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

INTRODUCTION
Aspects of the present application relates to solvate forms of apalutamide, process for the preparation thereof and pharmaceutical composition of solvate forms 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 prostrate 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)actylate 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 solvate form of Apalutamide (VK1, VK2, VK3, VK4, VK5 and VK6) with enhanced storage stability, solubility and processability.
SUMMARY
In an aspect, the present application provides acetic acid solvate of Apalutamide (VK1), characterized by its X-ray powder diffractogram as substantially shown in FIG.1
In another aspect, the present application provides a process for the preparation of acetic acid solvate of Apalutamide (VK1), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from acetic acid, toluene or mixtures thereof; and
b) isolating the acetic acid solvate of Apalutamide (VK1).
In an aspect, the present application provides a propionic acid solvate of Apalutamide (VK2), characterized by its X-ray powder diffractogram as substantially shown in FIG.2
In another aspect, the present application provides a process for the preparation of propionic acid solvate of Apalutamide (VK2), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from propionic acid, toluene or mixtures thereof; and
b) isolating the propionic acid solvate of Apalutamide (VK2).
In an aspect, the present application provides a racemic propylene glycol solvate of Apalutamide (VK3), characterized by its X-ray powder diffractogram as substantially shown in FIG.3
In another aspect, the present application provides a process for the preparation of racemic propylene glycol solvate of Apalutamide (VK3), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from racemic propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the racemic propylene glycol solvate of Apalutamide (VK3).
In an aspect, the present application provides a R-propylene glycol solvate of Apalutamide (VK4), characterized by its X-ray powder diffractogram as substantially shown in FIG.4
In another aspect, the present application provides a process for the preparation of R-propylene glycol solvate of Apalutamide (VK4), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from R-propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the R-propylene glycol solvate of Apalutamide (VK4).
In an aspect, the present application provides a S-propylene glycol solvate of Apalutamide (VK5), characterized by its X-ray powder diffractogram as substantially shown in FIG.5
In another aspect, the present application provides a process for the preparation of S-propylene glycol solvate of Apalutamide (VK5), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from S-propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the S-propylene glycol solvate of Apalutamide (VK5).
In an aspect, the present application provides a methyl acetate solvate of Apalutamide (VK6), characterized by a PXRD pattern comprising the peaks at about 9.73 and 13.06 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of methyl acetate solvate of Apalutamide (VK6), comprising the steps of:
a) dissolving or suspending Apalutamide in methyl acetate;
b) optionally seeding the solution or suspension obtained in step a) with methyl acetate solvate of Apalutamide (VK-6);and
c) isolating the methyl acetate solvate of Apalutamide (VK6).
In another aspect, the present application provides a pharmaceutical composition comprising solvate forms of Apalutamide with atleast one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of acetic acid solvate of Apalutamide (VK1) prepared by the method of Example No 2.
Figure 2 is an illustrative X-ray powder diffraction pattern of propionic acid solvate of Apalutamide (VK2) prepared by the method of Example No 3.
Figure 3 is an illustrative X-ray powder diffraction pattern of racemic propylene glycol solvate of Apalutamide (VK3) prepared by the method of Example No 6.
Figure 4 is an illustrative X-ray powder diffraction pattern of R-propylene glycol solvate of Apalutamide (VK4) prepared by the method of Example No 8.
Figure 5 is an illustrative X-ray powder diffraction pattern of S-propylene glycol solvate of Apalutamide (VK5) prepared by the method of Example No 10.
Figure 6 is an illustrative X-ray powder diffraction pattern of methyl acetate solvate of Apalutamide (VK6) prepared by the method of Example No 12.
DETAILED DESCRIPTION
Aspects of the present application provide solvate forms of Apalutamide and process for the preparation thereof.
In an aspect, the present application provides acetic acid solvate of Apalutamide (VK1), characterized by its X-ray powder diffractogram as substantially shown in FIG.1
In another aspect, the present application provides a process for the preparation of acetic acid solvate of Apalutamide (VK1), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from acetic acid, toluene or mixtures thereof; and
b) isolating the acetic acid solvate of Apalutamide (VK1).
In an embodiment, step a) may be carried out by dissolving or suspending Apalutamide in acetic acid, toluene or a mixture thereof and any other solvent. Alternatively, the solution or suspension may be provided by taking the reaction mixture containing Apalutamide in acetic acid, toluene or a mixture thereof.
In an embodiment, the Apalutamide may be suspended in acetic acid, toluene or a mixture thereof at suitable temperature of about 20°C to reflux temperature.
In an embodiment, the Apalutamide may be suspended in acetic acid, toluene or a mixture thereof for sufficient time to complete the formation of acetic acid solvate of Apalutamide (VK1) of about one hour or more.
In an embodiment, the Apalutamide may be dissolved in acetic acid, toluene or a mixture thereof optionally by heating the mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment, the solution of Apalutamide in acetic acid, toluene or a mixture thereof may be cooled to precipitate the solids to a suitable temperature at which acetic acid solvate of Apalutamide (VK1) is formed and / or is stable.
Isolation of acetic acid solvate of Apalutamide (VK1) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, acetic acid solvate of Apalutamide (VK1) 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 acetic acid solvate of Apalutamide (VK1) 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 acetic acid solvate of Apalutamide (VK1) 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 propionic acid solvate of Apalutamide (VK2), characterized by its X-ray powder diffractogram as substantially shown in FIG.2
In another aspect, the present application provides a process for the preparation of propionic acid solvate of Apalutamide (VK2), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from propionic acid, toluene or mixtures thereof; and
b) isolating the propionic acid solvate of Apalutamide (VK2).
In an embodiment, step a) may be carried out by dissolving or suspending Apalutamide in propionic acid, toluene or a mixture thereof and any other solvent. Alternatively, the solution or suspension may be provided by taking the reaction mixture containing Apalutamide in propionic acid, toluene or a mixture thereof.
In an embodiment, the Apalutamide may be suspended in propionic acid, toluene or a mixture thereof at suitable temperature of about 20°C to reflux temperature.
In an embodiment, the Apalutamide may be suspended in propionic acid, toluene or a mixture thereof for sufficient time to complete the formation of propionic acid solvate of Apalutamide (VK2) of about one hour or more.
In an embodiment, the Apalutamide may be dissolved in propionic acid, toluene or a mixture thereof optionally by heating the mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment, the solution of Apalutamide in propionic acid, toluene or a mixture thereof may be cooled to precipitate the solids to a suitable temperature at which propionic acid solvate of Apalutamide (VK2) is formed and / or is stable.
Isolation of propionic acid solvate of Apalutamide (VK2) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, propionic acid solvate of Apalutamide (VK2) 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 propionic acid solvate of Apalutamide (VK2) 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 propionic acid solvate of Apalutamide (VK2) 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 racemic propylene glycol solvate of Apalutamide (VK3), characterized by its X-ray powder diffractogram as substantially shown in FIG.3
In another aspect, the present application provides a process for the preparation of racemic propylene glycol solvate of Apalutamide (VK3), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from racemic propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the racemic propylene glycol solvate of Apalutamide (VK3).
In an embodiment, step a) may be carried out by dissolving or suspending Apalutamide in racemic propylene glycol, methyl tertiary-butyl ether or a mixture thereof and any other solvent. Alternatively, the solution or suspension may be provided by taking the reaction mixture containing Apalutamide in racemic propylene glycol, methyl tertiary-butyl ether or a mixture thereof.
In an embodiment, the Apalutamide may be suspended in racemic propylene glycol, methyl tertiary-butyl ether or a mixture thereof at suitable temperature of about 20°C to reflux temperature.
In an embodiment, the Apalutamide may be suspended in racemic propylene glycol, methyl tertiary-butyl ether or a mixture thereof for sufficient time to complete the formation of racemic propylene glycol solvate of Apalutamide (VK3) of about one hour or more.
In an embodiment, the Apalutamide may be dissolved in racemic propylene glycol, methyl tertiary-butyl ether or a mixture thereof optionally by heating the mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment, the solution of Apalutamide in racemic propylene glycol, methyl tertiary-butyl ether or a mixture thereof may be cooled to precipitate the solids to a suitable temperature at which racemic propylene glycol solvate of Apalutamide (VK3) is formed and / or is stable.
Isolation of racemic propylene glycol solvate of Apalutamide (VK3) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, racemic propylene glycol solvate of Apalutamide (VK3) 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 racemic propylene glycol solvate of Apalutamide (VK3) 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 racemic propylene glycol solvate of Apalutamide (VK3) 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 R-propylene glycol solvate of Apalutamide (VK4), characterized by its X-ray powder diffractogram as substantially shown in FIG.4
In another aspect, the present application provides a process for the preparation of R-propylene glycol solvate of Apalutamide (VK4), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from R-propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the R-propylene glycol solvate of Apalutamide (VK4).
In an embodiment, step a) may be carried out by dissolving or suspending Apalutamide in R-propylene glycol, methyl tertiary-butyl ether or a mixture thereof and any other solvent. Alternatively, the solution or suspension may be provided by taking the reaction mixture containing Apalutamide in R-propylene glycol, methyl tertiary-butyl ether or a mixture thereof.
In an embodiment, the Apalutamide may be suspended in R-propylene glycol, methyl tertiary-butyl ether or a mixture thereof at suitable temperature of about 20°C to reflux temperature.
In an embodiment, the Apalutamide may be suspended in R-propylene glycol, methyl tertiary-butyl ether or a mixture thereof for sufficient time to complete the formation of R-propylene glycol solvate of Apalutamide (VK4) of about one hour or more.
In an embodiment, the Apalutamide may be dissolved in R-propylene glycol, methyl tertiary-butyl ether or a mixture thereof optionally by heating the mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment, the solution of Apalutamide in R-propylene glycol, methyl tertiary-butyl ether or a mixture thereof may be cooled to precipitate the solids to a suitable temperature at which R-propylene glycol solvate of Apalutamide (VK4) is formed and / or is stable.
Isolation of R-propylene glycol solvate of Apalutamide (VK4) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, R-propylene glycol solvate of Apalutamide (VK4) 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 R-propylene glycol solvate of Apalutamide (VK4) 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 R-propylene glycol solvate of Apalutamide (VK4) 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 S-propylene glycol solvate of Apalutamide (VK5), characterized by its X-ray powder diffractogram as substantially shown in FIG.5
In another aspect, the present application provides a process for the preparation of S-propylene glycol solvate of Apalutamide (VK5), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from S-propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the S-propylene glycol solvate of Apalutamide (VK5).
In an embodiment, step a) may be carried out by dissolving or suspending Apalutamide in S-propylene glycol, methyl tertiary-butyl ether or a mixture thereof and any other solvent. Alternatively, the solution or suspension may be provided by taking the reaction mixture containing Apalutamide in S-propylene glycol, methyl tertiary-butyl ether or a mixture thereof.
In an embodiment, the Apalutamide may be suspended in S-propylene glycol, methyl tertiary-butyl ether or a mixture thereof at suitable temperature of about 20°C to reflux temperature. In an embodiment, the Apalutamide may be suspended in S-propylene glycol, methyl tertiary-butyl ether or a mixture thereof for sufficient time to complete the formation of S-propylene glycol solvate of Apalutamide (VK5) of about one hour or more.
In an embodiment, the Apalutamide may be dissolved in S-propylene glycol, methyl tertiary-butyl ether or a mixture thereof optionally by heating the mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment, the solution of Apalutamide in S-propylene glycol, methyl tertiary-butyl ether or a mixture thereof may be cooled to precipitate the solids to a suitable temperature at which S-propylene glycol solvate of Apalutamide (VK5) is formed and / or is stable.
Isolation of S-propylene glycol solvate of Apalutamide (VK5) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, S-propylene glycol solvate of Apalutamide (VK5) 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 S-propylene glycol solvate of Apalutamide (VK5) 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 S-propylene glycol solvate of Apalutamide (VK5) is stable and for any time period required for obtaining a desired quality, such as from about 5 minutes to 10 hours or longer.
In an aspect, the present application provides a methyl acetate solvate of Apalutamide (VK6), characterized by a PXRD pattern comprising the peaks at about 9.73 and 13.06 ± 0.2° 2?. In an embodiment, the application provides methyl acetate solvate of Apalutamide (VK6), characterized by a PXRD pattern having one or more additional peaks at about 14.36, 15.70, 17.94, 20.65, 23.19, 23.71, 25.05 and 26.63±0.2° 2?. In an embodiment, the application provides methyl acetate solvate of Apalutamide (VK6), characterized by a PXRD pattern of figure 6.
In another aspect, the present application provides a process for the preparation of methyl acetate solvate of Apalutamide (VK6), comprising the steps of:
a) dissolving or suspending Apalutamide in methyl acetate;
b) optionally seeding to the solution or suspension obtained in step a) with methyl acetate solvate of Apalutamide (VK-6); and
c) isolating the methyl acetate solvate of Apalutamide (VK6).
In an embodiment, step a) may be carried out by dissolving or suspending Apalutamide in methyl acetate and any other solvent. Alternatively, the solution or suspension may be provided by taking the reaction mixture containing Apalutamide in methyl acetate.
In an embodiment, the Apalutamide may be suspended in methyl acetate at suitable temperature of about 20°C to reflux temperature.
In an embodiment, the Apalutamide may be suspended in methyl acetate for sufficient time to complete the formation of methyl acetate solvate of Apalutamide (VK6) of about one hour or more.
In an embodiment, the Apalutamide may be dissolved in methyl acetate by heating the mixture to obtain a homogenous solution. The solution may be optionally filtered to make it particle free.
In an embodiment, the solution of Apalutamide in methyl acetate may be cooled to precipitate the solids to a suitable temperature at which methyl acetate solvate of Apalutamide (VK6) is formed and / or is stable.
In an embodiment, optionally the solution or suspension of Apalutamide may be seeding with methyl acetate solvate of Apalutamide (VK-6).
Isolation of methyl acetate solvate of Apalutamide (VK6) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, methyl acetate solvate of Apalutamide (VK6) 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 methyl acetate solvate of Apalutamide (VK6) 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 methyl acetate solvate of Apalutamide (VK6) is stable and for any time period required for obtaining a desired quality, such as from about 5 minutes to 10 hours or longer.
Starting materials used for the preparation of solvate forms of Apalutamide (VK1, VK2, VK3, VK4, VK5 and VK6) 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 solvate forms of Apalutamide (VK1, VK2, VK3, VK4, VK5 and VK6) 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 solvate forms of Apalutamide (VK1, VK2, VK3, VK4, VK5 and VK6) 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 solvate forms of Apalutamide (VK1, VK2, VK3, VK4, VK5 and VK6) 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.

EXAMPLES
Example-1: Preparation of acetic acid solvate of Apalutamide (VK1)
Apalutamide (800 mg) was suspended in acetic acid (2 mL) at 25°C and the reaction mixture was stirred for 8 hours. The resulted thick precipitate was left aside at room temperature for 3 days. Toluene (10 mL) was added to thick precipitate at 25°C. The resulted slurry was filtered and washed with toluene (5 mL). The solid was dried under vacuum at 42°C for 3 hours to obtain the title compound.
Example-2: Preparation of acetic acid solvate of Apalutamide (VK1)
Apalutamide (800 mg) was suspended in acetic acid (2 mL) and toluene (15 mL) at 25°C and the reaction mixture was stirred for 12 hours. The resulted slurry was filtered under vacuum. The solid was dried under vacuum at 50°C for 3 hours to obtain the title compound.
Example-3: Preparation of propionic acid solvate of Apalutamide (VK2)
Apalutamide (800 mg) was suspended in propionic acid (2 mL) at 25°C and the reaction mixture was stirred for 8 hours. The resulted thick precipitate was left aside at room temperature for 3 days. Toluene (10 mL) was added to thick precipitate at 25°C. The resulted slurry was filtered and washed with toluene (5 mL). The solid was dried under vacuum at 42°C for 3 hours to obtain the title compound.
Example-4: Preparation of racemic propylene glycol solvate of Apalutamide (VK3)
Apalutamide (1 g) was suspended in racemic propylene glycol (15 mL) at 25°C and the reaction mixture was stirred for 18 hours. The resulted slurry was filtered under vacuum to obtain the title compound.
Example-5: Preparation of racemic propylene glycol solvate of Apalutamide (VK3)
Apalutamide (800 mg) was suspended in racemic propylene glycol (2 mL) at 25°C and the reaction mixture was stirred for 8 hours. The resulted thick precipitate was left aside at room temperature for 3 days. methyl tertiary-butyl ether(10 mL) was added to thick precipitate at 25°C. The resulted slurry was filtered and washed with methyl tertiary-butyl ether(5 mL). The solid was dried under vacuum at 42°C for 3 hours to obtain the title compound.
Example-6: Preparation of racemic propylene glycol solvate of Apalutamide (VK3)
Apalutamide (800 mg) was suspended in racemic propylene glycol (2 mL) and methyl tertiary-butyl ether(15 mL) at 25°C and the reaction mixture was stirred for 12 hours. The resulted slurry was filtered under vacuum. The solid was dried under vacuum at 50°C for 3 hours to obtain the title compound.
Example-7: Preparation of R-propylene glycol solvate of Apalutamide (VK4)
Apalutamide (800 mg) was suspended in R-propylene glycol (2 mL) at 25°C and the reaction mixture was stirred for 8 hours. The resulted thick precipitate was left aside at room temperature for 3 days. methyl tertiary-butyl ether(10 mL) was added to thick precipitate at 25°C. The resulted slurry was filtered and washed with methyl tertiary-butyl ether(5 mL). The solid was dried under vacuum at 42°C for 3 hours to obtain the title compound.
Example-8: Preparation of R-propylene glycol solvate of Apalutamide (VK4)
Apalutamide (800 mg) was suspended in R-propylene glycol (2 mL) and methyl tertiary-butyl ether(15 mL) at 25°C and the reaction mixture was stirred for 12 hours. The resulted slurry was filtered under vacuum. The solid was dried under vacuum at 50°C for 3 hours to obtain the title compound.
Example-9: Preparation of S-propylene glycol solvate of Apalutamide (VK5)
Apalutamide (800 mg) was suspended in S-propylene glycol (2 mL) at 25°C and the reaction mixture was stirred for 8 hours. The resulted thick precipitate was left aside at room temperature for 3 days. methyl tertiary-butyl ether(10 mL) was added to thick precipitate at 25°C. The resulted slurry was filtered and washed with methyl tertiary-butyl ether(5 mL). The solid was dried under vacuum at 42°C for 3 hours to obtain the title compound.
Example-10: Preparation of S-propylene glycol solvate of Apalutamide (VK5)
Apalutamide (800 mg) was suspended in S-propylene glycol (2 mL) and methyl tertiary-butyl ether(15 mL) at 25°C and the reaction mixture was stirred for 12 hours. The resulted slurry was filtered under vacuum. The solid was dried under vacuum at 50°C for 3 hours to obtain the title compound.
Example-11: Preparation of methyl acetate solvate of Apalutamide (VK6)
Apalutamide (1 g) was dissolved in methyl acetate (6 mL) at 75°C. The resulted clear solution was allowed to evaporate slowly at 25°C to obtain the title compound.
Example-12: Preparation of methyl acetate solvate of Apalutamide (VK6)
Apalutamide (1 g) was dissolved in methyl acetate (6 mL) at 75°C. The resulted clear solution was seed with Form VK-6 and allowed to evaporate slowly at 25°C to obtain the title compound.
,CLAIMS:
WE CLAIM:
1. A process for the preparation of acetic acid solvate of Apalutamide (VK1), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from acetic acid, toluene or mixtures thereof; and
b) isolating the acetic acid solvate of Apalutamide.
2. A process for the preparation of propionic acid solvate of Apalutamide (VK2), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from propionic acid, toluene or mixtures thereof; and
b) isolating the propionic acid solvate of Apalutamide.
3. A process for the preparation of racemic propylene glycol solvate of Apalutamide (VK3), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from racemic propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the racemic propylene glycol solvate of Apalutamide.
4. A process for the preparation of R-propylene glycol solvate of Apalutamide (VK4), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from R-propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the R-propylene glycol solvate of Apalutamide.
5. A process for the preparation of S-propylene glycol solvate of Apalutamide (VK5), comprising the steps of:
a) dissolving or suspending Apalutamide in a solvent selected from S-propylene glycol, methyl tertiary-butyl ether or mixtures thereof; and
b) isolating the S-propylene glycol solvate of Apalutamide.
6. A process for the preparation of methyl acetate solvate of Apalutamide (VK6), comprising the steps of:
a) dissolving or suspending Apalutamide in methyl acetate;
b) optionally seeding the solution or suspension obtained in step a) with methyl acetate solvate of Apalutamide; and
c) isolating the methyl acetate solvate of Apalutamide.

7. A pharmaceutical composition comprising the solvate form of Apalutamide according to any one of claims 1-6, and at least one pharmaceutically acceptable excipient.