BOMMAREDDY AGGI RAMIREDDY (IN)
JAYACHANDRA SURESHBABU (IN)
SEBASTIAN SONNY (IN)
RAO JAGADEESHWAR (IN)
VEMULA LAKSHMINARYANA (IN)
PATEL MAHESH NAGIN (IN)
| WO2013184681A1 | 2013-12-12 | |||
| WO2016124149A1 | 2016-08-11 | |||
| WO2016124149A1 | 2016-08-11 |
| US8445507B2 | 2013-05-21 | |||
| US8461243B2 | 2013-06-11 | |||
| US9481663B2 | 2016-11-01 | |||
| US9994545B2 | 2018-06-12 | |||
| US20180258067A1 | 2018-09-13 |
| We claim: 1. Crystalline Form M6 of Apalutamide. 2. The crystalline Apalutamide Form M6 as claimed in claim 1, is characterized by PXRD pattern having peaks at 4.5, 4.7, 6.9, 7.2, 9.1, 9.4, 10.5,11.0, 11.8, 13.2, 13.7, 14.1, 14.8, 15.3, 15.9, 16.2, 16.50, 16.8, 17.2, 18.1, 18.3, 18.8, ±0.2° degrees 2Q. 3. The crystalline Apalutamide Form M6 as claimed in claim 1, is prepared comprising the steps of: a) suspending Apalutamide in an organic solvent or water, b) isolating crystalline Form M6 of Apalutamide. 4. The crystalline Apalutamide Form M6 as claimed in claim 1, is prepared comprising the steps of: a) dissolving Apalutamide in an organic solvent, b) adding water to step a, c) isolating crystalline Form M6 of Apalutamide. 5. The process as claimed in claims 3 or 4, wherein the organic solvent is selected from 1 -butanol or 2-butanol. 6. The crystalline Apalutamide Form M6 as claimed in claim 1, is a solvate or a solvate hydrate. 7. Crystalline premix of Apalutamide Form M6. 8. The crystalline premix of Apalutamide Form M6 as claimed in claim 7, is prepared comprising the steps of: a) suspending Apalutamide in water, b) adding a pharmaceutically acceptable excipient, and c) removing the solvent to isolate crystalline premix of Apalutamide Form M6. 9. The crystalline premix of Apalutamide Form M6 as claimed in claim 7, is prepared comprising the steps of: a) dissolving Apalutamide in an organic solvent, b) adding water and pharmaceutically acceptable excipient, and c) removing the solvent to isolate crystalline premix of Apalutamide Form M6. 10. The process as claimed in claims 8 and 9, wherein the pharmaceutically acceptable excipient is selected from microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, silicon dioxide or magnesium stearate. 11. Crystalline Form M4 of Apalutamide. 12. The crystalline Apalutamide Form M4 as claimed in claim 11, is characterized by PXRD pattern having peaks at 3.9, 6.9, 7.4, 8.0, 8.5, 9.1, 9.8, 11.5, 12.1, 12.4, 13.0, 14.0, 14.2, 15.0, 15.8, 16.0, 16.5, 16.8, 17.1, 18.1, 19.1, 19.4, 19.8, 20.2, 21.0 ±0.2° degrees 2Q. 13. The crystalline Apalutamide Form M4 as claimed in claim 11, is prepared comprising the steps of: a) dissolving Apalutamide in an organic solvent, b) adding an anti-solvent, c) isolating crystalline Form M4 of Apalutamide. 14. The process as claimed in claim 13, wherein the solvent is dimethylformamide and antisolvent is water. 15. A process for the preparation of amorphous Apalutamide comprising the steps of: a) dissolving Apalutamide in a solvent, b) removing the solvent, and c) isolating amorphous Apalutamide. 16. The process as claimed in claim 15, wherein the solvent is selected from methanol, 2-butanol, 1, 4-dioxane, or mixtures thereof and the isolation is by distillation, spray drying, agitated thin film drying or lyophilization. 17. A process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of: a) dissolving Apalutamide and a pharmaceutically acceptable excipient in an organic solvent, b) removing the solvent, and c) isolating amorphous solid dispersion of Apalutamide. 18. A process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of: a) dissolving Apalutamide in an organic solvent, b) adding a pharmaceutically acceptable excipient, c) removing the solvent, and d) isolating amorphous solid dispersion of Apalutamide. 19. The process as claimed in claims 17 and 18, wherein the pharmaceutically acceptable excipient is selected from Plasdone S-630, Povidone K-30, aeropril 300 and the organic solvent is selected from methanol, ethanol, isopropanol, n- butanol, acetone, methyl isobutyl ketone, methyl amyl ketone. 20. Crystalline Form M5 of Apalutamide. 21. The crystalline Apalutamide Form M5 as claimed in claim 20, is characterized by PXRD pattern having peaks at 3.6, 4.0, 7.3, 8.1, 10.1, 11.0, 12.2, 13.0, 14.0, 14.7, 15.1, 15.9, 16.2, 16.7, 17.2, 17.5, 18.3, 19.2, 19.8, 20.3, 21.1 ± 0.2° degrees 2Q. 22. The crystalline Apalutamide Form M5 as claimed in claim 20, is prepared comprising the steps of: a) dissolving Apalutamide in Dimethyl formamide. b) Isolating crystalline Form M5 of Apalutamide by slow evaporation or distillation. |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of Indian Provisional Patent Application Nos. IN201841000194 filed on date January 02, 2018; IN201841003298 filed on date January 29, 2018 and IN201841020088 filed on date May 29, 2018, all of which are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION:
The present invention relates to novel polymorphs of Apalutamide and their preparation process thereof. The present invention further relates to processes for the preparation of amorphous and 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 and represented by Formula-I, is approved for the treatment of prostate cancer. It is similar to enzalutamide both structurally and pharmacologically, acting as a selective competitive antagonist of the androgen receptor (AR), but shows some advantages, including greater potency and reduced central nervous system permeation.
Formula I
Apalutamide was first disclosed in US 8445507B2 patent.
US patent, 8,461,243 B2, disclosed the preparation and purification of Apalutamide. US patent, US9481663B 1 disclosed crystalline Form B and amorphous forms along with their preparations thereof. US patent, US 9994545B1 disclosed crystalline Form A and its preparation thereof.
US patent publication, US20180258067 disclosed Apalutamide crystalline forms C, D, E, F, G, H, I and J. International patent publication WO2016124149 disclosed crystalline forms of Apalutamide form I & form II.
The present inventors developed an economic and cost-effective process for the preparation of amorphous Apalutamide and amorphous solid dispersion of Apalutamide. The inventors further developed novel polymorphic forms of Apalutamide with improved chemical purity which are stable and suitable for formulation development. The novel polymorphic forms and their processes of current invention may provide single purification step to obtain desired product quality or purer product from crude Apalutamide thereby addressing the major industrial challenges in purification and can also be prepared conveniently at a low cost.
SUMMARY OF THE INVENTION:
The present invention provides a process for the preparation of amorphous Apalutamide and amorphous solid dispersion of Apalutamide. The present invention further provides novel crystalline forms of Apalutamide designated as Form Ml, Form M2, Form M3, Form M4, Form M5 and Form M6 and their preparation process thereof.
One aspect of the present invention provides a process for the preparation of amorphous Apalutamide comprising the steps of:
a) dissolving Apalutamide in a solvent,
b) removing the solvent, and
c) isolating amorphous Apalutamide.
Another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of: a) dissolving Apalutamide and pharmaceutically acceptable excipient in organic solvent,
b) removing the solvent, and
c) isolating amorphous solid dispersion of Apalutamide.
Yet another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of:
a) dissolving Apalutamide in an organic solvent,
b) adding a pharmaceutically acceptable excipient,
c) removing the solvent, and
d) isolating amorphous solid dispersion of Apalutamide.
Yet in another aspect, the present invention provides novel crystalline form of Apalutamide form Ml characterized by powder X-ray diffraction pattern shown having peaks at 4.7, 13.9, 16.1, 20.6, 21.4, 22.2, 22.7, 25.7, 26.5, 27.6, 28.5, 30.1 ± 0.2° degrees 2Q.
Yet in another aspect, the crystalline Apalutamide Form Ml of Apalutamide may be characterized by the powder X-ray diffraction pattern in Figure 4.
Yet in another aspect, the present invention provides a process for the preparation of crystalline Form Ml of Apalutamide comprising the steps of:
a) dissolving Apalutamide in a solvent,
b) Isolating crystalline Form Ml of Apalutamide.
Yet in another aspect, the present invention provides a novel crystalline form M2 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 4.1, 6.9, 7.4, 7.6, 8.3, 12.0, 13.2 16.4, 20.1 ±0.2° degrees 20.
Yet in another aspect, the crystalline Form M2 of Apalutamide may be characterized by the powder X-ray diffraction pattern in Figure 5.
Yet in another aspect, the present invention provides a process for the preparation of crystalline Form M2 of Apalutamide comprising the steps of: a) dissolving Apalutamide in a solvent,
b) Isolating crystalline Form M2 of Apalutamide.
Yet in another aspect, the present invention provides a novel crystalline form M3 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 4.1, 5.0, 6.9, 7.5, 9.1, 12.0, 13.6, 14.1, 15.2, 16.4, 17.4, 19.5, 20.9 ±0.2° degrees 2Q.
Yet in another aspect, crystalline Form M3 of Apalutamide may be characterized by the powder X-ray diffraction pattern in Figure 6.
Yet in another aspect, the present invention provides a process for the preparation of crystalline Form M3 of Apalutamide comprising the steps of:
a) dissolving Apalutamide in an organic solvent,
b) adding an anti- solvent, and
c) Isolating crystalline Form M3 of Apalutamide.
Yet in another aspect, the present invention provides novel crystalline form M4 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 3.9, 6.9, 7.4, 8.0, 8.5, 16.5 ±0.2° degrees 2Q.
Yet in another aspect, crystalline Form M4 of Apalutamide may be characterized by the powder X-ray diffraction pattern in Figure 7.
Yet in another aspect, the present invention provides a process for the preparation of crystalline Form M4 of Apalutamide comprising the steps of:
a) dissolving Apalutamide in an organic solvent, and
b) adding an anti- solvent,
c) Isolating crystalline Form M4 of Apalutamide.
Yet in another aspect, the present invention provides a novel crystalline form M5 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 3.6, 4.0, 7.3, 8.1, 10.1, 12.2, 17.2, 20.3, 21.1 ± 0.2° degrees 2Q. Yet in another aspect, the present invention provides a crystalline Apalutamide Form M5.
Yet in another aspect, crystalline Apalutamide Form M5 may be characterized by the powder X-ray diffraction pattern in Figure 8.
Yet in another aspect, the present invention provides a process for the preparation of crystalline Form M5 of Apalutamide comprising the steps of:
a) dissolving Apalutamide in Dimethyl formamide,
b) Isolating crystalline Form M5 of Apalutamide.
Yet in another aspect, the present invention provides a novel crystalline Apalutamide Form M6.
Yet in another aspect, the crystalline Form M6 of Apalutamide is characterized by powder X-ray diffraction pattern having peaks at 4.5, 4.7, 6.9, 7.2, 9.1, 9.4, 10.5,11.0,
11.8, 13.2, 13.7, 14.1, 14.8, 15.3, 15.9, 16.2, 16.50, 16.8, 17.2, 18.1, 18.3, 18.8, 19.3,
19.9, 20.2, 20.4, 20.8, 21.3, 21.8, 22.4, 22.9, 23.5, 23.9, 24.4, 24.9, 25.5, 26.1, 27.1,
27.6, 28.1, 28.4, 29.8, 30.5, 31.0, 32.0, 32.5, 33.8, 34.2, 34.9, 36.4, 37.1, 38.3, 38.9,
40.1, 43.1, 45.0, 46.8, 48.4, 48.9+0.2° degrees 2Q.
Yet in another aspect, the crystalline Form M6 of Apalutamide may be characterized by the powder X-ray diffraction pattern as given in Figure 9.
Yet in another aspect, the present invention is to provide a process for the preparation of crystalline Form M6 of Apalutamide comprising the steps of:
a) suspending Apalutamide in an organic solvent or water,
b) isolating crystalline Form M6 of Apalutamide.
Yet in another aspect, the present invention provides crystalline premix of Apalutamide Form M6.
Yet in another aspect, the crystalline premix of Apalutamide Form M6 may be characterized by the powder X-ray diffraction pattern as given in Figure 10. Yet in another aspect, the present invention provides a process for the preparation of crystalline premix of Apalutamide Form M6 comprising the steps of:
a) suspending Apalutamide in water,
b) adding a pharmaceutically acceptable excipient, and
c) removing the solvent to isolate crystalline premix of Apalutamide Form M6.
Yet in another aspect, the present invention provides crystalline premix of Apalutamide Form Ml.
Yet in another aspect, the crystalline premix of Apalutamide Form Ml may be characterized by the powder X-ray diffraction pattern as given in Figure 11.
In yet another aspect, the present invention provides a process for the preparation of crystalline premix of Apalutamide Form Ml comprising the steps of:
a) dissolving Apalutamide in an organic solvent,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) adding a pharmaceutically acceptable excipient, and
e) removing the solvent to isolate crystalline premix of Apalutamide Form
Ml.
BRIEF DESCRIPTION OF THE FIGURES:
Figure 1 shows a powder X-ray diffraction (PXRD) pattern of amorphous Apalutamide.
Figure 2 shows a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Apalutamide as per example 5.
Figure 3 shows a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Apalutamide as per example 6.
Figure 4 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form Ml. Figure 5 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M2. Figure 6 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M3. Figure 7 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M4. Figure 8 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M5. Figure 9 shows a powder X-ray diffraction (PXRD) pattern of Apalutamide form M6. Figure 10 shows a powder X-ray diffraction (PXRD) pattern of Crystalline premix of Apalutamide Form M6 with 50%w/w Silicon dioxide.
Figure 11 shows a powder X-ray diffraction (PXRD) pattern of Crystalline premix of Apalutamide Form Ml with 50%w/w Silicon dioxide.
DETAIL DESCRIPTION:
The present invention relates to an improved process for the preparation of amorphous Apalutamide and amorphous solid dispersion of Apalutamide. The present invention further relates to novel crystalline forms of Apalutamide designated as Forms Ml, M2, M3, M4, Form M5 and M6 and their preparation thereof.
One embodiment of the present invention relates to an improved process for the preparation of amorphous Apalutamide comprising the steps of:
a) dissolving Apalutamide in a solvent,
b) removing the solvent, and
c) isolating amorphous Apalutamide.
According to the present invention, Apalutamide may be dissolved in a solvent selected from methanol, 2-butanol, 1, 4-dioxane, or mixtures thereof and the resulting solution may be removed by conventional technique such as evaporation, Spray drying, Lyophilization or agitated thin film drier (ATFD) to obtain Apalutamide in amorphous form.
According to the present invention, the amorphous form of Apalutamide may be obtained by evaporation or lyophilization.
According to the present invention, the amorphous form of Apalutamide may be obtained by feeding the material into the spray dryer with feed rate of the solution at 5ml/min and inlet temperature at 70°C.
Another embodiment of the present invention relates to an improved process for the preparation of amorphous solid dispersion of Apalutamide comprising the steps of: a) dissolving Apalutamide and a pharmaceutically acceptable excipient in an organic solvent,
b) removing the solvent, and
c) isolating amorphous solid dispersion of Apalutamide.
According to the present invention, Apalutamide and a pharmaceutically acceptable excipient selected from Plasdone S-630, Povidone K-30 or Aeropril 300 may be dissolved in a sufficient amount of solvent selected from methanol, ethanol, isopropanol, n-butanol, acetone, ethyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl amyl ketone (MAK) to form a clear solution. The solvent may be removed by evaporation 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: a) dissolving Apalutamide in an organic solvent,
b) adding a pharmaceutically acceptable excipient,
c) removing the solvent, and
d) isolating amorphous solid dispersion of Apalutamide.
According to the present invention, Apalutamide may be dissolved in a solvent selected from methanol, ethanol, isopropanol, n-butanol, acetone, ethyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl amyl ketone (MAK), and added with a pharmaceutically acceptable excipient selected from Plasdone S-630, Povidone K- 30 or Aeropril 300 and the like. The solvent may be removed by conventional technique such as evaporation to obtain amorphous solid dispersion of Apalutamide.
Yet in another embodiment, the present invention relates to crystalline Form Ml of Apalutamide characterized by powder X-ray diffraction pattern having peaks at 4.7, 7.1, 9.3, 10.7, 11.7,13.1, 13.9, 14.9,16.1, 16.8, 18.5, 20.1, 20.6, 21.4, 22.2, 22.7, 23.9, 24.7, 25.1, 25.7, 26.5, 27.6, 28.5, 30.1, 31.1, 31.8, 32.1, 32.9, 34.1, 34.5, 35.3, 36.7, 37.6, 38.0, 38.9, 40.3, 43.5, 45.5 ± 0.2° degrees 2Q.
Yet in another embodiment, the present invention relates to crystalline Form Ml of Apalutamide characterized by powder X-ray diffraction as depicted in Figure 4. Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form Ml of Apalutamide comprising the steps of:
a) dissolving Apalutamide in a solvent,
b) Isolating crystalline Form Ml of Apalutamide
According to the present invention, Apalutamide may be dissolved in a suitable solvent preferably Toluene, 2-butanol, ethanol, methanol, 1 -butanol, 1 -propanol, 1- pentanol. The clear solution may be cooled and the precipitated solid may be filtered and dried to obtain crystalline form-Ml of Apalutamide.
Yet in another embodiment, the present invention relates to crystalline form M2 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 4.1, 5.0, 6.9, 7.4, 7.6, 8.3, 10.0, 12.0, 12.6, 13.2, 13.7, 14.2, 15.3, 16.0, 16.4, 16.6, 17.3,17.7, 19.2, 20.1, 21.3, 21.9, 22.0, 23.6, 23.9, 24.8, 25.5, 25.8, 27.8, 28.7, 30.2,
31.5, 32.2, 33.3, 35.4, 37.7, 41.1 ± 0.2° degrees 2Q.
Yet in another embodiment, crystalline Form M2 of Apalutamide may be characterized by the powder X-ray diffraction pattern as depicted in Figure 5.
Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form M2 of Apalutamide comprising the steps of:
a) dissolving Apalutamide in a solvent,
b) Isolating crystalline Form M2 of Apalutamide
According to the present invention, Apalutamide may be dissolved in a suitable solvent selected from the group consisting of Methyl isobutyl ketone, acetone, methyl butyl ketone, methyl ethyl ketone & isopropyl ether and slowly cooled. The resultant solid may be filtered and dried to obtain crystalline Form M2 of Apalutamide.
Yet in another embodiment, the present invention relates to crystalline Form M3 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 4.1, 5.0, 6.9, 7.5, 8.2, 9.1, 10.0, 12.0, 13.6, 14.1, 15.2, 15.9, 16.4, 16.6, 17.4, 17.7,
19.5, 20.9, 21.3, 21.8, 22.3, 23.3, 23.6, 23.9, 24.9,25.4, 25.8, 26.2, 27.7, 28.9, 29.2, 30.2, 30.5, 31.4, 31.8, 32.5, 33.2, 34.7, 35.3, 37.6, 41.0 ± 0.2° degrees 2Q. Yet in another embodiment, crystalline Form M3 of Apalutamide characterized by the powder X-ray diffraction pattern as depicted in Figure 6.
Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form M3 of Apalutamide comprising the steps of:
a) dissolving Apalutamide in an organic solvent,
b) adding an anti- solvent,
c) Isolating crystalline Form M3 of Apalutamide.
According to the present invention, Apalutamide may be dissolved in an organic solvent selected from acetone, methyl butyl ketone or methyl ethyl ketone. The clear solution may be added with a suitable antisolvent selected from ethers such as isopropyl ether, methyl tert-butyl ether, diethyl ether preferable isopropyl ether. The solid precipitated may be filtered and dried to obtain crystalline Form M3 of Apalutamide
Yet in another embodiment, the present invention relates to crystalline form M4 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 3.9, 6.9, 7.4, 8.0, 8.5, 9.1, 9.8, 11.5, 12.1, 12.4, 13.0, 14.0, 14.2, 15.0, 15.8, 16.0, 16.5, 16.8, 17.1, 18.1, 19.1, 19.4, 19.8, 20.2, 21.0, 21.4, 22.3, 23.3, 23.7, 24.2, 24.8, 26.0, 26.8, 27.3, 28.4, 29.0,30.0, 30.4, 31.0, 31.6, 33.0, 34.5, 36.5 ± 0.2° degrees 2Q.
Yet in another embodiment, crystalline Form M4 of Apalutamide may be characterized by the powder X-ray diffraction pattern as depicted in Figure 7.
Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form M4 of Apalutamide comprising the steps of:
a) dissolving Apalutamide in an organic solvent,
b) adding an anti-solvent,
c) isolating crystalline Form M4 of Apalutamide.
According to the present invention, Apalutamide may be dissolved in an organic solvent selected from Dimethylformamide. The clear solution may be added with a suitable antisolvent selected from water, methyl tert-butyl ether, Isopropyl ether. The solid precipitated may be filtered and dried to obtain crystalline Form M4 of Apalutamide.
According to the present invention, all major impurities are washed-out by making Apalutamide Form-M4.
The crystalline Form M4 of Apalutamide prepared according to the present invention is a dimethyl formamide hemi solvate.
Yet in another embodiment, the present invention relates to crystalline form M5 of Apalutamide characterized by powder X-ray diffraction pattern shown having peaks at 3.6, 4.0, 7.3, 8.1, 10.1, 11.0, 12.2, 13.0, 14.0, 14.7, 15.1, 15.9, 16.2, 16.7, 17.2, 17.5, 18.3, 19.2, 19.8, 20.3, 21.1, 21.5, 22.3, 23.7, 24.5, 25.8, 26.4, 28.5, 29.1, 30.1, 30.5 33.5, 36.3, 42.0±0.2° degrees 2Q.
Yet in another embodiment, crystalline Apalutamide Form M5 may be characterized by the powder X-ray diffraction pattern as depicted in Figure 8.
Yet in another embodiment of the present invention further provides, crystalline Apalutamide Form M5 may be prepared by a process comprising the steps of:
a) dissolving Apalutamide in dimethyl formamide.
b) isolating crystalline Form M5 of Apalutamide.
According to the present invention, Apalutamide may be dissolved in Dimethylformamide and the clear solution may be allowed for slow evaporation or distilled completely to obtain of crystalline Form M5 of Apalutamide.
The crystalline Form M5 of Apalutamide prepared according to the present invention is a dimethyl formamide solvate.
Yet in another embodiment, the present invention relates to crystalline form of Apalutamide designated as Form M6. Yet in another embodiment, the present invention relates to crystalline Form M6 of Apalutamide is characterized by powder X-ray diffraction pattern having peaks at 4.5, 4.7, 6.9, 7.2, 9.1, 9.4, 10.5,11.0, 11.8, 13.2, 13.7, 14.1, 14.8, 15.3, 15.9, 16.2, 16.50,
16.8, 17.2, 18.1, 18.3, 18.8, 19.3, 19.9, 20.2, 20.4, 20.8, 21.3, 21.8, 22.4, 22.9, 23.5,
23.9, 24.4, 24.9, 25.5, 26.1, 27.1, 27.6, 28.1, 28.4, 29.8, 30.5, 31.0, 32.0, 32.5, 33.8, 34.2, 34.9, 36.4, 37.1, 38.3, 38.9, 40.1, 43.1, 45.0, 46.8, 48.4, 48.9±0.2° degrees 2Q.
Yet in another embodiment, the crystalline Form M6 of Apalutamide may be characterized by the powder X-ray diffraction pattern as depicted in Figure 9.
Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form M6 of Apalutamide comprising the steps of:
a) suspending Apalutamide in an organic solvent or water,
b) isolating crystalline Form M6 of Apalutamide.
According to the present invention, Apalutamide may be suspended in a solvent such as water or 2-butanol at ambient temperature for 2-3 hours. The resultant reaction mass may be filtered and the solid obtained may be dried under vacuum to isolate crystalline Form M6 of Apalutamide.
Yet in another embodiment, the present invention relates to a process for the preparation of crystalline Form M6 of Apalutamide comprising the steps of:
a) dissolving Apalutamide in an organic solvent,
b) adding water to step a,
c) isolating crystalline Form M6 of Apalutamide.
According to the present invention, Apalutamide may be dissolved in a solvent such as 2-butanol and cooled slowly to room temperature. The resultant reaction mass may be added with water, maintained under stirring for about an hour and filtered. The solid obtained may be dried under vacuum to isolate crystalline Form M6 of Apalutamide.
According to the present invention, the crystalline Form M6 of Apalutamide is a solvate. According to the present invention, the crystalline Form M6 of Apalutamide is a solvate hydrate.
According to the present invention, the crystalline Form M6 of Apalutamide is a 2- butanol solvate hydrate.
Yet in another embodiment, crystalline Form M6 of Apalutamide may be prepared by placing Apalutamide in a petri-dish and exposed to 90% relative humidity for 24hours.
Yet in another embodiment, the present invention relates to crystalline premix of Apalutamide Form M6.
Yet in another embodiment, the crystalline premix of Apalutamide Form M6 may be characterized by the powder X-ray diffraction pattern as depicted in Figure 10.
Yet in another embodiment, the present invention relates to a process for the preparation of crystalline premix of Apalutamide Form M6 comprising the steps of: a) suspending Apalutamide in water,
b) adding a pharmaceutically acceptable excipient, and
c) removing the solvent to isolate crystalline premix of Apalutamide Form M6.
According to the present invention, Apalutamide may be suspended in water and added with a pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, silicon dioxide, magnesium stearate or mixtures thereof preferably Silicon dioxide. The resultant reaction mass may be filtered and the solid obtained may be dried at 50°C under vacuum to isolate crystalline premix of Apalutamide Form M6.
Yet in another embodiment, the present invention relates to a process for the preparation of crystalline premix of Apalutamide Form M6 comprising the steps of: a) dissolving Apalutamide in an organic solvent, b) adding water and pharmaceutically acceptable excipient, and
c) removing the solvent to isolate crystalline premix of Apalutamide Form M6.
According to the present invention, Apalutamide may be dissolved in an organic solvent such as alcohols such as methanol, enthanol or 2-butanol and gradually cooled to room temperature. Water may be added followed by addition of pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, silicon dioxide, magnesium stearate or mixtures thereof preferably Silicon dioxide. The resultant reaction mass may be filtered and the solid obtained may be dried at 50°C under vacuum to isolate crystalline premix of Apalutamide Form M6.
In yet another embodiment, physical and chemical stability of Apalutamide crystalline Form M6 and Crystalline premix of Form M6 with 50%w/w Si02 samples were determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) for 3 months. There was no change in PXRD pattern and HPLC purity when stored for 3 months at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions as mentioned in below Table 1.
Table 1
In yet another embodiment, the present invention relates to crystalline premix of Apalutamide Form Ml.
In yet another embodiment, the crystalline premix of Apalutamide Form Ml may be characterized by the powder X-ray diffraction pattern as given in Figure 11.
In yet another embodiment, the present invention relates to a process for the preparation of crystalline premix of Apalutamide Form Ml comprising the steps of: a) dissolving Apalutamide in an organic solvent;
b) heating the reaction mixture
c) cooling the reaction mixture
d) adding a pharmaceutically acceptable excipient; and
e) removing the solvent to isolate crystalline premix of Apalutamide Form
Ml.
According to the present invention, Apalutamide may be dissolved in an organic solvent such as 2-butanol and heated to about 70 to 90°C followed by cooling to room temperature. To the resultant reaction mixture, a pharmaceutically acceptable excipient selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, silicon dioxide, magnesium stearate, and mixtures thereof preferably Silicon dioxide may be added and maintained for about an hour. The resultant reaction mass may be filtered and the solid obtained may be dried at 50°C under vacuum to isolate crystalline premix of Form Ml of Apalutamide.
In yet another embodiment, the present invention relates to a process for the preparation of amorphous form of apalutamide.
According to the present invention, amorphous Apalutamide may be prepared by heating Apalutamide Form M6 using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from about 25-l40°C followed by slow cooling to 30°C.
According to the present invention, making of amorphous form or amorphous solid dispersion by drying of Apalutamide Form-M6 or crystalline premix of Form M6 is more advantageous in scale up than the prior art process.
In yet another embodiment, physical and chemical stability of amorphous solid dispersion of Apalutamide with 50%w/w Si02 samples were determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) for 3 months. The samples were analyzed by PXRD and HPLC. There was no change in PXRD pattern and HPLC purity when stored for 3 months at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions as mentioned in below Table 2.
Table 2
Yet in another embodiment, the present invention relates to a pharmaceutical composition wherein the composition comprises of amorphous apalutamide and at least one pharmaceutically acceptable excipient and/or a pharmaceutically acceptable carrier. Yet in another embodiment, the present invention relates to a pharmaceutical composition wherein the composition comprises of amorphous solid dispersion of apalutamide and at least one pharmaceutically acceptable excipient and/or a pharmaceutically acceptable carrier.
Yet in another embodiment, the present invention relates to a pharmaceutical composition wherein the composition comprises of apalutamide crystalline forms Ml or M2 or M3 or M4 or M5 or M6 and at least one pharmaceutically acceptable excipient and/or a pharmaceutically acceptable carrier.
Apalutamide, as prepared by the processes described herein, may be formulated into a pharmaceutical dosage form, for example, one for oral administration such as tablets or capsules. Such tablets or capsules may include other pharmaceutically acceptable excipients such as colloidal silicon dioxide, microcrystalline cellulose, starch, sodium starch glycolate, stearic acid, ammonium chloride, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, povidone, hydroxypropyl methyl cellulose, mannitol, fumaric acid, sodium hydroxide, crospovidone, talc, and artificial colorings and flavorings.
Oral dosage forms containing the substantially pure Apalutamide as prepared by methods disclosed herein may be particularly useful in the treatment of prostate cancer.
The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.
EXAMPLES:
Example 1:
Apalutamide (0.5g) was dissolved in 2-butanol (5mL) at 75±5°C. Filtered through hyflo to remove any undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 65±5°C. The solid obtained was identified as apalutamide amorphous form.
Yield: 0.4g Example 2:
Apalutamide (0.5g) was dissolved in 1, 4-dioxane (3mL) at 25±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to Lyophilisation using Labocon lyophilizer (ModeLFD-BT-l04) to yield apalutamide amorphous form.Yield: 0.4g
Example 3:
Dissolve apalutamide (3g) in methanol (30mL) at 25±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with feed rate of the solution 5ml/min and inlet temperature at 70°C to yield apalutamide amorphous form.
Yield: l.5g
Example 4:
Apalutamide (0.5g) and Plasdone S-630 (0.5g) were dissolved in methanol (5mL) at 25±5°C. Filtered through hyflo to remove any undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 65±5°C. The solid obtained was identified as amorphous solid dispersion of apalutamide.
Yield: 0.7g
Example 5:
Apalutamide (0.5g) and Povidone K-30 (0.5g) were dissolved in methanol (5mL) at 25±5°C. Filtered through hyflo to remove undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 65±5°C. The solid obtained was identified as amorphous solid dispersion of apalutamide.
Yield: 0.7g
Example 6:
Apalutamide (0.5g) was dissolved in methanol (5mL) at 25±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates. Added aeropril 300 (0.5g) to the clear solution and distilled completely under vacuum using rotary evaporator at 65±5°C. The solid obtained was identified as amorphous solid dispersion of apalutamide. Yield: 0.7g Example 7:
Apalutamide (0.5g) was dissolved in Toluene (5 ml) at 95°C and the obtained clear solution was gradually cooled to 25±5°C and stirred for 30 min. The precipitated solid was filtered and washed with Toluene (4ml). The wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-Ml
Example 8:
Apalutamide (0.5g) was dissolved in 2-butanol (7.5 ml) at 65°C and the obtained clear solution was gradually cooled to 25±5°C and stirred for 60 min. The precipitated solid was filtered and washed with 2-butanol (2ml). The wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-Ml
Example 9:
Apalutamide (0.5g) was dissolved in Methyl isobutyl ketone (2.5 mL) at 35-40°C and stirred for 30 min and the solution was gradually cooled to 0-5°C. Stirred for lh at 0- 5°C, filtered the solid and washed the solid with chilled methyl isobutyl ketone (1 ml). The solid obtained was dried at 50°C under vacuum to get the apalutamide crystalline form- M2.
Example 10:
Apalutamide (0.5g) was dissolved in acetone (5mL) at 25±5°C. To the resulting clear solution, Isopropyl ether (25 ml) was added slowly and stirred for 1 h. The precipitated solid was filtered and washed with isopropyl ether (5ml). The wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-M3.
Example 11:
Apalutamide (0.5g) was dissolved in dimethyl formamide (5 ml) at 80°C and water (5 ml) was added to the clear solution and stirred for 30 min. The mixture was cooled and stirred for lh to 25-30°C. The precipitated solid was filtered and washed with water (5ml). The wet solid was dried at 50°C under vacuum to get the apalutamide crystalline form-M4. Example 12:
Apalutamide (50 mg) was dissolved in Dimethyl formamide (0.5 mL) at 25±5°C. The resulting clear solution was taken into a test tube and allowed for slow evaporation at 25±5°C for 24h. The solid obtained was identified as apalutamide crystalline Form M5. sExample 13:
Apalutamide (100 mg) was dissolved in Dimethyl formamide (lmL) at 25±5°C. Filtered through hyflo to remove any undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 75±5°C. The solid obtained was identified as apalutamide crystalline Form M5.
Example 14:
Apalutamide (lg) was dissolved in Dimethyl formamide (lOmL) at 25±5°C. Filtered through hyflo to remove any undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporator at 75±5°C. The solid obtained was identified as apalutamide crystalline Form M5.
Example 15: Preparation of crystalline Form M6 of Apalutamide.
Apalutamide form Ml (1.0 g) was suspended in water (20 ml) and maintained under stirring at 25-30°C for 2-3 hours. The reaction mixture was filtered, washed with water (10 ml) and dried the wet material at 50-55°C under vacuum to obtain crystalline Form M6 of Aplutamide. Water content: 2.82%
Example 16: Preparation of crystalline Form M6 of Apalutamide.
Apalutamide form Ml (1.0 g) was suspended in 2-butanol (20 ml) and maintained under stirring at 25-30°C for 2-3 hours. The reaction mixture was filtered, washed with 2-butanol (5 ml) and dried the wet material at 50-55°C under vacuum to get crystalline Form M6 of Apalutamide. Water content: 2.51%
Example 17: Preparation of crystalline Form M6 of Apalutamide. Apalutamide form Ml (1.0 g) was placed in a petri-dish and exposed to 90% relative humidity for 24h. The product obtained was tested by PXRD analysis and identified as crystalline Form M6 of Apalutamide.
Example 18: Preparation of crystalline premix of Apalutamide Form Ml.
Apalutamide (lg) was dissolved in 2-butanol (20 ml) at 85°C and the resulting clear solution was gradually cooled to 25±5°C and stirred for 60 min. Then added Silicon dioxide (lg) and stirred at 25±5°C for 60min. The reaction mass was filtered, washed with 2-butanol (2ml) and the wet solid was dried at 50°C under vacuum for 6h. The solid obtained was identified as crystalline premix of apalutamide Form Ml.
Example 19: Preparation of Crystalline premix of Apalutamide Form M6
Apalutamide form Ml (lg) was suspended in water (10 ml) and maintained under stirring at 25-30°C for 2 hours. Then added Silicon dioxide (lg) and stirred at 25±5°C for lh. The reaction mass was filtered, washed with water (2ml) and the wet solid was dried at 50°C under vacuum for 6h. The solid obtained was identified as crystalline premix of apalutamide Form M6.
Example 20: Preparation of Apalutamide amorphous form
Apalutamide Form M6 (0.2g) was heated using variable temperature powder XRD tool on Bruker D8 X-Ray Diffractometer from 30-l30°C and followed by slow cooling to 30°C. The resulting solid was identified as Apalutamide amorphous form.
Example 21: Preparation of Crystalline Apalutamide Form M6
Apalutamide (lg) was dissolved in 2-butanol (20 ml) at 85°C and the resulting clear solution was gradually cooled to 25±5°C and stirred for 60 min. Then added water (lOml) and stirred at 25±5°C for 60min. The reaction mass was filtered and dried at 50°C under vacuum for 6h. The solid obtained was identified as crystalline Apalutamide Form M6.
Example 22: Preparation of Apalutamide amorphous form
Apalutamide Form M6 (0.5g) was dried at l20-l30°C for lh and followed by slow cooling to 30°C. The resulting solid was identified as Apalutamide amorphous Form. Example 23: Preparation of Crystalline premix of Apalutamide Form M6
Apalutamide (lg) was dissolved in 2-butanol (20 ml) at 85°C and the resulting clear solution was gradually cooled to 25±5°C and stirred for 60 min. Then added water (lOml) and stirred at 25±5°C for 60min. Then added Silicon dioxide (lg) and stirred at 25±5°C for 60min. The reaction mass was filtered and dried at 50°C under vacuum for 6h. The solid obtained was identified as crystalline premix of apalutamide Form M6.
Example 24: Preparation of amorphous solid dispersion of Apalutamide
Crystalline premix of apalutamide Form M6 with Silicon dioxide (0.5g) was dried at l20-l30°C for lh and followed by slow cooling to 30°C. The resulting solid was identified as amorphous solid dispersion of Apalutamide.