FIELD OF THE INVENTION
The present invention relates to solid forms of Apalutamide (1) and process for preparation thereof. Specifically, the present invention relates to crystalline forms Al and A2 of Apalutamide (1) and amorphous form of Apalutamide (1).
BACKGROUND OF THE INVENTION
Apalutamide is a nonsteroidal antiandrogen (NSAA) drug used in the treatment of prostate cancer. Apalutamide was first described in 2007 and approved in February 2018 by the FDA as ERLEADA for the treatment of patients with non-metastatic prostate cancer that is resistant to treatment with hormone therapy. It is the first medication to be approved specifically for the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC).
US9481663 patent discloses crystalline forms A, B, C, D, E, F, G, H, I and J of Apalutamide (1) and the process for the preparation of the same.
WO2016124149 application teaches about the crystalline forms Form I and Form II of Apalutamide (1) and the process for the preparation of the same.
WO2018112001 application discloses crystalline forms Tl to T17 of Apalutamide (1) and the process for the preparation of the same.
WO2019016747 application discloses amorphous solid dispersions and pre-mix of Apalutamide (1) with different pharmaceutically active excipient, co amorphous form of Apalutamide with L (+) Tartaric acid, citric acid, saccharin and sucralose and the process of preparing the same.
As per the FDA label, Apalutamide is practically insoluble in aqueous media over a wide range of pH values, hence difficult to design an ideal formulation, which may affect the solubility, bioavailability and other physiochemical properties of Apalutamide. Hence, there remains a need to develop alternate suitable solid forms which may have better stability, aqueous solubility, bioavailability and other physiochemical properties. Hence, the present inventors hereby disclose solid forms

Apalutamide (1) and the process for the preparation of the same with better physiochemical parameters, which could be advantageous in preparation of better formulations and manufacture.
OBJECTIVE OF THE INVENTION
The primary objective of the invention is to provide solid forms of solid forms of Apalutamide (1), wherein the solid forms comprises of the crystalline forms Al and A2 of Apalutamide (1).
In another objective of the present invention is to provide amorphous form of Apalutamide (1).
Another objective of the invention is to provide process for the preparation of crystalline forms of crystalline forms Al and A2 of Apalutamide (1).
A further objective of the invention is to provide process for the preparation of amorphous forms of Apalutamide (1).
SUMMARY OF THE INVENTION
Accordingly, the present invention provides solid forms of Apalutamide (1).
In another aspect, the present invention provides the crystalline forms Al and A2 of Apalutamide (1).
In another aspect, the present invention provides amorphous forms of Apalutamide (D-
In another aspect, the present invention provides crystalline form A1 of Apalutamide (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(0) values of 3.98, 4.22, 4.80, 7.03, 7.26, 7.90, 8.48, 9.47, 10.65, 11.07, 12.76, 14.20, 14.92, 15.43, 16.09, 16.86, 18.24, 18.88, 20.02, 20.97, 21.31, 21.76, 22.15, 22.89, 23.36,23.76, 24.08, 24.52, 26.47, 28.51, 30.14, 30.92, 32.32, 32.84, 33.48, 34.69, 38.43, 38.98 and 42.88 ± (0.2) degrees.

In another aspect, the present invention provides crystalline form A2 of Apalutamide (1), characterized by X-ray powder diffraction (XRPD) pattern having 2 theta values at 3.72, 6.62, 7.40, 8.04, 8.99, 10.32, 11.02, 11.52, 12.56, 13.19, 14.81, 15.28, 15.60, 16.06, 16.08, 16.48, 16.83, 17.68, 17.92, 18.48, 19.03, 20.00, 20.34, 21.14, 21.52, 22.33, 23.44, 23.84, 24.16, 24.8, 25.12,25.68, 26.34, 27.87, 30.58, 31.09, 32.64, 33.34, 33.85, 34.19, 34.74, 36.92,37.36, 38.05 and 42.30+ 0.2 degrees.
In yet another aspect, the present invention provides crystalline form Al and A2 of Apalutamide (1) which is characterized by X-ray powder diffraction pattern substantially as shown in figure 1 and figure 2.
In some aspect, the present invention provides a process for preparing crystalline Al of Apalutamide (1), comprising:
i. Suspending Apalutamide (1), in a mixture of suitable solvents; ii. heating the reaction mixture to 40 °C to 80 °C; iii. adding the reaction mixture of step ii) to the suitable solvent
precooled at -30 °C to - 60°C; iv. isolating the crystalline forms of Apalutamide (1), and v. optionally, drying crystalline Apalutamide (1), using a suitable technique at a suitable temperature.
In some aspect, the present invention provides a process for preparing crystalline A2 of Apalutamide (1), comprising:
1. suspending Apalutamide (1), in a suitable first solvent;
2. adding a suitable second solvent;
3. heating the reaction mixture to 40 °C to 80 °C;
4. filtering the reaction mixture;
5. optionally adding a suitable third solvent at a suitable temperature;
6. isolating the crystalline forms of Apalutamide (1); and
7. optionally, drying crystalline Apalutamide (1), at a suitable temperature.

In some aspect, the present invention provides amorphous form of Apalutamide (1), which is characterized by X-ray powder diffraction pattern substantially as shown in figure 3.
In another aspect, the present invention is to provides a process for the preparation amorphous form of Apalutamide (1), comprising:
A. suspending Apalutamide (1), in a suitable first solvent;
B. heating the reaction mixture to 25 °C to 60 °C;
C. filtering the reaction mixture;
D. adding step C) filtrate to the suitable second solvent at -30 °C to -60 °C;
E. isolating the amorphous forms of Apalutamide (1); and
F. optionally, drying amorphous Apalutamide (1), using a suitable technique.
In another aspect, the present invention provides amorphous form of Apalutamide (1) which are characterized by X-ray powder diffraction pattern substantially as shown in figure 4.
A further aspect is to provide an alternative process for the preparation of amorphous form of Apalutamide (1) comprising:
a) suspending Apalutamide (1) in a mixture of first and second solvent;
b) heating the reaction mixture to 50 °C to 80 °C;
c) filtering the reaction mixture;
d) cooling the reaction mixture to a suitable temperature;
e) optionally, adding suitable third solvent and cooling;
f) optionally, adding suitable fourth solvent;
g) isolating the amorphous forms of Apalutamide (1); and
h) optionally, drying amorphous Apalutamide (1), using a suitable technique.
In another embodiment, the solid forms of Apalutamide (1) obtained by any of the above method was having purity more than equal to 99.0 % by HPLC.
BRIEF DESCRIPTION OF DRAWINGS

Figure 1: X-Ray powder diffraction (XPRD) pattern of crystalline form Al of
Apalutamide (1) prepared by example-1.
Figure 2: X-Ray powder diffraction (XPRD) pattern of crystalline form A2 of
Apalutamide (1) prepared by example-2.
Figure 3: X-Ray powder diffraction (XPRD) pattern of amorphous form of
Apalutamide (1) prepared by example-3.
Figure 4: X-Ray powder diffraction (XPRD) pattern of amorphous form of
Apalutamide (1) prepared by example-4.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the first embodiment of the present invention provides solid forms of Apalutamide (1).
In another embodiment, the present invention provides the crystalline forms Al and A2 of Apalutamide (1).
Yet another embodiment, the present invention provides amorphous forms of Apalutamide (1).
In another embodiment, the present invention provides crystalline form Al of Apalutamide (1) characterized by its X-ray powder diffraction pattern having peaks at about 2(9) values of 3.98, 4.22, 4.80, 7.03, 7.26, 7.90, 8.48, 9.47, 10.65, 11.07, 12.76, 14.20, 14.92, 15.43, 16.09, 16.86, 18.24, 18.88, 20.02, 20.97, 21.31, 21.76, 22.15, 22.89, 23.36,23.76, 24.08, 24.52, 26.47, 28.51, 30.14, 30.92, 32.32, 32.84, 33.48, 34.69, 38.43, 38.98 and 42.88 ± (0.2) degrees.
In some embodiment, the present invention provides process for the preparation of crystalline form Al of Apalutamide (1) as characterized by the by X-ray powder diffraction pattern substantially as shown in figure 1.
In some embodiment, the present invention provides a process for preparing crystalline Al of Apalutamide (1), comprising:
i. suspending Apalutamide (1), in a mixture of suitable solvents;

ii. heating the reaction mixture to 40 °C to 80 °C; iii. adding the reaction mixture of step ii) to the suitable solvent precooled at -
30 to -60°C; iv. isolating the crystalline forms of Apalutamide (1), and v. optionally, drying crystalline Apalutamide (1), using a suitable technique at a suitable temperature.
In some embodiment, the present invention provides process for the preparation of crystalline forms Al of Apalutamide (1) by suspending Apalutamide (1) in a mixture of suitable solvents at 25 °C -35 °C. The reaction mixture was then heated to a temperature of 40 °C -80 °C; preferably 60 °C to 65°C and filtered. The filtrate was then added to another suitable solvent which was cooled to -30 °C to -60°C; preferably to -50°C to -55 °C. The reaction mixture was then stirred and the solid formed was isolated. The obtained solid was dried using a suitable technique to yield crystalline form Al of Apalutamide (1).
In another embodiment, the present invention provides crystalline form A2 of Apalutamide (1), characterized by X-ray powder diffraction (XRPD) pattern having 2 theta values at 3.72, 6.62, 7.40, 8.04, 8.99, 10.32, 11.02, 11.52, 12.56, 13.19, 14.81, 15.28, 15.60, 16.06, 16.08, 16.48, 16.83, 17.68, 17.92, 18.48, 19.03, 20.00, 20.34, 21.14, 21.52, 22.33, 23.44, 23.84, 24.16, 24.8, 25.12,25.68, 26.34, 27.87, 30.58, 31.09, 32.64, 33.34, 33.85, 34.19, 34.74, 36.92,37.36, 38.05 and 42.30+ 0.2 degrees.
In some embodiment, the present invention provides process for the preparation of crystalline form A2 of Apalutamide (1) as characterized by the by X-ray powder diffraction pattern substantially as shown in figure 2.
In some aspect, the present invention provides a process for preparing crystalline A2 of Apalutamide (1), comprising:
1. suspending Apalutamide (1), in a suitable first solvent;
2. adding a suitable second solvent;
3. heating the reaction mixture to 40 °C to 80 °C;

4. filtering the reaction mixture;
5. optionally adding a suitable third solvent at a suitable temperature;
6. isolating the crystalline forms of Apalutamide (1), from a third solvent; and
7. optionally, drying crystalline Apalutamide (1), at a suitable temperature.
In some embodiment, the present invention provides process for the preparation of crystalline forms A2 of Apalutamide (1) by suspending Apalutamide (1) in a suitable first solvent and adding a second solvent at 25 °C -35 °C. The reaction mixture was then heated to a temperature of 40 °C - 80 °C; preferably 60 °C -65 °C and filtered. The filtrate was cooled to 0 °C - 40 °C, preferably to 25 °C -35 °C and the solid formed was isolated from the third solvent. The obtained solid was dried using a suitable technique to yield crystalline form A2 of Apalutamide (1).
In some embodiment, the solvents used to suspend Apalutamide (1) may be selected from a group comprising of but not limited to organic or inorganic solvents, preferably organic solvent may be used which may be selected from a group of protic or aprotic solvent comprising of tetrahydrofuran, acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, dimethyl sulfoxide ethyl acetate, N, N-dimethylformamide (DMF), N-Methyl-2-pyrrolidone (NMP), methyl tertiary butyl ether, hexane, isobutyl acetate , butyl acetate, hexane, cyclohexane, heptane, toluene, tetrahydrofuran, water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, 2-ethoxy ethanol or the like. Preferably, tetrahydrofuran, acetone and water may be used for preparing crystalline form Al and N, N-dimethylformamide (DMF), isobutyl acetate and heptane may be used for preparing the crystalline form A2 of Apalutamide (1).
In some embodiment, the present invention provides process for the preparation of amorphous form of Apalutamide (1) as characterized by the by X-ray powder diffraction pattern substantially as shown in figure 3.
In another embodiment, the present invention is to provides a process for the preparation amorphous form of Apalutamide (1), comprising: A. suspending Apalutamide (1), in a suitable first solvent;

B. heating the reaction mixture to 25 °C to 50 °C;
C. filtering the reaction mixture;
D. adding the filtrate of step C) to the suitable second solvent at -30 °C to - 60
°C;
E. isolating the amorphous forms of Apalutamide (1); and
F. optionally, drying amorphous Apalutamide (1), using a suitable technique.
In some embodiment, the present invention involves a process for the preparation of amorphous form of Apalutamide (1) by suspending Apalutamide (1) in a suitable first solvent and heating the reaction mixture to 25 °C - 50 °C; preferably to 35 °C - 40 °C and filtered. The filtrate was added to a suitable second solvent, which was cooled at a temperature of-30 °C to - 60° C; preferably -45 °C to -50 °C. The solid formed was isolated and dried using a suitable technique to yield amorphous form of Apalutamide (1).
In some embodiment, the present invention provides process for the preparation of amorphous form of Apalutamide (1) as characterized by the by X-ray powder diffraction pattern substantially as shown in figure 4.
In some embodiment, the present invention provides an alternative process for the preparation of amorphous form of Apalutamide (1) comprising:
a) suspending Apalutamide (1) in a mixture of first and second solvent;
b) heating the reaction mixture to 50°C to 80 °C;
c) filtering the reaction mixture;
d) cooling the reaction mixture to a suitable temperature;
e) optionally, adding suitable third solvent and cooling;
f) optionally, adding suitable fourth solvent;
g) isolating the amorphous forms of Apalutamide (1); and
h) optionally, drying amorphous Apalutamide (1), using a suitable technique.
In yet another embodiment, the present invention involves an alternative process for the preparation of amorphous form of Apalutamide (1) by suspending Apalutamide (1) in a mixture of first and second solvent and heating the reaction

mixture to 50 °C - 80 °C; preferably to 55 °C - 60 °C and filtered. The filtrate was added to a suitable third solvent, at a temperature of-10 °C to 10 °C; preferably 0 °C - 5°C. Further a suitable fourth solvent was added to the reaction mixture at 10 to 10°C; preferably 0 °C - 5°C. The solid formed was isolated and dried using a suitable technique to yield amorphous form of Apalutamide (1).
In some embodiment, the solvents used for preparing amorphous forms of Apalutamide (1) may be selected from a group comprising of organic or inorganic solvents, preferably organic solvents may be used. Organic solvents may be selected from protic or aprotic solvents, which may be selected from but not limited to acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, dimethyl sulfoxide ethyl acetate, N, N-dimethylformamide (DMF), N-Methyl-2-pyrrolidone (NMP), methyl tertiary butyl ether, hexane, butyl acetate cyclohexane, toluene, xylene, tetrahydrofuran, water, methanol, ethanol, isopropyl alcohol, benzyl alcohol, 2-ethoxy ethanol or the like. Preferably tetrahydrofuran, n-heptane, xylene and water were used in the present invention.
In another embodiment the solid forms obtained in the present invention may be isolated and dried by a suitable technique comprising of but not limited to filtration, precipitation, cooling, re-crystallization, concentrating the mass, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin-film drying, freeze-drying or the like , preferably precipitation and filtration were used in the present invention.
In another embodiment of the present application, drying of crystalline forms of Apalutamide (1) may be carried out using suitable drying technique comprising of but not limited to air tray dryer, vacuum tray dryer, fluidized bed dryer or the like. Preferably air tray dryer (ATD) is used for the drying in the present invention. The drying can be carried out at a suitable temperature ranging from 30 °C to about 80°C, preferably from 30 °C to about 45 °C.

In another embodiment, the crystalline form Al of Apalutamide (1) as obtained in example 1 was having X-Ray diffraction (XRD) pattern as shown in figure 1 and the 2 theta values provided in Table 1. Table 1:
2 theta deg. Relative Intensity (%)
3.98 3^9
4.22 9X)
4.80 9L9
T03 9^5
"726 8?8
7.90 Z8
"8^48 12
~9A7 18?7
10.65 8T
11.07 7^8
12.76 7^2
14.20 100
14.92 5T0
15.43 160
16.09 190
16.86 190
18.24 120
18.88 8^80 20.02 3^60 20.97 150 21.31 4~80 21.76 420 22.15 4T0
22.88 4T0 23.36 190

23.76 I 4.90
24.08 620
24.52 7^90
26.47 190 28.51 4T0 30.14 3^80 30.92 4^50 32.32 4^60 32.84 3^80
33.47 3M 34.69 430 38.43 5^00 38.98 5^50
42.88 2~90
I
In another embodiment, the crystalline form A2 of Apalutamide (1) as obtained in example 2 was having X-Ray diffraction (XRD) pattern as shown in figure 2 and the 2 theta values provided in Table 2 Table 2:
2 theta deg. Relative Intensity (%)
"172 54T9
6.62 105
7.40 100 '
8.04 222
8.99 122
10.32 362
11.02 108
11.52 9^50
12.56 14T
13.19 1L9

14.81 I 11.6
15.28 15^9
15.60 1X9
16.08 1X0
16.48 19^8
16.83 3l?7
17.68 T8J
17.92 19!4
18.48 162
19.03 1L3
20.0 24^4
20.34 222
21.14 206
21.52 222 '
22.33 28l
23.44 110
23.84 14~9
24.16 1X5
lAS 19/7
25.12 18X
25.68 163
26.34 203
27.87 1X9
30.58 14J
31.09 1X5
32.64 14Tl
33.34 14~9
33.85 1X5
34.19 1X7
34.74 12^9

36.92 I 11.9
37.36 9XX)
38.05 9^80
42.30 9XX)
The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE- 1: Preparation of crystalline form Al of Apalutamide (1)
2.0g of Apalutamide (1) was suspended in a mixture of 18mL tetrahydrofuran and 2mL water at 25 °C - 30 °C. The reaction mixture was heated to 60 °C - 65 °C and stirred for 15-20 mins. The hot reaction mixture was added to 20 mL of acetone which was precooled at -50 °C to -55 °C to form a gummy mass. The reaction mass was stirred for l-3hrs. The solid was filtered and dried under vacuum, followed by drying in air tray dryer (ATD) at 40 °C - 45 °C to obtain crystalline form Al of Apalutamide (1). Yield: 90%; XRD: Figure 1.
EXAMPLE- 2: Preparation of crystalline form A2 of Apalutamide (1)
l.Og of Apalutamide (1) was suspended in 4 mL N, N, dimethylformamide at 25 °C -30 °C. The reaction mixture was heated to 60 °C - 65 °C and stirred for 15-20 mins and filtered. The clear filtrate was then added to 30 mL of n-heptane at 25 °C -35 °C. The solid formed was filtered and vacuum dried, followed by drying in air tray dryer (ATD) at 30 °C - 45 °C to obtain crystalline form A2 of Apalutamide (1). Yield: 82%; XRD: Figure 2.
EXAMPLE-3: Preparation of amorphous form of Apalutamide (1)
l.Og of Apalutamide (1) was suspended in 10 mL of N, N, dimethylformamide at 25 °C - 30 °C. The reaction mixture was then heated to 35 °C - 40 °C and filtered. The filtrate was then added to 40mLof n-heptane which was precooled at -45 °C to - 50 °C resulting in the precipitation of solid. The solid so formed was filtered, dried

under vacuum and further dried in air tray dryer (ATD) at 30 °C - 35 °C to obtain amorphous form of Apalutamide (1). Yield: 80%; XRD: figure 3.
EXAMPLE- 4: Preparation of amorphous form of Apalutamide (1)
l.Og of Apalutamide (1) was suspended in a mixture of 20 ml of tetrahydrofuran and water at 25 °C - 30 °C. The reaction mixture was then heated at 55 °C - 60 °C, stirred and filtered. The filtrate was cooled to 25 °C - 30 °C and 30ml of n-heptane was added to it. The reaction mixture was further cooled to 0 °C -5 °C and xylene was added to the reaction mixture. The solid formed was filtered, dried under vacuum and further dried in air tray dryer (ATD) at 30 °C - 35 °C to obtain amorphous form of Apalutamide (1). Yield: 80%; XRD: figure 4.