Crystalline forms of tyrosine kinase inhibitors and their salts

1. A method of treating pain in a patient, comprising:

administering to a patient in need of said treating, a crystalline polymorph Form A of Compound I, sodium 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate, with the following structure:

characterized by having x-ray powder diffraction pattern peak positions at degree two-theta of 10.0±0.3, 20.1±0.3, and 23.6±0.3.

2. The method of claim 1 , wherein the administered crystalline polymorph is further characterized by having x-ray powder diffraction pattern peak positions at degree two-theta of 14.5±0.3 and 18.1±0.3.

3. The method of claim 1 , wherein the administered crystalline polymorph is further characterized by having x-ray powder diffraction pattern peak positions at degree two-theta of 9.7±0.3 and 21.2±0.3.

4. The method of claim 1 , wherein the administered crystalline polymorph is further characterized by having x-ray powder diffraction pattern peak positions at degree two-theta of 14.5±0.3, 18.1±0.3, 9.7±0.3, and 21.2±0.3.

5. The method of claim 1 , wherein the administered crystalline polymorph exhibits an x-ray powder diffraction pattern that is substantially similar to that of FIG. 4 .

6. The method of claim 1 , wherein the administered crystalline polymorph exhibits a Raman spectrum that is substantially similar to that of FIG. 5 .

7. The method of claim 1 , wherein the administered crystalline polymorph exhibits a differential scanning calorimetry thermogram having an endotherm with an onset of about 244° C.

8. The method of claim 1 , wherein the administered crystalline polymorph exhibits a differential scanning calorimetry thermogram having an endotherm with a peak of about 250° C.

9. The method of claim 1 , wherein said pain is neuropathic pain.

10. A method of treating pain in a patient, comprising:

administering to a patient in need of said treating, a crystalline polymorph Form A of Compound I, sodium 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate, with the following structure:

characterized by having an x-ray powder diffraction pattern exhibiting three or more peak positions at degree two-theta selected from the group consisting of: 7.160, 8.757, 9.820, 10.161, 12.459, 14.641, 15.219, 17.680, 18.240, 19.104, 20.220, 21.381, 22.579, 23.721, 24.898, 25.761, 25.522, 27.161, 28.321, 29.481, 30.921, and 34.281.

11. The method of claim 10 , wherein the administered crystalline polymorph exhibits an x-ray powder diffraction pattern having five or more peak positions at degree two-theta selected from the group consisting of: 7.160, 8.757, 9.820, 10.161, 12.459, 14.641, 15.219, 17.680, 18.240, 19.104, 20.220, 21.381, 22.579, 23.721, 24.898, 25.761, 25.522, 27.161, 28.321, 29.481, 30.921, and 34.281.

12. The method of claim 10 , wherein the administered crystalline polymorph exhibits an x-ray powder diffraction pattern having seven or more peak positions at degree two-theta selected from the group consisting of: 7.160, 8.757, 9.820, 10.161, 12.459, 14.641, 15.219, 17.680, 18.240, 19.104, 20.220, 21.381, 22.579, 23.721, 24.898, 25.761, 25.522, 27.161, 28.321, 29.481, 30.921, and 34.281.

13. The method of claim 10 , wherein the administered crystalline polymorph exhibits an x-ray powder diffraction pattern having ten or more peak positions at degree two-theta selected from the group consisting of: 7.160, 8.757, 9.820, 10.161, 12.459, 14.641, 15.219, 17.680, 18.240, 19.104, 20.220, 21.381, 22.579, 23.721, 24.898, 25.761, 25.522, 27.161, 28.321, 29.481, 30.921, and 34.281.

14. The method of claim 10 , wherein the administered crystalline polymorph exhibits an x-ray powder diffraction pattern having peak positions at degree two-theta of: 7.160, 8.757, 9.820, 10.161, 12.459, 14.641, 15.219, 17.680, 18.240, 19.104, 20.220, 21.381, 22.579, 23.721, 24.898, 25.761, 25.522, 27.161, 28.321, 29.481, 30.921, and 34.281.

15. The method of claim 10 , wherein said pain is neuropathic pain.

16. A method of treating pain in a patient, comprising administering to a patient in need of said treating a composition, comprising:

a) a crystalline polymorph Form A of Compound I, sodium 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate, with the following structure:

characterized by having x-ray powder diffraction pattern peak positions at degree two-theta of 10.0±0.3, 20.1±0.3, and 23.6±0.3;

or

b) a combination of said crystalline polymorph Form A of Compound I and an amorphous form of Compound I;

and

one or more pharmaceutically acceptable excipients.

17. The method of claim 16 , wherein said pain is neuropathic pain.

18. A method of treating pain in a patient, comprising administering to a patient in need of said treating a solid or semi-solid dosage form, comprising:

a) a crystalline polymorph Form A of Compound I, sodium 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate, with the following structure:

characterized by having x-ray powder diffraction pattern peak positions at degree two-theta of 10.0±0.3, 20.1±0.3, and 23.6±0.3; or

b) a combination of said crystalline polymorph Form A of Compound I and an amorphous form of Compound I.

19. The method of claim 18 , wherein the administered solid or semi-solid dosage form comprises one or more of a tablet, hard capsule, soft capsule, powder, suppository, and gel.

20. The method of claim 18 , wherein the administered solid or semi-solid dosage form comprises one or more of an injectable form, a transdermal patch, a sprayable form, and an implantable depot.

21. The method of claim 18 , wherein said pain is neuropathic pain.

22. The method of claim 1 , wherein said pain is inflammatory pain.

23. The method of claim 10 , wherein said pain is inflammatory pain.

24. The method of claim 16 , wherein said pain is inflammatory pain.

25. The method of claim 18 , wherein said pain is inflammatory pain.

26. The method of claim 1 , wherein said patient is a human.

27. The method of claim 16 , wherein said patient is a human.

28. The method of claim 18 , wherein said patient is a human.

29. The method of claim 16 , wherein the combination is formulated for oral, transdermal, or transmucosal administration.

30. The method of claim 29 , wherein the combination, for oral administration is in the form of a tablet, a lozenge, an aqueous suspension, an oily suspension, a capsule, granules, a powder, an emulsion, a syrup, or an elixir.

31. The method of claim 16 , further comprising administering an opioid receptor agonist.