Pseudopolymorphs of an HCV NS5A inhibitor and uses thereof
View Patent ↗The present invention relates to novel Pseudopolymorphs of Compound A, compositions comprising at least one Pseudopolymorph of Compound A, and methods of using the Pseudopolymorphs of Compound A for preparing compositions useful for treating or preventing HCV infection in a patient, wherein Compound A has the structure.
1. A crystalline form of the compound having the structure:
wherein said crystalline form is selected from the following forms: Form A (methanolate), Form B (ethanolate), Form C (1-propanolate), Form D (2-propanolate), Form E (acetonate), Form F (1-butanolate), Form G (ethylene glycolate), Form H (propylene glycolate), Form I (methyl isobutyl ketone/propylene glycol mixed solvate), Form J (hydrate) and Form K (1,5-naphthalene disulfonic acid salt).
2. The crystalline form according to claim 1 , which is pharmaceutically acceptable.
3. The crystalline form of claim 1 , which is the 1,5-napthalene disulfonic acid salt of Compound A.
4. A pharmaceutical composition comprising an effective amount of the crystalline form of claim 1 and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition according to claim 4 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
6. A pharmaceutical composition comprising:
(1) the crystalline form of claim 1 ;
(2) a concentration-enhancing polymer, where the concentration-enhancing polymer increases the bioavailability or enhances the dissolution behavior of the crystalline form of claim 1 , and is water soluble or readily disperses in water; and
(3) optionally one or more surfactants.
7. The crystalline form of claim 1 , which is Form A (methanolate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 6.19±0.2, 10.10±0.2, 15.76±0.2, 17.27±0.2 and 21.24±0.2.
8. The crystalline form of claim 1 , which is Form B (ethanolate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 6.13±0.2, 10.05±0.2, 13.30±0.2, 15.66±0.2 and 17.53±0.2.
9. The crystalline form of claim 1 , which is Form C (1-propanolate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 6.23±0.2, 10.16±0.2, 12.49±0.2, 18.37±0.2 and 19.62±0.2.
10. The crystalline form of claim 1 , which is Form D (2-propanolate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of 6.12±0.2, 10.03±0.2, 13.38±0.2, 17.57±0.2 and 18.33±0.2.
11. The crystalline form of claim 1 , which is Form E (acetonate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 5.92±0.2, 8.52±0.2, 11.97±0.2, 17.07±0.2 and 20.39±0.2.
12. The crystalline form of claim 1 , which is Form F (1-butanolate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 5.68±0.2, 9.88±0.2, 11.69±0.2, 18.38±0.2 and 19.29±0.2.
13. The crystalline form of claim 1 , which is Form G (ethylene glycolate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 9.87±0.2, 13.08±0.2, 17.23±0.2, 19.86±0.2 and 20.93±0.2.
14. The crystalline form of claim 1 , which is Form H (propylene glycolate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 6.08±0.2, 9.99±0.2, 13.28±0.2, 15.64±0.2 and 17.43±0.2.
15. The crystalline form of claim 1 , which is Form I (methyl isobutyl ketone/propylene glycol mixed solvate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 4.89±0.2, 5.74±0.2, 11.82±0.2, 18.66±0.2 and 19.42±0.2.
16. The crystalline form of claim 1 , which is Form J (hydrate), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 6.31±0.2, 10.01±0.2, 10.34±0.2, 12.54±0.2 and 17.39±0.2.
17. The crystalline form of claim 1 , which is Form K (1,5-napthalene disulfonic acid salt), having an X-ray powder diffraction pattern comprising diffraction peaks at 2-theta values, when measured using Cu K α radiation, of about 15.16±0.2, 18.77±0.2, 19.43±0.2, 23.11±0.2 and 24.34±0.2.