CRYSTALLINE FORMS OF GFT-505, PROCESSES FOR PREPARATION AND USE THEREOF

Abstract

The present disclosure relates to novel crystalline forms of GFT-505, processes for preparation and uses thereof. The crystalline form CS1, crystalline form CS2, crystalline form CS5 and crystalline form CS6 of GFT-505 provided by the present disclosure have high purity, good stability, low hygroscopicity, good solubility and good mechanical stability. The present disclosure provides a new and better choice for the preparation of drug products containing GFT-505 and is of great significance for drug development.

Claims

1. A crystalline form CS1 of compound (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 10.5°±0.2°, 14.8°±0.2° and 16.9°±0.2° using CuKα radiation.

2. The crystalline form CS1 according to claim 1, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 18.7°±0.2°, 20.4°±0.2° and 26.6°±0.2° using CuKα radiation.

3. The crystalline form CS1 according to claim 1, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 11.4°±0.2°, 23.5°±0.2° and 25.1°±0.2° using CuKα radiation.

4. A process for preparing crystalline form CS1 according to claim 1, wherein the process comprises: (1) Dissolving GFT-505 in a solvent of ketones, adding an anti-solvent, stirring, isolating and drying to obtain the solid; or (2) Dissolving GFT-505 in a solvent mixture comprising aromatic hydrocarbons and ketones at 40-70° C., precipitating the crystal at 0-10° C., isolating and drying to obtain the solid.

5. The process for preparing crystalline form CS1 according to claim 4, wherein: In method (1), said ketone includes acetone, methyl ethyl ketone or a solvent mixture of acetone and methyl ethyl ketone, said alkane includes n-hexane, n-heptane, n-octane or a solvent mixture of n-hexane, n-heptane, and n-octane, the volume ratio of said ketone and alkane is 1:20-20:1; In method (2), said aromatic hydrocarbon includes toluene, ethylbenzene or a solvent mixture of toluene and ethylbenzene, said ketone includes acetone, methyl ethyl ketone, methyl isobutyl ketone or a solvent mixture of acetone, methyl ethyl ketone, and methyl isobutyl ketone, the volume ratio of said aromatic hydrocarbon and ketone is 1:20-20:1, said high temperature is 50° C. and the low temperature is 4° C.

6. The process for preparing crystalline form CS1 according to claim 5, wherein: In method (1), said ketone is acetone, said hydrocarbon is n-heptane, said volume ratio of ketone and hydrocarbon is 1:20; In method (2), said aromatic hydrocarbon is toluene, said ketone is methyl isobutyl ketone, said volume ratio of aromatic hydrocarbon and ketone is 13:1.

7. A crystalline form CS2 of compound (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 15.2°±0.2°, 15.9°±0.2° and 25.8°±0.2° using CuKα radiation.

8. The crystalline form CS2 according to claim 7, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 11.7°±0.2°, 12.2°±0.2° and 19.4°±0.2° using CuKα radiation.

9. The crystalline form CS2 according to claim 7, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 20.0°±0.2°, 26.8°±0.2° and 27.5°±0.2° using CuKα radiation.

10. A process for preparing crystalline form CS2 according to claim 7, wherein the process comprises: (1) Suspending GFT-505 in water or a solvent mixture comprising alcohols and water, stirring, isolating and drying to obtain the solid; or (2) Dissolving GFT-505 in a solvent of alcohols, adding water as an anti-solvent, stirring, isolating and drying to obtain the solid; or (3) Dissolving GFT-505 in a solvent mixture comprising alcohols and alkanes, adding polymer and evaporating at 10-50° C. to obtain the solid.

11. The process for preparing crystalline form CS2 according to claim 10, wherein: In method (1), said alcohol includes methanol, ethanol, isopropanol or a solvent mixture of methanol, ethanol, and isopropanol, said volume ratio of alcohol and water is 1:5-5:1; In method (2), said alcohol includes methanol, ethanol, isopropanol or a solvent mixture of methanol, ethanol, and isopropanol, said volume ratio of alcohol and water is 1:10-10:1; In method (3), said alcohol includes methanol, ethanol, isopropanol or a solvent mixture of methanol, ethanol, and isopropanol, said alkane includes hexane, n-heptane, n-octane or a solvent mixture of hexane, n-heptane, and n-octane, said volume ratio of alcohol and alkane is 1:15-15:1, said evaporation temperature is room temperature.

12. The process for preparing crystalline form CS2 according to claim 11, wherein: In method (1), said alcohol is ethanol, said volume ratio of alcohol and water is 4:5; In method (2), said alcohol is methanol, aid volume ratio of alcohol and water is 1:7; In method (3), said alcohol is ethanol, said alkane is n-heptane, said volume ratio of alcohol and alkane is 15:4.

13. A crystalline form CS5 of compound (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 7.4°±0.2°, 14.6°±0.2° and 18.7°±0.2° using CuKα radiation.

14. The crystalline form CS5 according to claim 13, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 25.3°±0.2°, 15.4°±0.2° and 25.9°±0.2° using CuKα radiation.

15. The crystalline form CS5 according to claim 13, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 19.5°±0.2°, 27.5°±0.2° and 28.9°±0.2° using CuKα radiation.

16. A process for preparing crystalline form CS5 according to claim 13, wherein the process comprises: dissolving GFT-505 in a solvent mixture comprising ketones and aromatic hydrocarbons or a solvent mixture comprising esters and aromatic hydrocarbons, evaporating at 10-50° C. to obtain the solid.

17. The process for preparing crystalline form CS5 according to claim 16, wherein: said ketone includes acetone, methyl ethyl ketone or a solvent mixture of acetone and methyl ethyl ketone, said aromatic hydrocarbon includes toluene, ethylbenzene or a solvent mixture of toluene and ethylbenzene, said ester is ethyl acetate, isopropyl acetate or a solvent mixture of ethyl acetate and isopropyl acetate, said volume ratio of ketones and aromatic hydrocarbons or esters and aromatic hydrocarbons is 1:3-3:1, said evaporation temperature is room temperature.

18. The process for preparing crystalline form CS5 according to claim 17, wherein: said ketone is acetone, said aromatic hydrocarbon is toluene, said ester is ethyl acetate, said volume ratio of ketones and aromatic hydrocarbons or esters and aromatic hydrocarbons is 1:1.

19. A crystalline form CS6 of compound (I), wherein said crystalline form CS6 is an acetic acid solvate, and the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 12.5°±0.2°, 19.4°±0.2° and 23.6°±0.2° using CuKα radiation.

20. The crystalline form CS6 according to claim 19, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 15.2°±0.2°, 20.7°±0.2° and 26.4°±0.2° using CuKα radiation.

21. The crystalline form CS6 according to claim 19, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2theta values of 6.6°±0.2°, 10.3°±0.2° and 18.2°±0.2° using CuKα radiation.

22. A process for preparing crystalline form CS6 according to claim 19, wherein the process comprises: placing GFT-505 in a closed container which contains solvent atmosphere of acetic acid to obtain the solid by solid vapor diffusion.

23. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CS1 according to claim 1 and pharmaceutically acceptable carriers, diluents or excipients.

24. A method for treating nonalcoholic steatohepatitis and/or type 2 diabetes and/or dyslipidemia and/or atherosclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline form CS1 according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0105] FIG. 1 shows an XRPD pattern of Form CS1 according to example 1.

[0106] FIG. 2 shows a .sup.1H NMR spectrum of Form CS1 according to example 1.

[0107] FIG. 3 shows a DSC curve of Form CS1 according to example 1.

[0108] FIG. 4 shows a TGA curve of Form CS1 according to example 1.

[0109] FIG. 5 shows an XRPD pattern of Form CS2 according to example 4.

[0110] FIG. 6 shows a .sup.1H NMR spectrum of Form CS2 according to example 4.

[0111] FIG. 7 shows a DSC curve of Form CS2 according to example 4.

[0112] FIG. 8 shows a TGA curve of Form CS2 according to example 4.

[0113] FIG. 9 shows an XRPD pattern of Form CS5 according to example 7.

[0114] FIG. 10 shows a .sup.1H NMR spectrum of Form CS5 according to example 7.

[0115] FIG. 11 shows a DSC curve of Form CS5 according to example 7.

[0116] FIG. 12 shows a TGA curve of Form CS5 according to example 7.

[0117] FIG. 13 shows an XRPD pattern of Form CS6 according to example 9.

[0118] FIG. 14 shows a .sup.1H NMR spectrum of Form CS6 according to example 9.

[0119] FIG. 15 shows a DSC curve of Form CS6 according to example 9.

[0120] FIG. 16 shows a TGA curve of Form CS6 according to example 9.

[0121] FIG. 17 shows a DVS plot of Form CS1.

[0122] FIG. 18 shows an XRPD pattern overlay of Form CS1 before and after DVS test (top: XRPD pattern before DVS; bottom: XRPD pattern after DVS)

[0123] FIG. 19 shows a DVS plot of Form CS2.

[0124] FIG. 20 shows an XRPD pattern overlay of Form CS2 before and after DVS test (top: XRPD pattern before DVS; bottom: XRPD pattern after DVS)

[0125] FIG. 21 shows a DVS plot of Form CS5.

[0126] FIG. 22 shows an XRPD pattern overlay of Form CS5 before and after DVS test (top: XRPD pattern before DVS; bottom: XRPD pattern after DVS).

[0127] FIG. 23 shows an XRPD pattern overlay of Form CS1 before and after stored at 25° C./60% RH for 6 months (top: XRPD pattern before stored at 25° C./60% RH, bottom: XRPD pattern after stored at 25° C./60% RH)

[0128] FIG. 24 shows an XRPD pattern overlay of Form CS1 before and after stored at 40° C./75% RH for 6 months (top: XRPD pattern before stored at 40° C./75% RH, bottom: XRPD pattern after stored at 40° C./75% RH)

[0129] FIG. 25 shows an XRPD pattern overlay of Form CS1 before and after stored at 60° C./75% RH for 1 months (top: XRPD pattern before stored at 60° C./75% RH, bottom: XRPD pattern after stored at 60° C./75% RH)

[0130] FIG. 26 shows an XRPD pattern overlay of Form CS2 before and after stored at 25° C./60% RH for 6 months (top: XRPD pattern before stored at 25° C./60% RH, bottom: XRPD pattern after stored at 25° C./60% RH)

[0131] FIG. 27 shows an XRPD pattern overlay of Form CS2 before and after stored at 40° C./75% RH for 6 months (top: XRPD pattern before stored at 40° C./75% RH, bottom: XRPD pattern after stored at 40° C./75% RH)

[0132] FIG. 28 shows an XRPD pattern overlay of Form CS2 before and after stored at 60° C./75% RH for 1 months (top: XRPD pattern before stored at 60° C./75% RH, bottom: XRPD pattern after stored at 60° C./75% RH)

[0133] FIG. 29 shows an XRPD pattern overlay of Form CS5 before and after stored at 25° C./60% RH for 6 months (top: XRPD pattern before stored at 25° C./60% RH, bottom: XRPD pattern after stored at 25° C./60% RH)

[0134] FIG. 30 shows an XRPD pattern overlay of Form CS5 before and after stored at 40° C./75% RH for 6 months (top: XRPD pattern before stored at 40° C./75% RH, bottom: XRPD pattern after stored at 40° C./75% RH)

[0135] FIG. 31 shows an XRPD pattern overlay of Form CS5 before and after stored at 60° C./75% RH for 1 months (top: XRPD pattern before stored at 60° C./75% RH, bottom: XRPD pattern after stored at 60° C./75% RH).

[0136] FIG. 32 shows an XRPD pattern overlay of Form CS1 before and after grinding (top: XRPD pattern before grinding, bottom: XRPD pattern after grinding).

[0137] FIG. 33 shows an XRPD pattern overlay of Form CS2 before and after grinding (top: XRPD pattern before grinding, bottom: XRPD pattern after grinding).

[0138] FIG. 34 shows an XRPD pattern overlay of Form CS5 before and after grinding (top: XRPD pattern before grinding, bottom: XRPD pattern after grinding).

[0139] FIG. 35 shows an XRPD pattern overlay of Form CS6 before and after grinding (top: XRPD pattern before grinding, bottom: XRPD pattern after grinding).

[0140] FIG. 36 shows morphology comparison of Form CS1 and oily substance. (left: morphology of Form CS1 of the present disclosure, right: morphology of oily substance prepared from the prior art).

DETAILED DESCRIPTION

[0141] 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.

[0142] The abbreviations used in the present disclosure are explained as follows:

[0143] XRPD: X-ray Powder Diffraction

[0144] DSC: Differential Scanning calorimetry

[0145] TGA: Thermal Gravimetric Analysis

[0146] DVS: Dynamic Vapor Sorption

[0147] HPLC: High Performance Liquid Chromatography

[0148] .sup.1H NMR: Proton Nuclear Magnetic Resonance

[0149] PSD: Particle Size Distribution

[0150] Instruments and Methods Used for Data Collection

[0151] 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:

[0152] X-ray Reflection: Cu, Kα

[0153] Kα1 (Å): 1.540598; Kα2 (Å): 1.544426

[0154] Kα2/Kα1 intensity ratio: 0.50

[0155] Voltage: 45 (kV)

[0156] Current: 40 (mA)

[0157] Scan range: from 3.0 degree to 40.0 degree

[0158] 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:

[0159] Heating rate: 10° C./min unless otherwise specified.

[0160] Purge gas: nitrogen

[0161] Thermal gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q500. The parameters of the TGA method of the present disclosure were as follows:

[0162] Heating rate: 10° C./min

[0163] Purge gas: nitrogen

High Performance Liquid Chromatography (HPLC) data in the present disclosure were collected from an Agilent 1260 with Ultraviolet variable wavelength detector (VWD).
The HPLC method parameters for purity test in the present disclosure are as follows:

[0164] 1. Column: Waters XBridge C18 150×4.6 mm, 5 μm

[0165] 2. Mobile Phase: A: 0.1% Phosphate in H.sub.2O [0166] B: Acetonitrile

Gradient:

[0167]

TABLE-US-00001 Time (min) % B 0.0 25 25.0 80 30.0 80 30.1 25 35.0 25

[0168] 3. Flow rate: 1.0 mL/min

[0169] 4. Injection Volume: 5 μL

[0170] 5. Detection wavelength: 350 nm

[0171] 6. Column Temperature: 40° C.

[0172] 7. Diluent: Acetonitrile

[0173] Dynamic Vapor Sorption (DVS) was measured via an SMS (Surface Measurement Systems Ltd.) Intrinsic DVS instrument. Typical Parameters for DVS test are as follows:

[0174] Temperature: 25° C.

[0175] Gas and flow rate: N.sub.2, 200 mL/min

[0176] dm/dt: 0.002%/min

[0177] RH range: 0% RH to 95% RH

[0178] Proton nuclear magnetic resonance spectrum data (.sup.1H NMR) were collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. 1-5 mg of sample was weighed, and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to obtain a solution with a concentration of 2-10 mg/mL.

[0179] The particle size distribution data in the present disclosure were acquired by an S3500 laser particle size analyzer of Microtrac. Microtrac S3500 is equipped with an SDC (Sample Delivery Controller). The test is carried out in wet mode, and the dispersion medium is Isopar G (0.2% lecithin).

[0180] Unless otherwise specified, the following examples were conducted at room temperature.

[0181] Raw materials of GFT-505 used in the following examples were prepared by known methods in the prior art, for example, the method disclosed in CN100548960C.

Example 1

[0182] 7.2 mg of GFT-505 was dissolved in 0.1 mL of acetone and the solution was filtered. 2.0 mL of n-heptane was added into the filtrate drop by drop as an anti-solvent, followed by stirring at room temperature. The solid was collected, centrifuged and vacuum dried at RT. The obtained solid was confirmed to be Form CS1 of the present disclosure, of which the XRPD pattern is depicted in FIG. 1 and the XRPD data are listed in Table 1.

[0183] The .sup.1H NMR data of Form CS1 obtained in example 1 are as follow: .sup.1HNMR (400 MHz, DMSO) δ 8.10 (d, J=8.5 Hz, 2H), 7.82 (d, J=15.5 Hz, 1H), 7.66-7.54 (m, 3H), 7.40 (d, J=8.5 Hz, 2H), 2.57 (s, 3H), 2.22 (s, 6H), 1.39 (s, 6H). The .sup.1H NMR spectrum is substantially as depicted FIG. 2.

[0184] The DSC curve of Form CS1 obtained in example 1 is depicted in FIG. 3, and the TGA curve is displayed in FIG. 4.

TABLE-US-00002 TABLE 1 2θ (±0.2°) d spacing Intensity % 8.02 11.03 17.70 10.45 8.47 35.74 11.35 7.80 23.35 12.34 7.17 17.06 14.82 5.98 100.00 16.31 5.44 10.64 16.89 5.25 64.41 17.02 5.21 42.36 18.73 4.74 23.77 20.40 4.35 24.78 23.46 3.79 35.86 25.12 3.54 20.07 25.92 3.44 11.30 26.63 3.35 39.14 27.35 3.26 5.27 28.76 3.10 14.05

Example 2

[0185] 20.5 mg of GFT-505 was dissolved in 0.7 mL of solvent mixture of toluene and methyl isobutyl ketone (the volume ratio of toluene and methyl isobutyl ketone is 13:1) at 50° C. The solution was filtered and cooled to 4° C. to precipitate the crystal, and the crystalline solid was obtained by centrifuging and vacuum drying at room temperature. The crystalline solid was characterized to be Form CS1 of the present disclosure, of which the XRPD data are listed in Table 2.

TABLE-US-00003 TABLE 2 2θ (±0.2°) d spacing Intensity % 3.38 26.14 0.40 8.04 11.00 26.15 10.45 8.46 50.11 11.35 7.79 37.94 12.36 7.16 18.40 14.84 5.97 100.00 16.30 5.44 15.31 16.90 5.25 99.98 18.75 4.73 42.21 20.42 4.35 29.56 23.45 3.79 43.38 25.11 3.55 16.15 25.92 3.44 16.19 26.68 3.34 48.48 28.76 3.10 14.39

Example 3

[0186] 1.0 g of GFT-505 was suspended in 4.5 mL of solvent mixture of ethanol and water (the volume ratio of ethanol and water was 4:5) and the suspension was stirred at room temperature. Form CS2 of the present disclosure was obtained by isolating and vacuum drying. The XRPD pattern is depicted in FIG. 5. The XRPD data are listed in Table 3.

[0187] The .sup.1H NMR data of Form CS2 obtained in this example are as follow: .sup.1HNMR (400 MHz, DMSO) δ 8.09 (d, J=8.5 Hz, 2H), 7.82 (d, J=15.5 Hz, 1H), 7.67-7.52 (m, 3H), 7.40 (d, J=8.5 Hz, 2H), 2.57 (s, 3H), 2.22 (s, 6H), 1.39 (s, 6H). The .sup.1H NMR spectrum is displayed in FIG. 6.

[0188] The DSC curve of Form CS2 obtained in this example is depicted in FIG. 7, and the TGA curve is displayed in FIG. 8.

TABLE-US-00004 TABLE 3 2θ (±0.2°) d spacing Intensity % 9.68 9.13 3.76 11.17 7.92 9.76 11.66 7.59 41.04 12.17 7.28 44.01 14.74 6.01 19.59 15.21 5.82 93.64 15.89 5.58 99.14 16.53 5.36 9.11 19.06 4.66 51.10 19.24 4.61 63.21 19.35 4.59 66.96 20.02 4.43 29.96 21.38 4.16 16.10 22.20 4.00 5.34 22.91 3.88 6.45 23.40 3.80 7.62 24.63 3.61 5.48 25.39 3.51 9.84 25.75 3.46 100.00 26.29 3.39 5.19 26.77 3.33 18.14 27.50 3.24 23.27 29.19 3.06 7.80 29.53 3.03 5.87 30.75 2.91 10.29 36.09 2.49 7.44

Example 4

[0189] 103.5 mg of GFT-505 was dissolved in 1.0 mL of methanol, and 7.0 mL of water was added at room temperature as an anti-solvent. The solid was centrifuged and dried after stirring for 24 hours, and was characterized to be Form CS2 of the present disclosure. The XRPD data are listed in Table 4.

TABLE-US-00005 TABLE 4 2θ (±0.2°) d spacing Intensity % 9.65 9.16 7.78 11.17 7.92 10.05 11.63 7.61 48.14 12.16 7.28 28.74 14.72 6.02 16.51 15.21 5.83 67.12 15.90 5.57 98.50 16.51 5.37 10.32 19.03 4.66 42.92 19.33 4.59 100.00 20.00 4.44 38.97 21.37 4.16 10.01 22.19 4.01 4.30 23.40 3.80 8.33 25.75 3.46 77.65 26.75 3.33 16.29 27.50 3.24 18.33 29.16 3.06 6.87 30.72 2.91 7.29 32.17 2.78 2.39 35.96 2.50 1.75

Example 5

[0190] 7.5 mg of GFT-505 was dissolved in 0.6 mL of solvent mixture of ethanol and n-heptane (the volume ratio of ethanol and n-heptane was 15:4). The solution was filtrated. Polymer comprising equal amount of polycaprolactone, polyoxyethylene, polymethyl methacrylate, hydroxyethyl cellulose, and sodium alginate was added into the filtrate. The solution was sealed with perforated Parafilm and evaporated at room temperature for about 5 days to get solid. The solid was confirmed to be Form CS2, and XRPD data of which are listed in Table 5.

TABLE-US-00006 TABLE 5 2θ (±0.2°) d spacing Intensity % 11.18 7.92 5.66 11.65 7.60 22.81 12.15 7.29 26.34 14.72 6.02 15.20 15.21 5.82 65.10 15.89 5.58 56.45 16.51 5.37 7.81 19.03 4.66 43.77 19.31 4.60 74.42 20.02 4.43 19.48 21.39 4.15 16.80 22.20 4.00 5.29 22.91 3.88 7.88 24.63 3.61 6.62 25.80 3.45 100.00 26.77 3.33 14.92 27.55 3.24 24.47 29.61 3.02 6.88 30.87 2.90 10.45 35.06 2.56 4.92 36.10 2.49 6.77 39.07 2.31 6.25

Example 6

[0191] 6.4 mg of GFT-505 was dissolved in 0.6 mL of solvent mixture comprising acetone and toluene (the volume ratio of acetone and toluene was 1:1). The solution was filtrated and sealed with perforated parafilm. The filtrate was evaporated at room temperature for about 3 days, and the solid was characterized to be Form CS5 of the present disclosure. The XRPD pattern is displayed in FIG. 9 and the XRPD data are listed in Table 6.

[0192] The .sup.1H NMR data of the Form CS5 in this example are as follow: .sup.1HNMR (400 MHz, DMSO) δ 8.09 (d, J=8.5 Hz, 2H), 7.81 (d, J=15.6 Hz, 1H), 7.66-7.53 (m, 3H), 7.40 (d, J=8.5 Hz, 2H), 2.56 (s, 3H), 2.22 (s, 6H), 1.39 (s, 6H). The .sup.1H NMR spectrum is displayed in FIG. 10.

[0193] The DSC curve of Form CS5 in this example is depicted in FIG. 11, and the TGA curve is displayed in FIG. 12.

TABLE-US-00007 TABLE 6 2θ (±0.2°) d spacing Intensity % 7.37 11.99 57.43 14.32 6.19 21.43 14.58 6.08 100.00 15.44 5.74 45.41 16.71 5.31 6.78 17.66 5.02 9.37 18.68 4.75 79.74 19.47 4.56 10.85 21.48 4.14 2.85 25.32 3.52 43.73 25.85 3.45 64.55 27.51 3.24 30.47 28.88 3.09 12.67

Example 7

[0194] 18.5 mg of GFT-505 was dissolved in 1.5 mL of solvent mixture comprising acetone and toluene (the volume ratio of acetone and toluene was 1:2), then the solution was filtrated and sealed with perforated Parafilm. The filtrate was evaporated at room temperature for about 10 days, and the solid was characterized to be Form CS5, XRPD data of which are listed in Table 7.

TABLE-US-00008 TABLE 7 2θ (±0.2°) d spacing Intensity % 7.26 12.17 46.05 14.56 6.08 71.42 15.18 5.84 31.66 15.43 5.74 22.46 16.78 5.28 5.44 17.56 5.05 21.90 18.71 4.74 100.00 19.47 4.56 19.66 20.31 4.37 1.56 21.58 4.12 3.12 22.03 4.04 4.32 22.98 3.87 3.76 24.24 3.67 5.48 25.44 3.50 8.89 26.00 3.43 14.08 26.81 3.33 2.82 27.60 3.23 9.54 28.86 3.09 14.67

Example 8

[0195] 8.0 mg of GFT-505 was dissolved in 0.5 mL of solvent mixture comprising ethyl acetate and toluene (the volume ratio of ethyl acetate and toluene was 1:1), then the solution was filtered and sealed with perforated Parafilm. The filtrate was evaporated at room temperature for about 3 days, and the solid was characterized to be Form CS5.

Example 9

[0196] 10.9 mg of GFT-505 was weighed into a 3-mL glass vial. The 3-mL vial was placed into the 20-mL glass vial which contained 3 mL of acetic acid. The 20-mL vial was sealed and standing for one week, then the solid was collected.

[0197] The solid was characterized to be Form CS6, XRPD pattern of which is displayed in FIG. 13 and the XRPD data are listed in Table 8.

[0198] The .sup.1H NMR data of Form CS6 in this example are as follow: .sup.1HNMR (400 MHz, DMSO) δ 8.09 (d, J=8.6 Hz, 2H), 7.81 (d, J=15.5 Hz, 1H), 7.57 (s, 3H), 7.40 (d, J=8.6 Hz, 2H), 2.57 (s, 3H), 2.22 (s, 6H), 1.91 (s, 3H), 1.39 (s, 6H). The .sup.1H NMR spectrum is displayed in FIG. 14.

[0199] The DSC curve is depicted in FIG. 15, and the TGA curve is displayed in FIG. 16.

TABLE-US-00009 TABLE 8 2θ (±0.2°) d spacing Intensity % 6.60 13.40 31.51 10.33 8.57 61.94 11.14 7.94 20.54 12.50 7.08 63.30 13.25 6.68 20.50 14.97 5.92 51.20 15.19 5.83 100.00 16.24 5.46 31.07 16.96 5.23 35.83 18.21 4.87 37.41 19.39 4.58 43.47 19.76 4.49 14.69 20.74 4.28 42.06 22.59 3.94 13.99 23.13 3.85 21.58 23.55 3.78 68.43 25.11 3.55 16.03 26.38 3.38 81.16 26.99 3.30 19.01 29.68 3.01 7.79 32.64 2.74 3.95

Example 10: Purity Comparison Among Oily Substance of the Prior Art, Form CS1 and Form CS2 of the Present Disclosure

[0200] The purities of oily substance prepared according to the prior art, Form CS1 of the present disclosure and Form CS2 of the present disclosure were measured by HPLC, and the results are listed in Table 9.

TABLE-US-00010 TABLE 9 Form Oily substance Form CS1 Form CS2 Purity 83.87% 99.25% 99.56%

[0201] The purity of drug substance is significant for ensuring the drug efficacy and safety and preventing adverse side effect. The impurity content in oily substance of the prior art is extremely high, which may lead to obviously low drug substance content and decrease of activity. High impurity may result in a significant increase in toxicity and side effects as well, thus the oily substance of the prior art cannot be used as active pharmaceutical ingredient in the preparation of drug products.

[0202] The purity of the crystalline forms of the present disclosure is relatively high, which is beneficial for industrial production. The crystalline forms of the present disclosure have better purification effect. Drug substance with higher purity can be obtained by crystallization process with less residual solvent problems. The residual solvent of the sample is easy to meet the standard and the quality requirements, which is suitable for medicinal use.

Example 11: Hygroscopicity Study of Form CS1, Form CS2 and Form CS5

[0203] Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS1, Form CS2 and Form CS5 of the present disclosure with about 10 mg of samples at 25° C. The results indicate that:

[0204] The weight gain of Form CS1 under 80% RH is 0.042%. Form CS1 is almost non hygroscopic. The DVS plot of Form CS1 is depicted in FIG. 17. Furthermore, the crystalline form of Form CS1 before and after DVS was tested by XRPD, and the results are displayed in FIG. 18 (at the top is the XRPD pattern before DVS and bottom is the XRPD pattern after DVS). The XRPD overlay indicates that no form change of Form CS1 is observed before and after DVS test.

[0205] The weight gain of Form CS2 from 30% RH to 80% RH is 0.101%. Form CS2 is almost non hygroscopic and convenient for long-term storage. The DVS plot of Form CS2 is depicted in FIG. 19. Furthermore, the crystalline form before and after DVS was tested by XRPD, and the results are displayed in FIG. 20 (top: XRPD pattern before DVS; bottom: XRPD pattern after DVS). The XRPD overlay indicates that no form change of Form CS2 is observed before and after DVS test.

[0206] The weight gain of Form CS5 under 80% RH is 0.325%. Form CS5 is slightly hygroscopic. The DVS plot of Form CS5 is depicted in FIG. 21. Furthermore, the crystalline form before and after DVS was tested by XRPD, and the results are displayed in FIG. 22 (top: XRPD pattern before DVS; bottom: XRPD pattern after DVS), and the XRPD overlay indicates that no form change of Form CS5 is observed before and after DVS test.

[0207] Description and definition of hygroscopicity (Chinese Pharmacopoeia 2015 edition general principle 9103 Drug hygroscopic test guidelines, test at 25° C.+/−1° C., 80% RH.).

Deliquescent: Sufficient water is absorbed to form a liquid;
Very hygroscopic: Increase in mass is equal to or greater than 15 percent;
Hygroscopic: Increase in mass is less than 15 percent and equal to or greater than 2 percent;
Slightly hygroscopic: Increase in mass is less than 2 percent and equal to or greater than 0.2 percent.
Non hygroscopic or almost non hygroscopic: Increase in mass is less than 0.2%.

Example 12: Stability Study of Form CS1, Form CS2 and Form CS5

[0208] Form CS1 of the present disclosure was stored under different conditions of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH in open dishes. Crystalline form was checked by XRPD. The XRPD overlays of the solid before and after storage are shown in FIG. 23, FIG. 24, and FIG. 25. The stability results are listed in Table 10:

TABLE-US-00011 TABLE 10 Crystalline form Initial solid form Condition Time after storage Form CS1 25° C./60% RH 6 months Form CS1 (top in FIG. 23) (Bottom in FIG. 23) Form CS1 40° C./75% RH 6 months Form CS1 (top in FIG. 24) (Bottom in FIG. 24) Form CS1 60° C./75% RH 1 months Form CS1 (top in FIG. 25) (Bottom in FIG. 25)

[0209] Form CS1 of the present disclosure is stable for 6 months at 25° C./60% RH and 40° C./75% RH. Form CS1 is stable for 1 month at 60° C./75% RH. It can be seen that Form CS1 of the present disclosure has good stability.

[0210] Form CS2 of the present disclosure was stored under different conditions of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH in open dishes. Crystalline form was checked by XRPD. The XRPD overlays of the solid before and after storage are shown in FIG. 26, FIG. 27, and FIG. 28. The stability results are listed in Table 11:

TABLE-US-00012 TABLE 11 Crystalline form Initial solid form Condition Time after storage Form CS2 25° C./60% RH 6 months Form CS2 (Top in FIG. 26) (Bottom in FIG. 26) Form CS2 40° C./75% RH 6 months Form CS2 (Top in FIG. 27) (Bottom in FIG. 27) Form CS2 60° C./75% RH 1 months Form CS2 (Top in FIG. 28) (Bottom in FIG. 28)

[0211] Form CS2 of the present disclosure is stable for 6 months at 25° C./60% RH and 40° C./75% RH. Form CS2 is stable for 1 month at 60° C./75% RH. It can be seen that Form CS2 of the present disclosure has good stability.

[0212] Form CS5 of the present disclosure was stored under different conditions of 25° C./60% RH, 40° C./75% RH and 60° C./75% RH in open dishes. Crystalline form was checked by XRPD. The XRPD overlays of the solid before and after storage are shown in FIG. 29, FIG. 30, and FIG. 31. The stability results are listed in Table 12:

TABLE-US-00013 TABLE 12 Crystalline form Initial solid form Condition Time after storage Form CS5 25° C./60% RH 6 months Form CS5 (Top in FIG. 29) (Bottom in FIG. 29) Form CS5 40° C./75% RH 6 months Form CS5 (Top in FIG. 30) (Bottom in FIG. 30) Form CS5 60° C./75% RH 1 months Form CS5 (Top in FIG. 31) (Bottom in FIG. 31)

[0213] Form CS5 of the present disclosure is stable for 6 months at 25° C./60% RH and 40° C./75% RH. Form CS5 is stable for 1 month at 60° C./75% RH. It can be seen that Form CS5 of the present disclosure has good stability.

[0214] The stability of drug is very important, especially during the shelf life of the drug in market. Good stability could reduce the risk of the crystal transformation which may cause the change of drug dissolution rate and bioavailability, and is of great significance to ensure the efficacy and safety of the drug and prevent the occurrence of adverse drug reactions. Crystalline form with better stability is controllable during the crystallization process and not easy to produce mixed crystal. Meanwhile, during the formulation and storage processes, crystalline form with better stability is hard to convert into other crystal forms. As a result, consistent and controllable of product quality can be ensured, and the dissolution profile will not change with the storage time.

[0215] The results indicate that Form CS1, Form CS2 and Form CS5 of the present disclosure have good stability and meet the stringent requirements in the drug application and formulation process.

Example 13: Dynamic Solubility Study of Form CS1, Form CS2, Form CS5, and Form CS6

[0216] In order to test the solubility of Form CS1, CS2, CS5, and CS6 of the present disclosure, the following experiments have been conducted by the inventors:

[0217] Saturated solutions of Form CS1, Form CS2, and Form CS5 of the present disclosure were prepared with SGF (Simulated gastric fluids), pH5.0 FeSSIF (Fed state simulated intestinal fluids), pH6.5 FaSSIF (Fasted state simulated intestinal fluids) and H.sub.2O. After equilibrated for 1 h, 4 h, and 24 h, concentrations of drug substance in the saturated solutions were measured by HPLC. Saturated solutions of Form CS6 of the present disclosure were prepared with SGF (Simulated gastric fluids), pH5.0 FeSSIF (Fed state simulated intestinal fluids) and pH6.5 FaSSIF (Fasted state simulated intestinal fluids). After equilibrated for 1 h, 4 h, and 24 h, concentrations of drug substance in the saturated solutions were measured by HPLC. The solubility results of Form CS1 are listed in Table 13. The solubility results of Form CS2 are listed in Table 14. The solubility results of Form CS5 are listed in Table 15. The solubility results of Form CS6 are listed in Table 16.

TABLE-US-00014 TABLE 13 Solubility of Form CS1 in SGF, FeSSIF, FaSSIF and H.sub.2O Time SGF FeSSIF FaSSIF H.sub.2O Solubility 1 hour 7.9 122.6 417.0 4.6 (μg/mL)  4 hours 5.5 141.5 428.6 10.2 24 hours 3.9 139.8 420.4 4.8

TABLE-US-00015 TABLE 14 Solubility of Form CS2 in SGF, FeSSIF, FaSSIF and H.sub.2O Time SGF FeSSIF FaSSIF H.sub.2O Solubility 1 hour 0.7 30.3 35.9 3.7 (μg/mL)  4 hours 1.7 31.9 42.2 15.2 24 hours 1.5 27.5 37.5 37.4

TABLE-US-00016 TABLE 15 Solubility of Form CS5 in SGF, FeSSIF, FaSSIF and H.sub.2O Time SGF FeSSIF FaSSIF H.sub.2O Solubility 1 hour 14.3 86.0 187.2 0.7 (μg/mL)  4 hours 24.4 123.2 300.2 16.6 24 hours 42.4 114.3 321.0 42.2

TABLE-US-00017 TABLE 16 Solubility of Form CS6 in SGF, FeSSIF and FaSSIF Time SGF FeSSIF FaSSIF Solubility 1 hour 1.4 34.0 6.2 (μg/mL)  4 hours 6.5 84.0 29.0 24 hours 17.0 180.0 27.0

[0218] Solubility is one of the key properties of drugs, which directly affects the absorption of drugs in the human body. The solubility of different crystalline forms may have obvious difference, and the absorption dynamics in vivo may also change, resulting in differences in bioavailability, which ultimately affects the clinical safety and efficacy of the drug.

[0219] The results indicate that the solubility of Form CS1, Form CS2, and Form CS5 of the present disclosure in SGF, FaSSIF, FeSSIF, and H.sub.2O and the solubility of Form CS6 of the present disclosure in SGF, FaSSIF, and FeSSIF meet the medicinal requirements. The solubility in FaSSIF (Fasted state simulated intestinal fluids) and FeSSIF (Fed state simulated intestinal fluids) is relatively high. The favorable solubility of Form CS1, Form CS2, Form CS5, and Form CS6 of the present disclosure can reduce the dose of the drug while ensuring its efficacy, thereby reducing the side effects and improving the safety of the drug. The necessary therapeutic blood concentration after the oral administration can be achieved without high dose, which is beneficial to the absorption of drugs in vivo, achieving ideal bioavailability and efficacy of drugs and meeting the medicinal requirements.

Example 14: Mechanical Stability Study of Form CS1, Form CS2, Form CS5, and Form CS6

[0220] Approximately 20 mg of Form CS1, Form CS2, Form CS5, and Form CS6 of the present disclosure were ground manually with a mortar for 5 minutes, and the solid before and after grinding were tested by XRPD. The results of Form CS1 are displayed in FIG. 32 (top: XRPD pattern before grinding, bottom: XRPD pattern after grinding). The results of Form CS2 are displayed in FIG. 33 (top: XRPD pattern before grinding, bottom: XRPD pattern after grinding). The results of Form CS5 are displayed in FIG. 34 (top: XRPD pattern before grinding, bottom: XRPD pattern after grinding). The results of Form CS6 are displayed in FIG. 35 (top: XRPD pattern before grinding, bottom: XRPD pattern after grinding). As can be seen from the figures, the crystalline forms of Form CS1, Form CS2, Form CS5, and Form CS6 of the present disclosure does not change and the crystallinity is still good.

[0221] Crystalline forms with better mechanical stability have good physicochemical properties and remain stable under certain mechanical stress. The crystalline drug with better mechanical stability has low requirements on the crystallization equipment, and no special post-treatment condition is required. It is more stable in the formulation process, can significantly reduce the development cost of the drug products, enhance the quality of the drug, and has strong economic value.

[0222] The results indicate that Form CS1, Form CS2, Form CS5, and Form CS6 of the present disclosure have better mechanical stability in the downstream preparation process and provide more choices for the following formulation process. For example, the Form CS1, Form CS2, Form CS5, and Form CS6 can be ground by subsequent dry grinding to obtain drug substance with smaller particle sizes.

Example 15: Morphology Comparison Among Oily Substance of Prior Art, Form CS1, Form CS2, Form CS5, and Form CS6 of the Present Disclosure

[0223] The comparison picture of Form CS1 of the present disclosure and oily substance is displayed in FIG. 36. Form CS1, Form CS2, Form CS5, and Form CS6 are all light yellow powders, which are convenient for sampling and quantification. While the light yellow oily substance prepared according to the prior art is sticky honey-like (right in FIG. 36). The sampling and quantification of oily substance is relatively difficult. Meanwhile, the oily substance has low purity and relatively poor stability, which are not suitable for drug storage. Furthermore, special and complex processing procedures are often needed when the oily substance is used as the active pharmaceutical ingredient to make into solid drug products, which will increase the preparation cost and is difficult for the preparation of formulation.

[0224] 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.