DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to the filing date of Indian Provisional Application No. IN 201941034391, filed on Aug 27, 2019;

FIELD OF THE INVENTION:
The present invention relates to novel crystalline form of Apalutamide and its preparation process thereof. The present invention further relates to process for the preparation of amorphous solid dispersion of Apalutamide.

BACKGROUND OF THE INVENTION:
Apalutamide, chemically known as 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide is represented by Formula-I.

Formula I

Apalutamide, the active ingredient of ERLEADA, is an androgen receptor inhibitor approved for the treatment of prostate cancer in February 2018. It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC). It is similar to enzalutamide both structurally and pharmacologically but shows some advantages like greater potency and reduced central nervous system permeation. It acts as a selective competitive antagonist of the androgen receptor (AR).

Apalutamide was first disclosed in US 8445507B2.

US 9481663 disclosed crystalline Form B and amorphous forms of Apalutamide and their preparation thereof.

US 9994545B1 disclosed crystalline Form A of Apalutamide and its preparation thereof.

US 10308630B1 disclosed crystalline Form I of Apalutamide and its preparation thereof.

US patent publication, US20180258067 disclosed Apalutamide crystalline forms C, D, E, F, G, H, and J.

International patent publication WO2016124149 disclosed crystalline forms of Apalutamide form I & form II.

The inventors of the present invention developed novel crystalline form of Apalutamide suitable for formulation.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention provides novel crystalline form of Apalutamide designated as Form M7 and its preparation thereof.

In one aspect, the present invention provides crystalline form of Apalutamide designated as form M7 and characterized by powder X-ray diffraction pattern shown having peaks at 4.76, 7.34, 13.77, 14.17, 16.0, 16.35, 16.57, 16.81, 17.40, 18.0, 19.94, 21.4, 24.4, 24.92 ±0.2° degrees 2?.

In another aspect, the crystalline Form M7 of Apalutamide may be characterized by the powder X-ray diffraction pattern as depicted in Figure 1.

Yet in another aspect, the present invention provides a process for the preparation of crystalline Form M7 of Apalutamide comprising the steps of:
a) dissolving apalutamide in a solvent or solvent mixture,
b) heating the reaction mass,
c) adding water,
d) cooling the reaction mass,
e) isolating crystalline Form M7 of Apalutamide

Yet in another aspect, the present invention provides process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of:
a) suspending apalutamide in water,
b) adding a pharmaceutically acceptable excipient,
c) isolating amorphous solid dispersion of Apalutamide.

Yet in another aspect, the present invention provides process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of:
a) dissolving apalutamide in an organic solvent and water,
b) heating the reactions mass,
c) adding water,
d) cooling the reaction mass,
e) adding a pharmaceutically acceptable excipient,
f) isolating amorphous solid dispersion of Apalutamide.

Brief description of the figures:

Figure 1: Illustrates the powder X-ray diffraction (PXRD) pattern of crystalline Apalutamide form M7.

Figure 2: Illustrates the powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Apalutamide

Figure 3: Profile fitting data of Apalutamide Form M7 by Rietveld refinement showing complete fit of the theoretical (blue) to a measured (red) PXRD pattern. The difference plot is shown in grey and reflection positions are indicated by vertical markers on the x-axis.

DETAIL DESCRIPTION OF THE INVENTION:

The present invention relates to novel crystalline form of Apalutamide designated as
Forms M7 and its preparation process thereof. The present invention further relates to process for the preparation of amorphous solid dispersion of Apalutamide.

In one embodiment, the present invention relates to crystalline Form M7 of Apalutamide characterized by powder X-ray diffraction pattern having peaks at 4.76, 7.34, 13.77, 14.17, 16.0, 16.35, 16.57, 16.81, 17.40, 18.0, 19.94, 21.4, 24.4, 24.92 ± 0.2° degrees 2?.

In another embodiment, the present invention relates to crystalline Form M7 of Apalutamide characterized by powder X-ray diffraction as depicted in Figure 1.

Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form M7 of Apalutamide comprising the steps of:
a) dissolving apalutamide in a solvent or solvent mixture,
b) heating the reaction mass,
c) adding water,
d) cooling the reaction mass,
e) isolating crystalline Form M7 of Apalutamide

According to the present invention, Apalutamide may be dissolved in a solvent mixture selected from N, N-dimethyl acetamide and water. The clear solution thus formed may be heated to about 70 to 80°C followed by slight cooling to about 65°C, added with water and maintained. The resultant reaction mass may be cooled and the solid formed may be filtered and dried under vacuum to obtain crystalline Form M7 of Apalutamide.

Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form M7 of Apalutamide comprising the steps of:
a) dissolving apalutamide in an organic solvent,
b) adding water,
c) isolating crystalline Form M7 of Apalutamide
According to the present invention, Apalutamide may be dissolved in an organic solvent like N, N-dimethyl acetamide to form a clear solution. Water may be added to the above solution and the solid formed may be filtered and dried under vacuum to obtain crystalline Form M7 of Apalutamide.

Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form M7 of Apalutamide comprising the steps of:
a) dissolving apalutamide in an organic solvent,
b) adding the solution of step a to water,
c) isolating crystalline Form M7 of Apalutamide

According to the present invention, Apalutamide may be dissolved in an organic solvent like N, N-dimethyl acetamide to form a clear solution and this solution may be added to water. The solid formed may be filtered and dried under vacuum to obtain crystalline Form M7 of Apalutamide.

Yet in another embodiment, the present invention relates to a process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of:
d) suspending apalutamide in water,
e) adding a pharmaceutically acceptable excipient,
f) isolating amorphous solid dispersion of Apalutamide.

According to the present invention, apalutamide and water may be taken in a flask and added pharmaceutically acceptable excipient such as silicon dioxide. The reaction mass may be maintained for about 2 hours at about 20 to 30 °C and the resultant solid may be filtered, washed with water and dried under vacuum to obtain amorphous solid dispersion of Apalutamide.

Yet in another embodiment, the present invention relates to a process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of:
g) dissolving apalutamide in an organic solvent and water,
h) heating the reactions mass,
i) adding water,
j) cooling the reaction mass,
k) adding a pharmaceutically acceptable excipient,
l) isolating amorphous solid dispersion of Apalutamide.

According to the present invention, apalutamide may be taken in an organic solvent like N, N-dimethyl acetamide and water and heated to about 70 to 80°C. The clear solution may be cooled to about 65°C and added with water and further cooled to 20 to 30°C and maintained. A pharmaceutically acceptable excipient like silicon dioxide may to be added to the reaction mass and maintained. The resultant solid may be filtered, washed with water and dried under vacuum to obtain amorphous solid dispersion of Apalutamide.

In yet another embodiment, the physical and chemical stability of Apalutamide Form M7 was determined by storing the samples at 5±3°C, 25°C and 60% relative humidity (RH) and 40°C and 75% relative humidity (RH) conditions for six months and the samples were analyzed by PXRD and purity by HPLC. The results are shown in below Table 1. The Apalutamide Form M7 was found to be physically and chemically stable at 5±3°C and at 25°C and 60% relative humidity (RH) conditions up to six months whereas at 40°C and 75% relative humidity (RH) conditions residual contamination of Form B was observed.
Table 1
Conditions/ Polymorph Apalutamide Form M7
PXRD Purity (%)
at 25°C/60% RH
Initial Crystalline form 99.95
1 month Stable 99.94
2 months Stable 99.93
3 months Stable 99.91
6 months Stable 99.86
at 5±3°C
Initial Crystalline form 99.95
1 month Stable 99.94
2 months Stable 99.94
3 months Stable 99.92
6 months Stable 99.89
at 40°C/75% RH
Initial Crystalline form 99.95
1 month Stable 99.93
2 months Unstable 99.93
3 months Unstable 99.91
6 months Unstable 99.90
Phase purity Assessment and unit cell determination of Form M7 by Rietveld refinement:
The long scan PXRD data of Form M7 was measured using Bruker AXS D8 Advance powder X-ray diffractometer equipped with a goniometer of ?/? configuration, Lynx-Eye detector. The Cu-anode X-ray tube was operated at 40kV and 40mA. The experiments were conducted over the 2? range of 2.0°-50.0° with 0.03° step size and a total scan time of 10hrs. Rietveld analysis was carried out using Topas software V5 on Form M7 PXRD data to determine the phase purity and crystal structure determination. The profile fitting data shows the complete fit of the measured powder X-ray diffraction pattern with no unrefined peaks (Figure 1) indicating that Form M7 is pure phase which crystallizes into the monoclinic C2 space group. The unit cell parameters of Form M7 derived from Rietveld analysis is shown in Table 2.

Table 2
Space Group Apalutamide Form M7
Space group C2
a (Å) 40.26
b (Å) 13.59
C (Å) 17.48
ß (°) 100.90
Cell volume (Å3) 9390.36
Rwp 1.77

A pharmaceutical composition comprising crystalline Apalutamide Form M7 prepared according to the present invention and a pharmaceutically acceptable excipient.

A pharmaceutical composition comprising amorphous solid dispersion of Apalutamide prepared according to the present invention and a pharmaceutically acceptable excipient.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in anyway.

EXPERIMENTAL PROCEDURE:
Example 1:
Charged Apalutamide (5g), Dimethylacetamide (20mL) and water (5mL) into the RBF at 25±5°C. The clear solution was heated to 70-75°C and stirred for 2h at 70-75°C. The reaction mass was cooled to 60±5°C, added water (75mL) and stirred for 1 h at 60±5°C. The reaction mass was cooled to 25±5°C and stirred for 16h. The obtained solid was filtered and dried under vacuum at 50°C for 16 h. The solid obtained was identified as crystalline Form M7 of Apalutamide.
Yield=4.6g
Example 2:
Charged Apalutamide (7g), Dimethylacetamide (28mL) and water (7mL) into the RBF at 25±5°C. The clear solution was heated to 70-75°C and stirred for 24-30h at 70-75°C. The reaction mass was cooled to 60±5°C, added water (105mL) and stirred for 1 h at 60±5°C. The reaction mass was cooled to 25±5°C and stirred for 2-3h. The obtained solid was filtered, washed with water (14mL) and dried under vacuum at 50°C for 16 h. The solid obtained was identified as crystalline Form M7 of Apalutamide.
Yield=6.6g
Example 3:
Charged Apalutamide (4g), Dimethylacetamide (16mL) and water (4mL) into the RBF at 25±5°C. The clear solution was heated to 70-75°C and stirred for 20-24h at 70-75°C. The reaction mass was cooled to 60±5°C and added water (60mL). The reaction mass was cooled to 25±5°C and stirred for 1-2h. The obtained solid was filtered, washed with water (8mL) and dried under vacuum at 50°C for 16h. The solid obtained was identified as Crystalline Form M7 of Apalutamide.
Yield=3.6g
Example-4:
Apalutamide (5g) was dissolved in N,N-Dimethyl acetamide (20 ml) at 25±5°C. To the clear solution added water (80mL) at 25±5°C and stirred for 2h. The reaction mass was filtered, washed with water (20ml) and dried at 60°C under vacuum for 15h. The solid obtained was identified as Crystalline Form M7 of Apalutamide.
Yield=4.4g
Example-5:
Apalutamide (1g) was dissolved in N,N-Dimethyl acetamide (4 ml) at 25±5°C. The clear solution was added slowly to the water (16mL) and stirred for 2h. The reaction mas was filtered, washed with water (4ml) and dried under vacuum at 60°C for 15h. The obtained solid was identified as Crystalline Form M7 of Apalutamide.
Yield=0.8g
Example 6:
Charged Apalutamide Form M7 (0.5g) and water (10mL) into the RBF at 25±5°C. The suspension was stirred for 5 min and charged Silicon dioxide (0.5g) into the RBF. Stirred the reaction mass for 2h at 25±5°C. The obtained solid was filtered, washed with water(2mL) and dried under vacuum at 120°C for 1h. The solid obtained was identified as amorphous solid dispersion (ASD) of Apalutamide.
Yield=0.8g
Example 7:
Charged Apalutamide (2g), Dimethylacetamide (8mL) and water (2mL) into the RBF at 25±5°C. The clear solution was heated to 70-75°C and stirred for 20-24h at 70-75°C. The clear solution was cooled to 60±5°C and added water (30mL). Cooled reaction mass to 25±5°C and stirred for 1-2h. Added silicon dioxide (2g) to the reaction mass and stirred for 1-2h. The reaction mass was filtered washed with water (4mL) and dried under vacuum at 120°C for 1h. The solid obtained was identified as amorphous solid dispersion (ASD) of Apalutamide.
Yield=3.4g

Example 8:
Apalutamide (10g) was dissolved in N, N-Dimethyl acetamide (40 ml) at 25±5°C. To the clear solution slowly added water (320 mL) at 25±5°C and stirred for 3h. The reaction mass was filtered, washed with water (40 ml) and dried at 50°C under vacuum for 15h. The solid obtained was identified as crystalline Form M7 of Apalutamide.
Yield: 9.5gm
,CLAIMS:Crystalline Form M7 of Apalutamide.
2. The crystalline form of Apalutamide Form M7 as claimed in claim 1, is characterized by PXRD pattern comprising the peaks at 4.76, 7.34, 13.77, 14.17, 16.0, 16.35, 16.57, 16.81, 17.40, 18.0, 19.94, 21.4, 24.4, 24.92 ± 0.2°, degrees 2?.
3. The crystalline Apalutamide Form M7 as claimed in claim 1, is prepared comprising the steps of:
a) dissolving Apalutamide in a solvent or solvent mixture,
b) heating the reaction mass,
c) adding water,
d) cooling the reaction mass,
e) isolating crystalline Form M7 of Apalutamide.
4. The crystalline Apalutamide Form M7 as claimed in claim 1, is prepared comprising the steps of:
a) dissolving Apalutamide in an organic solvent,
b) adding water,
c) isolating crystalline Form M7 of Apalutamide.
5. The crystalline Apalutamide Form M7 as claimed in claim 1, is prepared comprising the steps of:
a) dissolving Apalutamide in an organic solvent,
b) adding the solution of step (a) to water,
c) isolating crystalline Form M7 of Apalutamide
6. A process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of:
a) dissolving Apalutamide in an organic solvent and water,
b) heating the reactions mass,
c) adding water,
d) cooling the reaction mass,
e) adding a pharmaceutically acceptable excipient,
f) isolating amorphous solid dispersion of Apalutamide.
7. The process as claimed in preceding claims, wherein the organic solvent is selected from N, N-dimethyl acetamide and water.
8. A process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of:
a) suspending Apalutamide in water,
b) adding a pharmaceutically acceptable excipient,
c) isolating amorphous solid dispersion of Apalutamide.

9. The process as claimed in claim 6 or 8, wherein the pharmaceutically acceptable
excipient is silicon dioxide.
10. A pharmaceutical composition comprising crystalline Form M7 of Apalutamide or amorphous solid dispersion of Apalutamide prepared according to the preceding claims and atleast one pharmaceutically acceptable excipient.