AMORPHOUS SOLID DISPERSIONS OF APALUTAMIDE AND PROCESS FOR

THE PREPARATION THEREOF INTRODUCTION

Aspects of the present application relates to amorphous solid dispersions of apalutamide, coamorphous forms 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-thiox o-5,7- diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenza-mide 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. US9884054B2 discloses method of treating non-metastatic castration-resistant prostate cancer with apalutamide.

WO20131 84681 A1 discloses crystalline Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I and Form J of apalutamide. WO20161 24149A1 discloses crystalline Form I and Form II of apalutamide. WO2016090098A1 discloses solid dispersion of apalutamide with HPMCAS. WO2016090101 A1 discloses solid dispersion of apalutamide with a poly(meth)acrylate copolymer. WO20160901 05A1 discloses solid dispersion of apalutamide with a poly(meth)actylate copolymer and HPMCAS. US201 60346207A1 discloses solid pharmaceutical composition comprising apalutamide, carrier and surfactant.

An aspect of the invention particular solid pharmaceutical formulations for oral adminstration of apalutamide, where such formulations have an improved stability, a longer shelf life, or provide for a reduced pill burden for the patient, in particular the cancer patient can be reduced, and hence therapy adherence and therapy efficiency can be improved.

Therefore, there remains a need for alternate solid forms of apalutamide and preparative processes thereof. Particularly, an amorphous form of a drug may exhibit a higher bioavailability than its crystalline counterparts, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage form development. Additionally, the solubility of crystalline form is lower than its amorphous form in some instances, particularly aqueous solubility, which may result in the difference in their in-vivo bioavailability. Therefore, it is desirable to have an amorphous form of a drug to meet the needs of drug development which is stable and also a reproducible process for their preparation. Hence, it is desirable to provide a stable amorphous solid dispersion apalutamide and coamorphous forms of apalutamide with coformer.

SUMMARY

In an aspect, the present application provides an amorphous solid dispersion of apalutamide with a pharmaceutically acceptable excipient selected from hydroxyl propyl methylcellulose phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, prosolv, hydroxypropyl methylcellulose or mixtures thereof.

In an aspect, the present application provides amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate, characterized by its X-ray powder diffractogram as substantially shown in Figures 4, 14,16,28,29 and 30

In another aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with HPMC phthalate comprising the steps of:

a) providing a solution of apalutamide and HPMC phthalate in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide with HPMC phthalate.

In an aspect, the present application provides amorphous solid dispersion of apalutamide with copovidone, characterized by its X-ray powder diffractogram as substantially shown in figures 1 , 8, 1 5 and 1 7.

In another aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with copovidone comprising the steps of:

a) providing a solution of apalutamide and copovidone in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide with copovidone.

In an aspect, the present application provides amorphous solid dispersion of apalutamide with cellulose acetate phthalate, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 24 and 25.

In another aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with cellulose acetate phthalate comprising the steps of:

a) providing a solution of apalutamide and cellulose acetate phthalate in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide with cellulose acetate phthalate.

In an aspect, the present application provides amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 26 and 27.

In another aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate comprising the steps of:

a) providing a solution of apalutamide and polyvinyl acetate phthalate in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate.

In an aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide, the process comprising the steps of:

a) providing a solution of apalutamide and pharmaceutically acceptable excipient in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide.

In another aspect, the present application provides a process for the preparation of amorphous apalutamide, the process comprising the steps of:

a) providing a solution of apalutamide in a solvent selected from acetone, ethanol or mixtures thereof; and

b) isolating the amorphous form of Apalutamide. In an aspect, the present application provides coamorphous form of apalutamide with L(+) tartaric acid, characterized by its X-ray powder diffractogram as substantially shown in FIG. 20.

In another aspect, the present application provides a process for the preparation of coamorphous form of apalutamide with L(+) tartaric acid comprising the steps of:

a) providing a solution of apalutamide and L(+) tartaric acid in one or more solvents; and

b) isolating the coamorphous form of apalutamide with L(+) tartaric acid.

In an aspect, the present application provides coamorphous form of apalutamide with citric acid, characterized by its X-ray powder diffractogram as substantially shown in FIG. 21 .

In another aspect, the present application provides a process for the preparation of coamorphous form of apalutamide with citric acid comprising the steps of:

a) providing a solution of apalutamide and citric acid in one or more solvents; and

b) isolating the coamorphous form of apalutamide with citric acid.

In an aspect, the present application provides coamorphous form of apalutamide with saccharin, characterized by its X-ray powder diffractogram as substantially shown in FIG. 22.

In another aspect, the present application provides a process for the preparation of coamorphous form of apalutamide with saccharin comprising the steps of:

a) providing a solution of apalutamide and saccharin in one or more solvents; and

b) isolating the coamorphous form of apalutamide with saccharin.

In an aspect, the present application provides coamorphous form of apalutamide with sucralose, characterized by its X-ray powder diffractogram as substantially shown in FIG. 23.

In another aspect, the present application provides process for the preparation of coamorphous form of apalutamide with sucralose comprising the steps of:

a) providing a solution of apalutamide and sucralose in one or more solvents; and

b) isolating the coamorphous form of apalutamide with sucralose.

In another aspect, the present application provides a pharmaceutical composition comprising amorphous form of apalutamide or coamorphous 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 amorphous solid dispersion of apalutamide with copovidone VA 64 prepared by the method of Example No 1 .

Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with ethyl cellulose prepared by the method of Example No 2.

Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with polyvinylpyrrolidone-K90 and hydroxypropyl cellulose prepared by the method of Example No 3.

Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate prepared by the method of Example No 4.

Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with methyl cellulose prepared by the method of Example No 5.

Figure 6 is an illustrative X-ray powder diffraction pattern of solid dispersion of apalutamide with prosolv HD 40 prepared by the method of Example No 6.

Figure 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose prepared by the method of Example No 7.

Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous premix of apalutamide with copovidone VA 64 and syloid 244 NF prepared by the method of Example No 8.

Figure 9 is an illustrative X-ray powder diffraction pattern of amorphous premix of apalutamide with hydroxypropyl methylcellulose and syloid 244 prepared by the method of Example No 9.

Figure 1 0 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with polyvinylpyrrolidone-K90 prepared by the method of Example No 10.

Figure 1 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl cellulose prepared by the method of Example No 1 1 .

Figure 1 2 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 12.

Figure 1 3 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 13.

Figure 14 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate HP- 55 prepared by the method of Example No 14.

Figure 1 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with copovidone VA64NF prepared by the method of Example No 1 5.

Figure 1 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate HP- 55 prepared by the method of Example No 16.

Figure 1 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with copovidone VA64 prepared by the method of Example No 1 7.

Figure 1 8 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 18.

Figure 1 9 is an illustrative X-ray powder diffraction pattern of amorphous form of apalutamide prepared by the method of Example No 19.

Figure 20 is an illustrative X-ray powder diffraction pattern of coamorphous form of apalutamide with L(+) tartaric acid prepared by the method of Example No 20.

Figure 21 is an illustrative X-ray powder diffraction pattern of coamorphous form of apalutamide with citric acid prepared by the method of Example No 21 .

Figure 22 is an illustrative X-ray powder diffraction pattern of coamorphous form of apalutamide with saccharin prepared by the method of Example No 22

Figure 23 is an illustrative X-ray powder diffraction pattern of coamorphous form of apalutamide with sucralose prepared by the method of Example No 23

Figure 24 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with cellulose acetate phthalate in 1 :0.315 w/w ratio prepared by the method of Example No 24

Figure 25 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with cellulose acetate phthalate in 1 :3 w/w ratio prepared by the method of Example No 25

Figure 26 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate in 1 :0.16 w/w ratio prepared by the method of Example No 26

Figure 27 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate in 1 :3 w/w ratio prepared by the method of Example No 27

Figure 28 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with HPMC phthalate in 1 :3 w/w ratio prepared by the method of Example No 28

Figure 29 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with HPMC phthalate in 1 :4 w/w ratio prepared by the method of Example No 29

Figure 30 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of apalutamide with HPMC phthalate in 1 :0.6 w/w ratio prepared by the method of Example No 30

DETAILED DESCRIPTION

In an aspect, the present application provides an amorphous solid dispersion of apalutamide with a pharmaceutically acceptable excipient selected from hydroxyl propyl methylcellulose phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, hydroxypropyl cellulose, methyl cellulose, prosolv, hydroxypropyl methylcellulose or mixtures thereof.

In an aspect, the present application provides amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate, characterized by its X-ray powder diffractogram as substantially shown in Figures 4, 14,16,28,29 and 30 In an aspect, the present application provides amorphous solid dispersion of apalutamide with copovidone, characterized by its X-ray powder diffractogram as substantially shown in figures 1 , 8, 15 and 17

In an aspect, the present application provides amorphous solid dispersion of apalutamide with cellulose acetate phthalate, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 24 and 25.

In an aspect, the present application provides amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 26 and 27.

In another aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with HPMC phthalate comprising the steps of:

a) providing a solution of apalutamide and HPMC phthalate in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide with HPMC phthalate.

In another aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with copovidone comprising the steps of:

a) providing a solution of apalutamide and copovidone in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide with copovidone.

In another aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with cellulose acetate phthalate comprising the steps of:

a) providing a solution of apalutamide and cellulose acetate phthalate in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide with cellulose acetate phthalate.

In another aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate comprising the steps of:

a) providing a solution of apalutamide and polyvinyl acetate phthalate in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate.

In an embodiment, the solvent may be selected from acetone, methanol, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, ethanol, 2-propanol, 1 -butanol, 2- butanol, 1 -pentanol, 2-pentanol, 3-pentanol or mixtures thereof.

In an embodiment, providing a solution at step a) may be carried out by taking the reaction mixture containing apalutamide and polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, directly or by dissolving apalutamide and polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate 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 polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate 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 polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate 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 of step b), the isolation of amorphous solid dispersion of Apalutamide may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, amorphous solid dispersion of 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, melt-extrusion technique, 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 80°C or any other suitable temperatures.

Amorphous solid dispersion of apalutamide with polymer is selected from HPMC phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate 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 an aspect, the present application provides a process for the preparation of the amorphous solid dispersion of apalutamide, comprising the steps of:

a) providing a solution of apalutamide and pharmaceutically acceptable excipient in one or more solvents; and

b) isolating the amorphous solid dispersion of apalutamide.

In an embodiment, the solvent at step a) of this aspect may be selected from halogenated hydrocarbons,Ci-C6 alcohols, C3-C6 ketones, Cs-Cs aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, water or mixtures thereof.

In preferred embodiment, the 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, water or mixtures thereof.

In an embodiment, atleast one pharmaceutically acceptable excipient selected from hydroxyl propyl methylcellulose phthalate, copovidone, cellulose acetate phthalate, polyvinyl acetate phthalate, ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), prosolv HD 40, syloid, syloid 244 NF, polyvinylpyrrolidone vinylacetate, polyvinylacetal diethylaminoacetate (AEA®), polysorbate 80, polyoxyethylene- polyoxypropylene copolymers (Poloxamer® 1 88), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 1 88, pluronic F-68, methylcellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, D- alpha-tocopheryl polyethylene glycol 1000 succinate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; homopolymers and copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, high molecular weight polyalkylene oxides, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, oligo- and polysaccharides or mixtures thereof organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

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 of step b), the isolation of amorphous solid dispersion of Apalutamide may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, amorphous solid dispersion of 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, melt-extrusion technique, 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 an embodiment, the application provides amorphous form of Apalutamide, characterized by its X-ray powder diffractogram as substantially shown in figures 1 2, 13, 1 8 and 1 9.

In another aspect, the present application provides a process for the preparation of amorphous Apalutamide, the process comprising the steps of:

a) providing a solution of Apalutamide in a solvent selected from acetone, ethanol or mixtures thereof; and

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 mixtures thereof. Alternatively, the solution may be provided by taking the reaction mixture containing Apalutamide in a solvent selected from acetone, ethanol or mixtures thereof.

In an embodiment of step a), the Apalutamide may be dissolved in a solvent selected from acetone, ethanol or mixtures 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 aspect, the present application provides coamorphous form of apalutamide with L(+) tartaric acid, characterized by its X-ray powder diffractogram as substantially shown in FIG. 20.

In another aspect, the present application provides a process for the preparation of coamorphous form of apalutamide with L(+) tartaric acid comprising the steps of:

a) providing a solution of apalutamide and L(+) tartaric acid in one or more solvents; and

b) isolating the coamorphous form of apalutamide with L(+) tartaric acid.

In an aspect, the present application provides coamorphous form of apalutamide with citric acid, characterized by its X-ray powder diffractogram as substantially shown in FIG. 21 .

In another aspect, the present application provides process for the preparation of coamorphous form of apalutamide with citric acid comprising the steps of:

a) providing a solution of apalutamide and citric acid in one or more solvents; and

b) isolating the coamorphous form of apalutamide with citric acid.

In an aspect, the present application provides a coamorphous form of apalutamide with saccharin, characterized by its X-ray powder diffractogram as substantially shown in FIG. 22.

In another aspect, the present application provides a process for the preparation of coamorphous form of apalutamide with saccharin comprising the steps of:

a) providing a solution of apalutamide and saccharin in one or more solvents; and

b) isolating the coamorphous form of apalutamide with saccharin.

In an aspect, the present application provides coamorphous form of apalutamide with sucralose, characterized by its X-ray powder diffractogram as substantially shown in FIG. 23.

In another aspect, the present application provides a process for the preparation of coamorphous form of apalutamide with sucralose comprising the steps of:

a) providing a solution of apalutamide and sucralose in one or more solvents; and

b) isolating the coamorphous form of apalutamide with sucralose.

In an embodiment of step a), the solvent may be selected from methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3-pentanol, dichloromethane, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran or mixtures thereof.

In an embodiment, providing a solution at step a) may be carried out by taking the reaction mixture containing apalutamide and coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose directly or by dissolving apalutamide and coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose 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 coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose 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 coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose 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 of step b), the isolation of coamorphous form of apalutamide may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, coamorphous form of 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, melt-extrusion technique, 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 80°C, or any other suitable temperatures.

In preferred embodiment, coamorphous form of apalutamide with coformer is selected from L(+) tartaric acid, citric acid, saccharin or sucralose 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.

The present application provides amorphous form of apalutamide or amorphous solid dispersion of apalutamide or coamorphous form of apalutamide comprising apalutamide having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.

Starting materials used for the preparation of amorphous form of apalutamide or amorphous solid dispersion of apalutamide or coamorphous form 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 amorphous form of apalutamide or amorphous solid dispersion of apalutamide or coamorphous form 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.

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 1 1 , 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, where the particle size of the API in the solid dispersion is reduced to its molecular size. 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. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.

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 "Cs-Csaliphatic 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.

The term "Coamorphous" when used in the present application, denotes "Co- amorphous mixtures consist of two (or more) types of small molecules which interact on molecular level without detectable crystallization" or "A co-amorphous system is characterized by the use of only low molecular weight components that are mixed into a homogeneous single-phase co-amorphous blend"

EXAMPLES

Example-1 : Preparation of amorphous solid dispersion of apalutamide with copovidone VA 64

Apalutamide (500 mg), copovidone VA 64 (500 mg) and dichloromethane (50 imL) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 5 minutes at 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 40°C for over 10 minutes.

Example-2: Preparation of amorphous solid dispersion of apalutamide with ethyl cellulose

Apalutamide (500 mg), ethyl cellulose NF (500 mg) and dichloromethane (50 imL) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 5 minutes at 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 40°C for over 10 minutes. Example-3: Preparation of amorphous solid dispersion of apalutamide with Polyvinylpyrrolidone-K90 and hydroxypropyl cellulose

Apalutamide (250 mg), polyvinylpyrrolidone-K90 (250 mg), hydroxypropyl cellulose (250 mg), dichloromethane (50 ml_) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 20 minutes at 35°C. Methanol (5 imL) was added to the reaction mass at 25°C. The reaction mass was stirred for 15 minutes at 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 40°C for over 10 minutes.

Example-4: Preparation of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose phthalate

Apalutamide (500 mg), hydroxypropyl methylcellulose phthalate (500 mg), dichloromethane (50 imL) and methanol (5 imL) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 5 minutes at 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 40°C for over 10 minutes.

Example-5: Preparation of amorphous solid dispersion of apalutamide with methyl cellulose

Apalutamide (500 mg), methyl cellulose (1 000 mg), dichloromethane (50 imL) and methanol (20 imL) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 60 minutes at 30°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 50°C for over 25 minutes.

Example-6: Preparation of solid dispersion of apalutamide with prosolv HD 40

Apalutamide (200 mg), prosolv HD 40 (1 000 mg) and dichloromethane (50 imL) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 5 minutes at 25°C. The reaction mass was evaporated under vacuum at 25°C for over 5 minutes.

Example-7: Preparation of amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose

Apalutamide (500 mg), hydroxypropyl methylcellulose (500 mg), dichloromethane (50 imL) and methanol (5 imL) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 10 minutes at 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 40°C for over 5 minutes. The dried product was grinded into fine powder using mortar and pestle at 25°C.

Example-8: Preparation of amorphous premix of apalutamide with copovidone VA 64 and syloid 244 NF

Amorphous solid dispersion of apalutamide with copovidone VA 64 (800 mg), syloid 244 NF (400 mg) were charged into a mortar at 25°C. The reaction mixture was physically mixed using mortar pestle for 5 minutes at 25°C.

Example-9: Preparation of amorphous premix of apalutamide with hydroxypropyl methylcellulose and syloid 244

Amorphous solid dispersion of apalutamide with hydroxypropyl methylcellulose (800 mg) and syloid 244 (400 mg) were charged into a mortar at 25°C. The reaction mixture was physically mixed using mortar pestle for 5 minutes at 25°C.

Example-10: Preparation of amorphous solid dispersion of apalutamide with polyvinylpyrrolidone-K90

Apalutamide (500 mg), polyvinylpyrrolidone-K90 (500 mg), dichloromethane (100 mL) and Methanol (10 mL) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 5 minutes at 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 50°C for over 10 minutes. The dried product was grinded into fine powder using mortar and pestle.

Example-11 : Preparation of amorphous solid dispersion of apalutamide with hydroxypropyl cellulose

Apalutamide (500 mg), hydroxypropyl cellulose (500 mg), dichloromethane (1 00 mL) and Methanol (10 mL) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 30 minutes at 30°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 50°C for over 10 minutes.

Example-12: Preparation of amorphous form of Apalutamide

Apalutamide (1 g) 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-13: Preparation of amorphous form of 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-14: Preparation of amorphous solid dispersion of Apalutamide with hydroxypropyl methylcellulose phthalate HP-55

Apalutamide (1 g), hydroxypropyl methylcellulose phthalate HP-55 (1 g), methanol (50 mL) and dichloromethane (1 0 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-15: Preparation of amorphous solid dispersion of Apalutamide with copovidone VA64NF

Apalutamide (1 g), copovidone VA64NF (1 g) 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-16: Preparation of amorphous solid dispersion of Apalutamide with hydroxypropyl methylcellulose phthalate HP-55

Apalutamide (1 8g), 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-17: 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-18: Preparation of amorphous form of 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: 0.41 g

Example-19: Preparation of amorphous form of 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

Example-20: Preparation of coamorphous form of apalutamide with L(+) Tartaric acid.

Apalutamide (0.8 g) and L(+) tartaric acid (0.252 g) were dissolved in methanol

(50ml_) at 26°C. The reaction mass was heated to 65°C. The resulted solution was evaporated under vacuum at 65°C to obtain the title compound.

Example-21 : Preparation of coamorphous form of apalutamide with citric acid.

Apalutamide (0.8 g) and citric acid (0.322 g) were dissolved in methanol (50ml_) at 27°C. The reaction mass was heated to 65°C. The resulted solution was evaporated under vacuum at 65°C to obtain the title compound.

Example-22: Preparation of coamorphous form of apalutamide with saccharin.

Apalutamide (0.8 g) and saccharin (0.307 g) were dissolved in methanol (50ml_) at 26°C. The reaction mass was heated to 66°C. The resulted solution was evaporated under vacuum at 66°C, the isolated solid was further dried at 65°C for about 30 minutes to obtain the title compound.

Example-23: Preparation of coamorphous form of apalutamide with sucralose.

Apalutamide (0.8 g) and sucralose (0.667 g) were dissolved in methanol (50ml_) at 26°C. The reaction mass was heated to 66°C. The resulted solution was evaporated under vacuum at 67°C and the isolated solid was further dried at 65°C for about 1 .5 hours to obtain the title compound.

Example-24: Preparation of amorphous solid dispersion of apalutamide with cellulose acetate phthalate. Apalutamide (0.5g) and cellulose acetate phthalate (0.158g) were dissolved in acetone (50ml_) at 65°C. The clear solution was completely evaporated under vacuum at 65°C, the isolated solid was further dried at 65°C for about 30 minutes to obtain the title compound.

Example-25: Preparation of amorphous solid dispersion of apalutamide with cellulose acetate phthalate.

Apalutamide (0.25g) and celluloase acetate phthalate (0.75g) were dissolved in acetone (50ml_) at 65°C. The clear solution was completely evaporated under vacuum at 65°C, the isolated solid was further dried at 65°C for about 45 minutes to obtain the title compound.

Example-26: Preparation of amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate.

Apalutamide (0.5g) and polyvinyl acetate phthalate (0.08g) were dissolved in methanol (50ml_) at 65°C. The clear solution was completely evaporated under vacuum at 65°C to obtain the title compound.

Example-27: Preparation of amorphous solid dispersion of apalutamide with polyvinyl acetate phthalate.

Apalutamide (0.25g) and polyvinyl acetate phthalate (0.75g) were dissolved in methanol (50ml_) at 65°C. The clear solution was completely evaporated under vacuum at 66°C to obtain the title compound.

Example-28: Preparation of amorphous solid dispersion of apalutamide with HPMC phthalate.

Apalutamide (0.25g) and HPMC phthalate (0.75g) were dissolved in methanol (40ml_) and dichloromethane (10ml_) at 25°C. The reaction mass was heated to 65°C. The resulted solution was completely evaporated under vacuum at 66°C, the isolated solid was further dried at 65°C for about 40 minutes to obtain the title compound.

Example-29: Preparation of amorphous solid dispersion of apalutamide with HPMC phthalate.

Apalutamide (0.25g) and HPMC phthalate (1 g) were dissolved in methanol (40ml_) and dichloromethane (10ml_) at 26°C. The reaction mass was heated to 65°C. The resulted solution was completely evaporated under vacuum at 65°C to obtain the title compound.

Example-30: Preparation of amorphous solid dispersion of apalutamide with HPMC phthalate.

Apalutamide (0.5g) and HPMC phthalate (0.3g) were dissolved in methanol (40ml_) and dichloromethane (10ml_) at 25°C. The reaction mass was heated to 66°C. The resulted solution was completely evaporated under vacuum at 66°C, the isolated solid was further dried at 65°C for about 30 minutes to obtain the title compound.