CRYSTALLINE FORM OF TOLEBRUTINIB AND PREPARATION METHOD THEREOF

Abstract

Disclosed is a crystalline form of Tolebrutinib (hereinafter referred to as “Compound I”) and preparation methods thereof, pharmaceutical compositions containing the crystalline form, and uses of the crystalline form for preparing BTK inhibitor drugs and drugs for treating multiple sclerosis. The provided crystalline form of Tolebrutinib has one or more improved properties and has significant value for future drug optimization and development.

##STR00001##

Claims

1. A crystalline form of Compound I, wherein the X-ray powder diffraction pattern comprises at least one characteristic peak at 2 theta values of 7.7°±0.2°, 11.0°±0.2°, and 22.8°±0.2° using CuKα radiation ##STR00003##

2. The crystalline form of Compound I according to claim 1, wherein the X-ray powder diffraction pattern comprises at least one characteristic peak at 2 theta values of 12.0°±0.2°, 16.1°±0.2°, and 18.5°±0.2° using CuKα radiation.

3. The crystalline form of Compound I according to claim 1, wherein the X-ray powder diffraction pattern comprises at least one characteristic peak at 2 theta values of 13.6°±0.2°, 20.1°±0.2°, and 24.8°±0.2° using CuKα radiation.

4. The crystalline form of Compound I according to claim 1, wherein the X-ray powder diffraction pattern is substantially as depicted in FIG. 2 using CuKα radiation.

5. A process for preparing the crystalline form according to claim 1, wherein the process comprises: adding the solid of Compound I into a ketone or an ether, stirring and separating to obtain the crystalline form.

6. The process according to claim 5, wherein said ketone is a ketone of C3-C6, and said ether is an ether of C5.

7. The process according to claim 5, wherein said ketone is 4-methyl-2-pentanone, and said ether is methyl tert-butyl ether.

8. The process according to claim 5, wherein a temperature of stirring is from room temperature to 55° C., and a time of stirring is more than 25 hours.

9. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of the crystalline form according to claim 1, and pharmaceutically acceptable excipients.

10. A method of inhibiting BTK, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form according to claim 1.

11. A method of treating multiple sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIG. 1 shows an XRPD pattern of sample 1 according to example 1.

[0041] FIG. 2 shows an XRPD pattern of Form CSI according to example 2.

[0042] FIG. 3 shows an XRPD pattern of Form CSI according to example 3.

[0043] FIG. 4 shows an XRPD pattern of Form CSI according to example 4.

[0044] FIG. 5 shows a TGA curve of Form CSI.

[0045] FIG. 6 shows a DSC curve of Form CSI.

[0046] FIG. 7 shows an XRPD pattern overlay of Form CSI before and after storage (from top to bottom: initial, stored at 25° C./60% RH (open package) for 6 months, stored at 25° C./60% RH (sealed package) for 6 months, stored at 40° C./75% RH (open package) for 6 months, stored at 40° C./75% RH (sealed package) for 6 months, stored at 60° C./75% RH (open package) for 1 months, stored at 60° C./75% RH (sealed package) for 1 months).

[0047] FIG. 8 shows a DVS plot of Form CSI.

[0048] FIG. 9 shows a DVS plot of prior art amorphous.

[0049] FIG. 10 shows an XRPD pattern overlay of Form CSI before and after formulation process (from top to bottom: excipients, after formulation process, and Form CSI).

[0050] FIG. 11 shows an XRPD pattern overlay of Form CSI drug product stored under different conditions (from top to bottom: initial drug product, stored under 25° C./60% RH for 3 months, stored under 40° C./75% RH for 3 months).

DETAILED DESCRIPTION

[0051] 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 changes in the materials and methods can be accomplished without departing from the scope of the present disclosure.

[0052] The abbreviations used in the present disclosure are explained as follows:

[0053] XRPD: X-ray Powder Diffraction

[0054] DSC: Differential Scanning calorimetry

[0055] TGA: Thermo Gravimetric Analysis

[0056] DVS: Dynamic Vapor Sorption

[0057] .sup.1H NMR: Proton Nuclear Magnetic Resonance

[0058] RH: Relative humidity

[0059] UPLC: Ultra Performance Liquid Chromatography

[0060] LC: Liquid Chromatography

[0061] PE: Polyethylene

[0062] LDPE: Low Density Polyethylene

[0063] HDPE: High Density Polyethylene

[0064] Instruments and methods used for data collection:

[0065] X-ray powder diffraction patterns in the present disclosure were acquired by a Bruker X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows:

[0066] X-Ray: Cu, Kα

[0067] Kα1 (Å): 1.54060; Kα2 (A): 1.54439

[0068] Kα2/Kα1 intensity ratio: 0.50

[0069] Thermo gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q500. The parameters of the TGA method of the present disclosure are as follows:

[0070] Heating rate: 10° C./min

[0071] Purge gas: nitrogen

[0072] 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: Heating rate: 10° C./min

[0073] Purge gas: nitrogen

[0074] Dynamic Vapor Sorption (DVS) was measured via an SMS (Surface Measurement Systems Ltd.) intrinsic DVS instrument. Typical Parameters for DVS test are as follows:

[0075] Temperature: 25° C.

[0076] Gas and flow rate: nitrogen, 200 mL/min

[0077] RH range: 0% RH to 95% RH

[0078] 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.

[0079] The related substance in the present disclosure was detected by UPLC and the parameters are shown below.

TABLE-US-00001 TABLE 1 Instrument Waters ACQUITY UPLC H-Class with PDA Column ACE Excel 3 C18 Mobile phase A: 0.1% H.sub.3PO.sub.4 in H.sub.2O (pH4.0, TEA) B: Acetonitrile Gradient Time (min) % B  0.0 10  0.3 10  3.5 45  9.0 80 11.0 80 11.1 10 18.0 10 Run time 18.0 min Stop time  0.0 min Injection volume 1 μL Detector 226 nm wavelength Column 40° C. temperature Sample Room temperature temperature Diluent 0.01% TFA in Acetonitrile

[0080] In the present disclosure, said “stirring” is accomplished by using a conventional method in the field such as magnetic stirring or mechanical stirring and the stirring speed is 50 to 1800 r/min. Preferably the magnetic stirring speed is 300 to 900 r/min and mechanical stirring speed is 100 to 300 r/min.

[0081] Said “separation” is accomplished by using a conventional method in the field such as centrifugation or filtration. The operation of “centrifugation” is as follows: the sample to be separated is placed into the centrifuge tube, and then centrifuged at a rate of 10000 r/min until the solid all sink to the bottom of the tube.

[0082] Said “drying” is accomplished by using a conventional method in the field such as vacuum drying, blast drying or free-air drying. The drying temperature can be room temperature or higher. Preferably the drying temperature is from room temperature to about 60° C., or to 50° C., or to 40° C. The drying time can be 2 to 48 hours, or overnight. Drying is accomplished in a fume hood, forced air convection oven or vacuum oven.

[0083] Said “room temperature” is not a specific temperature, but a temperature range of 10-30° C.

[0084] Said “open packaged” is putting the sample into a glass vial, covering the vial with aluminum foil, and punching 5-10 holes on the foil.

[0085] Said “sealed packaged” is putting the sample into a glass vial, capping the vial tightly, and sealing the vial in an aluminum foil bag.

[0086] Said “characteristic peak” refers to a representative diffraction peak used to distinguish crystals, which usually can have a deviation of ±0.2° using CuKα radiation.

[0087] In the present disclosure, “crystal” or “crystalline form” refers to the crystal or the crystalline form being identified by the X-ray diffraction pattern shown herein. Those skilled in the art are able to understand that the experimental errors depend on the instrument conditions, the sample preparation and the purity of samples. The relative intensity of the diffraction peaks in the X-ray diffraction pattern may also vary with the experimental conditions; therefore, the order of the diffraction peak intensities cannot be regarded as the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystals, and the diffraction peak intensities shown herein are illustrative and identical diffraction peak intensities are not required. Thus, it will be understood by those skilled in the art that a crystalline form of the present disclosure is not necessarily to have exactly the same X-ray diffraction pattern of the example shown herein. Any crystalline forms whose X-ray diffraction patterns have the same or similar characteristic peaks should be within the scope of the present disclosure. Those skilled in the art can compare the patterns shown in the present disclosure with that of an unknown crystalline form in order to identify whether these two groups of patterns reflect the same or different crystalline forms.

[0088] In some embodiments, Form CSI of the present disclosure is pure and substantially free of any other crystalline forms. In the present disclosure, the term “substantially free” when used to describe a novel crystalline form, means that the content of other crystalline forms in the novel crystalline form is less than 20% (w/w), specifically less than 10% (w/w), more specifically less than 5% (w/w) and furthermore specifically less than 1% (w/w).

[0089] In the present disclosure, the term “about” when referring to a measurable value such as weight, time, temperature, and the like, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0090] Unless otherwise specified, the following examples were conducted at room temperature.

[0091] According to the present disclosure, Compound I and/or its salt used as a raw material is solid (crystalline or amorphous), oil, liquid form or solution. Preferably, Compound I used as a raw material is a solid.

[0092] Raw materials of Compound I and/or a salt thereof used in the following examples were prepared by known methods in the prior art, for example, the method disclosed in WO2016196840A1.

Example 1: Attempts for Preparing Compound I Solid Form

[0093] The inventors of the present disclosure tried various methods and regulated various process conditions for preparing solid forms, such as solvent (alcohols, ketones, esters, ethers, acids, water, nitriles, amides, halogenated hydrocarbons, aromatic hydrocarbons, alkanes, sulfoxides, etc.), temperature, time, evaporation rate, additives, and other factors. More than one hundred experiments were carried out, while only amorphous was obtained. Some of the experimental methods and results are listed in Table 2-6.

TABLE-US-00002 TABLE 2 Methods Regulated influencing factors Results Stirring Solvent (alcohols, esters, acids, water, nitriles, aromatic Amorphous hydrocarbons, mixtures thereof, etc.), temperature, time Evaporation Solvent (alcohols, ketones, esters, ethers, acids, water, Amorphous halogenated hydrocarbons, amides, mixtures thereof, etc.), additives, time, evaporation rate Solid vapor Solvent (alcohols, esters, ethers, water, alkanes, Amorphous diffusion amides, sulfoxides, etc.), temperature Liquid Solvent (alcohols, ketones, esters, ethers, acids, water, Amorphous vapor alkanes, amides, sulfoxides, etc.), time diffusion Summary Solvent (alcohols, ketones, esters, ethers, acids, water, Amorphous nitriles, amides, halogenated hydrocarbons, aromatic hydrocarbons, alkanes, sulfoxides, etc.), temperature, time, evaporation rate, additives

Method 1: Stirring

[0094] According to Table 3, a certain mass of Compound I solid was weighed into a glass vial, followed by an addition of a certain volume of solvent. After stirring at certain temperature for a period, the solid was separated. All the obtained solids were confirmed to be amorphous by XRPD. The XRPD pattern of sample 1 is substantially as depicted in FIG. 1.

TABLE-US-00003 TABLE 3 Weight Solvent Volume Temperature Stirring Sample (mg) (v/v) (mL) (° C.) time Solid form 1 9.6 Methanol 0.2 Room 1 day Amorphous temperature 2 8.9 Ethyl acetate 0.2 Room 1 day Amorphous temperature 3 9.9 Toluene 0.2 Room 1 day Amorphous temperature 4 9.8 Water 0.2 Room 1 day Amorphous temperature 5 9.2 Acetonitrile 0.2 Room 1 day Amorphous temperature 6 19.0 Isopropyl alcohol 0.2 50 1 day Amorphous 7 17.9 Acetic acid/Water 0.2 50 1 day Amorphous (36/64) 8 18.1 Isopropyl acetate 0.4 50 5 days Amorphous

Method 2: Evaporation

[0095] According to Table 4, a certain mass of Compound I solid was weighed into a glass vial. After adding a certain volume of solvent and an additive, the system was evaporated at room temperature. All the obtained solids were confirmed to be amorphous by XRPD.

TABLE-US-00004 TABLE 4 Weight Solvent Volume Evaporation Sample (mg) (v/v) (mL) Additive Time rate Solid form 1 8.7 Chloroform 0.2 N/A 4 days Slow Amorphous 2 8.0 Tetrahydrofuran 0.2 N/A 4 days Slow Amorphous 3 8.0 Ethyl acetate 0.6 N/A 4 days Slow Amorphous 4 8.5 Acetone/Water 1.0 N/A 4 days Slow Amorphous (97/3) 5 7.6 Acetone/Water 1.0 N/A 4 days Slow Amorphous (91/9) 6 8.0 N,N-Dimethylformamide/ 1.0 N/A 4 days Slow Amorphous Water (94/6) 7 7.6 Propionic acid 0.4 Polyacetal 1 month Fast Amorphous 8 8.4 Tetrahydrofuran/ 1.6 Chlorosulfonated 4 days Fast Amorphous Methanol (3/2) polyethylene

[0096] Fast evaporation: the sample vial is open for evaporation without cap.

[0097] Slow evaporation: the sample vial is sealed with cap which has small holes.

Method 3: Solid Vapor Diffusion

[0098] According to Table 5, a certain mass of Compound I solid was weighed into a glass vial. The vial was put into a larger glass vial containing about 5 mL of corresponding solvent. The larger vial was sealed with a cap and placed at a certain temperature for sufficient contact of solvent atmosphere and the solid in the vial. All the solids were taken out for XRPD test after 1 day and were confirmed to be amorphous.

TABLE-US-00005 TABLE 5 Weight Sample (mg) Solvent Temperature (° C.) Solid form 1 7.0 n-Hexane Room temperature Amorphous 2 8.0 Water Room temperature Amorphous 3 7.6 Dimethyl sulfoxide Room temperature Amorphous 4 9.9 N,N- Room temperature Amorphous Dimethylacetamide 5 13.0 Benzyl alcohol 5 Amorphous 6 9.7 L-Ethyl lactate 5 Amorphous 7 13.1 Petroleum ether 5 Amorphous 8 11.3 1,3-Dioxolane 5 Amorphous

Method 4: Liquid Vapor Diffusion

[0099] According to Table 6, a certain mass of Compound I solid was weighed into a glass vial and dissolved with a certain volume of solvent. The vial was put into a larger glass vial containing about 5 mL of corresponding anti-solvents, then the larger vial was sealed with a cap and placed at a certain temperature to allow the anti-solvent vapor diffusing into the inner vial sufficiently. All the solids were isolated and confirmed to be amorphous by XRPD after diffusion for different times.

TABLE-US-00006 TABLE 6 Weight Volume Sample (mg) Solvent (mL) Anti-solvent Time Solid form 1 9.8 Acetic acid 0.2 Methanol 86 days Amorphous 2 10.3 Acetic acid 0.3 Methyl 86 days Amorphous tert-butyl ether 3 11.0 Dimethyl sulfoxide 0.3 Isopropyl 86 days Amorphous acetate 4 11.7 Dimethyl sulfoxide 0.3 n-Hexane 86 days Amorphous 5 9.7 N -methylpyrrolidone 0.3 Methyl 86 days Amorphous isobutyl ketone 6 10.3 N,N-dimethylacetamide 0.3 Water  1 day Amorphous 7 11.8 N, 0.3 Water  9 days Amorphous N-dimethylformamide 8 12.4 N, 0.3 Methyl 86 days Amorphous N-dimethylformamide tert-butyl ether

[0100] The above experimental results indicate that Compound I is difficult to crystallize and amorphous is easily obtained. The inventors of the present disclosure further tried various unconventional solvents and improved the preparation and post-treatment conditions, as described in Example 2-4, and the crystal form of Compound I was finally obtained unexpectedly.

Example 2: Preparation Method of Form CSI

[0101] 300.8 mg of Compound I solid was weighed into a 3-mL glass vial, followed by the addition of 2.0 mL of methyl isobutyl ketone. After stirring at 50° C. for about 39 hours, a solid was isolated. The obtained solid is confirmed to be Form CSI of the present disclosure. The XRPD pattern is substantially as depicted in FIG. 2, and the XRPD data are listed in Table 7.

TABLE-US-00007 TABLE 7 2θ (°) d spacing (Å) Relative intensity (%) 7.69 11.50 81.95 7.89 11.21 10.33 10.07 8.78 5.49 10.55 8.39 4.24 11.00 8.04 41.35 11.88 7.45 26.12 12.04 7.35 34.15 13.22 6.70 21.79 13.64 6.49 33.48 14.02 6.32 16.90 15.02 5.90 3.83 15.47 5.73 7.44 15.80 5.61 8.05 16.10 5.51 47.60 17.36 5.11 3.12 18.47 4.80 92.44 18.73 4.74 57.54 19.24 4.61 10.58 20.14 4.41 18.59 20.83 4.26 8.44 21.36 4.16 10.50 21.62 4.11 12.80 22.30 3.99 6.58 22.79 3.90 100.00 23.66 3.76 21.01 23.83 3.73 21.02 24.18 3.68 8.80 24.46 3.64 9.62 24.85 3.58 31.33 26.29 3.39 8.42 27.45 3.25 4.21 27.77 3.21 7.89 28.25 3.16 2.45 28.89 3.09 9.70 29.14 3.06 6.68 30.32 2.95 11.30 31.09 2.88 6.06 32.41 2.76 5.91 33.41 2.68 2.46 34.08 2.63 4.17 36.11 2.49 1.14 36.84 2.44 3.09

Example 3: Preparation Method of Form CSI

[0102] 300.1 mg of Compound I solid was weighed into a 3-mL glass vial, followed by the addition of 2.0 mL of methyl isobutyl ketone. After stirring at 50° C. for about 6 days, a solid was isolated. The obtained solid is confirmed to be Form CSI of the present disclosure by XRPD. The XRPD pattern is substantially as depicted in FIG. 3, and the XRPD data are listed in Table 8.

TABLE-US-00008 TABLE 8 2θ (°) d spacing (Å) Relative intensity (%) 7.64 11.57 64.68 10.06 8.79 5.16 10.53 8.40 4.30 10.98 8.06 37.82 12.03 7.36 40.10 13.21 6.70 17.22 13.63 6.50 31.16 14.00 6.32 16.13 15.04 5.89 4.71 15.47 5.73 10.37 15.79 5.61 10.80 16.09 5.51 46.03 17.36 5.11 3.85 18.46 4.81 76.52 18.73 4.74 56.08 19.26 4.61 10.27 20.12 4.41 21.12 20.81 4.27 10.44 21.36 4.16 15.59 21.63 4.11 13.59 22.29 3.99 7.89 22.79 3.90 100.00 23.68 3.76 27.31 23.82 3.74 29.20 24.15 3.69 11.27 24.44 3.64 12.52 24.83 3.59 32.01 26.31 3.39 10.77 27.43 3.25 5.57 27.77 3.21 7.24 28.27 3.16 2.98 28.91 3.09 10.74 29.18 3.06 7.70 30.39 2.94 12.58 31.04 2.88 7.39 32.42 2.76 7.07 33.44 2.68 2.63 34.03 2.63 3.54 36.13 2.49 1.61 36.85 2.44 2.20

Example 4: Preparation of Form CSI

[0103] 300.4 mg of Compound I solid was weighed into a glass vial, followed by the addition of 3.0 mL of methyl tert-butyl ether. After stirring at 50° C. for about 68 hours, a solid was isolated. After vacuum drying at 75° C. for 1 hour, the obtained solid is confirmed to be Form CSI of the present disclosure, and the XRPD data are shown in FIG. 9 and Table 4.

[0104] The TGA curve is substantially as depicted in FIG. 5, which shows about 0.4% weight loss when heated from 31° C. to 160° C.

[0105] The DSC curve is substantially as depicted in FIG. 6. It shows one endothermic peak at around 170° C. (onset temperature), which is the melting endothermic peak of Form CSI. The .sup.1H NMR data are as follows: .sup.1HNMR (400 MHz, DMSO) δ (ppm) 7.75 (d, 1H), 7.52-7.36 (m, 4H), 7.21 (t, 1H), 7.14 (t, J=7.8 Hz, 4H), 6.98 (d, 1H), 6.91-6.76 (m, 1H), 6.13 (dd, J=16.5, 7.0 Hz, 1H), 5.69 (dd, J=16.7, 10.8 Hz, 1H), 4.82 (s, 2H), 4.50 (t, J=14.3 Hz, 1H), 4.15 (dd, J=33.9, 12.5 Hz, 2H), 3.76 (t, J=13.0 Hz, 0.5H), 3.16 (t, J=12.7 Hz, 0.5H), 2.79-2.61 (m, 0.5H), 2.45-2.29 (m, J=13.0, 9.1 Hz, 1H), 2.10-1.74 (m, 2H), 1.66-1.37 (m, 1H). (According to the structure of Compound I, the peak of one piperidine hydrogen appears at δ 3.33-3.76 ppm. Harf of this hydrogen is spitted and covered by the signal of water since it is close to the peak of water.)

TABLE-US-00009 TABLE 9 2θ (°) d spacing (Å) Relative intensity (%) 7.67 11.53 36.95 7.88 11.22 10.54 10.07 8.78 6.04 10.56 8.38 6.47 11.00 8.04 54.02 12.03 7.36 45.91 13.21 6.70 15.50 13.63 6.50 32.17 14.02 6.32 14.97 15.06 5.88 6.22 15.49 5.72 11.71 16.08 5.51 35.68 17.33 5.12 2.04 18.47 4.80 42.70 18.73 4.74 43.49 19.26 4.61 6.38 20.11 4.42 22.02 20.85 4.26 9.97 21.34 4.16 15.95 21.65 4.11 12.00 22.32 3.98 7.77 22.79 3.90 100.00 23.68 3.76 24.11 24.18 3.68 8.70 24.46 3.64 11.52 24.82 3.59 23.38 26.30 3.39 9.10 27.49 3.25 5.45 27.79 3.21 6.74 28.90 3.09 6.79 30.38 2.94 11.72 31.14 2.87 2.74 32.42 2.76 7.51 34.13 2.63 3.52 36.12 2.49 1.82 36.90 2.44 2.04

Example 5: Physical and Chemical Stability of Form CSI

[0106] A certain amount of Form CSI of the present disclosure and prior art amorphous were weighed and stored under 25° C./60% RH, 40° C./75% RH and 60° C./75% RH conditions, respectively. The purity and solid form were determined by UPLC and XRPD. The results are listed in Table 10, and the XRPD overlay of Form CSI before and after stability evaluation is shown in FIG. 7.

TABLE-US-00010 TABLE 10 Impurity number exceed the Initial solid Storage Packing Storage Solid Purity qualificated form condition condition time form Purity change threshold Form CSI Initial N/A N/A Form CSI 99.86% N/A 0 25° C./60% RH Sealed 6 months Form CSI 99.89% 0.03% 0 packaged 25° C./60% RH Open 6 months Form CSI 99.81% −0.05% 0 packaged 40° C./75% RH Sealed 6 months Form CSI 99.92% 0.06% 0 packaged 40° C./75% RH Open 6 months Form CSI 99.81% −0.05% 0 packaged 60° C./75% RH Sealed 1 month Form CSI 99.85% −0.01% 0 packaged 60° C./75% RH Open 1 month Form CSI 99.86% 0.00% 0 packaged Amorphous Initial N/A N/A Amorphous 99.80% N/A 1 25° C./60% RH Sealed 6 months Amorphous 99.65% −0.15% 1 packaged 25° C./60% RH Open 6 months Amorphous 99.57% −0.23% 1 packaged 40° C./75% RH Sealed 6 months Amorphous 99.18% −0.62% 2 packaged 40° C./75% RH Open 6 months Amorphous 96.34% −3.46% 4 packaged 60° C./75% RH Sealed 1 month Amorphous 97.04% −2.76% 2 packaged 60° C./75% RH Open 1 month Amorphous 93.48% −6.32% 4 packaged

[0107] Remark: The qualificated threshold refer to INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE, IMPURITIES IN NEW DRUG SUBSTANCES Q3A (R2).

[0108] The dose of Compound I is 60 mg once daily.

[0109] The results show that Form CSI is stable for at least 6 months under 25° C./60% RH and 40° C./75% RH conditions, and the solid form and purity remain basically unchanged, indicating Form CSI has good stability under both long-term and accelerated conditions. After storage under 60° C./75% RH condition for 1 month, the solid form and purity remain basically unchanged, indicating Form CSI has good stability under stressed condition as well. The impurity content of Form CSI drug substance does not exceed the qualificated threshold throughout the stability investigation processes, which meets the requirements of pharmaceutical development. After storage at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH, the purity of prior art amorphous decreased significantly, which is far below the requirements of pharmaceutical development. After storage at 40° C./75% RH for 6 months with open package, the purity decreased by 3.46%, and the number of impurities exceeding the qualificated threshold increased to four. After storage at 60° C./75% RH for only 1 month with sealed package, the purity decreased by 2.76%, and the number of impurities exceeding the qualificated threshold increased to two. After storage at 60° C./75% RH for only 1 month with open package, the purity decreased over 6.3%, and the number of impurities exceeding the qualificated threshold increased to four. The results indicate that Form CSI of the present disclosure has outstanding chemical stability when compared with prior art amorphous.

Example 6: Stability of Form CSI at High Temperature

[0110] Approximately 10 mg of Form CSI of the present disclosure and prior art amorphous were stored at 80° C. for 2 days, and the initial and final purities were determined by UPLC, as shown in Table 11.

TABLE-US-00011 TABLE 11 Initial solid Storage Initial Final Purity form Package condition time purity purity change Form CSI Glass vial with cap 2 days 99.94% 99.95%  0.01% Amorphous Glass vial with cap 2 days 99.80% 98.64% −1.16%

[0111] The results indicate that the chemical purity of Form CSI basically remains unchanged for 2 days at 80° C., while significant degradation of amorphous is observed under the same condition. Form CSI of the present disclosure has superior stability at high temperature compared with the prior art amorphous.

Example 7: Hygroscopicity of Form CSI

[0112] Certain amounts of Form CSI of the present disclosure and prior art amorphous were sampled for hygroscopicity tests using dynamic vapor sorption (DVS) instrument. The weight change at each relative humidity is recorded during the cycle of 0% RH-95% RH-0% RH at 25° C., and the experimental results are listed in Table 12. The DVS plots of Form CSI and amorphous are as depicted in FIG. 8 and FIG. 9, respectively.

TABLE-US-00012 TABLE 12 Form Weight gain at 80% RH Form CSI 0.53% Prior art solid 3.69%

[0113] The results show that Form CSI is slightly hygroscopic with a weight gain of 0.53% at 80% RH, while prior art solid is hygroscopic with a weight gain of 3.69% at 80% RH. The hygroscopicity of Form CSI is superior to that of prior art.

[0114] Description and definition of hygroscopicity (general notice 9103 drug hygroscopicity test guidelines in 2020 edition of Chinese Pharmacopoeia, experimental condition: 25±1° C., 80±2% RH): Deliquescent: sufficient water is absorbed to form a liquid.

[0115] Very hygroscopic: increase in mass is equal to or greater than 15.0 percent.

[0116] Hygroscopic: increase in mass is less than 15.0 percent and equal to or greater than 2.0 percent.

[0117] Slightly hygroscopic: increase in mass is less than 2.0 percent and equal to or greater than 0.2 percent.

[0118] Non hygroscopic or almost non hygroscopic: increase in mass is less than 0.2 percent.

[0119] (The definition of hygroscopicity in the 10.sup.th European Pharmacopoeia 5.11 is similar to the Chinese Pharmacopoeia.)

Example 8: Preparation of Form CSI Drug Product

[0120] According to the formulation and process in Table 13 and Table 14, the drug products were prepared with an appropriate amount of Form CSI of the present disclosure. XRPD were tested before and after formulation. The XRPD overlay is shown in FIG. 10, indicating Form CSI of the present disclosure is physically stable before and after formulation process.

TABLE-US-00013 TABLE 13 No. Component mg/unit % (w/w) Function 1 Form CSI 20 20 API 2 Microcrystalline Cellulose 69.5 69.5 Fillers 3 Hydroxypropyl methyl cellulose 3.0 3.0 Adhesives 4 Crospovidone 6.0 6.0 Disintegrants 5 Colloidal silicon dioxide 0.5 0.5 Glidants 6 Magnesium stearate 1.0 1.0 Lubricants Total 100.0 100.0 /

TABLE-US-00014 TABLE 14 Stage Procedure Pre-blending According to the formulation, No. 1-6 materials were weighed into a LDPE bag and blended for 2 minutes. Simulation of The pre-mixed powders were tableted by the ENERPAC single punch manual dry granulation tablet press equipped with a round die of φ 20 mm (tablet weight: 500 ± 100 mg; pressure: 5 ± 1 KN). The obtained tablets were pulverized and sieved through a 20-mesh sieve, and then the final mixed powders were obtained. Tableting The final mixed powders were tableted by the ENERPAC single punch manual tablet press equipped with a die of φ 9 * 4 mm (tablet weight: 100 ± 10 mg; pressure: 5 ± 1 KN). Packing one tablet of drug product and 1 g of desiccant were placed in a sealed 35 cc HDPE bottle.

Example 9: The Stability of Form CSI Drug Product

[0121] To evaluate the stability of Form CSI in drug products, the packaged drug products prepared in Example 8 were stored under 25° C./60% RH and 40° C./75% RH conditions for 3 months, and the XRPD overlay of drug products before and after storage is as depicted in FIG. 11. The results indicate that the drug products of Form CSI are stable under 25° C./60% RH and 40° C./75% RH conditions for at least 3 months.

[0122] 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.