Crystal form of dabrafenib mesylate and preparation method thereof
View Patent ↗The present invention involves novel crystal forms of Dabrafenib mesylate and preparation method thereof, wherein the novel crystal forms are more stable in water or an aqueous system, and have greater solubility and dissolution rate in water, thus having better stability and bioavailability compared with the existing crystal forms.
1. A Crystal Form IV of Dabrafenib methanesulfonate with the structural formula shown below, and Crystal Form IV is a hydrate,
wherein the Crystal Form IV of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern measured using Cu—Kα radiation having the characteristic peaks at the diffraction angle 2θ of 4.7±0.2°, 9.2±0.2°, 12.8±0.2°, 13.8±0.2°, 15.0±0.2° and 16.3±0.2°.
2. The Crystal Form IV of Dabrafenib methanesulfonate according to claim 1 , wherein the Crystal Form IV of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern having the characteristic peaks at the diffraction angle 2θ of 4.7±0.2°, 9.2±0.2°, 12.8±0.2°, 13.8±0.2°, 15.0±0.2°, 16.3±0.2°, 18.0±0.2°, 18.6±0.2°, 20.6±0.2°, 22.9±0.2°, 23.8±0.2° and 24.3±0.2°.
3. The Crystal Form IV of Dabrafenib methanesulfonate according to claim 2 , wherein the Crystal Form IV of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern having the following characteristic peaks at the diffraction angles 2θ and their relative intensities:
Diffraction angle 2θ
Relative intensity %
4.7 ± 0.2°
25.5
9.2 ± 0.2°
100.0
12.8 ± 0.2°
46.1
13.8 ± 0.2°
34.2
15.0 ± 0.2°
40.3
16.3 ± 0.2°
49.3
18.0 ± 0.2°
25.4
18.6 ± 0.2°
34.7
20.6 ± 0.2°
32.9
22.9 ± 0.2°
18.6
23.4 ± 0.2°
16.5
23.8 ± 0.2°
41.5
24.3 ± 0.2°
41.0
24.8 ± 0.2°
11.8
25.6 ± 0.2°
11.5
27.1 ± 0.2°
16.1.
4. A method of preparing Crystal Form IV of Dabrafenib methanesulfonate according to claim 1 , comprising:
1) dissolving Crystal Form I of Dabrafenib methanesulfonate in a mixed solution of methanol and tetrahydrofuran, evaporating to recrystallize, then separating and drying the precipitated crystals to get the Crystal Form IV of Dabrafenib methanesulfonate;
wherein the volume ratio of methanol to tetrahydrofuran is 0.1:1 to 100:1; or
2) dissolving Crystal Form I of Dabrafenib methanesulfonate in acetone, evaporating to crystallize, then separating and drying the precipitated crystals to get the Crystal Form IV of Dabrafenib methanesulfonate; or
3) dissolving Crystal Form I of Dabrafenib methanesulfonate in isopropanol, adding polyacrylic acid, evaporating to crystallize, then separating and drying the precipitated crystals to get the Crystal Form IV of Dabrafenib methanesulfonate;
wherein the amount of the polyacrylic acid is 0.1 wt % to 10 wt % of that of the Crystal Form I;
wherein the average molecular weight of the polyacrylic acid is 2,000 to 5,000;
and in the above three preparation methods, the amount of the Crystal Form I is 0.1 to 1 times of its solubility in the corresponding solution at room temperature;
the crystallizing temperature is room temperature to 40° C.; the duration of crystallizing is 1 to 14 days;
and the drying temperature is 30° C. to 120° C.; the duration of drying is 10 to 72 hours; or
4) storing Crystal Form II or Crystal Form V of Dabrafenib methanesulfonate to get the Crystal Form IV of Dabrafenib methanesulfonate;
wherein the storage temperature is room temperature to 40° C.; the duration of storage is 15 minutes to 7 days; or
5) heating Crystal Form II of Dabrafenib methanesulfonate to 120° C., and then naturally cool it to room temperature to get the Crystal Form IV of Dabrafenib methanesulfonate;
wherein the rate of heating is 5° C. to 15° C./minute.
5. A pharmaceutical composition, comprising a therapeutically effective amount of the Crystal Form IV of Dabrafenib methanesulfonate according to claim 1 , and at least one pharmaceutical acceptable excipient.
6. The pharmaceutical composition according to claim 5 , wherein the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, capsules, suspensions, disintegrating tablets, immediate release tablets, slow release tablets and controlled release tablets.
7. A method of treating cancer by inhibition of one or more Raf-family kinases, comprises administering to a mammalian subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 6 .
8. The method of claim 7 , wherein the cancer is melanoma.
9. The method of claim 7 , wherein the cancer is selected from the group consisting of Barret's adenocarcinoma, biliary tract carcinoma, breast cancer, cervical carcinoma, cholangiocarcinoma, central nervous system tumors, colorectal cancer, gastric carcinoma, head and neck cancer, leukemia, lymphoma, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin's lymphoma, non Hodgkin's lymphoma, megakaryocytic leukemia, multiple myeloma, erythroleukemia, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, ovarian cancer, endometrial carcinoma, pancreatic cancer, pituitary adenoma, prostate cancer, renal carcinoma, sarcoma, and thyroid carcinoma.