DESC:INTRODUCTION
Aspects of the present application relates to crystalline forms of apalutamide and process for the preparation thereof.
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 (VK10 and VK11) with enhanced storage stability, solubility and processability.
SUMMARY
In an aspect, the present application provides a crystalline form of apalutamide characterized by a PXRD pattern comprising the peak at about 4.07°, 6.64° and 9.63°± 0.2° 2?.
In another aspect, the present application provides process for the preparation of crystalline form of apalutamide characterized by a PXRD pattern comprising the peak at about 4.07°, 6.64° and 9.63°± 0.2° 2?, comprising the steps of:
a) dissolving apalutamide in organic solvent or mixture of organic solvent;
b) isolating the crystalline form of apalutamide.
In another aspect, the present application provides process for the preparation of crystalline form of apalutamide characterized by a PXRD pattern comprising the peak at about 4.07°, 6.64° and 9.63°± 0.2° 2?, comprising the steps of:
c) dissolving apalutamide in organic solvent or mixture of organic solvent;
d) isolating the crystalline form of apalutamide.
In an aspect, the present application provides a crystalline form of apalutamide (VK10) characterized by a PXRD pattern comprising the peak at about 4.07°, 6.64° and 9.63°± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of apalutamide (VK10), comprising the steps of:
a) dissolving apalutamide in mixture of benzyl alcohol and ethanol (90:10) or mixture of benzyl alcohol and butyl acetate (90:10); and
b) isolating the crystalline form of apalutamide (VK10).
In an aspect, the present application provides a crystalline form of apalutamide characterized by a PXRD pattern comprising the peak at about 6.65° and 9.74°±0.2° 2?.
In an aspect, the present application provides a process for the preparation of crystalline form of apalutamide characterized by a PXRD pattern comprising the peak at about 6.65° and 9.74°±0.2° 2?, comprising the steps of:
a) suspending apalutamide and benzoic acid in alcohols;
b) isolating the crystalline form of apalutamide.
In an aspect, the present application provides a crystalline form of apalutamide (VK11), characterized by a PXRD pattern comprising the peak at about 6.65° and 9.74°±0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of apalutamide (VK11), comprising the steps of:
a) suspending apalutamide and benzoic acid in 1-pentanol;
b) isolating the crystalline form of apalutamide (VK11).
In another aspect, the present application provides a pharmaceutical composition comprising crystalline forms of apalutamide (VK10 and VK11) 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 (VK10) prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline form of apalutamide (VK11) prepared by the method of Example No 3.
DETAILED DESCRIPTION
In an aspect, the present application provides a crystalline form of apalutamide characterized by a PXRD pattern comprising the peak at about 4.07°, 6.64° and 9.63° ± 0.2° 2?.
In another aspect, the present application provides process for the preparation of crystalline form of apalutamide characterized by a PXRD pattern comprising the peak at about 4.07°, 6.64° and 9.63°± 0.2° 2?, comprising the steps of:
a) dissolving apalutamide in organic solvent or mixture of organic solvent;
b) isolating the crystalline form of apalutamide.
In an embodiment of step a), apalutamide dissolves in organic solvent is selected from alcohols, esters or mixture thereof.
In an embodiment of step a), alcohol solvent is selected from methanol, ethanol, propanol, butanol, pentanol, benzyl alcohol or mixture thereof.
In an embodiment of step a), ester solvent is selected from ethyl acetate, methyl acetate, butyl acetate or mixture thereof.
In an embodiment of step b), the reaction mixture of apalutamide may be kept aside for about 10-20 hours or longer to precipitate the solid.
In an embodiment of step b), the isolation of crystalline apalutamide may be carried out by any methods known in the art or procedures described in the present application.
In an embodiment of step b), crystalline apalutamide 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 aspect, the present application provides a crystalline form of apalutamide (VK10), characterized by a PXRD pattern comprising the peak at about 4.07°, 6.64° and 9.63° ± 0.2° 2?.
In an embodiment, the application provides crystalline apalutamide (VK10), characterized by a PXRD pattern having one or more additional peaks at about 12.10°, 16.13°, 16.95° and 22.78°±0.2° 2?.
In an embodiment, the application provides crystalline apalutamide (VK10), 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 (VK10), comprising the steps of:
a) dissolving apalutamide in mixture of benzyl alcohol and ethanol (90:10) or mixture of benzyl alcohol and butyl acetate (90:10); and
b) isolating the crystalline form of apalutamide (VK10).
In an embodiment, step a) may be carried out by dissolving apalutamide in mixture of benzyl alcohol and ethanol (90:10) or mixture of benzyl alcohol and butyl acetate (90:10). Alternatively, the solution may be provided by taking the reaction mixture containing apalutamide in mixture of benzyl alcohol and ethanol (90:10) or mixture of benzyl alcohol and butyl acetate (90:10).
In an embodiment of step a), apalutamide may be dissolved in mixture of benzyl alcohol and ethanol (90:10) or mixture of benzyl alcohol and butyl acetate (90:10) at any suitable temperature to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment of step b), the reaction mixture of apalutamide may be kept aside for about 10-20 hours or longer to precipitate the solid.
In an embodiment of step b), the isolation of crystalline apalutamide (VK10) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline apalutamide (VK10) 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 aspect, the present application provides a crystalline form of apalutamide, characterized by a PXRD pattern comprising the peak at about 6.65° and 9.74°±0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of apalutamide, comprising the steps of:
a) suspending apalutamide and benzoic acid in alcohols or mixture of alcohols;
b) isolating the crystalline form of apalutamide.
In an embodiment of step a), the reaction mixture of apalutamide and benzoic acid suspending in alcohols or mixture of alcohols.
In an embodiment of step a), alcohol solvent is selected from methanol, ethanol, propanol, butanol, pentanol, benzyl alcohol or mixture thereof.
In an embodiment of step a), the reaction mixture of apalutamide and benzoic acid may be suspending in alcohol solvent by using mortar and pestle.
In an embodiment of step b), the reaction mixture of Apalutamide and benzoic acid may be kept aside for 10-20 minutes or longer to precipitate the solid.
In an embodiment, optionally drying the crystalline Apalutamide may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out at about 25°C or above at which crystalline Apalutamide 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 (VK11), characterized by a PXRD pattern comprising the peak at about 6.65° and 9.74°±0.2° 2?.
In an embodiment, the application provides crystalline apalutamide (VK11), characterized by a PXRD pattern having one or more additional peaks at about 4.10°, 8.17°,14.03°, 16.03°, 16.42°, 16.74°, 17.23°, 19.23°and 23.13°±0.2° 2?.
In an embodiment, the application provides crystalline apalutamide (VK11), 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 (VK11), comprising the steps of:
c) suspending apalutamide and benzoic acid in 1-pentanol;
d) isolating the crystalline form of apalutamide (VK11).
In an embodiment, step a) may be carried out by suspending apalutamide and benzoic acid in 1-pentanol. Alternatively, the solution may be provided by taking the reaction mixture containing apalutamide and benzoic acid in 1-pentanol.
In an embodiment of step a), the reaction mixture of apalutamide and benzoic acid may be suspending in 1-pentanol by using mortar and pestle.
In an embodiment of step b), the reaction mixture of Apalutamide and benzoic acid may be kept aside for 10-20 minutes or longer to precipitate the solid.
In an embodiment, optionally drying the crystalline Apalutamide (VK11) may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out at about 25°C or above at which crystalline Apalutamide (VK11) 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 pharmaceutical composition comprising crystalline forms of apalutamide (VK10 and VK11) with atleast one pharmaceutically acceptable excipient.
Starting materials used for the preparation of crystalline VK10 and VK11 of apalutamide may be any crystalline or amorphous in nature. Further, these starting material 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 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 forms of apalutamide 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 forms of apalutamide 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 crystalline Apalutamide (VK10)
Amorphous form of Apalutamide (0.8g) was dissolved in 3 ml of benzyl alcohol and ethanol mixture (90:10) at 26°C. The resulting clear solution was stirred for 14 hours at 26°C. The reaction mixture was kept aside for 18 hours at 26°C for crystallization. The resulting slurry was filtered under vacuum at 25°C to obtain the title compound.

Example-2: Preparation of crystalline Apalutamide (VK10)
Amorphous form of Apalutamide (0.8g) was dissolved in 3 ml of benzyl alcohol and butyl acetate mixture (90:10) at 26°C. The resulting clear solution was stirred for 14 hours at 26°C. The reaction mixture was kept aside for 18 hours at 26°C for crystallization. The resulting slurry was filtered under vacuum at 25°C to obtain the title compound.

Example-3: Preparation of crystalline Apalutamide (VK11)
Apalutamide (240 mg), benzoic acid (62.5 mg) and 1-pentanol (1 mL) were charged into mortar and pestle. The reaction mixture was ground for 15 minutes at 25°C. The resulting material was air dried to obtain the title compound.
,CLAIMS:We claim:
1. A crystalline form of apalutamide characterized by a PXRD pattern comprising the peaks at about 4.07°, 6.64° and 9.63°± 0.2° 2?.
2. The process for the preparation of crystalline form of apalutamide as claimed in claim 1, the process comprising the steps of:
a) dissolving apalutamide in organic solvent;
b) isolating the crystalline form of apalutamide.
3. The process for the preparation of crystalline form of apalutamide as claimed in claim 2, wherein the organic solvent is selected from alcohols, esters or mixture thereof.
4. The process for the preparation of crystalline form of apalutamide as claimed in claim 3, wherein the alcohol solvent is selected from methanol, ethanol, propanol, butanol, pentanol or benzyl alcohol.
5. The process for the preparation of crystalline form of apalutamide as claimed in claim 3, wherein the ester solvent is selected from ethyl acetate, methyl acetate or butyl acetate.
6. A crystalline form of apalutamide characterized by a PXRD pattern comprising the peak at about 6.65° and 9.74°±0.2° 2?.
7. The process for the preparation of crystalline form of apalutamide as claimed in claim 6, the process comprising the steps of:
a) suspending mixture of apalutamide and benzoic acid in alcohols or mixture of alcohols;
b) isolating the crystalline form of apalutamide.
8. The process for the preparation of crystalline form of apalutamide as claimed in claim 6, wherein the alcohol solvent is selected from methanol, ethanol, propanol, butanol, pentanol or benzyl alcohol.