SOLID FORMS OF (5S)-CYCLOPROPYL-5-[3-[(3S)-4-(3,5-DIFLUOROPHENYL)-3-METHYL-PIPERAZIN-1-YL]-3-OXO-PROPYL]IMIDAZOLIDINE-2,4-DIONE
The present invention relates to solid forms of (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazin-1-yl]-3 -oxo-propyl]imidazolidine-2,4-dione and to pharmaceutical preparations comprising them and methods of their manufacture, as well as the use of said solid forms or preparations for the prophylaxis and/or treatment of inflammatory conditions, muscular disease, fibrotic diseases, viral infection, and/or diseases involving degradation of cartilage and/or disruption of cartilage homeostasis, especially osteoarthritis.
1 . A solid form of a compound according to Formula I:
or a pharmaceutically acceptable solvate thereof.
2 . The solid form according to claim 1 characterized by an X-ray powder diffraction pattern comprising peaks at 6.2, 12.5, 15.7, 19.1, 25.2, 26.4±0.2° 2θ using Cu Kα radiation.
3 . The solid form according to claim 1 characterized by an X-ray powder diffraction pattern comprising peaks at 6.2, 12.5, 14.1, 15.7, 19.1, 21.4, 22.4, 25.2, 26.4±0.2° 2θ using Cu Kα radiation
4 . The solid form according to claim 1 characterized by an X-ray powder diffraction pattern comprising peaks at 6.2, 12.5, 14.1, 14.6, 15.6, 15.7, 17.8, 18.0, 18.8, 19.1, 19.7, 20.8, 21.4, 22.4, 25.2, 26.4, 28.9, 29.0±0.2° 2θ using Cu Kα radiation.
5 . The solid form according to any one of claims 1 to 3 having an X-ray powder diffraction profile substantially as shown in FIG. 1 .
6 . The solid form according to any one of claims 1 to 5 having an endothermic transition at about 80° C., as measured by differential scanning calorimetry.
7 . The solid form according to any one of claims 1 , characterized by an X-ray powder diffraction pattern comprising peaks at 10.3, 15.3, 15.7, 16.7, 18.6±0.2° 2θ using Cu Kα radiation.
8 . The solid form of claim 7 further characterized by an X-ray powder diffraction pattern comprising peaks at 16.7, 24.5, 30.4±0.2° 2θ using Cu Kα radiation.
9 . The solid form of claim 7 or 8 further characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.6, 13.2, 13.6, 14.7, 18.3, 20.3, 20.8, 22.9, 27.2±0.2° 2θ using Cu Kα radiation.
10 . The solid form according to any one of claims 1 and 7 to 9 having an X-ray powder diffraction pattern substantially as shown in FIG. 2 .
11 . The solid form according to any one of claims 1 and 7 to 10 having an endothermic transition at about 159° C., as measured by differential scanning calorimetry.
12 . A process for the preparation of a solid form according to any one of claims 2 - 6 comprising:
a) Admixing amorphous (5S)-cyclopropyl-5-[3- [(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione and isopropyl alcohol,
b) Heating the mixture to about 40° C.,
c) Adding a first batch of water,
d) Cooling the mixture to about 5° C. at a rate of about 0.3° C./min
e) Adding a second batch of water,
f) Filtrating the mixture,
g) Washing the cake with cooled water,
h) Drying the solid.
13 . A process for the preparation of a solid form according to any one of claims 7 - 11 comprising:
a) Admixing amorphous (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione and isopropyl alcohol,
b) Heating the mixture to about 40° C.,
c) Cooling the mixture to about 25° C. at a rate of about 0.1° C./min,
d) Adding methyl cyclohexane,
e) Cooling the mixture to about 5° C. at a rate of about 0.1° C./min,
f) Filtrating the mixture,
g) Washing the cake with cooled methlyl cyclohexane,
h) Drying the solid.
14 . A process for the preparation of a solid form according to any one of claims 7 - 11 comprising:
a) Admixing amorphous (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione and methyl isobutyl ketone,
b) heating the reaction to about 60° C.,
c) Adding diisopropyl ether,
d) Cooling the mixture to about 0° C. in steps of 10° C. at a rate of about 0.3° C./min with contact times of at least 60 min between each steps,
e) Filtrating the mixture,
f) Washing the cake with cooled diisopropyl ether,
g) Drying the solid.
15 . A pharmaceutical composition, comprising a compound or pharmaceutically acceptable salt thereof accord in to any one of claims 1 - 11 , and a pharmaceutically acceptable carrier.
16 . A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 11 , or a pharmaceutical composition according to claim 15 , for use in the treatment of prophylaxis and/or treatment of inflammatory conditions, muscular disease, fibrotic diseases, viral infection, and/or diseases involving degradation of cartilage and/or disruption of cartilage homeostasis.