CRYSTALLINE FORM OF FLUVATINIB OR FLUVATINIB METHANESULFONATE AND PREPARATION METHOD THEREFOR

Abstract

Disclosed in the present invention is a crystalline form of fluvatinib or fluvatinib methanesulfonate, and a preparation method therefor. The crystalline form I of the fluvatinib has characteristic diffraction peaks as shown in FIG. 1. The crystalline form of the fluvatinib methanesulfonate may take multiple forms, including seven crystalline forms, forms I-VII, wherein crystalline form III has characteristic diffraction peaks as shown in FIG. 9. Said crystalline forms are suited to manufacturing processes for fluvatinib methanesulfonate formulations.

Claims

1. A solid crystalline form of fluvatinib represented by formula I or fluvatinib mesylate, ##STR00004##

2. The crystalline form of fluvatinib represented by formula I according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 11.60±0.2°, 16.72±0.2°, and 20.25±0.2°.

3. The crystalline form according to claim 2, wherein its X-ray powder diffraction pattern further has characteristic diffraction peaks at 2θ degrees of 8.28±0.2°, 11.60±0.2°, 15.42±0.2°, 16.72±0.2°, 20.25±0.2°, 21.81±0.2°, 22.36±0.2° and 24.08±0.2°.

4. A method for preparing a crystalline form of fluvatinib represented by formula I according to claim 1, comprising dissolving fluvatinib in an organic solvent, stirring to form a suspension, filtering, and drying filter cake to obtain the crystalline form of fluvatinib.

5. The method according to claim 4, wherein the organic solvent is selected from the group consisting of methanol, ethanol, acetone, THE, isopropanol, ethyl acetate, and a mixed solvent thereof with water.

6. The crystalline form of fluvatinib mesylate according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 9.60±0.2°, 22.49±0.2° and 23.07±0.2°.

7. The crystalline form according to claim 6, wherein its X-ray powder diffraction pattern further has characteristic diffraction peaks at 2θ degrees of 10.74±0.2°, 16.79±0.2°, 17.51±0.2°, 18.50±0.2°, 20.64±0.2°, 20.85±0.2°, 21.51±0.2°, 23.73±0.2°, 24.84±0.2°, 26.51±0.2°, 27.05±0.2°, 27.88±0.2°, 28.60±0.2° and 29.74±0.2°.

8. The crystalline form of fluvatinib mesylate according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks as shown in FIG. 7.

9. The crystalline form of fluvatinib mesylate according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 6.28±0.2°, 10.65±0.2°, 17.87±0.2°, 19.48±0.2°, 23.57±0.2°, and 24.38±0.2°.

10. The crystalline form according to claim 9, wherein its X-ray powder diffraction pattern further has characteristic diffraction peaks at 2θ degrees of 10.25±0.2°, 14.44±0.2°, 15.28±0.2°, 18.91±0.2°, 19.98±0.2°, 20.86±0.2°, 21.77±0.2°, 22.78±0.2°, and 24.98±0.2°.

11. The crystalline form of fluvatinib mesylate according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks as shown in FIG. 11.

12. The crystalline form of fluvatinib mesylate according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks as shown in FIG. 12.

13. The crystalline form of fluvatinib mesylate according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks as shown in FIG. 13.

14. The crystalline form of fluvatinib mesylate according to claim 1, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks as shown in FIG. 14.

15. A method of preparing the crystalline form of fluvatinib mesylate according to claim 1, comprising mixing fluvatinib mesylate with an organic solvent to obtain a mixed solution, stirring the mixed solution at a temperature greater than 20° C., filtering to obtain a solid, and drying the solid to obtain the crystalline form of fluvatinib mesylate.

16. The method according to claim 15, wherein the temperature is greater than 20° C. and less than 70° C.

17. The method according to claim 15, wherein the stirring is performed for at least 1 hour.

18. The method according to claim 17, wherein the stirring is performed for 2-48 hours.

19. The method according to claim 15, wherein the temperature is 20-30° C.

20. The method according to claim 15, wherein the organic solvent is selected from the group consisting of methanol, ethanol, acetone, THE, isopropanol, ethyl acetate, acetonitrile, cyclohexane, n-hexane, n-heptane, 1,4-dioxane, dichloromethane and a mixed solvent of any combination thereof.

21. The method according to claim 20, wherein the organic solvent is ethanol.

22. The method according to claim 15, wherein the temperature is 20-30° C., and the stirring time is at least 2 hours or at least 12 hours, or at least 16 hours, or at least 24 hours, or 48 hours.

23. The method according to claim 15, wherein the temperature is 30-65° C., and the stirring time is 1-3 hours.

24. The method according to claim 15, the temperature is 20-30° C., and the stirring time is 1-2 hours.

25. The method according to claim 22, wherein the organic solvent is ethanol.

26. The method according to claim 15, wherein the organic solvent is a mixed solvent containing water.

27. The method according to claim 26, wherein the organic solvent is a mixed solvent of ethanol with water or a mixed solvent of THF with water.

28. A pharmaceutical composition, comprising a crystalline form of fluvatinib or a crystalline form of fluvatinib mesylate and a pharmaceutically acceptable adjuvant, wherein the crystalline form is selected from the group consisting of: the crystalline form of fluvatinib according to claim 2, the crystalline form of fluvatinib mesylate according to claim 6, and the crystalline form obtained according to the method of claim 15.

29. A method of treating a tumor, comprising administering the composition according to claim 28 to a subject in need thereof.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0073] FIG. 1 is XRPD pattern of the crystalline form I of fluvatinib;

[0074] FIG. 2 is DSC curve of the crystalline form I of fluvatinib;

[0075] FIG. 3 is TGA curve of the crystalline form I of fluvatinib;

[0076] FIG. 4 is XRPD pattern of the crystalline form I of fluvatinib mesylate;

[0077] FIG. 5 is DSC and TGA curves of the crystalline form I of fluvatinib mesylate;

[0078] FIG. 6 is a hygroscopicity DVS curve of the crystalline form I of fluvatinib mesylate;

[0079] FIG. 7 is XRPD pattern of the crystalline form II of fluvatinib mesylate;

[0080] FIG. 8 is DSC and TGA curves of the crystalline form II of fluvatinib mesylate;

[0081] FIG. 9 is XRPD pattern of the crystalline form III of fluvatinib mesylate;

[0082] FIG. 10 is DSC and TGA curves of the crystalline form III of fluvatinib mesylate;

[0083] FIG. 11 is XRPD pattern of the crystalline form IV of fluvatinib mesylate;

[0084] FIG. 12 is XRPD pattern of the crystalline form V of fluvatinib mesylate;

[0085] FIG. 13 is XRPD pattern of the crystalline form VI of fluvatinib mesylate;

[0086] FIG. 14 is XRPD pattern of the crystalline form VII of fluvatinib mesylate;

[0087] FIG. 15 are XRPD patterns of the crystalline form I of fluvatinib after the crystal transformation test in Example 9;

[0088] FIG. 16 is XRPD patterns of the crystalline form I of fluvatinib mesylate before and after the DVS test in Example 10;

[0089] FIG. 17 is XRPD pattern of the crystalline form III of fluvatinib mesylate obtained from the crystal transformation experiment in Example 11;

[0090] FIG. 18 are XRPD patterns of the crystalline form in high temperature suspension experiment in Example 11;

[0091] FIG. 19 are DVS curves of the crystalline form III of fluvatinib mesylate;

[0092] FIG. 20 are XRPD patterns of the crystalline form I of fluvatinib mesylate before and after tableting, and having been placed for 6 months; and

[0093] FIG. 21 are XRPD patterns of the crystalline form III of fluvatinib mesylate before and after tableting, and having been placed for 6 months.

DETAILED DESCRIPTION

[0094] The following examples are only illustrative and are given to further describe or aid in understanding the spirit of the present invention, but do not limit the scope of the present invention in any way, and any simple modifications within the scope of the spirit of the present invention also fall within the scope of the present invention.

[0095] In this disclosure, parameters of the crystalline forms were measured by X-ray powder diffraction pattern (XRPD), DSC and TGA, which are commonly used in the ar. The instruments specifically used are set forth as follows. Based on the instruments and errors resulted from test, the result has an error ranging within ±0.2 in XRPD.

[0096] X-Ray Powder Diffraction (XRPD) [0097] Model: Bruker D8 advance X-ray powder diffractometer [0098] Test method: approximately 10-20 mg sample for XRPD detection [0099] The detailed XRPD parameters are as follows: [0100] Light tube: Cu, kα, (λ=1.54056 Å). [0101] Light tube voltage: 40 kV, light tube current: 40 mA [0102] Divergence slit: 0.60 mm [0103] Detector slit: 10.50 mm [0104] Anti-scatter slit: 7.10 mm [0105] Scanning range: 4-40 deg [0106] Step: 0.02 deg [0107] Step size: 0.12 sec.

[0108] Differential Scanning Calorimeter (DSC) [0109] Test condition: about 0.5-1 mg of sample for DSC detection [0110] Method: the sample was heated from the room temperature to 300° C. or to 350° C. at a heating rate of 10° C./min in N.sub.2 at 50 mL/min.

[0111] Thermogravimetric Analyzer (TGA) [0112] Test conditions: about 2-5 mg of samples for TGA detection [0113] Method: the sample was heated from the room temperature to have a weight loss of 20% or to 300° C. at a heating rate of 10° C./min in N.sub.2 at 25 mL/min.

TABLE-US-00001 Dynamic Vapor Sorption (DVS) Temperature 25° C. Amount of the sample 10-30 mg Protective gas N.sub.2, 200 mL/min and flow rate dm/dt 0.002%/min Minimum dm/dt 10 min equilibration time Maximum equilibration time 180 min RH range 0% RH-95% RH-0% RH 10% (90% RH-0% RH-90% RH) RH gradient 5% (95% RH-90% RH and 90% RH-95% RH)

[0114] The sample was placed on a glass slide, and observed after being dispersed with a cover glass. Objective lens: 20/50 times.

[0115] Hereinafter, the present the present disclosure will be further described in conjunction with examples.

Example 1 Preparation of Crystalline Form I of Fluvatinib

[0116] The free base of fluvatinib of formula I (50 mg, 112.40 umol) was added into EtOH (2 mL), stirred at 15-20° C. for 12 h, filtered to obtain a filter cake. The filter cake was added to 200 mL of acetone, stirred at 15-20° C. for 12 h, and filtered. The filter cake was dried at 40° C. with spinning under reduced pressure, to obtain a fluvatinib solid, named as crystalline form I of fluvatinib. Its XRPD result is shown in FIG. 1, and its DSC and TGA test results are shown in FIG. 2 and FIG. 3.

Example 2 Preparation of the Crystalline Form I of the Fluvatinib Methanesulfonate (Also Called as “Fluvatinib Mesylate” Herein)

[0117] 4-[3-chloro-4-(cyclopropylaminocarbonylamino)-2-fluoro-phenoxy]-7-methoxy-quinoli ne-6-carboxamide, that is, fluvatinib (0.5 g, 1.12 mmol) was added to EtOH (10 mL) solvent, heated to 55-60° C. At this temperature, methanesulfonic acid (108.02 mg, 1.12 mmol, 80.02 μL, 1 eq) was added to the reaction flask under stirring. When the reaction solution became clear, the reaction solution was cooled to 20-30° C., stirred at this temperature for 1 h when a brown solid was precipitated, and filtered under reduced pressure. The filter cake was rinsed with ethanol (2 mL×2), and dried at 40-50° C. with spinning under reduced pressure, to obtain a solid product, named as the crystalline form I of fluvatinib mesylate. The product was detected by XRPD, DSC, and TGA. The XRPD test results are shown in Table 1 and FIG. 4. The DSC and TGA test results are shown in FIG. 5. The melting point was about 232-237° C.

TABLE-US-00002 TABLE 1 XRPD diffraction data of the crystalline form I of fluvatinib mesylate Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å] [%] 6.61 49.82 0.3070 13.37 7.82 9.59 336.03 0.1279 9.22 52.76 10.74 149.30 0.1535 8.24 23.44 16.79 81.84 0.2047 5.28 12.85 17.41 76.72 0.3070 5.09 12.04 18.52 192.97 0.1279 4.79 30.30 20.12 143.50 0.2047 4.41 22.53 20.64 374.14 0.1279 4.30 58.74 20.86 357.93 0.1279 4.26 56.19 21.54 160.09 0.1791 4.13 25.13 22.50 390.36 0.1535 3.95 61.29 23.09 636.96 0.2047 3.85 100.00 23.72 116.62 0.1535 3.75 18.31 24.84 140.89 0.2047 3.58 22.12 26.50 149.71 0.2047 3.36 23.50 27.06 80.66 0.2047 3.29 12.66 27.89 122.65 0.2558 3.20 19.26 28.63 93.67 0.1535 3.12 14.71 29.78 166.56 0.3070 3.00 26.15 35.35 27.07 0.6140 2.54 4.25

Example 3 Preparation of the Crystalline Form II of Fluvatinib Mesylate

[0118] The free base fluvatinib (55 g) was added to EtOH (1.1 L) solvent, heated to 55-60° C. The methanesulfonic acid (11.88 g) was added to the reaction flask under stirring (300 rpm), and cooled to 10-20° C. after the complete of the reaction. The reaction system was stirred at this temperature for 2 h when a brown solid precipitated, and filtered at reduced pressure. The filter cake was rinsed with ethanol (50 mL×2), dried at 40-50° C. with spinning under reduced pressure to obtain a product, which was a brown solid crystalline form (52.5 g). The product was detected by XRPD, TGA, and DSC, and named as the crystalline form II of fluvatinib mesylate (Form II). The results are shown in Table 2, FIG. 7 and FIG. 8.

TABLE-US-00003 TABLE 2 XRPD diffraction data of the crystalline form II of fluvatinib mesylate Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å] [%] 4.88 1134.08 0.1023 18.09 93.20 6.93 796.51 0.1279 12.76 65.46 9.77 1216.83 0.1791 9.05 100.00 10.93 760.87 0.2047 8.10 62.53 12.07 182.42 0.2047 7.33 14.99 14.81 242.22 0.2047 5.98 19.91 15.56 546.79 0.1535 5.69 44.94 17.72 446.01 0.1791 5.01 36.65 18.56 261.42 0.2558 4.78 21.48 19.74 282.58 0.2047 4.50 23.22 21.11 272.39 0.1279 4.21 22.39 21.73 188.45 0.1535 4.09 15.49 22.73 211.49 0.3070 3.91 17.38 24.68 164.93 0.3070 3.61 13.55 25.70 612.62 0.1791 3.47 50.35 26.19 535.08 0.1791 3.40 43.97 27.49 268.24 0.2814 3.24 22.04 34.99 43.59 0.6140 2.56 3.58

Example 4 Preparation of the Crystalline Form III of Fluvatinib Mesylate

[0119] Method 1: To a reaction flask, 100 g of fluvatinib (free base) was added to MeOH (2.2 L) solvent, and then methanesulfonic acid (16.64 mL) was added under stirring into the reaction flask to perform a reaction. The mixture was stirred at 20-30° C. for 4 h when a brown solid precipitated, and filtered at reduced pressure. The filter cake was rinsed with ethanol (50 mL×2), and dried at 40-50° C. with spinning under reduced pressure to obtain a solid product (106.2 g). The solid product (105 g) was added to 1 L of ethanol in a reaction flask, stirred at 20-30° C. for 48 h, and filtered at reduced pressure, to obtain a filter cake. The filter cake was dried at 40-50° C. under reduced pressure to obtain a solid crystalline product. The product was detected by XRPD, TGA, and DSC. The results are shown in Table 3, FIG. 9 and FIG. 10. The XRPD data show that the crystalline form of the product was the crystalline form III of fluvatinib mesylate (Form III). Its melting point was about 220-226° C.

[0120] Method 2: The crystalline form II of fluvatinib mesylate (52 g) obtained in Example 3 was added to 420 mL of ethanol, stirred mechanically at 20-30° C. (300 rpm) for 16 h, and filtered at reduced pressure. The filter cake was dried at 40-50° C. under reduced pressure to obtain a product. The product was detected by XRPD. As a result, its 2θ degrees in XRPD are basically consistent with those in FIG. 9, indicating that the obtained crystalline form is Form III.

[0121] Method 3: 0.5 g of fluvatinib free base was added to 10 mL of ethanol, and added with 0.1 mL of methanesulfonic acid. The mixture was suspended at 40° C. for 3-4 hours, centrifuged, filtered, and dried at 40° C. in an oven. The detection results show that the prepared product is crystalline form III of the methanesulfonate salt. Its 2θ degrees in XRPD are basically consistent with those in FIG. 9.

[0122] Method 4: 0.9 g of fluvatinib methanesulfonate was added to 7.2 mL of ethanol in a reaction flask under stirring. After the addition, the mixture was heated to 55-65° C., stirred at this temperature for about 2-3 h, and filtered at reduced pressure. The filter cake was rinsed with ethanol (0.5 mL×2) to obtain a filter cake, and dried at 45° C. under vacuum to obtain a product. Its 2θ degrees in XRPD are basically consistent with those in FIG. 9.

TABLE-US-00004 TABLE 3 XRPD diffraction data of the crystalline form III of fluvatinib mesylate Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å] [%] 6.28 1707.03 0.1023 14.09 67.71 10.25 983.92 0.1279 8.63 39.03 10.64 1502.23 0.1279 8.31 59.59 14.44 1215.18 0.1279 6.13 48.20 15.28 314.50 0.1023 5.80 12.47 16.34 103.69 0.1535 5.43 4.11 17.06 129.56 0.2047 5.20 5.14 17.87 2521.11 0.1535 4.97 100.00 18.91 899.67 0.1279 4.69 35.69 19.48 1268.38 0.2303 4.56 50.31 19.98 880.05 0.1279 4.44 34.91 20.86 1181.20 0.1279 4.26 46.85 21.39 288.79 0.1023 4.15 11.45 21.77 810.45 0.1279 4.08 32.15 22.54 460.84 0.1023 3.94 18.28 22.78 742.06 0.1279 3.90 29.43 23.57 1537.53 0.1791 3.78 60.99 24.38 1757.30 0.1535 3.65 69.70 24.98 1119.25 0.1279 3.56 44.40 25.23 621.29 0.1023 3.53 24.64

Example 5 Preparation of the Crystalline Form IV of Fluvatinib Mesylate

[0123] About 1.0 g of fluvatinib methanesulfonate was weighed and added to a mixed solvent system of 4 mL ethanol/4 mL water (1:1), to form a suspension. The suspension sample was stirred using a magnetic stirrer (20-30° C.) and became a brown suspension after 48 h, and filtered under reduced pressure. The filter cake was dried at 40-50° C. with spinning under reduced pressure, to obtain 625 mg of a dry solid crystalline product, with a yield of 62.5%. The product was detected by XRPD. The results shown in Table 4 and FIG. 11 indicate that the product is the crystalline form IV of fluvatinib mesylate.

TABLE-US-00005 TABLE 4 XRPD diffraction data of the crystalline form IV of fluvatinib mesylate Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å] [%] 6.22 1265.67 0.1535 14.22 67.64 8.29 319.16 0.1535 10.67 17.06 10.59 1692.34 0.1535 8.35 90.44 11.58 1224.15 0.1023 7.64 65.42 13.06 76.40 0.3070 6.78 4.08 14.41 993.01 0.1535 6.14 53.07 15.35 347.84 0.1535 5.77 18.59 15.52 279.28 0.1535 5.71 14.93 16.73 498.57 0.1023 5.30 26.64 17.93 1090.31 0.1279 4.95 58.27 18.84 815.02 0.1023 4.71 43.56 19.56 583.03 0.1023 4.54 31.16 20.00 321.38 0.1023 4.44 17.18 20.32 1871.18 0.1279 4.37 100.00 20.87 440.36 0.1279 4.26 23.53 21.32 222.29 0.1023 4.17 11.88 21.82 540.73 0.1279 4.07 28.90 22.43 627.86 0.1279 3.96 33.55 22.91 723.97 0.1279 3.88 38.69 23.58 933.68 0.1791 3.77 49.90 24.09 855.62 0.1279 3.69 45.73 24.59 884.95 0.1279 3.62 47.29 24.97 565.38 0.1279 3.57 30.22 25.25 304.05 0.1279 3.53 16.25 25.79 1462.26 0.1279 3.45 78.15 26.33 826.02 0.1279 3.39 44.14 27.01 466.74 0.1535 3.30 24.94 28.30 423.47 0.1535 3.15 22.63 29.24 143.19 0.2047 3.05 7.65 29.99 211.10 0.3582 2.98 11.28 30.62 196.94 0.1791 2.92 10.52 32.09 53.11 0.3070 2.79 2.84 33.53 109.79 0.1535 2.67 5.87 34.63 127.16 0.2047 2.59 6.80 35.38 203.67 0.1791 2.54 10.88 37.94 113.41 0.2047 2.37 6.06 38.58 91.48 0.2047 2.33 4.89

Example 6 Preparation of the Crystalline Form V of the Fluvatinib Methanesulfonate

[0124] About 1.0 g of fluvatinib methanesulfonate was weighed and added to a mixed solvent system of 4 mL tetrahydrofuran/4 mL water (1:1), to form a suspension. The suspension sample was stirred using a magnetic stirrer at 20-30° C., become a brown suspension after 48 h, and filtered. The filter cake was dried at 40-50° C. with spinning under reduced pressure, to obtain a dry sample 430 mg with a yield of 43.00%. The sample was detected by XRPD. The results are shown in Table 5 and FIG. 12, indicating that the sample is the crystalline form V of fluvatinib mesylate.

TABLE-US-00006 TABLE 5 XRPD diffraction data of the crystalline form V of fluvatinib mesylate Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å] [%] 4.81 889.42 0.1279 18.36 87.69 9.54 312.80 0.1023 9.27 30.84 10.64 1014.28 0.1535 8.31 100.00 10.99 444.45 0.1023 8.05 43.82 11.69 117.55 0.1535 7.57 11.59 14.74 139.06 0.1535 6.01 13.71 16.00 439.50 0.1023 5.54 43.33 17.83 219.37 0.1535 4.97 21.63 19.85 181.41 0.1535 4.47 17.89 20.50 601.68 0.1023 4.33 59.32 21.10 596.03 0.1279 4.21 58.76 21.97 332.97 0.1279 4.05 32.83 22.57 365.58 0.2558 3.94 36.04 23.18 198.16 0.2047 3.84 19.54 24.59 406.40 0.2303 3.62 40.07 25.57 531.76 0.1023 3.48 52.43 26.46 602.59 0.1279 3.37 59.41 27.44 148.11 0.4093 3.25 14.60 32.46 43.13 0.6140 2.76 4.25

Example 7 Preparation of the Crystalline Form VI of the Fluvatinib Methanesulfonate

[0125] About 2.0 g of fluvatinib free base was weighed and added to methanol in a reaction flask to form a suspension, and added with 0.32 mL of methanesulfonic acid while being stirred at 20-30° C. The reaction solution was stirred at 20-30° C. for 4 h, and filtered. The filter cake was dried at 40-50° C. with spinning under reduced pressure, to obtain a dry sample. The sample was detected by XRPD. The results are shown in Table 6 and FIG. 13, indicating that the sample is the crystalline form VI of fluvatinib mesylate (Form VI).

TABLE-US-00007 TABLE 6 XRPD diffraction data of the crystalline form VI of fluvatinib mesylate Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å] [%] 5.61 5735.70 0.1023 15.75 100.00 6.78 331.22 0.1279 13.05 5.77 9.98 4786.31 0.1279 8.86 83.45 10.61 2778.82 0.1279 8.34 48.45 11.18 842.59 0.1279 7.91 14.69 12.85 104.45 0.2047 6.89 1.82 13.51 564.63 0.1535 6.55 9.84 14.84 80.33 0.3070 5.97 1.40 15.58 345.24 0.1279 5.69 6.02 15.83 420.20 0.1279 5.60 7.33 16.84 1678.51 0.2558 5.27 29.26 20.14 2420.84 0.1535 4.41 42.21 20.89 1209.62 0.2047 4.25 21.09 22.04 155.45 0.2047 4.03 2.71 23.53 206.63 0.2047 3.78 3.60 24.80 833.72 0.1791 3.59 14.54 25.62 909.32 0.1791 3.48 15.85 27.56 97.82 0.3070 3.24 1.71 29.24 262.55 0.2047 3.05 4.58 30.18 79.27 0.3070 2.96 1.38 31.24 237.67 0.2047 2.86 4.14 32.04 410.66 0.2303 2.79 7.16 33.90 47.10 0.6140 2.64 0.82 36.95 62.03 0.3070 2.43 1.08

Example 8 Preparation of the Crystalline Form VII of Fluvatinib Methanesulfonate

[0126] About 0.2 g of the crystalline form VI of fluvatinib methanesulfonate obtained in Example 7 was weighed and added to ethanol solvent to form a suspension. The suspension was stirred at 20-30° C. using a magnetic stirrer for 4 h, and then filtered. The filter cake was dried at 40-50° C. with spinning under reduced pressure. The obtained dry sample was detected by XRPD. The results are shown in Table 7 and FIG. 14, indicating that the sample is the crystalline form VII of fluvatinib mesylate (Form VII).

TABLE-US-00008 TABLE 7 XRPD diffraction data of the crystalline form VII of fluvatinib mesylate Pos. Height FWHM Left d-spacing Rel. Int. [°2θ] [cts] [°2θ] [Å] [%] 5.57 1352.56 0.1023 15.86 80.05 6.17 521.82 0.1023 14.32 30.89 6.69 121.82 0.2047 13.21 7.21 9.93 1689.54 0.1023 8.91 100.00 10.56 1384.01 0.1279 8.38 81.92 11.15 189.94 0.1535 7.94 11.24 13.47 213.05 0.1279 6.57 12.61 14.34 359.10 0.1023 6.18 21.25 15.68 93.94 0.3070 5.65 5.56 16.81 488.60 0.1791 5.27 28.92 17.76 550.01 0.1023 4.99 32.55 18.77 108.72 0.2047 4.73 6.43 19.37 272.68 0.1279 4.58 16.14 20.10 563.56 0.1535 4.42 33.36 20.81 387.35 0.1535 4.27 22.93 21.26 168.67 0.1535 4.18 9.98 23.46 238.07 0.1535 3.79 14.09 24.29 268.93 0.1023 3.66 15.92 24.85 440.06 0.2303 3.58 26.05 25.60 497.89 0.1791 3.48 29.47 28.10 101.35 0.1535 3.18 6.00 29.16 187.94 0.2047 3.06 11.12 32.07 99.98 0.2047 2.79 5.92

Example 9 Investigation on Stability of the Crystalline Form I of Fluvatinib

[0127] The crystalline form I of fluvatinib was placed in an organic solvent and a water-containing organic solvent, and stirred at 40° C. for 2 days to investigate whether there was a crystal transformation.

[0128] A number parts of about 30 mg of the crystalline form I of fluvatinib (Form I) were respectively weighed and added to different glass bottles, and added with an appropriate amount of a single organic solvent or a mixture containing water (see Table 8) to form suspensions. The above-mentioned suspension samples were placed on magnetic stirrers (40° C.) to perform a stirring test. After being stirring at 40° C. for 2 days, the suspension samples were filtered. The filter cake samples were then dried overnight in a vacuum dry box (40° C.), and the dried samples were detected by XRPD (see Table 8 and FIG. 15). The results indicates that the crystalline form I of fluvatinib is stable in various solvents (especially in solvents containing water), without occurrence of crystal transformation, which is suitable for the industrial production of its preparations.

TABLE-US-00009 TABLE 8 Solvents and crystalline forms after stirring for 2 days state under amounts of stirring crystalline No. solvents solvents (mL) for 2 days form 1 methanol 0.4 suspension Form I 2 ethanol 0.4 suspension Form I 3 ethyl acetate 0.4 suspension Form I 4 acetone 0.4 suspension Form I 5 THF 0.4 suspension Form I 6 isopropanol 0.4 suspension Form I 7 methanol-water (3:1) 0.4 suspension Form I 8 ethanol-water (3:1) 0.4 suspension Form I 9 acetone-water (1:2) 0.4 suspension Form I 10 isopropanol-water (1:1) 0.4 suspension Form I 11 THF-water(1:1) 0.4 suspension Form I

Example 10 Investigation of the Stability of the Crystalline Form I of Fluvatinib Mesylate

[0129] The crystalline form I of fluvatinib mesylate was stored in acetone, ethanol and ethyl acetate to investigate whether there was a crystal transformation.

[0130] 3 parts of about 50 mg the crystalline form I of fluvatinib mesylate were weighed and respectively added to reaction flasks containing an appropriate amount of acetone, ethanol, or ethyl acetate solvent. The suspension samples were placed on magnetic stirrers, stirred for 10 h at room temperature, and filtered. The filter cake was dried at 40-50° C. with spinning under reduced pressure. The obtained dry samples were detected by XRPD. The test results shows that its 2θ degrees of XRPD are basically consistent with those in FIG. 4 (within the error range). It can be concluded that the crystalline form I of the fluvatinib methanesulfonate maintained its form in single solvent of ethanol, acetone, or ethyl acetate, indicating that the crystalline form I of fluvatinib mesylate has good stability.

[0131] At the same time, the crystalline form I of fluvatinib mesylate was tested for dynamic hygroscopicity by DVS to detect water content. The results show that the methanesulfonate salt has a hygroscopic weight gain of 1.3% (see FIG. 6) under the condition of 25° C./80% RH, indicating that the sample has slight hygroscopicity, and the crystalline form of the sample did not undergo crystal transformation after DVS measurements (see FIG. 16). This indicates again that the crystalline form I of fluvatinib mesylate has good stability.

Example 11 Investigation on Stability of the Crystalline Form III of Fluvatinib Mesylate

[0132] 1. Investigation of the Stability of the Crystalline Form III of Fluvatinib Mesylate in Air (Oxygen Gas)

[0133] To investigate the stability of the crystalline form III of fluvatinib mesylate (Form III), Form III was exposed to air and contacted with oxygen. The results are shown in Table 9. As can be seen from the results, the methanesulfonate salts can exist stably when exposed to the air at 20-30° C. and 60° C., and the methanesulfonate salts have stable oxdation resistance, without producing extra visible impurities.

TABLE-US-00010 TABLE 9 Stability data of the crystalline form III of fluvatinib mesylate in oxygen gas oxidation crystalline 20-30° C. 60° C. No. form 0 hour 24 hours 0 hour 24 hours 1 Form III 93.66% 94.10% 93.61% 94.00%

[0134] 2. Investigation of the Crystal Transformation in Organic Solvents

[0135] The crystalline form of the fluvatinib methanesulfonate was investigated on its stability in ethanol, to see whether there is crystal transformation.

[0136] About 0.15 g of the crystalline forms II (Form II), III (Form III), VI (Form VI) and VII (Form VII) of the fluvatinib mesylate were weighed and respectively added to reaction flasks containing ethanol, stirred magnetically for 2 days at room temperature, and filtered. The filter cakes were dried at 40-50° C. with spinning under reduced pressure. The obtained dried samples were detected by XRPD. The results showed that all samples were Form III, indicating that Form III did not undergo crystal transformation, whereas Form II, Form VI and Form VII undergone crystal transformation and converted to Form III as shown in FIG. 17. This indicates that the crystalline form III of fluvatinib mesylate has good stability, and is suitable and adaptable to the processing process of preparations, particularly for preparing tablets or granules of fluvatinib methanesulfonate by the granulation and tableting process containing ethanol as a binder or wetting agent.

[0137] 3. Investigation of the Stability of the Crystalline Form III of Fluvatinib Mesylate in Various Organic Solvents

[0138] The crystalline form III of fluvatinib mesylate was subjected to high temperature suspension experiments (50° C.), to investigate whether the crystalline form III of fluvatinib mesylate undergoes crystal transformation in various type of common organic solvents, and whether it is stable. The crystalline form III of fluvatinib mesylate was suspended in 12 types of organic solvents (in 1 mL of solvent) and water as set forth in Table 10 at a temperature of 50° C. and an amount of about 25 mg for 24 hours. The experiment conditions and results are shown in Table 10. The solids after being suspended in the organic solvents were detected by XRPD. The results shows that they all have the 2θ characteristic peaks of the crystal form III (see FIG. 18).

TABLE-US-00011 TABLE 10 High temperature suspension experiment and results solid solution weight volume XRD solvent No. solvent (mg) (mL) results 1 ethanol 25 1 Form III 2 isopropanol 25 1 Form III 3 acetone 25 1 Form III 4 cyclohexane 25 1 Form III 5 acetonitrile 25 1 Form III 6 tetrahydrofuran 25 1 Form III 7 ethyl acetate 25 1 Form III 8 n-hexane 25 1 Form III 9 n-heptane 25 1 Form III 10 1.4-dioxane 25 1 Form III 11 dichloromethane 25 1 Form III

Example 12 Investigation on the Hydrothermal Stability of the Crystalline Forms of Fluvatinib Mesylate

[0139] The crystalline forms I, III, IV, V, VI, and VII of fluvatinib mesylate of the present disclosure were placed in harsh environments to investigate their stability. They were placed under high temperature and high humidity conditions: 25° C. 92.5% R.H for 7 days, 40° C. 75% R.H for 14 days, and 60° C. for 14 days, and then detected by XRPD. The results are shown in Table 11.

TABLE-US-00012 TABLE 11 Experimental results of the hydrothermal stability of the crystalline forms of fluvatinib mesylate 25° C. 40° C. crystalline lot 92.5% R.H 75% R.H 60° C. form number for 7 days for 14 days for 14 days I P-JZ- no crystal no crystal no crystal 200303-CYM transfor- transfor- transfor- mation mation mation III P-200228-CYM no crystal no crystal no crystal transfor- transfor- transfor- mation mation mation V P-200418-XPY-2 converted to converted to converted to crystalline crystalline crystalline form III form III form III VI P-200422-XPY-1 converted to converted to converted to crystalline crystalline crystalline form III form III form III VII P-200422-XPY-2 converted to converted to converted to crystalline crystalline crystalline form III form III form III

[0140] The results in Table 11 show that the crystalline form I and crystalline form III of fluvatinib mesylate did not undergo crystal transformation under high temperature and high humidity conditions, exhibiting good stability. Whereas the crystalline forms V, VI, VII of fluvatinib mesylate undergone crystal transformation under high temperature and high humidity conditions, exhibiting instability to high temperature and high humidity.

Example 13 Hygroscopicity Investigation

[0141] The crystalline form III of fluvatinib mesylate was tested for hygroscopicity under humidity conditions of 25° C., 0-90% RH, using a dynamic moisture tester a dynamic vapor sorption (DVS) analyzer. The results are shown in FIG. 19.

[0142] The results in FIG. 19 show that the crystalline form III of fluvatinib mesylate has a hygroscopic weight of 0.44%, exhibiting low hygroscopicity and thus stability to moisture.

Example 14 Formulation

[0143]

TABLE-US-00013 formulation parts percentages by weight crystalline form I or III 30% of fluvatinib mesylate anhydrous lactose 45% direct compression starch 23% magnesium stearate  2%

[0144] The formula amounts of the crystalline form of fluvatinib mesylate, anhydrous lactose and direct compression starch were mixed, and then mixed with magnesium stearate. The mixture was prepared into tablets by direct compression method, with each table weighed 200 mg.

[0145] The crystalline forms before and after being prepared into tablets and after the tablets being placed in 40° C., 75% RH environment for 6 months were detected by XRPD. The results are shown in FIGS. 20 and 21, wherein A, B, and C represent XRPD patterns of the crystalline form before and after being prepared into tablets and after the tablets being placed for 6 months. The XRPD pattern comparison between the test sample and crystalline forms of the active pharmaceutical ingredients (API), shows that neither the crystalline form I of fluvatinib mesylate nor the crystalline form III of fluvatinib mesylate undergoes crystal transformation during the process of preparing tablets, and no crystal transformation occurred after the tablets being placed for 6 months.

[0146] The above test results show that the crystalline forms I and III of fluvatinib mesylate remain stable in the formulation processing, and exhibit good stability in high temperature and high humidity environments, indicating excellent stability of crystalline forms I and III.