55 °C which was maintained for ~ 1 hr. Then again, removal of solvent by distillation was performed under vacuum to afford solid dispersion of 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)- 5,5- dimethyl-4-oxo - 2- thioxo-imidazolidin -1-yl) -2- fluoro-N- methy lbenzamide .
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

Claims:
1) Amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide (I) and/or its solid dispersion with at least one pharmaceutically acceptable carrier.
Figure imgf000017_0001
2) 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-N-methyl benzamide and/or its solid dispersion, 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-N-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) in presence or absence of at least one pharmaceutically acceptable carrier;
f) Isolating the amorphous 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide or its solid dispersion.
3) 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-N-methyl benzamide and/or its solid dispersion, according to claim-2, wherein organic solvent in step a) is selected from C1-C2 alcohol and halohydrocarbon solvent. 4) 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-N-methylbenzamide and/or its solid dispersion, according to claim-2, wherein in step b) the reaction mixture is heated to a temperature ranging between 40-60 °C.
5) 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-N-methylbenzamide and/or its solid dispersion, according to claim-2, wherein step d) comprises drying which is carried out by distillation under reduced pressure conditions.
6) A process for the preparation of solid dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methyl benzamide, according to claim-2, wherein pharmaceutically acceptable carrier is used in quantity ranging between 5-50 % (w/w) w.r.t. quantity of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5- dimethyl - 4 - oxo- 2-thioxoimidazolidin-l-yl) -2-fluoro-N-methylbenzamide.
7) The solid dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methyl benzamide according to claim 2, wherein the pharmaceutically acceptable carrier is selected from polyvinylpyrrolidones, cellulose derivatives, polyvinyl alcohols, polyhydroxy alcohols, gelatins, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, propylene glycol derivatives, cyclodextrins or a mixture thereof.
8) The solid dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)- 5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methyl benzamide according to claim 7, wherein the pharmaceutically acceptable carrier is a polyvinylpyrrolidone or cellulose derivative selected from hydroxy propyl methyl celluloses (HPMC), hydroxyethyl cellulose (HEC), Hydroxy PropylCellulose (HPC), MethylCellulose (MC) or Low-substituted Hydroxy Propyl Cellulose (L-HPC). 9) Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, according to claim- 1, characterized by DSC isotherm comprising at least one exothermic peak ranging between 125 to 150 °C and at least one endo thermic peak ranging between 190 to 210 °C.
10) A solid dispersion of 4-(3-(4-cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide (I) comprising at least one pharmaceutically acceptable carrier.
PCT/IB2014/059443 2013-04-10 2014-03-05 Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-n-methylbenzamide WO2014167428A2 (en)

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