Polymorphs of Selinexor
The present invention relates to crystalline forms of the compound represented by Structural Formula I, and compositions comprising crystalline forms of the compound represented by Structural Formula I described herein. The crystalline forms of the compound of Structural Formula I and compositions comprising the crystalline forms of the compound of Structural Formula I provided herein, in particular, single crystalline Form A, can be incorporated into pharmaceutical compositions, which can be used to treat various disorders associated with CRM1 activity, including cancer. Also described herein are methods for preparing the compound of Structural Formula I and its single crystalline forms.
1. A composition, comprising particles of a single crystalline form of a compound represented by Structural Formula I:
wherein the single crystalline form is Form A and is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 4.4°, 19.9°, 21.3° and 22.0°; and
the particles have a unimodal particle size distribution characterized by a d(0.9) of 100 microns or less.
2. The composition of claim 1 , where the a unimodal particle size distribution characterized by a d(0.9) of 70 microns or less.
3. The composition of claim 1 , wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θangles of 4.4°, 19.9°, 21.3° and 22.0°.
4. The composition of claim 3 , wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θangles of 4.4°, 19.9°, 20.3°, 21.3°, 22.0°, 23.5° and 25.0°.
5. The composition of claim 4 , wherein the crystalline form is characterized by X-ray powder diffraction peaks at 2θangles of 4.4°, 13.1°, 15.8°, 18.2°, 19.9°, 20.3°, 21.3°, 22.0°, 23.5°, 23.7°, 25.0°, 27.0 °, 28.3° and 28.5°.
6. The composition of claim 1 , wherein the crystalline form is characterized by an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 1A .
7. The composition of claim 1 , wherein the crystalline form is further characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 179° C.
8. The compositions of claim 1 , wherein the particles have a particle size distribution characterized by a d(0.9) of from 10 microns to 100 microns.
9. The compositions of claim 1 , wherein the particles have a particle size distribution characterized by a d(0.9) of from 10 microns to 70 microns.
10. The composition of claim 1 , wherein the particles have a particle size distribution characterized by a d(0.5) of from 10 microns to 35 microns.
11. The composition of claim 1 , wherein the particles have a particle size distribution characterized by a d(0.1) of from 5 microns to 15 microns.
12. The composition of claim 1 , wherein the particles have a particle size distribution characterized by a d(0.9):d(0.1) ratio of from 2 to 10.
13. The composition of claim 1 , wherein the particles have a particle size distribution characterized by a d(0.9):d(0.5) ratio of from 1.5 to 4.5.
14. A pharmaceutical composition, comprising a composition of claim 1 and a pharmaceutically acceptable carrier.
15. A method for treating a disorder associated with CRM1 activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 14 , 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.
16. The method of claim 15 , wherein the disorder is cancer.
17. A method for promoting wound healing in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 14 .
18. The method of claim 16 , wherein the cancer is a leukemia, a myeloma or a lymphoma.
19. The method of claim 16 , wherein the cancer is multiple myeloma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, macroglobulinemia, lung, liposarcoma, alveolar soft part sarcoma, Ewing's sarcoma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, esophageal cancer, gastric cancer, prostate cancer, pancreatic cancer, salivary gland cancer, melanoma, gliomablastoma, malignant thymoma, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CIVIL) or chronic lymphocytic leukemia.
20. The method of claim 19 , wherein the cancer is multiple myeloma.
21. The method of claim 19 , wherein the cancer is diffuse large B-cell lymphoma.
22. A method for treating a disorder associated with CRM1 activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 1 , 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.
23. The method of claim 22 , wherein the disorder is cancer.
24. The method of claim 23 , wherein the cancer is a leukemia, a myeloma or a lymphoma.
25. The method of claim 23 , wherein the cancer is multiple myeloma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, macroglobulinemia, lung, liposarcoma, alveolar soft part sarcoma, Ewing's sarcoma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, esophageal cancer, gastric cancer, prostate cancer, pancreatic cancer, salivary gland cancer, melanoma, gliomablastoma, malignant thymoma, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CIVIL) or chronic lymphocytic leukemia.
26. The method of claim 25 , wherein the cancer is multiple myeloma.
27. The methodd of claim 25 , wherein the cancer is diffuse large B-cell lymphoma.
28. A method for promoting wound healing in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a composition of claim 1 .