NEW CRYSTAL FORM OF NERATINIB MALEATE AND PREPARATION METHOD THEREFOR

Abstract

The present invention relates to novel crystalline forms of Neratinib maleate and the preparation method thereof. The maleate novel crystalline forms of compound of Formula (I) in the present invention have high solubility, good stability, good processability, easy post-treatment process and other favorable properties. The preparation method is simple, low cost, and has an important value for future optimization and development of the drug.

##STR00001##

Claims

1-39. (canceled)

40. A maleate crystalline Form C of the compound of Formula (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 14.20.2, 15.20.2 and 23.50.2. ##STR00003##

41. The maleate crystalline Form C of the compound of Formula (I) according to claim 40, wherein the X-ray powder diffraction pattern further shows one or more of the characteristic peaks at 2theta values of 10.90.2, 21.40.2, 24.50.2, 23.00.2, 18.20.2 and 20.30.2.

42. The maleate crystalline Form C of the compound of Formula (I) according to claim 40, wherein the X-ray powder diffraction pattern is substantially as depicted in FIG. 7.

43. A process of preparing maleate crystalline Form C according to claim 40, wherein the process comprises: adding the compound of Formula (I) and maleic acid into an organic solvent or a mixture of several organic solvents, then stirring to get crystals; or stirring the amorphous maleate in an organic solvent or a mixture of several organic solvents to get crystals, and these mixed solvents are mixed in any ratio.

44. The process of preparing maleate crystalline Form C according to claim 43, wherein the organic solvent is selected from ketone solvents, alcohol solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, cyclic ether solvents, nitro-hydrocarbon and C3-C10 alkane solvents.

45. The process of preparing maleate crystalline Form C according to claim 44, wherein the organic solvent is selected from acetone, methanol, toluene, dichloromethane, acetonitrile, tetrahydrofuran, nitromethane, n-heptane and n-hexane.

46. The process of preparing maleate crystalline Form C according to claim 43, wherein the molar ratio of the compound of Formula (I) and maleic acid is from 1:1 to 1:1.5.

47. A pharmaceutical composition comprising maleate crystalline Form C according to claim 40 and pharmaceutically acceptable excipients.

48. A method of preventing, treating, or inhibiting cancer, comprising administering the maleate crystalline Form C according to claim 40.

49. A maleate crystalline Form A of compound of Formula (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 6.90.2, 13.90.2 and 22.50.2. ##STR00004##

50. The maleate crystalline Form A of compound of Formula (I) according to claim 49, wherein the X-ray powder diffraction pattern further shows one or more of the characteristic peaks at 2theta values of 5.10.2, 11.40.2, 18.30.2, 13.20.2, 15.20.2 and 21.60.2.

51. The maleate crystalline Form A of compound of Formula (I) according to claim 49, wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 1.

52. The maleate crystalline Form A of compound of Formula (I) according to claim 49, wherein crystalline Form A is an anhydrate.

53. A process of preparing maleate crystalline Form A according to claim 49, wherein the process comprises: adding the compound of Formula (I) and maleic acid into a single organic solvent or a mixture of several organic solvents, then stirring to get crystals, and these mixed organic solvents are mixed in any ratio.

54. The process of preparing maleate crystalline Form A according to claim 53, wherein the organic solvent is selected from ketone solvents, alcohol solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, nitrile solvents, cyclic ether solvents and C3-C10 alkane solvents.

55. The process of preparing maleate crystalline Form A according to claim 54, wherein the organic solvent is selected from acetone, ethanol, isopropanol, toluene, dichloromethane, acetonitrile, tetrahydrofuran, n-heptane and n-hexane.

56. The process of preparing maleate crystalline Form A according to claim 53, wherein the molar ratio of the compound of Formula (I) and maleic acid is between 1:2 to 1:5.

57. A pharmaceutical composition, comprising an effective amount of maleate crystalline Form A according to claim 49 and pharmaceutically acceptable excipients.

58. A method of preventing, treating, or inhibiting cancer, comprising administering the maleate crystalline Form A according to claim 49.

59. A maleate crystalline Form B of the compound of Formula (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 5.40.2, 13.50.2 and 19.60.2. ##STR00005##

60. The maleate crystalline Form B of the compound of Formula (I) according to claim 59, wherein the X-ray powder diffraction pattern further shows one or more of the characteristic peaks at 2theta values of 10.70.2, 12.10.2, 23.80.2, 9.90.2, 22.20.2 and 17.60.2.

61. The maleate crystalline Form B of the compound of Formula (I) according to claim 59, wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 4.

62. The maleate crystalline Form B of the compound of Formula (I) according to claim 59, wherein the crystalline Form B is a hydrate.

63. A process of preparing maleate crystalline Form B of the compound of Formula (I) according to claim 59, wherein the process comprises: stirring maleate crystalline Form A in water or a mixture of water and other solvents, or placing maleate crystalline Form A at 60% or above humidity conditions.

64. A pharmaceutical composition, comprising maleate crystalline Form B according to claim 59 and pharmaceutically acceptable excipients.

65. A method of preventing, treating, or inhibiting cancer, comprising administering the maleate crystalline Form B according to claim 59.

66. A pharmaceutical composition comprising effective amount of maleate crystalline Form A of the compound of Formula (I) according to claim 49, maleate crystalline Form B of the compound of Formula (I) according to claim 59, maleate crystalline Form C of the compound of Formula (I) according to claim 40, or a combination thereof and pharmaceutically acceptable excipients.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0054] FIG. 1 shows an XRPD pattern of maleate crystalline Form A

[0055] FIG. 2 shows a DSC thermogram of maleate crystalline Form A

[0056] FIG. 3 shows a TGA thermogram of maleate crystalline Form A

[0057] FIG. 4 shows an XRPD pattern of maleate crystalline Form B

[0058] FIG. 5 shows a DSC thermogram of maleate crystalline Form B

[0059] FIG. 6 shows a TGA thermogram of maleate crystalline Form B

[0060] FIG. 7 shows an XRPD pattern of maleate crystalline Form C

[0061] FIG. 8 shows a DSC thermogram of maleate crystalline Form C

[0062] FIG. 9 shows a TGA thermogram of maleate crystalline Form C

[0063] FIG. 10 shows a .sup.1HNMR spectrum of maleate crystalline Form A

[0064] FIG. 11 shows a .sup.1HNMR spectrum of maleate crystalline Form B

[0065] FIG. 12 shows a .sup.1HNMR spectrum of maleate crystalline Form C

[0066] FIG. 13 shows an XRPD overlay pattern of maleate crystalline Form B before and after storing at 5 C. for 90 days (the pattern above is before storing and the below one is after storing)

[0067] FIG. 14 shows an XRPD overlay pattern of maleate crystalline Form B before and after storing at 25 C./60% RH for 90 days (the pattern above is before storing and the below one is after storing)

[0068] FIG. 15 shows an XRPD overlay pattern of maleate crystalline Form B before and after storing at 40 C./75% RH for 90 days (the pattern above is before storing and the below one is after storing)

[0069] FIG. 16 shows a DVS plot of maleate crystalline Form C

[0070] FIG. 17 shows an XRPD overlay pattern of maleate crystalline Form C before and after storing at 5 C. for 330 days (the pattern above is before storing and the below one is after storing)

[0071] FIG. 18 shows an XRPD overlay pattern of maleate crystalline Form C before and after storing at 25 C./60% RH for 330 days (the pattern above is before storing and the below one is after storing)

[0072] FIG. 19 shows an XRPD overlay pattern of maleate crystalline Form C before and after storing at 40 C./75% RH for 330 days (the pattern above is before storing and the below one is after storing)

DETAILED DESCRIPTION OF THE INVENTION

[0073] The present invention will be further explained by the specific embodiments, but are not intended to limit the scope of the present invention. The skilled in the art can make improvements to the process of preparation and the used instruments within the scope of the claims, and those improvements should be considered as falling into the scope of the present invention. Therefore, the protective scope of the present invention patent should be defined by the claims.

[0074] The abbreviations used in the invention are explained as follows:

[0075] XRPD: X-ray Powder Diffraction

[0076] DSC: Differential Scanning calorimetry

[0077] TGA: Thermal Gravimetric Analysis

[0078] .sup.1HNMR: Proton Nuclear Magnetic Resonance

[0079] X-ray powder diffraction pattern in the present invention was acquired by a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present invention were as follows:

[0080] X-ray Reflection: Cu, K

[0081] K1 (): 1.540598; K2 (): 1.544426

[0082] K2/K1 intensity ratio: 0.50

[0083] Voltage: 45 (kV)

[0084] Current: 40 (mA)

[0085] Scan range: from 3.0 degree to 40.0 degree

[0086] Differential scanning calorimetry (DSC) data in the present invention were acquired by a TA Q2000. The parameters of the differential scanning calorimetry (DSC) method of the present invention were as follow: [0087] Heating rate: 10 C./min [0088] Purge gas: nitrogen.

[0089] Thermal gravimetric analysis (TGA) data in the present invention were acquired by a TA

[0090] Q5000. The parameters of the thermal gravimetric analysis (TGA) method of the present invention were as follow: [0091] Heating rate: 10 C./min; [0092] Purge gas: nitrogen.

Example 1

[0093] Process of preparing maleate crystalline Form A of the compound of Formula (I):

[0094] 101.2 mg of compound of Formula (I) was dissolved into 4.0 mL of dichloromethane, and 73.3 mg of maleic acid was added to the solution, then it was stirred at room temperature for 12 hours and centrifuged to give a solid.

[0095] .sup.1HNMR data of the maleate product prepared by the above process are in the following, and the data indicates that the molar ratio of the compound of the Formula (I) and maleic acid is 1:3, so the maleate above is a tri-maleate.

[0096] .sup.1HNMR (400 MHz, DMSO-d6) 9.81 (s, 1H), 9.76 (s, 1H), 8.95 (s, 1H), 8.60 (d, J=4.1 Hz, 1H), 8.54 (s, 1H), 7.88 (td, J1=7.7 Hz, J2=1.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.37-7.42 (m, 3H), 7.21-7.26 (m, 2H), 6.82-6.70 (m, 2H), 6.20 (s, 6H), 5.29 (s, 2H), 4.33 (q, J=6.9 Hz, 2H), 3.96 (d, J=5.4 Hz, 2H), 2.81 (s, 6H), 1.47 (t, J=6.9 Hz, 3H).

[0097] The XRPD data of the solid prepared in this example are listed in Table 1. The result shows the solid is maleate Form A. The DSC thermogram is displayed in FIG. 2, the TGA thermogram is displayed in FIG. 3 and the .sup.1H NMR spectrum is displayed in FIG. 10.

TABLE-US-00001 TABLE 1 2theta d spacing Relative intensity % 5.06 17.46 56.99 5.71 15.48 21.57 6.91 12.80 34.12 9.99 8.85 20.20 10.18 8.69 21.33 11.48 7.71 6.89 12.08 7.33 6.51 13.18 6.72 31.12 13.59 6.52 21.52 13.92 6.36 26.72 15.21 5.82 17.24 16.10 5.51 19.20 16.53 5.36 6.52 17.06 5.20 23.19 17.40 5.10 11.88 18.26 4.86 24.36 19.13 4.64 14.07 19.62 4.53 11.25 20.57 4.32 22.14 21.00 4.23 7.65 21.58 4.12 24.34 22.16 4.01 35.54 22.54 3.94 44.81 23.37 3.81 7.83 23.97 3.71 9.08 24.65 3.61 10.67 25.08 3.55 13.90 25.89 3.44 15.06 26.76 3.33 16.89 27.97 3.19 100.00 28.81 3.10 15.88 31.90 2.81 5.94

Example 2

[0098] Process of preparing maleate crystalline Form A of the compound of Formula (I):

[0099] 19.8 mg of compound of Formula (I) was added into 1.0 mL of acetone to obtain a suspension, and 13.0 mg of maleic acid was added into the suspension, then it was stirred at room temperature for 12 hours and centrifuged to give a solid.

[0100] The XRPD data of the solid prepared in this example are listed in Table 2 and the result indicates the solid is maleate crystalline Form A. The XRPD pattern is displayed in FIG. 1.

TABLE-US-00002 TABLE 2 2theta d spacing Relative intensity % 5.06 17.46 64.25 6.09 14.51 23.98 6.91 12.79 43.77 10.03 8.82 22.55 10.22 8.66 18.39 11.51 7.69 28.84 12.95 6.83 23.95 13.21 6.70 36.42 13.63 6.50 39.74 13.94 6.35 26.67 15.25 5.81 27.56 16.14 5.49 28.10 17.11 5.18 32.89 18.31 4.85 33.71 19.17 4.63 23.62 19.67 4.51 39.84 20.29 4.38 23.73 20.62 4.31 32.76 21.09 4.21 16.98 21.64 4.11 45.43 22.27 3.99 44.82 22.61 3.93 100.00 22.86 3.89 46.94 23.51 3.78 18.88 24.02 3.71 21.05 25.09 3.55 33.16 25.95 3.43 33.75 26.89 3.32 22.63 27.56 3.24 10.94 28.89 3.09 35.56 30.62 2.92 12.17 32.04 2.79 15.72

Example 3

[0101] Process of preparing maleate crystalline Form A of the compound of Formula (I):

[0102] 10.0 mg of compound of Formula (I) was added into 0.5 mL of isopropanol to obtain a suspension, then 6.0 mg of maleic acid was added into the suspension and 0.6 mL of n-hexane was added drop by drop when stirring, then it was stirred at room temperature for 12 hours and centrifuged to give a solid.

[0103] The XRPD data of the solid prepared in this example are listed in Table 3 and the result indicates the solid is maleate crystalline Form A.

TABLE-US-00003 TABLE 3 2theta d spacing Relative intensity % 5.06 17.46 15.35 6.04 14.63 100.00 6.84 12.92 28.14 9.57 9.25 26.21 11.38 7.78 40.16 12.25 7.23 20.00 13.12 6.75 47.16 13.86 6.39 24.84 15.23 5.82 21.12 15.90 5.57 18.03 17.32 5.12 21.34 18.19 4.88 18.73 19.33 4.59 27.89 20.16 4.40 24.13 21.54 4.13 27.97 22.10 4.02 45.25 22.51 3.95 39.73 23.48 3.79 27.07 25.03 3.56 24.17 26.05 3.42 28.90 27.83 3.21 17.59 28.75 3.10 14.77 29.86 2.99 10.84 33.89 2.65 4.38

Example 4

[0104] Process of preparing maleate crystalline Form B of the compound of Formula (I):

[0105] 93.2 mg of crystalline Form A prepared in example 1 was added into 2.0 mL of water to obtain a suspension, then it was stirred at room temperature for 2 hours and centrifuged to give a solid.

[0106] .sup.1HNMR data of the maleate product prepared by the above method are in the following, and the data indicates the molar rate of the compound of Formula (I) and maleic acid is 1:3, so the maleate salt above is a tri-maleate.

[0107] .sup.1HNMR (400 MHz, DMSO-d6) 9.81 (s, 1H), 9.78 (s, 1H), 8.95 (s, 1H), 8.60 (d, J=4.1 Hz, 1H), 8.55 (s, 1H), 7.88 (td, J1=7.7 Hz, J2=1.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.47-7.34 (m, 3H), 7.21-7.28 (m, 2H), 6.88-6.65 (m, 2H), 6.19 (s, 6H), 5.30 (s, 2H), 4.33 (q, J=6.9 Hz, 2H), 3.96 (d, J=5.3 Hz, 2H), 2.81 (s, 6H), 1.47 (t, J=6.9 Hz, 3H).

[0108] The XRPD data of the solid produced in this example are listed in Table 4. The result indicates the solid is maleate crystalline Form B. The DSC thermogram is displayed in FIG. 5, the TGA thermogram is displayed in FIG. 6 and the .sup.1HNMR spectrummm is displayed in FIG. 11.

TABLE-US-00004 TABLE 4 2theta d spacing Relative intensity % 5.41 16.34 55.81 6.23 14.20 33.26 8.01 11.04 27.69 9.85 8.98 81.55 10.72 8.26 47.20 12.14 7.29 69.13 13.47 6.57 100.00 14.55 6.09 43.14 16.09 5.51 50.92 17.58 5.05 52.81 19.60 4.53 95.16 22.20 4.00 55.36 23.84 3.73 56.71 26.10 3.41 36.73 27.57 3.24 25.35 29.24 3.05 23.21 30.15 2.96 18.92

Example 5

[0109] Process of preparing maleate crystalline Form B of the compound of Formula (I):

[0110] 9.91 mg of crystalline Form A prepared in example 1 was stored at 95% RH for 12 hours, then the solid was collected.

[0111] The XRPD data of solid prepared in this example are listed in Table 5 and the result indicates the solid is maleate crystalline Form B.

[0112] The XRPD pattern is displayed in FIG. 4.

TABLE-US-00005 TABLE 5 2theta d spacing Relative intensity % 5.41 16.34 17.24 6.34 13.93 100.00 9.88 8.95 40.52 10.77 8.21 21.45 11.67 7.58 31.40 12.16 7.28 24.55 13.43 6.59 31.85 13.93 6.36 22.47 14.58 6.07 17.93 15.62 5.68 25.91 16.12 5.50 16.52 17.67 5.02 31.29 18.59 4.77 12.88 19.64 4.52 51.09 20.79 4.27 25.00 22.39 3.97 32.87 23.84 3.73 54.56 25.35 3.51 28.18 26.16 3.41 36.66 27.00 3.30 33.61 28.05 3.18 16.72 29.40 3.04 9.74 30.19 2.96 16.29 34.27 2.62 8.54 35.75 2.51 7.23

Example 6

[0113] Stability assessment of maleate crystalline Form B of the compound of Formula (I)

[0114] Form B in the present invention were stored under 5 C., 25 C./60% relative humidity and 40 C./75% RH for 90 days. XRPD patterns were collected after storage. The result of stability assessment is tabulated in Table 6. The XRPD patterns of Form B before and after storing under the three stress conditions are displayed in FIG. 13, FIG. 14 and FIG. 15 (the above patterns of FIG. 13, FIG. 14 and FIG. 15 were the XRPD patterns of Form B before storing).

TABLE-US-00006 TABLE 6 Initial Form conditions Storage time Form Change Form B 5 C. 90 days Form B doesn't change (FIG. 13 below) 25 C./60% RH 90 days Form B doesn't change (FIG. 14 below) 40 C./75% RH 90 days Form B doesn't change (FIG. 15 below)

[0115] The result indicates that maleate Form B of the compound of Formula (I) remains unchanged after stored at 5 C., 25 C./60% RH and 40 C./75% RH for 90 days. The maleate crystalline Form B of the compound of Formula (I) has good stability.

Example 7

[0116] Process of preparing maleate crystalline Form C of the compound of Formula (I):

[0117] 50.0 mg of compound of Formula (I) was dissolved into 2.0 mL of nitromethane, and 12.1 mg of maleic acid was added into the solution, then it was stirred at room temperature for 12 hours and centrifuged to give a solid.

[0118] .sup.1HNMR data of the maleate product prepared by the above method are in the following, and the data indicates the molar rate of the compound of Formula (I) and maleic acid is 1:1, so the maleate salt above is a mono-maleate.

[0119] .sup.1HNMR (400 MHz, DMSO-d6) 9.79 (s, 1H), 9.66 (s, 1H), 8.93 (s, 1H), 8.60 (d, J=4.2 Hz, 1H), 8.50 (s, 1H), 7.88 (td, J1=7.7 Hz, J2=1.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.45-7.34 (m, 3H), 7.20-7.27 (m, 2H), 6.82-6.69 (m, 2H), 6.05 (s, 2H), 5.29 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 3.93 (d, J=3.5 Hz, 2H), 2.79 (s, 6H), 1.46 (t, J=7.0 Hz, 3H).

[0120] The XRPD data of the solid prepared in this example are listed in Table 7 and the result indicates the solid is maleate crystalline Form C. The XRPD pattern is displayed in FIG. 7, the DSC thermogram is displayed in FIG. 8, the TGA thermogram is displayed in FIG. 9 and the .sup.1HNMR spectrum is displayed in FIG. 12.

TABLE-US-00007 TABLE 7 2theta d spacing Relative intensity % 6.05 14.62 8.32 6.97 12.68 10.90 8.29 10.67 11.09 8.56 10.33 5.69 8.84 10.00 3.42 9.10 9.72 3.34 10.31 8.58 4.50 10.95 8.08 12.36 11.57 7.65 11.54 12.71 6.97 6.80 12.95 6.83 11.14 14.15 6.26 26.91 15.17 5.84 36.86 15.85 5.59 6.06 16.73 5.30 12.97 17.19 5.16 14.19 17.44 5.09 16.67 17.54 5.06 18.89 18.23 4.87 23.35 18.32 4.84 21.35 18.80 4.72 7.24 19.25 4.61 11.69 20.27 4.38 32.18 20.94 4.24 9.10 21.39 4.15 99.31 21.73 4.09 10.17 22.33 3.98 9.43 22.66 3.92 21.15 22.97 3.87 48.42 23.49 3.79 100.00 24.54 3.63 33.10 25.18 3.54 7.43 25.75 3.46 17.36 26.41 3.37 21.97 27.00 3.30 14.77 27.58 3.23 9.25 28.15 3.17 17.15 28.60 3.12 22.71 28.89 3.09 10.44 29.61 3.02 5.31 30.32 2.95 4.75 30.66 2.92 4.62 31.48 2.84 12.30 32.59 2.75 4.19 33.86 2.65 1.77 36.10 2.49 3.06 37.32 2.41 1.58 38.10 2.36 1.27 38.74 2.32 0.97

Example 8

[0121] Process of preparing maleate crystalline Form C of the compound of Formula (I):

[0122] Amorphous maleate of compound of Formula (I) was added into 0.2 mL of dichloromethane to obtain a suspension, and it was stirred at room temperature for 48 hours. The suspension was filtered and the wet cake was dried in a vacuum oven at 25 C. overnight to give a solid.

[0123] The XRPD data of the solid prepared in this example are listed in Table 8 and the result indicates the solid is maleate crystalline Form C.

TABLE-US-00008 TABLE 8 2theta d spacing Relative intensity % 8.55 10.34 6.73 10.96 8.07 15.31 14.16 6.26 24.74 15.19 5.83 30.21 16.73 5.30 6.56 17.20 5.15 12.20 17.51 5.06 9.00 18.33 4.84 12.58 19.19 4.62 4.59 20.29 4.38 19.47 21.40 4.15 100.00 22.67 3.92 14.59 22.98 3.87 32.96 23.49 3.79 68.50 24.54 3.63 12.44 25.77 3.46 9.47 26.41 3.37 20.03 26.99 3.30 9.98 27.59 3.23 7.87 28.16 3.17 9.51 28.60 3.12 12.93 28.86 3.09 8.66 31.48 2.84 6.52 8.55 10.34 6.73

Example 9

[0124] Hygroscopicity assessment of maleate Form C of the compound Formula (I)

[0125] Hygroscopicity of 10 mg of Form C of the present invention was tested using dynamic vapor sorption (DVS) at 25 C. The result is listed in Table. 9. The DVS isotherm plot is shown in FIG. 16.

TABLE-US-00009 TABLE 9 weight increment under 80% Relative Solid Form Humidity Form C 1.01%

[0126] About hygroscopicity characterization description and definition of hygroscopicity (Chinese Pharmacopoeia 2010 edition appendix XIXJ Drug hygroscopic test guidelines, test at 25 C.+/1 C., 80% Relative Humidity) [0127] deliquescent: sufficient water is absorbed to form a liquid; [0128] very hygroscopic: increase in mass is equal to or greater than 15 percent; [0129] hygroscopic: increase in mass is less than 15 percent and equal to or greater than 2 percent; [0130] slightly hygroscopic: increase in mass is less than 2 percent and equal to or greater than 0.2 percent. [0131] no or almost no hygroscopic: increase in mass is less than 0.2%

[0132] The result indicates that the weight increment of maleate crystalline Form C of the present invention is 1.01% when it is placed under 80% RH. The hygroscopicity is quite low, and Form C is suitable for long-term storage. On the other hand, due to the low hygroscopicity of the crystalline form, the preparation and post-treatment process is simple. And it is easy for the commercial production. Since moisture content of the crystalline form remained unchanged under different humidity conditions. There is no special requirement on the storage conditions. The cost of materials storage and quality control will be greatly reduced, with strong economic value.

Example 10

[0133] Stability comparison of maleate crystalline Form C in the present invention and maleate crystalline Form II in CN101918390B:

[0134] 10.0 mg of maleate crystalline Form C and maleate crystalline Form II in CN101918390B were mixed at a ratio of 1:1 and added into 1.0 mL of solvent to obtain a suspension. The suspension was magnetically stirred at 500 rpm at 25 C. for 24 hours, and centrifuged to give a solid which was tested by XRPD. The result is listed in Table 10.

TABLE-US-00010 TABLE 10 temper- Stirring Final No. ature solvent Initial form time form 1 5 C. nitromethane Form C and Form II 24 hours Form C in CN101918390B 2 25 C. nitromethane Form C and Form II 24 hours Form C in CN101918390B

[0135] The result shows that maleate crystalline Form II in CN101918390B transferred to crystalline Form C of the present invention. Form C of the present invention is more stable than maleate crystalline Form II of in CN101918390B.

Example 11

[0136] Stability assessment of Form C of maleate of the compound of Formula (I)

[0137] Form C of the present invention was stored under 5 C., 25 C./60% RH and 40 C./75% relative humidity for 330 days. XRPD patterns were collected after storage. The experiment result is shown in Table 11. The XRPD patterns of Form C before and after storing under the three stress conditions for 330 days are displayed in FIG. 17, FIG. 18 and FIG. 19 (the patterns above in FIG. 17, FIG. 18 and FIG. 19 were the XRPD patterns of Form C before storing).

TABLE-US-00011 TABLE 11 Initial Form conditions Storage time Form Change Form C 5 C. 330 days Form C doesn't change (FIG. 17 below) 25 C./60% RH 330 days Form C doesn't change (FIG. 18 below) 40 C./75% RH 330 days Form C doesn't change (FIG. 19 below)

[0138] The result indicates that maleate crystalline Form C of the compound of Formula (I) remains unchanged under 5 C., 25 C./60% RH and 40 C./75% RH for 330 days. The maleate crystalline Form C of the compound of Formula (I) has good stability.

Example 12

[0139] Solubility comparison study between crystalline forms of maleate of the present invention and crystalline Form II in CN101918390B.

[0140] Maleate crystalline Form A, Form B of the present invention and maleate Form II in CN101918390B were added in pH 1.8 SGF (simulated gastric fluid), and in high purity water to obtain suspensions. Concentrations in the saturation solutions were determined after 1 hour, 4 hours and 24 hours by HPLC. The result is listed in Table 12.

TABLE-US-00012 TABLE 12 Time pH 1.8 SGF H.sub.2O point Form Form Form Form Form Form (h) II A B II A B Solubility 1 3.3 >8.4 >6.7 1.0 >3.9 >5.4 (mg/mL) 4 3.2 >8.4 >6.7 0.94 >3.9 >5.4 24 3.1 >8.4 >6.7 0.94 >3.9 >5.4

[0141] The comparison results suggest that maleate crystalline Form A, or Form B of the present invention have higher solubility in pH 1.8 SGF (simulated gastric fluid) and in high purity water after 1 hour, 4 hours and 24 hours in comparison to maleate Form II in CN101918390B.