Crystalline salts and polymorphs of a P2X3 antagonist
Provided are novel salts and polymorphs of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide, which are potentially useful for modulating a condition mediated by a P2X3 or P2X2/3 receptor. Also provided are pharmaceutical formulations and methods of administration and dosing of these salts and polymorphs to subjects in need thereof.
1. A crystalline citrate Form A of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide characterized by having X-ray powder diffraction peaks at 2θ values of approximately 11.7, 16.2 and 21.1 degrees.
2. The crystalline citrate Form A of claim 1 , further characterized by having X-ray powder diffraction peaks at 2θvalues of approximately 9.4 and 26.3 degrees.
3. The crystalline citrate Form A of claim 2 , further characterized by having X-ray powder diffraction peaks at 2θvalues of approximately 14.4 and 19.5 degrees.
4. The crystalline citrate Form A of claim 1 further characterized by having an X-ray powder diffraction pattern substantially as depicted in FIG. 3 .
5. The crystalline citrate Form A of claim 1 , further characterized by having a proton nuclear magnetic resonance (NMR) signal showing a 1:1 Compound A to citrate ratio.
6. The crystalline citrate Form A of claim 1 , further characterized by having a TGA thermograms showing negligible weight loss up to 160° C., and stepwise weight loss of about 24 wt % between 160° C. and 250° C.
7. The crystalline citrate Form A of claim 1 , further characterized by having a TGA thermogram substantially as depicted in FIG. 4 .
8. The crystalline citrate Form A of claim 1 further characterized by having a DSC thermogram substantially as depicted in FIG. 4 .
9. A crystalline citrate Form A of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide characterized by having X-ray powder diffraction peaks at 2θvalues of approximately 11.7 and 16.2 degrees.
10. A crystalline citrate Form A of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide characterized by having X-ray powder diffraction peaks at 2θvalues of approximately 11.7, 16.2, 21.1 and 26.3 degrees.
11. A pharmaceutical composition comprising the crystalline citrate Form A of claim 1 and a pharmaceutically acceptable carrier.
12. A method of modulating a condition mediated by a P2X3 or P2X2/3 receptor, said method comprising administering an effective amount of the crystalline citrate Form A of claim 1 to a subject in need thereof.
13. The method of claim 12 , wherein the condition mediated by a P2X3 or P2X2/3 receptor is selected from cough, chronic cough and urge to cough.
14. The method of claim 12 , wherein the condition mediated by a P2X3 or P2X2/3 receptor is cough.
15. The method of claim 12 , wherein the condition mediated by a P2X3 or P2X2/3 receptor is chronic cough.
16. The method of claim 12 , wherein the condition is selected from pelvic hypersensitivity, bladder pain syndrome and endometriosis.
17. A method of treating a condition mediated by a P2X3 or P2X2/3 receptor, said method comprising administering an effective amount of the crystalline citrate Form A of claim 1 to a subject in need thereof.
18. The method of claim 17 , wherein the condition mediated by a P2X3 or P2X2/3 receptor is selected from cough, chronic cough and urge to cough.
19. The method of claim 17 , wherein the condition mediated by a P2X3 or P2X2/3 receptor is cough.
20. The method of claim 17 , wherein the condition mediated by a P2X3 or P2X2/3 receptor is chronic cough.