Crystal form of Dabrafenib mesylate and preparation method thereof

Abstract

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.

Claims

1. A Crystal Form II of Dabrafenib methanesulfonate with the structural formula shown below, and Crystal Form II is a hydrate, ##STR00003## wherein the Crystal Form II of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern measured using Cu-K radiation having the characteristic peaks at the diffraction angles 2 of 4.70.2, 9.30.2, 13.90.2, 15.40.2, 17.00.2 and 19.00.2.

2. The Crystal Form II of Dabrafenib methanesulfonate according to claim 1, wherein the Crystal Form II of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern having the characteristic peaks at the diffraction angles 2 of 4.70.2, 9.30.2, 12.90.2, 13.90.2, 15.40.2, 17.00.2, 17.90.2, 18.50.2, 19.00.2, 20.50.2, 23.60.2 and 24.80.2.

3. The Crystal Form II of Dabrafenib methanesulfonate according to claim 2, wherein the Crystal Form II of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern having the following characteristic peaks at the diffraction angles 2 and their relative intensities: TABLE-US-00011 Diffraction angle 2 Relative intensity % 4.7 0.2 29.2 9.3 0.2 100.0 12.4 0.2 20.9 12.9 0.2 30.1 13.9 0.2 32.1 14.5 0.2 19.0 15.4 0.2 35.3 16.3 0.2 26.5 17.0 0.2 18.9 17.9 0.2 34.8 18.5 0.2 36.8 19.0 0.2 27.0 19.7 0.2 14.9 20.5 0.2 45.3 22.6 0.2 14.9 23.6 0.2 49.1 24.1 0.2 33.3 24.8 0.2 40.9 26.5 0.2 18.7 27.3 0.2 12.5 27.8 0.2 19.6 28.9 0.2 13.5 37.4 0.2 15.6.

4. A method of preparing the Crystal Form II of Dabrafenib methanesulfonate according to claim 1, comprising: suspending Crystal Form IV of Dabrafenib methanesulfonate in water to form a suspension, stirring to recrystallize, and then separating the precipitated crystals without drying to get the Crystal Form II of Dabrafenib methanesulfonate, wherein the amount of the Crystal Form IV of Dabrafenib methanesulfonate is 1.1 to 20 times of its solubility in water at room temperature, wherein the recrystallizing temperature is room temperature to 40 C., and wherein the duration of recrystallizing is 0.5 to 25 minutes.

5. A Crystal Form III of Dabrafenib methanesulfonate with the structural formula shown below, ##STR00004## wherein the Crystal Form III of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern measured using Cu-K radiation having the characteristic peaks at the diffraction angles 2 of 4.20.2, 8.60.2, 13.20.2, 14.50.2, 17.40.2 and 19.50.2.

6. The crystal Form III of Dabrafenib methanesulfonate according to claim 5, wherein the crystal Form III of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern having the characteristic peaks at the diffraction angles 2 of 4.20.2, 8.60.2, 12.40.2, 13.20.2, 14.50.2, 17.40.2, 18.0=0.2, 18.60.2, 19.50.2, 20.10.2, 24.70.2 and 25.10.2.

7. The Crystal Form III of Dabrafenib methanesulfonate according to claim 6, wherein the crystal Form III of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern having the following characteristic peaks at the diffraction angles 2 and their relative intensities: TABLE-US-00012 Diffraction angle 2 Relative intensity % 4.2 0.2 25.5 8.6 0.2 100.0 9.6 0.2 20.7 12.4 0.2 30.5 13.2 0.2 90.5 14.5 0.2 52.4 16.4 0.2 21.5 17.4 0.2 41.5 18.0 0.2 26.5 18.6 0.2 33.1 19.5 0.2 59.3 20.1 0.2 45.1 21.8 0,2 17.5 23.2 0.2 21.1 24.7 0.2 44.4 25.1 0.2 33.8 28.7 0.2 22.5.

8. A method of preparing the Crystal Form III of Dabrafenib methanesulfonate according to claim 5, comprising: dissolving known Crystal Form I of Dabrafenib methanesulfonate into a mixed solvent of methanol and an organic solvent, evaporating to crystallize, then separating the precipitated crystals, without drying to get the Crystal Form III of Dabrafenib methanesulfonate; wherein the organic solvent is selected from the group consisting of ethyl ethyl acetate, butanone and C.sub.4-alkanol; wherein the amount of the known Crystal Form of Dabrafenib methanesulfonate is 0.1 to 1 times of its solubility in the mixed solvent at room temperature; wherein the volume ratio of methanol to the organic solvent is 0.1:1 to 100:1; wherein the crystallizing temperature is room temperature to 40 C.; and wherein the duration of crystallization is 1 to 60 minutes.

9. A Crystal Form V of Dabrafenib methanesulfonate with the structural formula shown below, ##STR00005## wherein the Crystal Form V of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern measured using Cu-K radiation having the characteristic peaks at the diffraction angles 2 of 8.90.2, 14.80.2, 15.80.2, 16.70.2, 17.90.2 and 19.00.2.

10. The Crystal Form V of Dabrafenib methanesulfonate according to claim 9, wherein the Crystal Form V of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern having the characteristic peaks at the diffraction angles 2 of 8.90.2, 14.80.2, 15.10.2, 15.80.2, 16.70.2, 17.90.2, 19.00.2, 23.80.2, 25.50.2, 31.10.2< and 36.10.2.

11. The Crystal Form V of Dabrafenib methanesulfonate according to claim 10, wherein the Crystal Form V of Dabrafenib methanesulfonate is characterized by a X-ray powder diffraction pattern having the following characteristic peaks at the diffraction angles 2 and their relative intensities: TABLE-US-00013 Diffraction angle 2 Relative intensity % 8.9 0.2 100.0 14.8 0.2 31.7 15.1 0.2 10.2 15.8 0.2 35.6 16.7 0.2 15.5 17.9 0.2 31.7 19.0 0.2 29.2 23.8 0.2 25.3 25.5 0.2 20.2 31.1 0.2 65.0 36.1 0.2 28.7.

12. A method of preparing the Crystal Form V of Dabrafenib methanesulfonate according to claim 9, comprising: storing Crystal Form IV of Dabrafenib methanesulfonate at a high temperature for a period of time to get the Crystal Form V of Dabrafenib methanesulfonate; wherein the high temperature is 40 C. to 120 C.; the duration of storage is 0.1 to 2 hours.

13. A pharmaceutical composition, comprising a therapeutically effective amount of the Crystal Form II of Dabrafenib methanesulfonate according to claim 1 and at least one pharmaceutical acceptable excipient.

14. The pharmaceutical composition according to claim 13, 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.

15. A method of treating the diseases associated with 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 13.

16. 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 13.

17. The method of claim 16, wherein the cancer is melanoma.

18. The method of claim 16, 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.

19. A pharmaceutical composition, comprising a therapeutically effective amount of the Crystal Form III of Dabrafenib methanesulfonate according to claim 5 and at least one pharmaceutical acceptable excipient.

20. A pharmaceutical composition, comprising a therapeutically effective amount of the Crystal Form V of Dabrafenib methanesulfonate according to claim 9 and at least one pharmaceutical acceptable excipient.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 is the X-ray powder diffraction pattern of Crystal Form IV of the present invention.

(2) FIG. 2 is the DSC thermogram of Crystal Form IV of the present invention.

(3) FIG. 3 is the TGA thermogram of Crystal Form IV of the present invention.

(4) FIG. 4 is the dynamic vapor sorption isothermal plot of Crystal Form IV of the present invention.

(5) FIG. 5 is the .sup.1HNMR spectrum of Crystal Form IV of the present invention.

(6) FIG. 6 is X-ray powder diffraction pattern of Crystal Form II of the present invention.

(7) FIG. 7 is the TGA thermogram of Crystal Form II of the present invention.

(8) FIG. 8 is the X-ray powder diffraction pattern of Crystal Form III of the present invention.

(9) FIG. 9 is the X-ray powder diffraction pattern of Crystal Form V of the present invention.

(10) FIG. 10 is the X-ray powder diffraction pattern of the Known Crystal Form I prepared by the method described in example 58a and 58d of patent documents WO2009/137391 or CN200980126781.6.

(11) FIG. 11 is the DSC thermogram of the Known Crystal Form I prepared by the method described in example 58a and 58d of patent documents WO2009/137391 or CN200980126781.6.

(12) FIG. 12 is the TGA thermogram of the Known Crystal Form I prepared by the method described in example 58a and 58d of patent documents WO2009/137391 or CN200980126781.6.

(13) FIG. 13 is the X-ray powder diffraction comparison patterns of the Known Crystal Form I at every stage in Experimental Example 1, wherein, the samples from top to bottom are: Dabrafenib free base hydrate, the sample obtained by stirring the Known Crystal Form I in water for 15 minutes, the Known Crystal Form I.

(14) FIG. 14 is the X-ray powder diffraction comparison patterns of the Crystal Form IV of the present invention at every stage in Experimental Example 1, wherein, the samples from top to bottom are: the Crystal Form IV, the sample obtained by stirring the Crystal Form IV in water for 15 minutes, the sample obtained by stirring the Crystal Form IV in water overnight, Dabrafenib free base hydrate.

(15) FIG. 15 is the comparison of dissolution profiles between Crystal Form IV and the Known Crystal Form I in Experimental Example 1 (.box-tangle-solidup. refers to Crystal Form IV, refers to the Known Crystal Form I).

(16) FIG. 16 is the X-ray powder diffraction comparison patterns of the Known Crystal Form I at every stage in Experimental Example 2, wherein, the samples from top to bottom are: the sample obtained from wet granulation (not including the Step 3 of compressing tablets) of the Known Crystal Form I as API, the sample obtained from physically mixing the Known Crystal Form I and the excipients at ratios per the formulation, the sample obtained from physically mixing lactose monohydrate and microcrystalline cellulose at ratios per the formulation, Dabrafenib free base hydrate, and the Known Crystal Form I.

(17) FIG. 17 is the X-ray powder diffraction comparison patterns of Crystal Form IV of the present invention at every stage in Experimental Example 2, wherein, the samples from top to bottom are: the sample obtained from wet granulation (not including the Step 3 of compressing tablets) of Crystal Form IV as API, the sample obtained from physically mixing Crystal Form IV and the excipients at ratios per the formulation, the sample obtained from physically mixing lactose monohydrate and microcrystalline cellulose at ratios per the formulation, and Crystal Form IV).

DETAILED DESCRIPTION OF EMBODIMENTS

(18) The present invention is defined with further reference to the following examples, which describe the preparation and usage of the crystal forms in the present invention in details. It is obvious to the technicians in this field that various changes in materials and methods may be embodied without deviating from the scope of the present invention.

(19) Instruments and Methods Used for Data Collection

(20) The instrument for X-ray powder diffraction (XPRD) is Bruker D8 Advance diffractometer, which equips -2 goniometer, Mo monochromator and Lynxeye detector. The acquisition software is Diffrac Plus XPRD Commander. Prior to use, the instrument is calibrated with the standard substance (generally corindon) attached. The testing conditions are: range of scanning angle 2: 340; step size: 0.02; speed: 0.2 s/step. The testing processes are: Use the Cu K X-ray with 1.54 nm in wavelength, under the operation conditions of 40 kV and 40 mA, the sample is examined at room temperature, and place the test sample on sample holder. Unless otherwise specified, samples are not ground before examining.

(21) The Differential Scanning calorimeter (DSC) data are collected by TA Instruments Q200 MDSC; the instrument control software is Thermal Advantage and the analysis software is Universal Analysis. Generally, take 110 mg of the sample and place it in an uncovered (unless otherwise specified) aluminum pan and under the protection of 50 mL/min dry N.sub.2, heat the sample from room temperature to 275 C. at the heating rate of 10 C./min; and heat changes of the sample during the course are recorded by TA software simultaneously. In the present application, the melting point is reported based on DSC onset temperature.

(22) The thermogravimetric analysis (TGA) data are collected by TA Instruments Q500 TGA; the instrument control software is Thermal Advantage and the analysis software is Universal Analysis. Generally, take 515 mg sample and place it in a platinum pan, adopt the segmental high-resolution testing mode, and under the protection of 50 mL/min dry N.sub.2, heat the sample from room temperature to 350 C. at the heating rate of 10 C./min, the weight changes of the sample during the course are recorded by TA software simultaneously.

(23) The dynamic vapor sorption analysis (DVS) data are collected by TA Instruments Q5000 TGA; the instrument control software is Thermal Advantage and the analysis software is Universal Analysis. Generally, take 110 mg of the sample and place it in a platinum pan, and the weight changes of the sample are recorded during the course of the relative humidity changing from 0% to 80% and then to 0%. According to the specifics of the samples, different adsorption and desorption steps may be used.

(24) The proton nuclear magnetic resonance spectroscopy (.sup.1HNMR) data are collected by Bruker Avance II DMX 400M HZ NMR spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL DMSO-d6 to get a 2 mg/mL-10 mg/mL solution.

(25) The analysis data of high performance liquid chromatography (HPLC) are collected by Agilent 1260 with the chemical working station of B.04. The corresponding HPLC parameters in this research are: chromatographic column SB-C18 2504.6 mm 5 m; column temperature 35 C.; flow rate 0.6 mL/min; flow phase as shown below; wavelength 254 nm; sample inject volume 20 l; operation time 30 min.

(26) TABLE-US-00005 Time Mobile phase A % Mobile phase B % (minutes) (ultrapure water) (acetonitrile) 0 70 30 3 70 30 18 10 90 23 10 90 28 70 30

(27) Unless otherwise specified, all the Examples are operated at room temperature, the range of temperature is 10 C.30 C.

(28) The ultrasonic operation is: keep the ultrasonic treatment for 5 minutes at the power of 40 Khz.

Preparation Example 1

(29) The Preparation of the Known Crystal Form I

(30) Refer to the preparation method described in example 58a and 58d of patent documents WO2009/137391 or CN200980126781.6, with the details as follows:

(31) Add N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (196 mg, 0.364 mmol) and 7M methanol solution of ammonia (8 mL 56 mmol) into a 25 mL autoclave, heat to 90 C. and react for 24 h; when the TLC shows complete reaction of the raw material, cool the above reaction system to room temperature, concentrate the solvent to dryness, then treat the residues by the column chromatography to get 90 mg N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, yield: 45%.

(32) Add methylsulfonic acid (0.131 ml, 0.393 mmol) into the isopropanol solution of N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (204 mg, 0.393 mmol) and stir the solution at room temperature for 3 h to obtain a white precipitate, filter the slurry and wash it with ethyl ether to obtain N-[3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazo-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide methanesulfonate, which is a white crystals (221 mg, 87% yield). .sup.1HNMR (400 MHz, DMSO-d6) ppm 10.85 (s, 1H) 7.92-8.05 (m, 1H), 7.56-7.72 (m, 1H), 6.91-7.50 (m, 7H), 5.83-5.98 (m, 1H), 2.18-2.32 (m, 3H), 1.36 (s, 9H).

(33) The X-ray powder diffraction pattern of the obtained crystals as shown in FIG. 10 is consistent with that mentioned in the patent documents WO2009/137391 or CN200980126781.6.

(34) The DSC thermogram is shown in FIG. 11: the melting range of the Known Crystal Form I is 247 C.250 C.

(35) The TGA thermogram is shown in FIG. 12: the decomposition temperature is 261 C.

Example 1

(36) Place 10.02 mg of Crystal Form IV (prepared via Example 7) in a 5 mL vial, add 0.5 mL water, sonicate it to get a suspension, stir it for 15 minutes at room temperature, centrifuge the suspension, and then separate the solids without drying to get Crystal Form II described by the present invention. The product is 10.00 mg and the yield is 99%.

(37) The X-ray powder diffraction pattern is shown in FIG. 6.

(38) The TGA thermogram is shown in FIG. 7: the weight loss of Crystal Form II prior to 50 C. is about 4.6% (approximately 1.5 water molecules), the weight loss of Crystal Form II from 50 C.155 C. is about 1.4% (approximately 0.5 water molecule), the decomposition temperature is 287 C.

Example 2

(39) Place 4.58 mg of the Known Crystal Form I in a 5 mL vial, add 1 mL methanol and 2 mL butanone (the amount of the Known Crystal Form I is 0.1 times of its solubility in the mixed solvent at room temperature), sonicate it for 5 min to get a clear solution, then filter it with 0.45 m organic filter membrane, place the filtrate in an uncovered 5 mL vial and evaporate it to recrystallize under nitrogen blowing, after 10 min, centrifuge to separate the solids, without drying, get Crystal Form III described by the present invention. The product is 4.02 mg and the yield is 88%.

(40) The X-ray powder diffraction pattern is as shown in FIG. 8.

Example 3

(41) Place 5.98 mg of the Known Crystal Form I in a 20 mL vial, add 5 mL methanol and 0.05 mL ethyl acetate (the amount of the Known Crystal Form I is 1 time of its solubility in the mixed solvent at room temperature), sonicate for 5 min to get a clear solution, then filter it with 0.45 m organic filter membrane, place the filtrate in an uncovered 20 mL vial and evaporate to recrystallize under nitrogen blowing at 40 C., after 60 min, separate the solids by centrifugation, without drying, get Crystal Form III described by the present invention. The solids are 3.22 mg and the yield is 54%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 8.

Example 4

(42) Place 5.54 mg of the Known Crystal Form I in a 5 mL vial, add 1.5 mL methanol and 0.3 mL ethyl ether (the amount of the Known Crystal Form I is 0.8 times of its solubility in the mixed solvent at room temperature), sonicate for 5 min to get a clear solution, then filter it with 0.45 m organic filter membrane, place the filtrate in an uncovered 5 mL vial and evaporate to recrystallize under nitrogen blowing, after 1 min, separate the solids by centrifugation, without drying, get Crystal Form III described by the present invention. The resulting solids are 4.85 mg and the yield is 87%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 8.

Example 5

(43) Place 3.31 mg of the Known Crystal Form I in a 5 mL vial, add 0.3 mL methanol and 3 mL sec-butyl alcohol (the amount of the Known Crystal Form I is 0.5 times of its solubility in the mixed solvent at room temperature), sonicate for 5 min to get a clear solution, then filter it with 0.45 m organic filter membrane, place the filtrate in an uncovered 5 mL vial and evaporate to recrystallize under nitrogen blowing, after 10 min, separate the solids by centrifugation, without drying, get Crystal Form III described the present invention. The product is 2.05 mg and the yield is 62%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 8.

Example 6

(44) Place 3.31 mg of the Known Crystal Form I in a 5 mL vial, add 0.5 mL methanol and 1 mL n-butanol (the amount of the Known Crystal Form I is 0.8 times of its solubility in the mixed solvent at room temperature), sonicate for 5 min to get a clear solution, then filter it with 0.45 m organic filter membrane, place the filtrate in an uncovered 5 mL vial and evaporate to recrystallize under nitrogen blowing, after 10 min, separate the solids by centrifugation, without drying, get Crystal Form III described by the present invention. The product is 3.00 mg and the yield is 91%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 8.

Example 7

(45) Place 44.20 mg of the Known Crystal Form I in a 20 mL vial, add 2 mL methanol and 5 mL tetrahydrofuran (the amount of the Known Crystal Form I is 1 time of its solubility in the mixed solvent at room temperature), sonicate for 5 min to get a clear solution, then filter it with 0.45 m organic filter membrane, place the filtrate in an uncovered 20 mL vial and evaporate to recrystallize at room temperature, separate the solids by centrifugation, vacuum drying for 16 hours at 40 C., get Crystal Form IV of the present invention. The product is 43.0 mg and the yield is 97%.

(46) The X-ray powder diffraction pattern is shown in FIG. 1.

(47) The DSC thermogram is shown in FIG. 2: the Crystal Form IV has a broad and large endothermic peak (the solvent peak) at 15 C.105 C., the melting range of the dehydrated sample is 132 C.148 C., followed by an exothermic form transformation peak at 200 C.245 C. and a melting point at 249 C.

(48) The TGA thermogram is shown in FIG. 3: the weight loss of Crystal Form IV prior to 65 C. is about 4.3% (approximately 1.5 water molecules), and the decomposition temperature is 291 C.

(49) The dynamic vapor sorption isothermal plot is shown in FIG. 4, showing a weight change of 2.0% between 20% RH-80% RH.

(50) The .sup.1HNMR is shown in FIG. 5, indicating a methanesulfonate salt.

Example 8

(51) Place 22.22 mg of the Known Crystal Form I in a 20 mL vial, add 15 mL acetone (the amount of the Known Crystal Form I is 0.8 times of its solubility in acetone at room temperature), sonicate for 5 min to get a clear solution, then filter it with 0.45 m organic filter membrane, place the filtrate in an uncovered 20 mL vial and evaporate to recrystallize at room temperature, separate the solids by centrifugation, vacuum drying the solids for 16 hours at 40 C., get Crystal Form IV described by the present invention. The product is 20.18 mg and the yield is 91%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 1.

Example 9

(52) Place 9.58 of mg the Known Crystal Form I in a 20 mL vial, add 15 mL isopropanol (the amount of the Known Crystal Form I is 0.5 times of its solubility in isopropanol at room temperature), sonicate for 5 min to get a clear solution, then filter it with 0.45 m organic filter membrane, place the filtrate in an uncovered 20 mL vial and add 0.35 mg of polyacrylic acid (the molecular weight is about 5000), evaporate to recrystallize at room temperature, separate the solids by centrifugation, vacuum drying the solids for 16 hours at 40 C., get Crystal Form IV described by the present invention. The product is 8.95 mg and the yield is 93%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 1.

Example 10

(53) Place 5.02 mg of the Crystal Form II in a 5 mL vial, vacuum drying the solids for 16 hours at 40 C., and get Crystal Form IV described by the present invention. The product is 4.90 mg and the yield is 98%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 1.

Example 11

(54) Take 4.20 mg of Crystal Form II and run it in TGA, using the following procedure: high-resolution sensitivity 3.00, resolution 5.00, heating to 120 C. at a rate of 10.00 C./min; after the procedure, let it cool naturally to room temperature; then, place the sample in air for 1 h to obtain Crystal Form IV described by the present invention. The product is 4.05 mg and the yield is 96%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 1.

Example 12

(55) Take 5.00 mg of the Crystal Form V (prepared by Example 13) and let it sit uncovered at room temperature for 30 min, and get Crystal Form IV described by the present invention. The product is 5.00 mg and the yield is 100%. The X-ray powder diffraction pattern is substantially consistent with that of FIG. 1.

Example 13

(56) Place 8.52 mg of the Crystal Form IV in a copper pan preheated to 60 C., kept it at 60 C. for 1 hour, and get Crystal Form V described by the present invention. The product is 8.07 mg and the yield is 95%. The X-ray powder diffraction pattern is as shown in FIG. 9.

Example 14

(57) Preparation of Capsules Containing the Crystal Forms of the Present Invention

(58) Components in each capsule: 71 mg Active Pharmaceutical Ingredient (API, selected from the group consisting of the crystal forms of Dabrafenib methanesulfonate of the present invention, including Crystal Form II, Crystal Form III, Crystal Form IV and Crystal Form V)+60 mg microcrystalline cellulose (Avicel)+13 mg sodium carboxymethyl starch (SSG).

(59) Each size 0# hard capsule contains 144 mg of powders. The weight of Avicel/SSG may be reasonably approximate.

(60) Steps

(61) 1) Appropriately/according to the actual need, separate thard capsules into halves and mark/identify each half.

(62) 2) Place the bottom halves of the capsules in capsule filling machine, with the filling funnel on the top.

(63) 3) Weigh each component (Avicel, SSG, API) on thin weighing paper (between each weighing, be sure to coat tar on the analytical balance).

(64) 4) Record the weight of each component.

(65) 5) Carefully and thoroughly mix the dry powders on the thin weighing paper with a small spatula.

(66) 6) Through the funnel, carefully transfer the mixed powders to the capsules.

(67) 7) Place the top halves of the capsules on the capsules, close tightly, then shake the capsules to blend/disperse the components.

(68) 8) If the powders are filled near the top of the capsules, slightly tap the capsule by hand to settle down the powders.

(69) 9) Place such capsules in a small appropriately marked bottle (which should be large enough to remove the capsules easily).

Example 15

(70) Preparation of Tablets Containing the Crystal Forms of the Present Invention

(71) TABLE-US-00006 Component Content (mg/tablet) % w/w Tablet Core API (selected from the group consisting 479.9 74.9 of the Crystal Forms of Dabrafenib methanesulfonate of the present invention) Lactose monohydrate 59.0 9.2 Polysorbate 80 1.0 0.2 Polyvinylpyrrolidone 40.0 6.2 Colloidal silicon dioxide 5.5 0.9 Cross-linked polyvinylpyrrolidone 51.0 8.0 Magnesium stearate 4.5 0.7 Purified water qs Film coating OpadryOrange, YS-1-13065-A 17.0 3.0 Purified water qs Note: qs in the above table means that such solvent or water will be removed in the final product.

(72) Steps

(73) 1) Sieve lactose monohydrate, colloidal silicon dioxide, cross-linked polyvinylpyrrolidone and half polyvinylpyrrolidone.

(74) 2) Add API (selected from the Crystal Forms of Dabrafenib methanesulfonate of the present invention, including Crystal Form II, Crystal Form III, Crystal Form IV and Crystal Form V).

(75) 3) Granulate the mixture in a high-shear granulator with granulating solution containing dissolved polysorbate 80 and other half polyvinylpyrrolidone in purified water.

(76) 4) Using Comil 197 with a 0.375 screen to grind the granules.

(77) 5) Using a fluidized bed dryer to dry the granules.

(78) 6) Using Comil 197 with a 0.075 screen to grind the granules.

(79) 7) Add cross-linked polyvinylpyrrolidone and magnesium stearate.

(80) 8) Mix for 5 min.

(81) 9) Compress the solids into tablets.

(82) 10) Coat the tablets with an aqueous film coating.

Experimental Example 1

(83) Compare the stability, the hygroscopicity, melting points, decomposition temperatures and dissolution profiles of Crystal Form IV prepared by Example 7 and the Known Crystal Form I. The results are shown in Table 1.

(84) The stability is performed by comparing the storage stability and the stirring test in water on crystalline forms.

(85) The storage stability is performed by placing the samples under a constant condition (i.e. under constant humidity or constant temperature) for a certain period of time, and then comparing their XRPDs before and after placement.

(86) The stirring test in water is performed by, for each crystalline form, adding an equal amount of the sample (10 mg) to an equal amount of water (1 mL) to form a suspension, stirring the suspensions for a certain time at room temperature, and then comparing their XRPDs.

(87) FIG. 13 is the XRPD comparison patterns of the Known Crystal Form I at every stage in Experimental Example 1, wherein, the samples from top to bottom are: Dabrafenib free base hydrate, the sample obtained from stirring the Known Crystal Form I in water for 15 min (this XRPD pattern shows this sample's crystalline form is consistent with the above-mentioned Dabrafenib free base hydrate), and the Known Crystal Form I.

(88) FIG. 14 is the XRPD comparison patterns of Crystal Form IV of the present invention at every stage in Experimental Example 1, wherein, the samples from top to bottom are: the Crystal Form IV, the sample obtained from stirring the Crystal Form IV in water for 15 min (this XRPD pattern shows this sample's crystalline form is consistent with the above-mentioned Crystal Form IV, indicating it remains Crystal Form IV), the sample obtained from stirring the Crystal Form IV in water overnight, and Dabrafenib free base hydrate.

(89) Compare melting points obtained by DSC tests.

(90) Compare decomposition temperatures obtained by TGA tests.

(91) Compare hygroscopicity in weight changes of samples between 20%-80% RH obtained by DVS tests.

(92) The comparison of dissolution profiles is performed by the following procedures: place about 6 mg the sample in a 20 mg vial, add 15 mL ultrapure water, and then seal the vial. A suspension is obtained from sonication with a working power of 40 Khz at room temperature, then take 1 mL of the suspension at 10 min, 30 min, 2 hr and 6 hr, respectively; filter it with 0.45 m organic filter membrane to, take the filtrate to be measured by HPLC; stir the remaining suspension for 16 hr at room temperature, and then filter it with 0.45 m organic filter membrane, take the filtrate to be measured by HPLC. FIG. 15 is the comparison plot of dissolution profiles of Crystal Form IV and the Known Crystal Form I in Experimental Example 1 (.box-tangle-solidup. refers to Crystal Form IV, refers to the Known Crystal Form I).

(93) TABLE-US-00007 TABLE 1 Property Comparison Results of Different Crystal Forms Items The Known Crystal Form I Crystal Form IV of the present invention Stability Storage at room After stored for 1 month at room temperature and at room temperature - temperature 97% RH, respectively, the crystal forms remained unchanged. Stirring test in After stirred in water for 15 After stirred in water for 15 min, it water min, it converted to the free remained as methanesulfonate and after base (FIG. 13) stirred overnight, it converted to the free base (FIG. 14). Melting point The melting range is 247~250 C. There is a broad and large endothermic (FIG. 11) peak (the dehydration peak) at 15 C.~105 C., a melting range of the dehydrated sample between132 to 148 C., an exothermic form conversion peak at 200 C.~245 C., and a melting point at 247~249 C. (FIG. 2) Decomposition temperature 261 C. (FIG. 12) 291 C. (FIG. 3) Hygroscopicity Non-hygroscopic; the form is The form is table at 25 C. and 20- stable at 25 C. and 20- 80% RH; the sample may dehydrate to 80% RH. form an anhydrate below 20% RH (e.g. under a drying N.sub.2 flow) (FIG. 3). Dissolution 10 minutes 1.20 10.sup.4 mg/mL 5.32 10.sup.4 mg/mL (FIG. 15) 30 minutes 7.23 10.sup.5 mg/mL 3.03 10.sup.4 mg/mL 2 hours 9.28 10.sup.5 mg/mL 3.76 10.sup.4 mg/mL 6 hours 8.88 10.sup.5 mg/mL 4.88 10.sup.4 mg/mL 6 hours + 7.48 10.sup.5 mg/mL 1.78 10.sup.4 mg/mL 16 hours Summary 1) Comparing the dissolution profiles from 0~22 h, the dissolution rate of Crystal Form IV is higher than that of the Known Crystal Form I at any test point; 2) The time to the end point in water during dissolution for Crystal Form IV is shorter than that of the Known Crystal Form I.

(94) The results are as shown in Table 1 and the conclusions are:

(95) 1) When stored for one month at room temperature or at room temperature97% RH, respectively, Crystal Form IV and the Known Crystal Form I remained unchanged.

(96) 2) The Known Crystal Form I converted to its free base after stirred for 15 minutes in the water suspension (converted to the free base monohydrate confirmed by TGA and its XRPD is consistent with that of the patent application PCT/CN2014/074883); while Crystal Form IV still remained as methanesulfonate after stirred for 15 minutes in the water suspension (the .sup.1HNMR spectrum is consistent with FIG. 5; its XRPD pattern is consistent with that of the above-mentioned Crystal Form IV, indicating it remained Crystal Form IV); Crystal Form IV converted to its free base after stirred overnight (confirmed by TGA as the free base monohydrate and its XRPD is consistent with that of the patent application PCT/CN2014/074883). These indicate that Crystal Form IV is better in maintaining in the state of methanesulfonate that has higher than that of free base, and Crystal Form IV has better stability in water or aqueous system.

(97) 3) Comparing the dissolution profiles from 022 h, the dissolution rate of Crystal Form IV is higher than that of the Known Crystal Form I at any test point. This indicates that Crystal Form IV has better dissolution rate and bioavailabilty.

Experimental Example 2

(98) The stability of the Known Crystal Form I of Dabrafenib methanesulfonate and Crystal Form IV of the present invention during wet granulation in formulation process was studied.

(99) The formulation is:

(100) TABLE-US-00008 Component Content (mg/tablet) API (the Known Crystal Form I or Crystal Form 118.5 IV of the present invention) Lactose (monohydrate) 280 Microcrystalline cellulose 112 Polyethylene glycol 6000 8

(101) Wet granulation experiments in the formulation process were parallel experiments. The specific steps are:

(102) 1) Blend API (the Known Crystal Form I or Crystal Form IV of the present invention), lactose (monohydrate) and microcrystalline cellulose uniformly.

(103) 2) Make the above mixture into soft materials by using appropriate amount of 50% aqueous ethanol solution, screen to produce wet granules.

(104) 3) Dry the wet granules and then granulate them, blend with polyethylene glycol 6000 uniformly and then compress them into tablets.

(105) Characterize the Known Crystal Form I and Crystal Form IV of the present invention samples obtained from the formulation process of: (1) the sample obtained from physically mixing lactose monohydrate and microcrystalline cellulose at the ratios per the formulation; (2) the sample obtained from physically mixing of API, lactose monohydrate and microcrystalline cellulose at the ratios per the formulation; (3) the wet granule sample obtained from the wet granulation process (excluding the compressed tablets in Step 3). See XRPDs in FIG. 16 and FIG. 17.

(106) According to FIG. 16 and FIG. 17:

(107) 1) With respect to the Known Crystal Form I, compared with the XRPD of the sample (2) obtained from physically mixing API, lactose monohydrate and microcrystalline cellulose at ratios per the formulation, the XRPD of the wet granule sample (3) obtained from the wet granulation process (excluding the compressed tablets in Step 3) shows that the API has partially or totally converted to Dabrafenib free base hydrate (confirmed by TGA as free base monohydrate and its XRPD is consistent with that of the patent application PCT/CN2014/074883). These indicate that the Known Crystal Form I is unstable in the wet granulation process.

(108) 2) With respect to Crystal Form IV, compared with the XRPD of the sample (2) obtained from physically mixing API, lactose monohydrate and microcrystalline cellulose at ratios per the formulation, the XRPD of the wet granule sample (3) obtained from the wet granulation process (excluding the compressed tablets in Step 3) shows that the API still kept as Dabrafenib methanesulfonate (the .sup.1HNMR spectrum is consistent with FIG. 5; the XRPD pattern shows that it is consistent with that of the above-mentioned Crystal Form IV, indicating that it remained as Crystal Form IV). These indicate that Crystal Form IV is stable in the wet granulation process.

(109) The above experiments show that, Crystal Form IV of the present invention is more stable in the wet granulation process and is easier to granulate; therefore, it is an advantageous crystal form.

(110) In addition, after the tablets of Crystal Form IV were stored for 1 month at 25 C./60% RH, its crystal form still is stable.

Experimental Example 3

(111) Compare the capsule dissolution rate of Crystal Form IV prepared by Example 7 with that of the Known Crystal Form I. The capsule formulation is:

(112) TABLE-US-00009 Component Content (mg/capsule) API (the Known Crystal Form I or Crystal 100 Form IV of the present invention) Mannitol 55 Talc 16 Magnesium stearate 4

(113) The dissolution rate was performed by reference of Chinese Pharmacopoeia 2010, using the paddle method. Use 500 mL 0.1% lauryl sodium sulfate aqueous solution as the dissolution medium, keep the temperature at 37 C. and the stirring speed at 50 rpm; withdraw a 3 mL specimen at each of the times: 2 min, 5 min, 10 min, 30 min, 60 min and 120 min; replace the aliquots withdrawn for analysis with equal volumes of 0.1% lauryl sodium sulfate aqueous solution. Perform HPLC analysis on samples from each time interval for concentration information. See results in Table 2.

(114) TABLE-US-00010 TABLE 2 Comparison of dissolution rate of different crystal forms from capsules Sampling Dissolution rate of the Known Dissolution rate of Crystal time Crystal Form I capsules Form IV capsules 2 min 8.01% 17.0% 5 min 16.3% 24.0% 10 min 23.0% 33.0% 30 min 32.3% 59.7% 60 min 75.0% 99.3% 120 min 101.3% 150.7%

(115) From the results in Table 2, it is concluded that comparing the dissolution quantity of 0120 min, the dissolution quantity of Crystal Form IV capsule is larger than that of the Known Crystal Form I capsule at any test point. This indicates that Crystal Form IV capsule has better dissolution rate and bioavailabilty.

(116) All patent documents and non-patent publications referred to herein are incorporated by reference entirely into the present application.

(117) In the present application, the above general description of the invention and the description of specific embodiments shall not be considered as the restriction on the technical scheme of such invention. The technicians in this field, according to the disclosure of the present application and under the precondition of not violating the elements constituting the related invention, may add, reduce or combine the technical features disclosed in the above general description or/and specific embodiments, so as to form other technical schemes within the present invention.