DESC:INTRODUCTION
Aspects of the present application relates to crystalline forms of apalutamide, amorphous solid dispersion of apalutamide and process for the preparation of amorphous form of apalutamide.
The drug compound having the adopted name “Apalutamide” has chemical name: 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide as below.

US8445507B2 discloses apalutamide or a pharmaceutically acceptable salt thereof, method for treating prostate cancer using apalutamide or a pharmaceutically acceptable salt thereof and pharmaceutical composition thereof. US20140088129A1 discloses method of treating non-metastatic castration-resistant prostate cancer with apalutamide.
US9481663B2 discloses crystalline Form B of apalutamide. US20170001977A1 discloses crystalline Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I and Form J of apalutamide.
WO2016124149A1 discloses crystalline Form I and Form II of apalutamide. WO2016090098A1 discloses solid dispersion of apalutamide with HPMCAS. WO2016090101A1 discloses solid dispersion of apalutamide with a poly(meth)acrylate copolymer.
WO2016090105A1 discloses solid dispersion of apalutamide with a poly(meth)acrylate copolymer and HPMCAS. US20160346207A1 discloses solid pharmaceutical composition comprising apalutamide, carrier and surfactant.
The physicochemical properties of a solid form is a critical parameter in the development of pharmaceutical dosage forms and these properties can affect the bioavailability, stability and processability of the active pharmaceutical ingredient. It is known that a solid active pharmaceutical ingredient can exist in amorphous and crystalline state. Crystalline solids may further exist as various polymorphs and solvates.
The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
The discovery of new forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, storage stability, and ease of purification. Accordingly, the present inventors have found novel crystalline form of Apalutamide (VK7, VK8 and VK9) with enhanced storage stability, solubility and processability.
SUMMARY
In an aspect, the present application provides a crystalline form of apalutamide (VK7), characterized by a PXRD pattern comprising the peak at about 4.16 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of apalutamide (VK7), comprising the steps of:
a) dissolving apalutamide in N,N Dimethyl formamide;
b) adding anti solvent to the solution obtained in step a);
c) cooling the reaction mixture obtained in step b);
d) isolating the crystalline form of apalutamide (VK7).
In an aspect, the present application provides a crystalline form of apalutamide (VK8), characterized by a PXRD pattern comprising the peak at about 6.61 and 17.57±0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of apalutamide (VK8), comprising the steps of:
a) dissolving apalutamide in ethyl acetate;
b) adding anti solvent to the solution obtained in step a);
c) cooling the reaction mixture obtained in step b);
d) isolating the crystalline form of apalutamide (VK8).
In an aspect, the present application provides a crystalline form of Apalutamide (VK9), characterized by a PXRD pattern comprising the peak at about 9.77, 12.81, 15.54 and 17.80±0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of apalutamide (VK9), comprising the steps of:
a) suspending apalutamide in dimethyl carbonate;
b) cooling the reaction mixture obtained in step b);
c) isolating the crystalline form of apalutamide (VK9).
In another aspect, the present application provides a process for the preparation of amorphous apalutamide, comprising the steps of:
a) dissolving apalutamide in a solvent selected from acetone, ethanol or mixture thereof;
b) isolating the amorphous form of Apalutamide.
In an aspect, the present application provides amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate HP-55, characterized by its X-ray powder diffractogram as substantially shown in FIG.6
In an aspect, the present application provides amorphous solid dispersion of apalutamide with copovidone VA64NF, characterized by its X-ray powder diffractogram as substantially shown in FIG.7
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of apalutamide with excipient selected from hydroxypropyl methylcellulose phthalate HP-55 and copovidone VA64NF or mixture thereof, comprising the steps of:
a) providing a solution of apalutamide and atleast one pharmaceutically acceptable excipient selected from hydroxypropyl methylcellulose phthalate HP-55 and copovidone VA64NF or mixture thereof in a suitable solvent;
b) isolating the amorphous solid dispersion of apalutamide with excipient selected from hydroxypropyl methylcellulose phthalate HP-55 and copovidone VA64NF or mixture thereof.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline forms of apalutamide (VK7, VK8 and VK9) or amorphous form of apalutamide or amorphous solid dispersion of apalutamide with atleast one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline form of apalutamide (VK7) prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline form of apalutamide (VK8) prepared by the method of Example No 3.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline form of apalutamide (VK9) prepared by the method of Example No 4.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 5.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 6.
Figure 6 is an illustrative X-ray powder diffraction pattern of apalutamide with hydroxypropyl methylcellulose phthalate HP-55 prepared by the method of Example No 7.
Figure 7 is an illustrative X-ray powder diffraction pattern of apalutamide with copovidone VA64NF prepared by the method of Example No 8.
Figure 8 is an illustrative X-ray powder diffraction pattern of apalutamide with hydroxypropyl methylcellulose phthalate HP-55 prepared by the method of Example No 9.
Figure 9 is an illustrative X-ray powder diffraction pattern of apalutamide with copovidone VA64 prepared by the method of Example No 10.
Figure 10 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 11.
Figure 11 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 12.
DETAILED DESCRIPTION
In an aspect, the present application provides a crystalline form of apalutamide (VK7), characterized by a PXRD pattern comprising the peak at about 4.16 ± 0.2° 2?. In an embodiment, the application provides crystalline apalutamide (VK7), characterized by a PXRD pattern having one or more additional peaks at about 7.44 and 8.21±0.2° 2?. In an embodiment, the application provides crystalline apalutamide (VK7), characterized by a PXRD pattern of figure 1.
In another aspect, the present application provides a process for the preparation of crystalline form of apalutamide (VK7), comprising the steps of:
a) dissolving apalutamide in N,N Dimethyl formamide;
b) adding anti solvent to the solution obtained in step a);
c) cooling the reaction mixture obtained in step b);
d) isolating the crystalline form of apalutamide (VK7).
In an embodiment, step a) may be carried out by dissolving apalutamide in N,N Dimethyl formamide. Alternatively, the solution may be provided by taking the reaction mixture containing apalutamide in N,N Dimethyl formamide.
In an embodiment of step a), the apalutamide may be dissolved in N,N Dimethyl formamide by heating the reaction mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In embodiments of step b), adding anti solvent selected from methyl-t-butyl ether, toluene, heptane, or mixtures thereof to the solution obtained in step a).
In embodiment of step b), the isolation may be effected by combining the solution of step a) with a suitable anti-solvent. Adding the solution obtained in step a) to the anti-solvent, or adding an anti-solvent to the solution obtained in step a), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In an embodiment of step c), the reaction mixture of apalutamide may be cooled to precipitate the solids to a suitable temperature at which crystalline apalutamide (VK7) is formed and / or is stable.
In an embodiment of step d), the isolation of crystalline apalutamide (VK7) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline apalutamide (VK7) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying crystalline apalutamide (VK7) may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out at about 30°C or above at which crystalline apalutamide (VK7) is stable and for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In an aspect, the present application provides a crystalline form of apalutamide (VK8), characterized by a PXRD pattern comprising the peak at about 6.61 and 17.57±0.2° 2?. In an embodiment, the application provides crystalline apalutamide (VK8), characterized by a PXRD pattern having one or more additional peaks at about 9.61, 12.80, 15.54, 21.76, 23.02, 23.89 and 26.08±0.2° 2?. In an embodiment, the application provides crystalline apalutamide (VK8), characterized by a PXRD pattern of figure 2.
In another aspect, the present application provides a process for the preparation of crystalline form of apalutamide (VK8), comprising the steps of:
a) dissolving apalutamide in ethyl acetate;
b) adding anti solvent to the solution obtained in step a);
c) cooling the reaction mixture obtained in step b);
d) isolating the crystalline form of apalutamide (VK8).
In an embodiment, step a) may be carried out by dissolving apalutamide in ethyl acetate. Alternatively, the solution may be provided by taking the reaction mixture containing apalutamide in ethyl acetate.
In an embodiment of step a), the apalutamide may be dissolved in ethyl acetate by heating the reaction mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In embodiments of step b), adding anti solvent selected from heptane, methyl-t-butyl ether, toluene, pentane, hexane, diisopropyl ether, pet ether or mixture thereof to the solution obtained in step a).
In embodiment of step b), the isolation may be effected by combining the solution of step a) with a suitable anti-solvent. Adding the solution obtained in step a) to the anti-solvent, or adding an anti-solvent to the solution obtained in step a), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In an embodiment of step c), the reaction mixture of Apalutamide may be cooled to precipitate the solids to a suitable temperature at which crystalline Apalutamide (VK8) is formed and / or is stable.
In an embodiment of step d), the isolation of crystalline Apalutamide (VK8) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Apalutamide (VK8) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying crystalline Apalutamide (VK8) may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out at about 30°C or above at which crystalline Apalutamide (VK8) is stable and for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In an aspect, the present application provides a crystalline form of Apalutamide (VK9), characterized by a PXRD pattern comprising the peak at about 9.77, 12.81, 15.54 and 17.80±0.2° 2?. In an embodiment, the application provides crystalline Apalutamide (VK9), characterized by a PXRD pattern having one or more additional peaks at about 7.03 7.81, 14.09, 14.50, 20.51 and 23.15±0.2° 2?. In an embodiment, the application provides crystalline Apalutamide (VK9), characterized by a PXRD pattern of figure 3.
In another aspect, the present application provides a process for the preparation of crystalline form of Apalutamide (VK9), comprising the steps of:
a) suspending Apalutamide in dimethyl carbonate;
b) cooling the reaction mixture obtained in step b);
c) isolating the crystalline form of Apalutamide (VK9).
In an embodiment of step a), the Apalutamide may be suspended in dimethyl carbonate at suitable temperature of about 20°C to reflux temperature. Alternatively, the suspension may be provided by taking the reaction mixture containing Apalutamide in dimethyl carbonate.
In an embodiment of step a), the Apalutamide may be suspended in dimethyl carbonate, for sufficient time to complete the formation of crystalline Apalutamide (VK9) of about 10 minutes or more.
In an embodiment of step b), the reaction mixture of Apalutamide may be cooled to precipitate the solids to a suitable temperature at which crystalline Apalutamide (VK9) is formed and / or is stable.
In an embodiment of step c), the isolation of crystalline Apalutamide (VK9) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Apalutamide (VK9) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying crystalline Apalutamide (VK9) may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out at about 30°C or above at which crystalline Apalutamide (VK9) is stable and for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another aspect, the present application provides a process for the preparation of amorphous Apalutamide, comprising the steps of:
a) dissolving Apalutamide in a solvent selected from acetone, ethanol or mixture thereof;
b) isolating the amorphous form of Apalutamide.
In an embodiment, step a) may be carried out by dissolving Apalutamide in a solvent selected from acetone, ethanol or mixture thereof. Alternatively, the solution may be provided by taking the reaction mixture containing Apalutamide in a solvent selected from acetone, ethanol or mixture thereof.
In an embodiment of step a), the Apalutamide may be dissolved in a solvent selected from acetone, ethanol or mixture thereof by heating the reaction mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment of step b), the isolation of amorphous Apalutamide may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, amorphous Apalutamide may be isolated by employing any of the techniques, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using rotavapor, spray drying, freeze drying, agitated thin film drying, filtration and the like.
In an embodiment, drying amorphous Apalutamide may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out at about 30°C or above at which amorphous Apalutamide is stable and for any time period required for obtaining a desired quality, such as from about 15 minutes to 17 hours or longer.
In an embodiment, the application provides amorphous form of Apalutamide, characterized by its X-ray powder diffractogram as substantially shown in figures 4,5,10 and 11.

In an aspect, the present application provides amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate HP-55, characterized by its X-ray powder diffractogram as substantially shown in FIG.6
In an aspect, the present application provides amorphous solid dispersion of apalutamide with copovidone VA64NF, characterized by its X-ray powder diffractogram as substantially shown in FIG.7
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of apalutamide with excipient selected from hydroxypropyl methylcellulose phthalate HP-55 and copovidone VA64NF or mixture thereof, comprising the steps of:
a) providing a solution of apalutamide and atleast one pharmaceutically acceptable excipient selected from hydroxypropyl methylcellulose phthalate HP-55 and copovidone VA64NF or mixture thereof in a suitable solvent;
b) isolating the amorphous solid dispersion of apalutamide with excipient selected from hydroxypropyl methylcellulose phthalate HP-55 and copovidone VA64NF or mixture thereof.
In an embodiment step a), the suitable solvent selected from halogenated hydrocarbons,C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, water or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group consisting of dichloromethane, methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran and mixtures thereof.
In an embodiment, providing a solution at step a) may be carried out by taking the reaction mixture containing apalutamide directly or by dissolving apalutamide and atleast one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
In an embodiment, a solution of apalutamide and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of apalutamide and the excipient may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using rotavapor, spray drying, freeze drying, agitated thin film drying, filtration and the like.
In preferred embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
Amorphous solid dispersion of apalutamide isolated at step b) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline forms of apalutamide (VK7, VK8 and VK9) or amorphous form of apalutamide or amorphous solid dispersion of apalutamide with atleast one pharmaceutically acceptable excipient.
Amorphous solid dispersion of apalutamide may be obtained alternatively either by employing a melt-extrusion technique.

Starting materials used for the preparation of crystalline VK7, VK8 and VK9 of apalutamide or amorphous form of apalutamide or amorphous solid dispersion of apalutamide according to any of the aspects of the present application may be any crystalline or amorphous in nature. Further, these starting materials may be purified according to any of the method known in the art such as recrystallization, slurrying, acid-base treatment i.e., salt making and breaking, chromatography, fractional distillation or any other separation methods, before using. Apalutamide that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example apalutamide may be prepared by the processes described in US8445507B2 and US8987452B2.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline forms of apalutamide (VK7, VK8 and VK9) or amorphous form of apalutamide or amorphous solid dispersion of apalutamide and atleast one additional pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like.
In another aspect, the present application provides crystalline form VK7, VK8 and VK9 of apalutamide or amorphous form of apalutamide or amorphous solid dispersion of apalutamide or a mixture thereof according to instant application and pharmaceutical compositions thereof, wherein the chemical purity of apalutamide may be more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another aspect, the present application provides crystalline form VK7, VK8 and VK9 of apalutamide or amorphous form of apalutamide or amorphous solid dispersion of apalutamide or a mixture thereof according to instant application and pharmaceutical compositions thereof, wherein particle size (D90) of Apalutamide may be less than 100 microns or less than 50 microns or less than 20 microns.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The term "solid dispersion" when used in the present application, denotes a state where most of the apalutamide, preferably 90%, 95% or all of the apalutamide of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
EXAMPLES
Example-1: Preparation of crystalline Apalutamide (VK7)
Apalutamide (2g) was dissolved in N,N Dimethyl formamide (2 mL) at 75°C. Methyl-t-butyl ether (50 mL) was added to the reaction mixture at 30°C. The reaction mixture was cooled to 5°C and stirred for 1 hour. The resulted slurry was filtered under vacuum to obtain the title compound. Yield: 1.4g
Example-2: Preparation of crystalline Apalutamide (VK7)
Apalutamide (2g) was dissolved in N,N Dimethyl formamide (2 mL) at 75°C. Toluene (25 mL) was added to the reaction mixture at 32°C. The reaction mixture was cooled to 5°C and stirred for 1.5 hour. The resulted slurry was filtered under vacuum to obtain the title compound. Yield: 1.1g
Example-3: Preparation of crystalline Apalutamide (VK8)
Apalutamide (3g) was dissolved in ethyl acetate (20 mL) at 50°C. n-heptane (60 mL) was added to the reaction mixture at 50°C. The reaction mixture was cooled to 0°C and stirred for 55 minutes. The resulted slurry was filtered under vacuum to obtain the title compound. Yield: 2.8g
Example-4: Preparation of crystalline Apalutamide (VK9)
Dimethyl carbonate (10 mL) was added to Apalutamide (0.5g). The resulting mixture was heated for 15 minutes at 80°C in a glass vial. The reaction mixture was cooled to 25°C. After about 30 hours, the resulted slurry was filtered under vacuum to obtain the title compound. Yield: 0.3g
Example-5: Preparation of amorphous Apalutamide
Apalutamide (1g) was dissolved in acetone (50 mL) at 75°C. The resulted solution was rotary evaporated under vacuum at 75°C. The solid was dried under vacuum at 65°C for 30 minutes to obtain the title compound. Yield: 1.2g
Example-6: Preparation of amorphous Apalutamide
Apalutamide (35g) was dissolved in acetone (550 mL) at 55°C. The resulted solution was filtered under vacuum. The clear solution was subjected to spray drying under nitrogen at a feed solution RPM of 80 or 5g/min and feed solution temperature was 30°C. The inlet temperature was kept at 80°C and the outlet temperature was kept at 40°C. The product was dried under VTD at 40°C for 17 hours to obtain the title compound. Yield: 21.0g
Example-7: Preparation of amorphous solid dispersion of Apalutamide with hydroxypropyl methylcellulose phthalate HP-55
Apalutamide (1g), hydroxypropyl methylcellulose phthalate HP-55 (1g), methanol (50 mL) and dichloromethane (10 mL) were charged into a rotavapor flask at 25°C. The reaction mixture was stirred for 10 minutes at 75°C. The reaction mixture was evaporated under vacuum at 75°C. The solid was dried under vacuum at 65°C for 1 hour to obtain the title compound. Yield: 1.8g
Example-8: Preparation of amorphous solid dispersion of Apalutamide with copovidone VA64NF
Apalutamide (1g), copovidone VA64NF (1g) and methanol (50 mL) were charged into a rotavapor flask at 25°C. The reaction mixture was stirred for 10 minutes at 75°C. The reaction mixture was evaporated under vacuum at 75°C. The solid was dried under vacuum at 65°C for 1 hour to obtain the title compound. Yield: 1.2g
Example-9: Preparation of amorphous solid dispersion of Apalutamide with hydroxypropyl methylcellulose phthalate HP-55
Apalutamide (18g), hydroxypropyl methylcellulose phthalate HP-55 (18g), methanol (450 mL) and dichloromethane (70 mL) were charged into a round bottom flask at 27°C. The reaction mixture was stirred for 15 minutes at 45°C. The resulted solution was filtered under vacuum. The clear solution was subjected to spray drying under nitrogen at a feed solution RPM of 80 or 5g/min. The inlet temperature was kept at 95°C and the outlet temperature was kept at 38°C. The product was dried in Vacuum Tray Dryer at 40°C for 17 hours to obtain the title compound. Yield: 21.7g
Example-10: Preparation of amorphous solid dispersion of Apalutamide with copovidone VA64
Apalutamide (18g), copovidone VA64 (18g) and methanol (500 mL) were charged into a round bottom flask at 25°C. The reaction mixture was stirred for 15 minutes at 65°C. The resulted solution was filtered under vacuum. The clear solution was subjected to spray drying under nitrogen at a feed solution RPM of 80 or 5g/min. The inlet temperature was kept at 90°C and the outlet temperature was kept at 42°C. The product was dried under VTD at 60°C for 3 hours to obtain the title compound. Yield: 21.7g
Example-11: Preparation of amorphous Apalutamide
Apalutamide (0.5g) was dissolved in mixture of dichloromethane (9.5mL) and ethanol (0.5mL) at 40°C. The resulted solution was rotary evaporated under vacuum at 55°C to obtain the title compound. Yield: 0.41g
Example-12: Preparation of amorphous Apalutamide
Apalutamide (0.5g) was dissolved in mixture of dichloromethane (9.5mL) and acetone (0.5mL) at 32°C. The resulted solution was rotary evaporated under vacuum at 56°C to obtain the title compound. Yield: 0.45g
,CLAIMS:We claim
1. A crystalline form of apalutamide (VK7), characterized by a PXRD pattern comprising the peak at about 4.16 ± 0.2° 2?.
2. The process for the preparation of crystalline form of apalutamide (VK7) according to claim 1, the process comprising the steps of:
a) dissolving apalutamide in N,N Dimethyl formamide;
b) adding anti solvent to the solution obtained in step a);
c) cooling the reaction mixture obtained in step b); and
d) isolating the crystalline form of apalutamide (VK7).
3. A process for the preparation of crystalline form of apalutamide (VK8) characterized by a PXRD pattern comprising the peaks at about 6.61 and 17.57±0.2° 2?, the process comprising the steps of:
a) dissolving apalutamide in ethyl acetate;
b) adding anti solvent to the solution obtained in step a);
c) cooling the reaction mixture obtained in step b); and
d) isolating the crystalline form of apalutamide (VK8).
4. The process according to claim 2 or 3, wherein the anti solvent is selected from methyl-t-butyl ether, toluene, pentane, hexane, heptane, diisopropyl ether or mixtures thereof.
5. A process for the preparation of crystalline form of apalutamide (VK9) characterized by a PXRD pattern comprising the peaks at about 9.77, 12.81, 15.54 and 17.80±0.2° 2?, the process comprising the steps of:
a) suspending apalutamide in dimethyl carbonate;
b) cooling the reaction mixture obtained in step b); and
c) isolating the crystalline form of apalutamide (VK9).
6. A process for the preparation of amorphous apalutamide comprising the steps of:
a) dissolving apalutamide in a solvent selected from acetone, ethanol or mixture thereof; and
b) isolating the amorphous form of Apalutamide.