Non-hygroscopic crystalline salts of a pyrazole compound, and pharmaceutical compositions and use thereof
View Patent ↗Provided herein are non-hygroscopic crystalline salts of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine and pharmaceutical compositions thereof. Also provided are methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.
1. A non-hygroscopic crystalline salt of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine or an isotopic variant thereof with an acid, wherein the acid is adipic acid, benzoic acid, or p-toluenesulfonic acid.
2. The non-hygroscopic crystalline salt of claim 1 , wherein the salt has a solubility of no greater than 10 mg/mL in water at 25° C.
3. The non-hygroscopic crystalline salt of claim 1 , wherein the acid is adipic acid.
4. The non-hygroscopic crystalline salt of claim 3 , having an X-ray powder diffractogram substantially as shown in FIG. 24 .
5. The non-hygroscopic crystalline salt of claim 1 , wherein the acid is benzoic acid.
6. The non-hygroscopic crystalline salt of claim 5 , having an X-ray powder diffractogram substantially as shown in FIG. 29 .
7. The non-hygroscopic crystalline salt of claim 1 , wherein the acid is p-toluenesulfonic acid.
8. The non-hygroscopic crystalline salt of claim 7 , having an X-ray powder diffractogram with a peak expressed in two-theta at approximately 5.5, 7.6, and 21.9°.
9. A pharmaceutical composition comprising the non-hygroscopic crystalline salt of claim 1 , and a pharmaceutically acceptable excipient.
10. The non-hygroscopic crystalline salt of claim 7 , wherein the salt comprises about one molar equivalent of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine and two molar equivalents of p-toluenesulfonic acid.
11. The non-hygroscopic crystalline salt of claim 7 , wherein the salt comprises about one molar equivalent of (1r,4r)-N 1 -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine and two molar equivalents of p-toluenesulfonic acid.
12. The non-hygroscopic crystalline salt of claim 7 , having an X-ray powder diffractogram with a peak expressed in two-theta at approximately 5.5, 7.6, 12.9, 14.9, 16.2, 17.3, 18.4, 18.6, 21.5, 21.9, 22.3, 22.5, 23.4, 23.8, 24.1, 26.2, 26.9, and 27.0, 28.8°.
13. The non-hygroscopic crystalline salt of claim 7 , having an X-ray powder diffractogram substantially as shown in FIG. 34 .
14. The non-hygroscopic crystalline salt of claim 7 , having a DSC thermogram comprising an endothermic peak at about 228° C.
15. The non-hygroscopic crystalline salt of claim 7 , having a DSC thermogram substantially as shown in FIG. 35 .
16. The non-hygroscopic crystalline salt of claim 7 , having a DVS isotherm graph substantially as shown in FIG. 36 .
17. The non-hygroscopic crystalline salt of claim 7 , wherein the salt is unsolvated.
18. The non-hygroscopic crystalline salt of claim 7 , wherein the salt has a solubility of about 2 mg/mL in water at 25° C.