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
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 solid dispersion comprising substantially amorphous (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) and a polymer, wherein the substantially amorphous Compound 1 comprises less than about 15% crystalline Compound 1.
2. The solid dispersion of claim 1 , wherein the substantially amorphous Compound 1 comprises less than about 10% crystalline Compound 1.
3. The solid dispersion of claim 1 , wherein the substantially amorphous Compound 1 comprises less than about 5% crystalline Compound 1.
4. The solid dispersion of claim 1 , wherein the polymer is present in the solid dispersion in an amount of from 10% by weight to 80% by weight of the solid dispersion.
5. The solid dispersion of claim 1 , wherein the polymer is selected from hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS).
6. A pharmaceutical composition comprising a solid dispersion, wherein the solid dispersion comprises substantially amorphous (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) and a polymer, wherein the substantially amorphous Compound 1 comprises less than about 15% crystalline Compound 1.
7. The pharmaceutical composition of claim 6 , wherein the substantially amorphous Compound 1 in the solid dispersion comprises less than about 10% crystalline Compound 1.
8. The pharmaceutical composition of claim 6 , wherein the substantially amorphous Compound 1 in the solid dispersion comprises less than about 5% crystalline Compound 1.
9. The pharmaceutical composition of claim 6 , wherein the polymer of the solid dispersion is present in an amount of from 10% by weight to 80% by weight of the solid dispersion.
10. The pharmaceutical composition of claim 6 , wherein the polymer of the solid dispersion is selected from hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS).
11. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition further comprises an additional therapeutic agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, and a nutritional agent.
12. The pharmaceutical composition of claim 11 , wherein the additional therapeutic agent is N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
13. A method of treating cystic fibrosis comprising administering to a patient a pharmaceutical composition comprising a solid dispersion comprising substantially amorphous (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) and a polymer, wherein the substantially amorphous Compound 1 comprises less than about 15% crystalline Compound 1.
14. The method of claim 13 , wherein the substantially amorphous Compound 1 comprises less than about 10% crystalline Compound 1.
15. The method of claim 13 , wherein the substantially amorphous Compound 1 comprises less than about 5% crystalline Compound 1.
16. The method of claim 13 , wherein the polymer of the solid dispersion is present in an amount of from 10% by weight to 80% by weight of the solid dispersion.
17. The method of claim 13 , wherein the polymer of the solid dispersion is selected from hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS).
18. The method of claim 13 , wherein the method further comprises administering an additional therapeutic agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, and a nutritional agent.
19. The pharmaceutical composition of claim 18 , wherein the additional therapeutic agent is N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.