Claims for Patent: 11,873,300

Summary for Patent: 11,873,300

Title:	Crystalline forms of CFTR modulators
Abstract:	Crystalline forms of Compound I: pharmaceutically acceptable salts thereof, and solvates and hydrates thereof are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.
Inventor(s):	Yi Shi, Kevin J. Gagnon, Jicong Li, Jennifer Lu, Ales Medek, Muna Shrestha, Michael Waldo, Beili Zhang, Carl L. Zwicker, Corey Don Anderson, Jeremy J. Clemens, Thomas Cleveland, Timothy Richard Coon, Bryan Frieman, Peter Grootenhuis, Sara Sabina Hadida Ruah, Jason McCartney, Mark Thomas Miller, Prasuna Paraselli, Fabrice Pierre, Sara E. Swift, Jinglan Zhou
Assignee:	Vertex Pharmaceuticals Inc
Application Number:	US16/992,441
Patent Claims:	1. Compound I calcium salt hydrate Form D 2. A pharmaceutical composition comprising the compound according to claim 1. 3. The pharmaceutical composition according to claim 2, further comprising one or more additional CFTR modulating compounds. 4. The pharmaceutical composition according to claim 3, wherein at least one additional CFTR modulating compound is a CFTR potentiator. 5. The pharmaceutical composition according to claim 3, wherein at least one additional CFTR modulating compound is a CFTR corrector. 6. The pharmaceutical composition according to claim 3, wherein the one or more additional CFTR modulating compounds are selected from: (a) Compound II: 7. A method of treating cystic fibrosis comprising administering the Compound I calcium salt hydrate Form D to a subject in need thereof. 8. The method of treating cystic fibrosis according to claim 7, wherein the Compound I calcium salt hydrate Form D is administered with one or more additional CFTR modulating compounds. 9. The method of treating cystic fibrosis according to claim 8, wherein the one or more additional CFTR modulating compound are selected from: 10. A method of preparing Compound I calcium salt hydrate Form D according to claim 1, comprising (a) charging Compound I calcium salt hydrate Form A with EtOH/water. (b) heating to 65° C., and (c) isolating the resulting solids, to provide Compound I calcium salt hydrate Form D. 11. The Compound I calcium salt hydrate Form D characterized by an X-ray powder diffractogram (XRPD) having signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta. 12. The Compound I calcium salt hydrate Form D of claim 11, characterized by an XRPD having (a) signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta; and (b) one or more signals selected from 5.5±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 19.7±0.2 degrees two-theta, 21.5±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.0±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta. 13. Compound I calcium salt hydrate Form D of claim 11, characterized by an XRPD having signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta. 14. The Compound I calcium salt hydrate Form D of claim 11, characterized by an XRPD having signals at 6.1±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, 19.7±0.2 degrees two-theta, 22.8±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta. 15. The Compound I calcium salt hydrate Form D of claim 1, characterized by an X-ray powder diffractogram substantially similar to FIG. 13 . 16. The Compound I calcium salt hydrate Form D characterized by a triclinic crystal system, a P1 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Cμ Kα radiation (λ=1.5478 Å) of a 12.78 ± .01 Å α 64.93 ± .02º b 16.64 ± .01 Å β 75.10 ± .02º c 18.19 ± .01 Å γ 68.22 ± .02º. 17. The Compound I calcium salt hydrate Form D characterized by a 13C solid state nuclear magnetic resonance (13C ss NMR) spectrum with one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm. 18. The substantially crystalline Compound I calcium salt hydrate Form D of claim 17 , characterized by a 13C ssNMR spectrum with one or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm. 19. The Compound I calcium salt hydrate Form D of claim 17, characterized by a 13C ssNMR spectrum with (a) one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm; and (b) one or more peaks selected from 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and 98.6±0.2 ppm. 20. The Compound I calcium salt hydrate Form D of claim 1, characterized by a 13C ssNMR spectrum substantially similar to FIG. 14 . 21. The pharmaceutical composition according to claim 2, wherein at least 85% of the Compound I is Compound I calcium salt hydrate Form D. 22. The pharmaceutical composition according to claim 2, wherein at least 95% of the Compound I is Compound I calcium salt hydrate Form D. 23. A pharmaceutical composition comprising Compound I and a pharmaceutically acceptable carrier, wherein the Compound I comprises Compound I calcium salt hydrate Form D 24. The composition according to claim 23, wherein at least 85% of the Compound I is Compound I calcium salt hydrate Form D. 25. The composition according to claim 23, wherein at least 95% of the Compound I is Compound I calcium salt hydrate Form D.