CRYSTALLINE FORMS OF SELECTIVE PROGESTERONE RECEPTOR MODULATOR, PROCESSES FOR PREPARATION THEREOF

Abstract

The present disclosure relates to novel crystalline forms of compound I and processes for preparation thereof. The present disclosure also relates to pharmaceutical composition containing crystalline forms, and use of crystalline forms for preparing drugs containing selective progesterone receptor modulator, and use of crystalline forms for preparing drugs treating uterine fibroids and/or endometriosis. The crystalline forms of the present disclosure have one or more improved properties compared with prior art and have significant values for future drug optimization and development.

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Claims

1. A crystalline form CS2 of BAY-1002670, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 4.0°±0.2°, 15.9°±0.2° and 17.9°±0.2° using CuKα radiation.

2. The crystalline form CS2 according to claim 1, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 19.0°±0.2°, 20.4°±0.2° and 21.4°±0.2° using CuKα radiation.

3. The crystalline form CS2 according to claim 1, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 11.8°±0.2°, 15.0°±0.2° and 25.1°±0.2° using CuKα radiation.

4. The crystalline form CS2 according to claim 1, wherein the crystalline form CS2 belongs to monoclinic system, the space group of crystalline form CS2 is C2, and the crystal axes are: a=21.432(2) Å, b=10.7076(10) Å, c=22.438(2) Å, the interaxial angles are: α=90°, β=98.346(3°), γ=90°.

5. A process for preparing crystalline form CS2 according to claim 1, wherein the process comprises: (1) adding BAY-1002670 into a mixture of ketones and water, and stirring to obtain crystalline form CS2; or (2) dissolving BAY-1002670 in alcohols, esters, or ketones, putting the solution in a closed system with water vapor to obtain crystalline form CS2 by liquid vapor diffusion; or (3) dissolving BAY-1002670 in ketones, putting the solution in a closed system with n-heptane vapor to obtain crystalline form CS2 by liquid vapor diffusion.

6. The process according to claim 5, wherein in method (1), said ketone is acetone; in method (2), said alcohol is methanol, said ester is ethyl acetate, said ketone is butanone; in method (3), said ketone is methyl isobutyl ketone.

7. A crystalline form CS4 of BAY-1002670, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 16.0°±0.2°, 16.6°±0.2° and 14.1°±0.2° using CuKα radiation.

8. The crystalline form CS4 according to claim 7, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 18.9°±0.2°, 21.5°±0.2° and 10.1°±0.2° using CuKα radiation.

9. The crystalline form CS4 according to claim 7, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 13.2°±0.2°, 23.5°±0.2° and 17.9°±0.2° using CuKα radiation.

10. A process for preparing crystalline form CS4 according to claim 7, wherein the process comprises: (1) adding BAY-1002670 into ethers, and stirring at 40° C.-60° C. to obtain crystalline form CS4; or (2) dissolving BAY-1002670 in 2-methyltetrahydrofuran, evaporating to obtain a solid, and heating the solid to obtain crystalline form CS4; or (3) adding BAY-1002670 in a closed system with alcohol or ester vapor to obtain crystalline form CS4 by solid vapor diffusion.

11. The process for preparing crystalline form CS4 according to claim 10, wherein in method (1), said ether is methyl tert-butyl ether, said stirring temperature is 50° C.; in method (2), said heating temperature is 160° C.; in method (3), said alcohol is ethanol, said ester is isopropyl acetate.

12. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CS2 according to claim 1 and pharmaceutically acceptable carriers, diluents or excipients.

13. A method of selectively modulating progesterone receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of crystalline form CS2 according to claim 1.

14. A method of treating uterine fibroids and/or endometriosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of crystalline form CS2 according to claim 1.

15. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CS4 according to claim 7 and pharmaceutically acceptable carriers, diluents or excipients.

16. A method of selectively modulating progesterone receptor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of crystalline form CS4 according to claim 7.

17. A method of treating uterine fibroids and/or endometriosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of crystalline form CS4 according to claim 7.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] FIG. 1 shows an XRPD pattern of Form CS2 in Example 1.

[0057] FIG. 2 shows a DSC curve of Form CS2 in Example 1.

[0058] FIG. 3 shows a TGA curve of Form CS2 in Example 1.

[0059] FIG. 4 shows an XRPD pattern of Form CS2 in Example 2.

[0060] FIG. 5 shows an XRPD pattern of Form CS4 in Example 6.

[0061] FIG. 6 shows a DSC curve of Form CS4 in Example 6.

[0062] FIG. 7 shows a TGA curve of Form CS4 in Example 6.

[0063] FIG. 8 shows an XRPD pattern of Form CS4 in Example 7.

[0064] FIG. 9 shows an XRPD pattern of Form CS4 in Example 8.

[0065] FIG. 10 shows an XRPD pattern overlay of Form CS2 before and after stored at 25° C./60% RH for 6 months (top: before storage, bottom: after storage).

[0066] FIG. 11 shows an XRPD pattern overlay of Form CS4 before and after stored at 25° C./60% RH for 6 months (top: before storage, bottom: after storage).

[0067] FIG. 12 shows an XRPD pattern overlay of the prior art solid before and after stored at 25° C./60% RH for 6 months (top: before storage, bottom: after storage).

[0068] FIG. 13 shows an XRPD pattern overlay of Form CS2 before and after stored at 40° C./75% RH for 6 months (top: before storage, bottom: after storage).

[0069] FIG. 14 shows an XRPD pattern overlay of Form CS4 before and after stored at 40° C./75% RH for 6 months (top: before storage, bottom: after storage).

[0070] FIG. 15 shows an XRPD pattern overlay of the prior art solid before and after stored at 40° C./75% RH for 6 months (top: before storage, bottom: after storage).

[0071] FIG. 16 shows an XRPD pattern overlay of Form CS2 before and after stored at 60° C./75% RH for 2 weeks (top: before storage, bottom: after storage).

[0072] FIG. 17 shows an XRPD pattern overlay of Form CS4 before and after stored at 60° C./75% RH for 2 weeks (top: before storage, bottom: after storage).

[0073] FIG. 18 shows an XRPD pattern overlay of the prior art solid before and after stored at 60° C./75% RH for 2 weeks (top: before storage, bottom: after storage).

[0074] FIG. 19 shows a PSD plot of Form CS2.

[0075] FIG. 20 shows a PSD plot of Form CS4.

DETAILED DESCRIPTION

[0076] The present disclosure is further illustrated by the following examples which describe the preparation and use of the crystalline forms of the present disclosure in detail. It is obvious to those skilled in the art that many changes in the materials and methods can be accomplished without departing from the scope of the present disclosure.

[0077] The abbreviations used in the present disclosure are explained as follows

[0078] XRPD: X-ray Powder Diffraction

[0079] DSC: Differential Scanning calorimetry

[0080] TGA: Thermo Gravimetric Analysis

[0081] DVS: Dynamic Vapor Sorption

[0082] PSD: Particle Size Distribution

[0083] Instruments and methods used for data collection:

[0084] X-ray powder diffraction patterns in the present disclosure were acquired by a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows:

[0085] X-ray Reflection: Cu, Kα

[0086] Kα1 (A): 1.54060; Kα2 (A): 1.54439

[0087] Kα2/Kα1 intensity ratio: 0.50

[0088] Voltage: 30 (kV)

[0089] Current: 10 (mA)

[0090] Scan range: from 3.0 degree to 40.0 degree

[0091] Differential scanning calorimetry (DSC) data in the present disclosure were acquired by a TA Q2000. The parameters of the DSC method of the present disclosure are as follows:

[0092] Heating rate: 10° C./min unless otherwise specified.

[0093] Purge gas: nitrogen

[0094] Thermo gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q500.

[0095] The parameters of the TGA method of the present disclosure are as follows:

[0096] Heating rate: 10° C./min

[0097] Purge gas: nitrogen

[0098] Dynamic Vapor Sorption (DVS) was collected via an SMS (Surface Measurement Systems Ltd.) intrinsic DVS instrument. Its control software is DVS-Intrinsic control software, and its analysis software is DVS-Intrinsic Analysis software. Typical Parameters for DVS test are as follows: [0099] Temperature: 25° C. [0100] Gas and flow rate: N.sub.2, 200 mL/min [0101] dm/dt: 0.002%/min [0102] RH range: 0% RH to 95% RH

[0103] Unless otherwise specified, the following examples were conducted at room temperature. Said “room temperature” is not a specific value, and refers to 10-30° C.

[0104] According to the present disclosure, BAY-1002670 used as a raw material is solid (crystalline or amorphous), semisolid, wax or oil. Preferably, compound I used as a raw material is a solid.

[0105] Raw materials of BAY-1002670 used in the following examples were prepared by known methods in the prior art, for example, the method disclosed in CN102482317A.

Example 1-5: Preparation of Form CS2

Example 1

[0106] 1022.4 mg of BAY-1002670 was added into a mixture of water and acetone (4:1, v/v). The mixture was stirred at room temperature for 2 days, and then filtered and dried under vacuum to obtain a solid.

[0107] The solid obtained in Example 1 was confirmed to be Form CS2. The XRPD pattern is substantially as depicted in FIG. 1 and the XRPD data are listed in Table 1.

TABLE-US-00002 TABLE 1 2θ d spacing Intensity % 4.00 22.10 28.00 7.94 11.14 6.02 8.62 10.26 2.83 9.20 9.61 5.56 9.76 9.07 6.80 10.27 8.61 5.61 11.76 7.53 27.38 12.29 7.20 9.38 13.46 6.58 6.45 14.53 6.10 15.88 14.95 5.93 48.82 15.55 5.70 20.49 15.91 5.57 98.65 16.51 5.37 16.36 16.92 5.24 34.11 17.31 5.12 29.47 17.87 4.96 100.00 18.47 4.80 26.49 18.96 4.68 72.28 19.59 4.53 17.53 20.43 4.35 66.46 21.39 4.15 40.32 22.16 4.01 14.70 23.25 3.83 18.68 24.24 3.67 7.77 25.06 3.55 22.49 26.28 3.39 8.06 26.94 3.31 12.06 28.86 3.09 9.18 29.40 3.04 6.67 30.13 2.97 12.15 31.91 2.81 6.07 32.58 2.75 8.26 33.54 2.67 4.31 38.46 2.34 4.93

[0108] The DSC curve of Form CS2 obtained in Example 1 is substantially as depicted in FIG. 2. The first endothermic peak at around 65° C. corresponds to the loss of water, and the second endothermic peak at around 206° C. corresponds to the melting process of Form CS2.

[0109] The TGA curve of Form CS2 obtained in Example 1 is substantially as depicted in FIG. 3, which shows about 2.9% weight loss when heated to 100° C.

Example 2-4

[0110] Certain amount of BAY-1002670 was weighed into glass vials and dissolved in corresponding solvents shown in Table 2. The uncapped glass vials were placed in closed glass containers with anti-solvent shown in table 2. Solids were obtained by liquid vapor diffusion. The solids obtained in Example 2-4 were labeled as samples 2-4.

[0111] The solids obtained in Example 2-4 were confirmed to be Form CS2. Sample 2 was selected for characterization, the XRPD pattern is substantially as depicted in FIG. 4 and the XRPD data are listed in Table 3.

TABLE-US-00003 TABLE 2 Amount Volume Anti- Example (mg) Solvent (mL) solvent Sample 2 9.5 butanone 0.5 water Sample 2 3 9.5 ethyl acetate 0.5 water Sample 3 4 10.9 methanol 0.5 water Sample 4

TABLE-US-00004 TABLE 3 2θ d spacing Intensity % 4.07 21.69 29.08 7.93 11.15 3.41 11.71 7.56 17.65 12.34 7.18 5.15 13.48 6.57 7.94 14.56 6.08 15.36 15.02 5.90 28.13 15.56 5.70 13.09 15.98 5.55 73.94 16.98 5.22 22.11 17.39 5.10 32.32 17.87 4.96 100.00 18.50 4.80 18.08 19.01 4.67 62.80 19.60 4.53 14.19 20.49 4.34 68.77 21.37 4.16 46.98 22.31 3.99 11.26 22.98 3.87 17.31 23.30 3.82 15.19 24.13 3.69 10.13 25.09 3.55 21.79 26.63 3.35 10.57 26.99 3.30 8.61 28.25 3.16 9.67 28.91 3.09 12.01 29.40 3.04 6.49 30.22 2.96 9.03 31.85 2.81 6.55 32.66 2.74 9.37 33.58 2.67 6.02 34.88 2.57 4.50 37.53 2.40 4.94 38.50 2.34 5.86

Example 5

[0112] 9.9 mg of BAY-1002670 was weighed into a glass vial and 0.5 mL of methyl isobutyl ketone was added to dissolve BAY-1002670 with stirring. The uncapped glass vials were placed in closed glass containers with n-heptane. The obtained solids were confirmed to be Form CS2. Form CS2 single crystals were obtained in this example. The single crystal X-ray diffraction and structural analysis data are listed in Table 4. The single crystal structure indicates that Form CS2 is a monohydrate.

TABLE-US-00005 TABLE 4 Molecular formula C.sub.27H.sub.29F.sub.5O.sub.4S•H.sub.2O Molecular weight 562.57 Crystal system monoclinic Space group C2 Unit cell dimensions a = 21.432(2) Å b = 10.7076(10) Å c = 22.438(2) Å α = 90° β = 98.346(3)° γ = 90° Volume of unit cell: V = 5094.4(8) Å.sup.3 Number of formula Z = 8 units in unit cell Calculated density 1.464 g/cm.sup.3 X-ray diffractometer Bruker D8 Venture X-ray source Model: TURBO X-RAY SOURCE high intensity microfocus rotating anode generator Wavelength: Mo/Kα (λ = 0.71073) Power: 2.5 KW Detector PHOTON 100 model CMOS 2D detector Goniometer Three-axis (ω, 2θ, φ) goniometer Test temperature 175.15K Computer program Initial structure solution: ShelXT (direct method) for structure analysis: Refinement: ShelXL 2017 (least square method)

Example 6-9: Preparation of Form CS4

Example 6

[0113] 102.8 mg of BAY-1002670 was added into 4.0 mL of methyl tert-butyl ether. The mixture was stirred at 50° C. for 18 days. Solid was collected by centrifugation and dried to obtain white crystals.

[0114] The obtained white crystals were confirmed to be Form CS4. The XRPD pattern is substantially as depicted in FIG. 5 and the XRPD data are listed in Table 5.

[0115] The DSC curve of Form CS4 obtained in Example 6 is substantially as depicted in FIG. 6. The first endothermic peak at around 217° C. corresponds to the melting process of Form CS4.

[0116] The TGA curve of Form CS4 obtained in Example 6 is substantially as depicted in FIG. 7, which shows about 1.7% weight loss when heated to around 170° C.

TABLE-US-00006 TABLE 5 2θ d spacing Intensity % 10.05 8.80 18.06 13.20 6.71 35.97 13.48 6.57 22.59 14.17 6.25 22.27 15.95 5.56 100.00 16.65 5.32 41.84 17.82 4.98 19.14 18.59 4.77 12.72 18.95 4.68 26.26 19.60 4.53 38.47 19.84 4.47 34.38 20.18 4.40 16.47 20.58 4.32 19.66 21.48 4.14 30.48 22.15 4.01 18.86 23.51 3.78 17.20 24.87 3.58 12.33 26.43 3.37 5.73 27.05 3.30 6.20 28.83 3.10 9.90 30.73 2.91 7.81 33.11 2.71 5.13 33.71 2.66 3.90 34.29 2.62 3.36 36.66 2.45 6.57 37.83 2.38 2.37

Example 7

[0117] 53.4 mg of BAY-1002670 was dissolved into 2.5 mL of 2-methyltetrahydrofuran. The solution was evaporated at room temperature to obtain a solid. The solid obtained by evaporation was heated to 160° C. at a rate of 10° C./min and hold at 160° C. for 10 min to obtain a solid. The obtained solid was confirmed to be Form CS4. The XRPD pattern is substantially as depicted in FIG. 8 and the XRPD data are listed in Table 6.

TABLE-US-00007 TABLE 6 2θ d spacing Intensity % 10.04 8.81 16.52 13.16 6.73 72.27 13.40 6.61 36.36 14.09 6.29 34.81 15.97 5.55 100.00 16.59 5.34 47.55 17.80 4.98 30.66 18.57 4.78 12.59 18.87 4.70 25.32 19.54 4.54 36.21 19.83 4.48 25.81 20.22 4.39 20.09 20.50 4.33 14.51 21.47 4.14 28.46 22.11 4.02 10.92 23.49 3.79 21.95 24.82 3.59 15.85 27.00 3.30 5.50 28.76 3.10 12.04 30.74 2.91 8.60 33.06 2.71 7.49 33.67 2.66 4.48 34.27 2.62 2.97 36.56 2.46 5.38 37.84 2.38 2.59

Example 8-9

[0118] Certain amount of BAY-1002670 was weighed into glass vials, and the uncapped glass vials were placed in closed glass containers with anti-solvent shown in table 7. The solids were obtained by solid vapor diffusion. The solids obtained were confirmed to be Form CS4. Sample 8 was selected for characterization. The XRPD pattern is substantially as depicted in FIG. 9 and the XRPD data are listed in Table 8.

TABLE-US-00008 TABLE 7 Example Amount (mg) Solvent Volume (mL) Sample 8 7.5 Ethanol 5.0 8 9 6.2 Isopropyl acetate 5.0 9

TABLE-US-00009 TABLE 8 2θ d spacing Intensity % 10.08 8.78 18.80 13.23 6.69 37.24 13.47 6.57 25.59 14.17 6.25 27.35 15.97 5.55 100.00 16.67 5.32 34.80 17.80 4.98 17.22 18.61 4.77 13.34 18.94 4.69 22.74 19.63 4.52 33.62 19.87 4.47 31.33 20.25 4.39 18.05 20.61 4.31 12.96 21.53 4.13 28.55 22.20 4.00 14.07 23.58 3.77 16.21 24.88 3.58 12.52 26.46 3.37 4.72 26.98 3.31 5.54 27.18 3.28 4.96 28.85 3.09 8.24 30.77 2.91 8.11 33.12 2.70 5.30 33.71 2.66 3.75 34.34 2.61 2.81 36.65 2.45 6.02 38.07 2.36 3.02

Example 10: Hygroscopicity of Form CS2, Form CS4 and the Prior Art Amorphous

[0119] Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS2, Form CS4 and the prior art amorphous with about 10 mg of samples. The results are listed in Table 9.

TABLE-US-00010 TABLE 9 Relative Humidity Weight gain under 80% Relative Weight Humidity Gain (%) (Hygroscopicity) Form CS2 0.23% Form CS4 0.12% Amorphous 1.89%

[0120] The result shows that Form CS2 and Form CS4 of the present disclosure have lower hygroscopicity compared with the prior art amorphous.

Example 11: Stability of Form CS2, Form CS4 and the Prior Art Amorphous

1. Physical and Chemical Stability Under Condition of 25° C./60% RH

[0121] Samples of Form CS2, Form CS4 and the prior art amorphous were stored under condition of 25° C./60% RH (open). Crystalline form and chemical impurity were tested. The results are shown in Table 10 and Table 11.

TABLE-US-00011 TABLE 10 Initial Solid Form Storage Condition Time Solid Form after Storage Form CS2 25° C./60% RH 6 months Form CS2 (FIG. 10, top) (FIG. 10, bottom) Form CS4 25° C./60% RH 6 months Form CS4 (FIG. 11, top) (FIG. 11, bottom) Amorphous 25° C./60%) RH 6 months Amorphous (FIG. 12, top) (FIG. 12, bottom)

TABLE-US-00012 TABLE 11 Purity after 6 Solid Form Initial Purity Months Change of Purity CS2 98.64% 98.58% 0.06% CS4 99.44% 99.31% 0.13% Amorphous 98.68% 97.88% 0.80%

[0122] The crystalline form of Form CS2 and Form CS4 of the present disclosure remained unchanged for at least 6 months when stored under the condition of 25° C./60% RH. The purity remained substantially unchanged during storage. The reduction in purity of Form CS2 and Form CS4 was only 0.06% and 0.13%, respectively, while the purity of amorphous was reduced by 0.80%. The above results indicate that Form CS2 and Form CS4 of the present disclosure have good physical and chemical stability, and the purity remained substantially unchanged during drug storage, Form CS2 and CS4 are more suitable for medicinal use. While the impurity of the prior art amorphous increased, which will lead to significantly lowered active ingredient content or reduced drug activity, and will also lead to significantly increased toxicity and side effects of the drug products.

2. Physical and Chemical Stability Under Accelerated Condition of 40° C./75% RH

[0123] Samples of Form CS2, Form CS4 and the prior art amorphous were stored under condition of 40° C./75% RH (open). Crystalline form and chemical impurity were tested. The results are shown in Table 12 and Table 13.

TABLE-US-00013 TABLE 12 Initial Solid Form Storage Condition Time Solid Form after Storage Form CS2 40° C./75% RH 6 months Form CS2 (FIG. 13, top) (FIG. 13, bottom) Form CS4 40° C./75% RH 6 months Form CS4 (FIG. 14, top) (FIG. 14, bottom) Amorphous 40° C./75% RH 6 months Amorphous + Form CS2 (FIG. 15, top) (FIG. 15, bottom)

TABLE-US-00014 TABLE 13 Purity after 3 Solid Form Initial Purity Months Change of Purity CS2 98.64% 98.37% 0.27% CS4 99.44% 99.42% 0.02% Amorphous 98.68% 97.60% 1.08%

[0124] The crystalline form of Form CS2 and Form CS4 of the present disclosure remained unchanged for at least 6 months when stored under the condition of 40° C./75% RH, while the prior art amorphous partially converted to Form CS2 after stored under the condition of 40° C./75% RH for 6 months. The purity of Form CS2 and Form CS4 of the present disclosure remained substantially unchanged when stored under the condition of 40° C./75% RH. The reduction in purity of Form CS2 and Form CS4 was only 0.27% and 0.02%, respectively, while the purity of amorphous was reduced by 1.08%. The above results indicate that, compared with the amorphous of the prior art, Form CS2 and Form CS4 of the present disclosure have good physical and chemical stability.

3. Physical and Chemical Stability Under Accelerated Condition of 60° C./75% RH

[0125] Samples of Form CS2, Form CS4 and the prior art amorphous were stored under condition of 60° C./75% RH (open). Crystalline form and chemical impurity were tested. The results are shown in Table 14 and Table 15.

TABLE-US-00015 TABLE 14 Initial Solid Form Storage Condition Time Solid Form after Storage Form CS2 60° C./75% RH 2 weeks Form CS2 (FIG. 16, top) (FIG. 16, bottom) Form CS4 60° C./75% RH 2 weeks Form CS4 (FIG. 17, top) (FIG. 17, bottom) Amorphous 60° C./75% RH 2 weeks Amorphous + Form CS2 (FIG. 18, top) (FIG. 18, bottom)

TABLE-US-00016 TABLE 15 Purity after 2 Solid Form Initial Purity Weeks Change of Purity CS2 98.64% 98.59% 0.05% CS4 99.44% 99.47% 0.03% Amorphous 98.68% 97.70% 0.98%

[0126] The crystalline form of Form CS2 and Form CS4 of the present disclosure remained unchanged for at least 2 weeks when stored under the condition of 60° C./75% RH, while the prior art amorphous partially converted to Form CS2 after stored under the condition of 40° C./75% RH for 2 weeks. The purity of Form CS2 and Form CS4 of the present disclosure remained substantially unchanged when stored under the condition of 60° C./75% RH. The reduction in purity of Form CS2 and Form CS4 was only 0.05% and 0.03%, respectively, while the purity of amorphous was reduced by 0.98%. The above results indicate that, compared with the amorphous of the prior art, Form CS2 and Form CS4 of the present disclosure have good physical and chemical stability.

Example 12: Residual Solvents of Form CS2, Form CS4 and the Prior Art Amorphous

[0127] Residual solvents of Form CS2, Form CS4 and the prior art amorphous were tested. The results show that Form CS2 and Form CS4 have almost no residual solvents, while the dichloromethane residue in the amorphous solid is 64185 ppm. According to the guideline of the International Council for Harmonization (ICH) on residual solvents, dichloromethane belongs to Class 2 solvents, and the residual solvent content must not exceed 600 ppm. It can be seen that the residue of dichloromethane in the amorphous solid is much higher than the limits of ICH guideline, and the amorphous not suitable for use as drug substance.

Example 13: Particle Size Distribution

[0128] Form CS2 and Form CS4 of the present disclosure were added into 10 mL of Isopar G (containing 0.2% lecithin). The mixture was mixed thoroughly and transferred into the SDC. The measurement was started when the sample amount indicator is in appropriate position. The average particle diameter calculated by volume, the diameter at which 10% mass is comprised of smaller particles, the diameter at which 50% mass is comprised of smaller particles and the diameter at which 90% mass is comprised of smaller particles were obtained in particle size distribution test. Subsequently, the particle size distribution plot of crystalline forms was obtained. The results are shown in Table 16.

TABLE-US-00017 TABLE 16 Solid Form MV(μm) D10 (μm) D50 (μm) D90 (μm) Form CS2 13.16 3.09 8.41 27.45 Form CS4 11.41 2.32 6.20 23.12

[0129] Notes:

[0130] MV: Average particle diameter calculated by volume.

[0131] D10: the size in microns below which 10 percent of the particles reside on a volume basis.

[0132] D50: the size in microns below which 50 percent of the particles reside on a volume basis, also known as the median diameter.

[0133] D90: the size in microns below which 90 percent of the particles reside on a volume basis.

[0134] The particle size distribution (PSD) plot of Form CS2 and Form CS4 are shown in FIG. 19 and FIG. 20, respectively. It can be seen that the particle size of Form CS2 and Form CS4 is in monodisperse normal distribution. The particle size is uniform and small.

[0135] Form CS2 and Form CS4 of the present disclosure have uniform and small particle size, which is helpful to simplify the post-treatment of the formulation process, for example, less grinding can save cost. Additionally, the uniform particle size distribution of Form CS2 and Form CS4 improves the uniformity of drug substance in drug products; smaller particle size distribution can increase the specific surface area of the drug substance, and improve the dissolution rate of the drug, thereby facilitating drug absorption and further improving bioavailability of the drug. The examples described above are only for illustrating the technical concepts and features of the present disclosure, and intended to make those skilled in the art being able to understand the present disclosure and thereby implement it, and should not be concluded to limit the protective scope of this disclosure. Any equivalent variations or modifications according to the spirit of the present disclosure should be covered by the protective scope of the present disclosure.