Solvate form M of trametinib dimethyl sulfoxide and methods of making and using thereof

1. A crystalline Form M of trametinib dimethyl sulfoxide solvate having the following formula,

wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.6±0.2°, 20.0±0.2°, 23.3±0.2° and 26.5±0.2°.

2. The crystalline Form M of trametinib dimethyl sulfoxide solvate according to claim 1 wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.4±0.2°, 18.6±0.2°, 20.0±0.2°, 20.3±0.2°, 23.3±0.2°, 26.5±0.2° and 27.9±0.2°.

3. The crystalline Form M of trametinib dimethyl sulfoxide solvate according to claim 2 , wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.4±0.2°, 18.6±0.2°, 20.0±0.2°, 20.3±0.2°, 20.9±0.2°, 21.1±0.2°, 23.3±0.2°, 25.4±0.2°, 26.5±0.2°, 27.9±0.2° and 28.3±0.2°.

4. The crystalline Form M of trametinib dimethyl sulfoxide solvate according to claim 1 , wherein the Fourier transform infrared spectrum of the Form M comprises the following characteristic peaks expressed by wavenumbers at 791, 1034, 1280, 1304, 1319, 1418, 1489, 1544, 1589, 1635 and 3079 cm −1 .

5. The crystalline Form M of trametinib dimethyl sulfoxide solvate according to claim 1 , wherein D 50 is at least 10 μm, and/or D 10 is at least 5 μm, and/or D 90 is at least 30 μm.

6. A pharmaceutical composition comprising an effective amount of the crystalline Form M of trametinib dimethyl sulfoxide solvate according to claim 1 and at least one pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6 , wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2 °, 11.4±0.2°, 16.8±0.2°, 18.4±0.2°, 18.6±0.2°, 20.0±0.2°, 20.3±0.2°, 23.3±0.2°, 26.5±0.2° and 27.9±0.2°.

8. The pharmaceutical composition according to claim 7 , wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.4±0.2°, 18.6±0.2°, 20.0±0.2°, 20.3±0.2°, 20.9±0.2°, 21.1±0.2°, 23.3±0.2°, 25.4±0.2°, 26.5±0.2°, 27.9±0.2° and 28.3±0.2°.

9. The pharmaceutical composition according to claim 6 , wherein the Fourier transform infrared spectrum of the Form M comprises the following characteristic peaks expressed by wavenumbers at 791, 1034, 1280, 1304, 1319, 1418, 1489, 1544, 1589, 1635 and 3079 cm −1 .

10. A pharmaceutical composition comprising an effective amount of the crystalline Form M of trametinib dimethyl sulfoxide solvate according to claim 1 and at least one pharmaceutically acceptable excipient, wherein the Form M is prepared according to a process selected from one of the following methods (1), (2), or (3):

(1) suspending trametinib in dimethyl sulfoxide, stirring at room temperature for 3-10 days to crystallize and recovering the crystalline Form M of trametinib dimethyl sulfoxide solvate;

(2) suspending another trametinib dimethyl sulfoxide solvate Form other than Form M in dimethyl sulfoxide, stirring at room temperature for 3-10 days to crystallize and recovering the crystalline Form M of trametinib dimethyl sulfoxide solvate; and

(3) cooling the solution of trametinib in dimethyl sulfoxide from 50° C. to 20° C. at a rate of 2-10° C./hour, stirring at 20° C. for 10-24 hours and recovering the crystalline Form M of trametinib dimethyl sulfoxide solvate.

11. A method for inhibiting mitogen-activated protein kinase activity in a patient having a hyperproliferative disorder, comprising administering to a patient in need thereof an effective amount of the crystalline Form M of trametinib dimethyl sulfoxide solvate according to claim 1 or the pharmaceutical composition according to claim 6 ,

wherein the hyperproliferative disorder is selected from the group consisting of brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, melanoma, neuroblastoma and sarcoma.

12. The method according to claim 11 , wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.4±0.2°, 18.6±0.2°, 20.0±0.2°, 20.3±0.2°, 23.3±0.2°, 26.5±0.2° and 27.9±0.2°.

13. The method according to claim 12 , wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.4±0.2°, 18.6±0.2°, 20.0±0.2°, 20.3±0.2°, 20.9±0.2°, 21.1±0.2°, 23.3±0.2°, 25.4±0.2°, 26.5±0.2°, 27.9±0.2° and 28.3±0.2°.

14. The method according to claim 11 , wherein the Fourier transform infrared spectrum of the Form M comprises the following characteristic peaks expressed by wavenumbers at 791, 1034, 1280, 1304, 1319, 1418, 1489, 1544, 1589, 1635 and 3079 cm −1 .

15. A process for preparing the crystalline Form M of trametinib dimethyl sulfoxide solvate according to claim 1 , which is selected from one of the following methods (1), (2), or (3):

(1) suspending trametinib in dimethyl sulfoxide, stirring at room temperature for 3-10 days to crystallize and recovering the crystalline Form M of trametinib dimethyl sulfoxide solvate;

(2) suspending another trametinib dimethyl sulfoxide solvate Form other than Form M in dimethyl sulfoxide, stirring at room temperature for 3-10 days to crystallize and recovering the crystalline Form M of trametinib dimethyl sulfoxide solvate; and

(3) cooling the solution of trametinib in dimethyl sulfoxide from 50° C. to 20° C. at a rate of 2-10° C./hour, stirring at 20° C. for 10-24 hours and recovering the crystalline Form M of trametinib dimethyl sulfoxide solvate.

16. The process according to claim 15 , wherein:

in method (1), the ratio of trametinib and dimethyl sulfoxide is 30-50 mg:1 mL, and the duration of crystallization is 3-7 days; and

in method (2), the ratio of another trametinib dimethyl sulfoxide solvate Form other than Form M and dimethyl sulfoxide is 30-50 mg: 1 mL, and the duration of crystallization is 3-7 days; and

in method (3), the concentration of the solution of trametinib in dimethyl sulfoxide is 30-60 mg/mL;

the solution is cooled from 40° C. to 20° C.;

the cooling rate is 2-5° C./hour; and

the duration of stirring is 10-16 hours.

17. The process according to claim 16 , wherein:

in method of (1), the ratio of trametinib and dimethyl sulfoxide is 40-50 mg:1 mL;

in method (2), the ratio of another trametinib dimethyl sulfoxide solvate Form other than Form M and dimethyl sulfoxide is 40-50 mg:1 mL; and

in method (3), the concentration of the solution of trametinib in dimethyl sulfoxide is 50-60 mg/mL.

18. A process for preparing a pharmaceutical composition comprising admixing an effective amount of a crystalline Form M of trametinib dimethyl sulfoxide solvate with at least one pharmaceutically acceptable excipient, wherein the crystalline Form M of trametinib dimethyl sulfoxide solvate has the following formula,

and wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.6±0.2°, 20.0±0.2°, 23.3±0.2° and 26.5±0.2°.

19. The process according to claim 18 , wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.4±0.2°, 18.6±0.2°, 20.0±0.2°, 20.3±0.2°, 23.3±0.2°, 26.5±0.2° and 27.9±0.2°.

20. The process according to claim 19 , wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.4±0.2°, 18.6±0.2°, 20.0±0.2°, 20.3±0.2°, 20.9±0.2°, 21.1±0.2°, 23.3±0.2°, 25.4±0.2°, 26.5±0.2°, 27.9±0.2° and 28.3±0.2°.

21. The process according to claim 18 , wherein the Fourier transform infrared spectrum of the Form M comprises the following characteristic peaks expressed by wavenumbers at 791, 1034, 1280, 1304, 1319, 1418, 1489, 1544, 1589, 1635 and 3079 cm −1 .

22. A crystalline Form M of trametinib dimethyl sulfoxide solvate having the following formula,

wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.6±0.2°, 20.0±0.2°, 23.3±0.2° and 26.5±0.2°,

wherein the Form M contains less than 0.15% by weight of A impurity,

23. A crystalline Form M of trametinib dimethyl sulfoxide solvate having the following formula,

wherein the Form M is characterized by a powder X-ray diffraction pattern measured using Cu-Kα radiation comprising the following specific peaks at 2θ values: 7.8±0.2°, 11.4±0.2°, 16.8±0.2°, 18.6±0.2°, 20.0±0.2°, 23.3±0.2° and 26.5±0.2°,

wherein when stored at 44% relative humidity under room temperature for 9 months, its X-ray diffraction pattern shows no signs of form change.