DEUCRAVACITINIB CRYSTAL FORM, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Disclosed are a crystal form of a compound (I) and a preparation method therefor, a pharmaceutical composition containing the crystal form, and the use of the crystal form in the preparation of a TYK2 inhibitor drug and a drug for treating psoriasis, systemic lupus erythematosus, and Crohn’s disease. The crystal form of compound I has one or more improved properties compared with the prior art and is of great value to the future optimization and development of the drug.

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Claims

1. A crystalline form CSIII of Compound I, wherein the X-ray powder diffraction pattern comprises characteristic peaks at 2theta values of 6.4°±0.2°, 11.3°±0.2° and 23.2°±0.2° using CuKα radiation ##STR00003##

2. The crystalline form CSIII of Compound I according to claim 1, wherein the X-ray powder diffraction pattern comprises one or two or three characteristic peaks at 2theta values of 10.1°±0.2°, 12.7°±0.2° and 19.3°±0.2° using CuKα radiation.

3. The crystalline form CSIII of Compound I according to claim 1, wherein the X-ray powder diffraction pattern comprises one or two or three characteristic peaks at 2theta values of 20.6°±0.2°, 25.9°±0.2° and 27.8°±0.2° using CuKα radiation.

4. A crystalline form CSIII of Compound I, wherein, the X-ray powder diffraction pattern is substantially as depicted in FIG. 1.

5. A process for preparing crystalline form CSIII of Compound I according to claim 1, comprising: dissolving Compound I solid in an amide solvent, evaporating to obtain crystalline form CSIII.

6. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CSIII of Compound I according to claim 1 and pharmaceutically acceptable excipients.

7. (canceled)

8. (canceled)

9. A method of inhibiting TYK2 receptor, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline form CSIII of Compound I according to claim 1.

10. A method for treating psoriasis, systemic lupus erythematosus, and Crohn’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline form CSIII of Compound I according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG. 1 shows an XRPD pattern of Form CSIII in Example 1.

[0038] FIG. 2 shows a DSC curve of Form CSIII in Example 1.

[0039] FIG. 3 shows a TGA curve of Form CSIII in Example 2.

[0040] FIG. 4 shows an XRPD pattern overlay of Form CSIII stored under different conditions (from top to bottom: initial, 25° C./60%RH for 3 months (sealed), 25° C./60%RH for 3 months(open), 40° C./75%RH for 3 months (sealed), 40° C./75%RH for 3 months (open), 60° C./75%RH for one month (sealed), 60° C./75%RH for one month (open)).

[0041] FIG. 5 shows an XRPD pattern overlay of Form CSIII before and after tableting under different pressures (from top to bottom: initial, tableting under 5 kN, tableting under 10 kN, tableting under 20 kN).

[0042] FIG. 6 shows an XRPD pattern overlay of Form CSIII before and after grinding (top: after grinding, bottom: before grinding).

[0043] FIG. 7 shows an XRPD pattern overlay of Form CSIII before and after DVS test (top: before DVS, bottom: after DVS).

DETAILED DESCRIPTION

[0044] 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.

[0045] The abbreviations used in the present disclosure are explained as follows:

[0046] XRPD: X-ray Powder Diffraction

[0047] DSC: Differential Scanning Calorimetry

[0048] TGA: Thermo Gravimetric Analysis

[0049] 1H NMR: Proton Nuclear Magnetic Resonance

[0050] HPLC: High Performance Liquid Chromatography

[0051] DVS: Dynamic Vapor Sorption

[0052] Instruments and methods used for data collection:

[0053] X-ray powder diffraction patterns in the present disclosure examples 1 and 7-8 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: [0054] X-ray source: Cu, Kα [0055] Kα1 (Å): 1.54060; Kα2 (Å): 1.54439 [0056] Kα2/Kα1 intensity ratio: 0.50 [0057] Voltage: 30 (kV) [0058] Current: 10 (mA) [0059] Scan range: from 3.0 degree to 40.0 degree

[0060] X-ray powder diffraction patterns in the present disclosure examples 4-6 were acquired by a Bruker D8 DISCOVER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure are as follows: [0061] X-ray source: Cu, Kα [0062] Ka1 (Å): 1.54060; Kα2 (Å): 1.54439 [0063] Kα2/Kα1 intensity ratio: 0.50 [0064] Voltage: 40 (kV) [0065] Current: 40 (mA) [0066] Scan range: from 4.0 degree to 40.0 degree

[0067] 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: [0068] Heating rate: 10° C./min [0069] Purge gas: N.sub.2

[0070] 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: [0071] Heating rate: 10° C./ min [0072] Purge gas: N.sub.2

[0073] Dynamic Vapor Sorption (DVS) is measured 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: [0074] Temperature: 25° C. [0075] Gas and flow rate: N.sub.2, 200 mL/min [0076] RH range: 0% RH to 95% RH

[0077] Proton nuclear magnetic resonance spectrum data (.sup.1H NMR) were collected from a Bruker Avance II DMX 400 M Hz NMR spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated chloroform to obtain a solution with a concentration of 2-10 mg/mL.

[0078] The parameters for kinetic solubility and related substance detection in the present disclosure are shown in Table 1.

TABLE-US-00001 HPLC Waters ACQUITY H-class UPLC with PDA detector Column Waters ACQUITY UPLC BEH C18, 2.1×50 mm, 1.7 .Math.m Mobile Phase A: 0.1 % Trifluoroacetic acid (TFA) in H.sub.2O (v/v) B: 0.1 % TFA in Acetonitrile (v/v) Gradient Time (min) % B 0.0 10 0.5 10 7.0 80 8.0 80 8.1 10 10.0 10 Running time 10.0 min Stop time 0 min Speed 0.5 mL/min Injection Volume 1 .Math.L Detection wavelength UV at 240 nm Column Temperature 40° C. Sample Temperature Room Temperature Diluent Acetonitrile: H.sub.2O = 50:50 (v/v)

[0079] Unless otherwise specified, the following examples were conducted at room temperature. Said “room temperature” is not a specific temperature, but a temperature range of 10-30° C.

[0080] According to the present disclosure, Compound I used as a raw material includes but not limited to solid (crystalline or amorphous), oil, liquid and solution. Preferably, Compound I used as the raw material is a solid.

[0081] Compound I used in the following examples can be prepared by known methods in the prior arts, for example, the method disclosed in WO2018183656A1.

EXAMPLES

Example 1 Preparation of Form CSIII

[0082] 10.4 mg of Compound I was weighed into a glass vial, and then 0.5 mL of N, N-dimethylformamide was added to form a clear solution. The solution was filtered and the filtrate was evaporated at 50° C. to obtain a crystalline solid.

[0083] The crystalline solid was confirmed to be Form CSIII of the present disclosure. The XRPD pattern of Form CSIII is shown in FIG. 1, and the XRPD data are listed in Table 2.

[0084] The DSC curve of Form CSIII is substantially as depicted in FIG. 2, which shows an endothermic peak at around 257° C. (onset temperature), corresponding to the melting endothermic peak.

TABLE-US-00002 Diffraction angle 2θ d spacing Intensity % 6.43 13.75 26.90 10.14 8.73 14.16 11.33 7.81 85.41 12.66 6.99 36.22 14.57 6.08 3.38 15.39 5.76 2.83 16.31 5.43 9.38 16.48 5.38 10.12 18.35 4.83 4.87 18.53 4.79 8.34 19.29 4.60 21.72 19.91 4.46 7.20 20.21 4.39 3.58 20.59 4.31 23.95 21.55 4.12 3.07 21.94 4.05 3.45 22.77 3.91 16.96 23.21 3.83 100.00 25.02 3.56 6.76 25.93 3.44 8.87 26.34 3.38 2.49 26.70 3.34 3.61 27.08 3.29 4.07 27.53 3.24 3.11 27.79 3.21 9.66 28.43 3.14 2.58 28.63 3.12 3.18

Example 2 Preparation of Form CSIII

[0085] 2.3151 g of Compound I was weighed into a glass vial, and then 140 mL of N, N-dimethylacetamide was added to form a clear solution. The solution was filtered, and 5 mL of the filtrate was evaporated at 50° C. to obtain a solid. The crude solid was dried at 50° C. The obtained solid was confirmed to be Form CSIII of Compound I.

[0086] The TGA curve of Form CSIII is substantially as depicted in FIG. 3, which shows about 0.4% weight loss when heated to 200° C.

Example 3 Preparation of Form CSIII

[0087] 58.3 mg of Compound I was weighed into a glass vial, then 4 mL of N, N-dimethylacetamide was added to form a clear solution. The solution was filtered, and the filtrate was evaporated at 50° C. to obtain a solid. The crude solid was dried at 100° C. The obtained solid was confirmed to be Form CSIII.

[0088] The .sup.1H NMR data of Form CSIII are: 1H NMR (400 MHz, CDC13) δ 10.98 (s, 1H), 9.29 (s, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.80 (dd, J = 7.9, 1.6 Hz, 1H), 7.51 (dd, J = 8.0, 1.5 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H), 1.79-1.72 (m, 1H), 1.16-1.06 (m, 2H), 0.93-0.86 (m, 2H).sub.o

Example 4 Kinetic Solubility of Form CSIII

[0089] When solubility test is used to predict the in vivo performance of a drug, it is critical to simulate in vivo conditions as closely as possible. Simulated gastric fluid (SGF), Fed-state simulated intestinal fluid (FeSSIF) and Fasted-state simulated intestinal fluid (FaSSIF) can be used to simulate the conditions in vivo and predict the effects of eating, thus solubilities in these media are closer to those in vivo.

[0090] 15-20 mg of Form CSIII of the present disclosure and 15-20 mg of Form A were suspended into 2.5 mL of SGF, 2.5 mL of FeSSIF, and 2.5 mL of FaSSIF to get suspensions. After equilibrated for 1 h and 4 h, concentrations of these solutions were measured by HPLC. The results are listed in Table 3.

TABLE-US-00003 Media Form A Form CSIII 1 hour 4 hours 1 hour 4 hours Concentration mg/mL Concentration mg/mL Concentration mg/mL Concentration mg/mL SGF 1.1141 0.6172 1.5824 1.2968 FeSSIF 0.0823 0.0688 0.1936 0.1793 FaSSIF 0.0135 0.0136 0.0490 0.0557

[0091] The results show that the solubility of Form CSIII in SGF, FeSSIF and FaSSIF are higher than those of Form A at 1 hour and 4 hours, indicating that Form CSIII has higher solubility.

Example 5 Stability of Form CSIII

[0092] Approximately 5 mg of Form CSIII samples was stored under different conditions of 25° C./60%RH, 40° C./75%RH, and 60° C./75%RH. Crystalline form and chemical purity were checked by XRPD and HPLC, respectively. The results are shown in Table 4, and the XRPD overlay is shown in FIG. 4.

[0092] TABLE-US-00004 Initial form Conditions Time Crystalline form Form CSIII Initial Form CSIII 25° C./60%RH (open) 3 months Form CSIII 25° C./60%RH (sealed) 3 months Form CSIII 40° C./75%RH (open) 3 months Form CSIII 40° C./75%RH (sealed) 3 months Form CSIII 60° C./75%RH (open) one month Form CSIII 60° C./75%RH (sealed) one month Form CSIII

[0093] The results show that Form CSIII is stable for at least 3 months at 25° C./60% RH and 40° C./75% RH. Form CSIII is stable for at least one month at 60° C./75% RH with only 0.07% changes in chemical purity. Form CSIII has good stability under long-term, accelerated and stress conditions.

Example 6 Physical Stability of Form CSIII Under Pressure

[0094] A certain amount of Form CSIII was compressed into tablets under 5 kN, 10 kN and 20 kN with suitable tableting die. Crystalline forms before and after tableting were checked by XRPD. The test results show that the crystalline state of Form CSIII does not change under different stress. The XRPD overlay is shown in FIG. 5.

Example 7 Physical Stability of Form CSIII Upon Grinding

[0095] Form CSIII sample was grounded manually for 5 minutes in a mortar. Crystalline forms before and after grinding were checked by XRPD. The results show that the crystalline state of Form CSIII does not change before and after grinding. The XRPD overlay is shown in FIG. 6.

Example 8 Physical Stability of Form CSIII Upon Humidity Change

[0096] Dynamic vapor sorption (DVS) was applied to test the stability of Form CSIII. A certain amount of Form CSIII was tested in a cycle of 0%-95%-0%RH at 25° C. The XRPD overlay of Form CSIII before and after DVS test is shown in FIG. 7. The test results show that the crystalline state of Form CSIII does not change after DVS test, indicating that Form CSIII has superior property.

Example 9 Density of Form CSIII

[0097] About 500 mg of powder were added into a 5-mL measuring cylinder and bulk volume was recorded. Then the powder was tapped for 1250 times by ZS-2E tap density tester to make it in the tightest state and the tapped volume was recorded. The bulk density and tapped density were calculated. Results of density of Form CSIII and Form A are shown in table 5.

[0097] TABLE-US-00005 Form Bulk density (g/mL) Tapped density (g/mL) Form A 0.3899 0.5199 Form CSIII 0.4276 0.5987

[0098] The results indicate that the density of Form CSIII is higher than that of Form A.

[0099] 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.