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Enzalutamide polymorphic forms and its preparation

a technology of enzalutamide and polymorphic forms, which is applied in the field of polymorphic forms of enzalutamide, can solve the problems of inability to predict the number of polymorphic forms of a given compound, and differences in pharmaceutical products in solubility, bioavailability, stability and other properties

Inactive Publication Date: 2015-08-27
DR REDDYS LAB LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes the discovery of two new crystalline forms of enzalutamide, designated as Form R1 and Form R2, and an amorphous form. These new forms have been characterized by their powder X-ray diffraction patterns. The patent also describes a process for preparing these new forms and pharmaceutical formulations containing them. The technical effect of the patent is the provision of new crystalline forms of enzalutamide with improved properties, such as increased solubility and stability, which can be used in the development of improved pharmaceutical formulations.

Problems solved by technology

This variation in solid forms may be significant and may result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties.
The existence and possible number of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance.

Method used

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  • Enzalutamide polymorphic forms and its preparation
  • Enzalutamide polymorphic forms and its preparation
  • Enzalutamide polymorphic forms and its preparation

Examples

Experimental program
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example 1

Preparation of Crystalline Enzalutamide Form R1

[0104]Methyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoate (45 g), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (95.6 g), dimethylsulphoxide (45 mL) and isopropyl acetate (90 mL) charged into round bottom flask, heated to 85° C. and maintained at 85° C. for 16 hours. Methanol (7.5 mL) was added to the reaction mixture at 65° C. and stirred at 65-68° C. for 30 minutes. Isopropyl acetate (360 mL) and water (180 mL) was added to the reaction mixture at 20° C. and stirred for 20 minutes. Layers were separated, charcoal (4.5 g) was added to the organic layer and stirred for 15 minutes. The resultant reaction mixture was passed through celite bed and filtrate solvent was evaporated under reduced pressure at below 50° C. followed by traces of isopropyl acetate was chased with isopropyl alcohol (90 mL). To the crude compound, isopropyl alcohol (450 mL) was added, heated to 75° C. and stirred at 75° C. for 20 minutes. The ...

example 2

Preparation of Crystalline Enzalutamide Form R1

[0106]Methyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoate (200 g), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (425 g), dimethylsulphoxide (200 mL) and isopropyl acetate (400 mL) charged into round bottom flask, heated to 85° C. and maintained at 83° C. for 14 hours. Methanol (30 mL) was added to the reaction mixture at 65° C. and stirred at 65-67° C. for 30 minutes. Isopropyl acetate (1400 mL), water (600 mL) and isopropyl alcohol (400 mL) was added to the reaction mixture at 20° C. and stirred for 15 minutes. Layers were separated and organic layer was dried over sodium sulphate. Charcoal (20 g) was added to the organic layer and stirred for 25 minutes. The resultant reaction mixture was passed through celite bed and filtrate solvent was evaporated under reduced pressure at below 50° C. To the crude compound, isopropyl alcohol (1600 mL) was added, heated to 75° C. and stirred at 75° C. for 20 minutes. The resu...

example 3

Preparation of Crystalline Enzalutamide Form R1

[0107]Enzalutamide (100 mg) and acetic acid (1 mL) was charged into a round bottom flask at 26° C. and stirred for 5 minutes. Water (10 mL) was added to the resultant reaction mass at 26° C. and stirred at 26° C. for 15 minutes. Separated solid was collected by filtration and dried at 50° C. under reduced pressure for 1 hour to afford the title compound.

[0108]Yield: 68 mg

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Abstract

The present application relates to crystalline and amorphous forms of Enzalutamide. The present application further relates to amorphous solid dispersions of Enzalutamide with pharmaceutically acceptable carriers. The present application also relates to a process for the preparation of Form R1 of Enzalutamide.

Description

INTRODUCTION[0001]Aspects of the present application relate to polymorphic forms of enzalutamide which are useful in making pharmaceutically acceptable dosage forms, and processes for its preparation.[0002]The drug compound having the adopted name enzalutamide, has a chemical name 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, and is represented by structure of formula[0003]Enzalutamide is an oral, once-daily investigational agent that is an androgen receptor signaling inhibitor used for the potential treatment of men with castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy. Enzalutamide inhibits androgen receptor signaling in three distinct ways: it inhibits 1) testosterone binding to androgen receptors; 2) nuclear translocation of androgen receptors; and 3) DNA binding and activation by androgen receptors. U.S. Pat. No. 7,709,517 discloses enzalutamide, method of use and it's ...

Claims

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Application Information

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IPC IPC(8): C07D233/86
CPCC07B2200/13C07D233/86A61P35/04H04L65/1016H04L65/1073H04L65/4061H04W4/10H04W12/069H04W12/086H04W60/005H04W76/45H04W76/50H04W4/90H04W12/06H04W12/08H04W60/00H04L9/40
Inventor PEDDY, VISHWESHWARBOGE, RAJESHAMMADIVADA, LOKESWARA RAO
Owner DR REDDYS LAB LTD
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