Solid forms of (
The present invention relates to solid forms of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1) in substantially crystalline form (Form A) or amorphous form, pharmaceutical compositions thereof, and methods of treatment therewith.
1. A method of treating a CFTR mediated disease in a subject comprising administering to the subject an effective amount of (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A characterized by one or more peaks at 19.3 to 19.7 degrees, 21.5 to 21.9 degrees, 16.9 to 17.3, and 20.2 to 20.6 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation, wherein the CFTR mediated disease is selected from male infertility and pancreatic insufficiency.
2. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by one or more peaks at about 19.5, 21.7, and 17.1 degrees.
3. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a peak at 20.2 to 20.6 degrees.
4. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a peak at about 20.4 degrees.
5. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is further characterized by a peak at 18.6 to 19.0 degrees.
6. The method of claim 5 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a peak at about 18.8 degrees.
7. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is further characterized by a peak at 24.5 to 24.9 degrees.
8. The method of claim 7 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a peak at about 24.7 degrees.
9. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is further characterized by a peak at 9.8 to 10.2 degrees.
10. The method of claim 9 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a peak at about 10.0 degrees.
11. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is further characterized by a peak at 4.8 to 5.2 degrees.
12. The method of claim 11 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is further characterized by a peak at about 5.0 degrees.
13. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is further characterized by a peak at 24.0 to 24.4 degrees.
14. The method of claim 13 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a peak at about 24.2 degrees.
15. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is further characterized by a peak at 18.3 to 18.7 degrees.
16. The method of claim 15 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a peak at about 18.5 degrees.
17. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a diffraction pattern substantially similar to that of FIG. 4 .
18. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A is characterized by a diffraction pattern substantially similar to that of FIG. 5 .
19. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A has a monoclinic crystal system, a C2 space group, and the following unit cell dimensions:
a=21.0952(16) Å α=90°
b=6.6287(5) Å β=95.867(6)°
c=17.7917(15) Å γ=90°.
20. The method of claim 1 , wherein the (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A additionally comprises a pharmaceutically acceptable carrier.
21. The method of claim 20 , wherein said (R)-1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropran-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide crystalline Form A further comprises an additional therapeutic agent.
22. The method of claim 21 , wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, or a nutritional agent.
23. The method of claim 1 , wherein the method comprises administering an additional therapeutic agent.
24. The method of claim 23 , wherein the therapeutic agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, or a nutritional agent.
25. The method of claim 24 , wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.