Crystalline form of Selinexor
The invention relates to a crystalline form of the compound represented by Structural Formula 1, and pharmaceutical compositions comprising the crystalline form of the compound represented by Structural Formula 1 described herein. The crystalline form of the compound of Structural Formula 1 and compositions comprising the crystalline form of the compound represented by Structural Formula 1 provided herein, can be incorporated into pharmaceutical compositions, which can be used to treat various disorders. Also described herein are methods for preparing the crystalline form of the compound represented by Structural Formula 1.
1 . A crystalline form of the compound represented by Structural Formula 1:
wherein
(i) the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 18.75°, 20.16°, 21.37°, and 23.49° in an x-ray powder diffractogram obtained in a transmittance mode with a ground sample of the crystalline form;
(ii) the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 12.61°, 16.90°, 21.26°, and 34.58° in an x-ray powder diffractogram obtained in a reflectance mode with an unground sample of the crystalline form; or
(iii) the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 16.8°, 20.1°, 21.4°, and 27.2° in an x-ray powder diffractogram obtained in a transmittance mode with an unground sample of the crystalline form.
2 . The crystalline form of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 18.75°, 20.16°, 21.37°, 23.49°, and 24.16° obtained in accordance with (i).
3 . The crystalline form of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 14.00°, 18.75°, 20.16°, 21.37°, 22.55°, 23.49°, 24.16°, and 27.21° obtained in accordance with (i).
4 . The crystalline form of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles of 14.00°, 15.89°, 16.77°, 18.75°, 20.16°, 20.72°, 20.98°, 21.37°, 22.55°, 22.96°, 23.49°, 24.16°, 27.21°, and 28.99° obtained in accordance with (i).
5 . The crystalline form of claim 1 , wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 1 or FIG. 9 .
6 . The crystalline form of claim 1 , wherein the crystalline form is characterized by a DSC thermogram having an endothermic event at about 184° C.
7 . The crystalline form of claim 1 , wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 5 .
8 . The crystalline form of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 8.33°, 12.61°, 15.23°, 16.62°, 16.90°, 17.28°, 19.97°, 21.26°, 21.63°, 30.10°, 34.58°, 39.10°, 43.57°, and 53.13° obtained in accordance with (ii).
9 . The crystalline form of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 13.5°, 14.0°, 16.8°, 20.1°, 20.7°, 20.9°, 21.4°, 22.5°, 23.0°, 23.5°, 24.2°, 26.9°, and 27.2° obtained in accordance with (iii).
10 . The crystalline form of claim 1 , wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 8 .
11 . A tablet, comprising the crystalline form of claim 1 and a pharmaceutically acceptable carrier.
12 . A method of preparing a crystalline form of the compound represented by Structural Formula 1:
wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 18.75°, 20.16°, 21.37°, and 23.49° in an x-ray powder diffractogram obtained in a transmittance mode with a ground sample of the crystalline form,
the method comprising:
combining crystalline Form A of the compound represented by Structural Formula 1 with a solvent, thereby generating a mixture;
thermally cycling the mixture at least once; and
isolating the solid particles of the crystalline form,
wherein thermally cycling the mixture comprises:
heating the mixture to a first temperature over a first period of time; and
cooling the mixture to a second temperature over a second period of time.
13 . The method of claim 12 , wherein the solvent comprises water and alcohol, and the solvent has an alcohol-to-water volume ratio from about 90/10 to about 10/90.
14 . The method of claim 13 , wherein the alcohol is selected from ethanol, 1-propanol, isopropanol, 1-butanol, or 2-butanol.
15 . The method of claim 12 , wherein the first temperature is from about 30° C. to about 90° C.
16 . The method of claim 12 , wherein the first period of time is from about 30 minutes to about 150 minutes.
17 . The method of claim 12 , wherein the second temperature is from about −20° C. to about 20° C.
18 . The method of claim 12 , wherein the second period of time is from about 90 minutes to about 240 minutes.
19 . The method of claim 12 , wherein the mixture is thermally cycled from 2 times to 10 times.
20 . A method for treating or preventing a CRM1-associated disease or disorder, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the crystalline form of claim 1 .
21 . The method of claim 20 , wherein the disorder is a proliferative disorder, cancer, an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder, a neurodegenerative disorder, a disorder of abnormal tissue growth, a disorder related to food intake, an allergic disorder, or a respiratory disorder.
22 . The method of claim 21 , wherein the disorder is cancer.
23 . The method of claim 21 , wherein the cancer is multiple myeloma.