RESMETIROM CRYSTAL, PREPARATION METHOD FOR SAME, AND USES THEREOF

Abstract

Novel crystalline forms of Resmetirom (Referred to as “Compound I”), and preparation methods thereof, pharmaceutical compositions containing the crystalline forms, and uses of the crystalline forms for preparing THR-β selective agonist drugs and drugs for treating NASH and HeFH. Compared with prior arts, the provided crystalline forms of Compound I have one or more improved properties, which is of great value to the optimization and development of the drugs containing Compound I.

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Claims

1. A crystalline form CSIV of Resmetirom, wherein the X-ray powder diffraction pattern comprises characteristic peaks at 2theta values of 6.3°±0.2°, 18.1°±0.2°, and 25.3°±0.2° using CuKα radiation, ##STR00003##

2. The crystalline form CSIV according to claim 1, wherein the X-ray powder diffraction pattern comprises one or two or three characteristic peaks at 2theta values of 10.4°±0.2°, 20.6°±0.2°, and 24.6°±0.2° using CuKα radiation.

3. The crystalline form CSIV according to claim 1, wherein the X-ray powder diffraction pattern comprises one or two characteristic peaks at 2theta values of 14.5°±0.2° and 28.6°±0.2° using CuKα radiation.

4. The crystalline form CSIV according to claim 1, wherein the X-ray powder diffraction pattern is substantially as depicted in FIG. 1.

5. A process for preparing crystalline form CSIV according to claim 1, wherein the process comprises: suspending Resmetirom solid in a nitrile, stirring, separating the obtained solid and drying to obtain crystalline form CSIV.

6. The process according to claim 5, wherein said nitrile is a C2-C4 nitrile.

7. The process according to claim 5, wherein said nitrile is acetonitrile, said drying temperature is 20-100° C.

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

9. A method of activating THR-β, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline form CSIV according to claim 1.

10. A method for treating NASH and HeFH, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline form CSIV according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0059] FIG. 1 shows an XRPD pattern of Form CSIV in Example 1

[0060] FIG. 2 shows a TGA curve of Form CSIV in Example 1

[0061] FIG. 3 shows a DSC curve of Form CSIV in Example 1

[0062] FIG. 4 shows an XRPD pattern of Form CSV in Example 3

[0063] FIG. 5 shows a TGA curve of Form CSV in Example 3

[0064] FIG. 6 shows an XRPD pattern overlay of Form CSIV before and after storage with sealed conditions (from top to bottom: initial, 25° C./60% RH for 6 months, 40° C./75% RH for 6 months, 60° C./75% RH for one month)

[0065] FIG. 7 shows an XRPD pattern overlay of Form CSV before and after storage under 40° C./75% RH (from top to bottom: initial, one month with open condition, one month with sealed condition)

[0066] FIG. 8 shows an XRPD pattern overlay of Form CSV before and after storage under 60° C./75% RH (from top to bottom: initial, one week with open condition, one week with sealed condition)

[0067] FIG. 9 shows a DVS curve of Form CSIV

[0068] FIG. 10 shows a DVS curve of Form CSV

[0069] FIG. 11 shows an XRPD pattern overlay of Form CSIV before and after tableting (top: before tableting; bottom: after tableting)

DETAILED DESCRIPTION

[0070] 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.

[0071] The abbreviations used in the present disclosure are explained as follows: [0072] XRPD: X-ray Powder Diffraction [0073] DSC: Differential Scanning calorimetry [0074] TGA: Thermo Gravimetric Analysis [0075] DVS: Dynamic Vapor Sorption [0076] .sup.1H NMR: Proton Nuclear Magnetic Resonance [0077] HPLC: High Performance Liquid Chromatography

Instruments and Methods Used for Data Collection

[0078] 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: [0079] X-Ray source: Cu, Kα [0080] Kα1 (Å): 1.54060; Kα2 (Å): 1.54439 [0081] Kα2/Kα1 intensity ratio: 0.50 [0082] Voltage: 30 (kV) [0083] Current: 10 (mA) [0084] Scan range (20): from 3.0 degree to 40.0 degree

[0085] 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: [0086] Heating rate: 10° C./min [0087] Purge gas: nitrogen

[0088] 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: [0089] Heating rate: 10° C./min [0090] Purge gas: nitrogen

[0091] Dynamic Vapor Sorption (DVS) was measured via an SMS (Surface Measurement Systems Ltd.) intrinsic DVS instrument. Typical Parameters for DVS test are as follows: [0092] Temperature: 25° C. [0093] Gas and flow rate: N2, 200 mL/min [0094] RH range: 0% RH to 95% RH

[0095] 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.

[0096] The parameters for related substance detection by HPLC in the present disclosure are shown in Table 1.

TABLE-US-00001 TABLE 1 UPLC Waters UPLC H-Class plus Column Waters ACQUITY UPLC BEH C18, 2.1 mm*50 mm, 1.7 μm Mobile Phase A: 0.1% Trifluoroacetic acid (TFA) in H.sub.2O B : 0.1% TFA in Acetonitrile Gradient Time (min) % B 0.00 10 0.50 10 2.50 50 6.50 90 8.00 90 8.10 10 10.00 10 Run time 10 min Stop time 0 min Flow rate 0.5 mL/min Injection 1 μL Volume Detector 215 nm wavelength Column 40° C. Temperature Sample Room Temperature Temperature Diluent Acetonitrile: H.sub.2O = 1:1(v/v)

[0097] 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.

[0098] According to the present disclosure, Compound I and/or its salt used as raw materials include, but are not limited to solid (crystalline and amorphous), semisolid, wax, oil, liquid form or solution. Preferably, Compound I and/or its salt used as a raw material is a solid.

[0099] Compound I used in the following examples can be prepared by known methods in the prior arts, for example, the method disclosed in WO2014043706A1.

EXAMPLES

Example 1: Preparation of Form CSIV

[0100] 145.2 mg of Compound I solid was weighed into a glass vial. 1.5 mL of acetonitrile was added, and then stirred at room temperature for three days to form a suspension. The suspension was centrifuged to obtain a solid. The obtained solid was dried under vacuum at 100° C. for 3.5 hours to obtain Form CSIV.

[0101] The XRPD pattern of Form CSIV obtained in this example is shown in FIG. 1, and the XRPD data are listed in Table 2.

[0102] The TGA curve of Form CSIV is substantially as depicted in FIG. 2, which shows about 0.1% weight loss when heated to 200° C.

[0103] The DSC curve of Form CSIV is substantially as depicted in FIG. 3, which shows an exothermic peak and an endothermic peak. The peak at around 245° C. (onset temperature) is an exothermic peak of crystal transformation, and the endothermic peak at around 334° C. (onset temperature) corresponds to melting.

[0104] The .sup.1H NMR data of Form CSIV are: .sup.1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.24 (s, 1H), 7.78 (s, 2H), 7.45 (s, 1H), 3.05 (m, 1H), 1.20 (d, J=6.9 Hz, 6H)

TABLE-US-00002 TABLE 2 Relative 2θ (°) d spacing (Å) intensity % 6.26 14.13 15.68 7.88 11.21 3.93 10.40 8.50 6.46 14.48 6.12 19.94 14.57 6.08 18.19 15.32 5.78 7.55 15.51 5.72 8.63 16.39 5.41 2.88 17.08 5.19 3.69 18.10 4.90 71.67 19.65 4.52 13.55 20.60 4.31 17.34 20.98 4.23 10.25 23.21 3.83 20.11 23.85 3.73 16.01 24.58 3.62 74.11 25.31 3.52 100.00 26.08 3.42 7.51 27.11 3.29 4.29 28.55 3.13 21.78 30.05 2.97 14.73 31.02 2.88 6.02 31.67 2.83 10.20 32.94 2.72 14.56 34.03 2.63 7.50 34.76 2.58 5.80 35.50 2.53 5.77 36.76 2.45 2.33 37.43 2.40 2.42 38.80 2.32 5.18

Example 2: Preparation of Form CSIV

[0105] A certain amount of Compound I solid was put in 30 mL of acetonitrile and stirred at −20° C. for about 37.5 h. The obtained solid was separated and dried under vacuum at 50° C. for about 23.5 h to obtain Form CSIV of the present disclosure.

Example 3: Preparation of Form CSV

[0106] 2.0742 g of Compound I solid was weighed into a glass vial, 30 mL of dimethyl carbonate was added, and then stirred at 5° C. for 19 hours to form a suspension. The suspension was centrifugated and the separated solid was dried under vacuum at 50° C. for 4 hours to obtain a dry solid. 54.9 mg of the dry solid was weighed into a glass vial, 1 mL of isopropyl alcohol was added, and then stirred at 5° C. for 1.5 hours to obtain Form CSV.

[0107] The XRPD pattern of Form CSV obtained in this example is shown in FIG. 4, and the XRPD data are listed in Table 3.

[0108] The TGA curve of Form CSV is substantially as depicted in FIG. 5, which shows about 0.1% weight loss when heated to 200° C.

[0109] The .sup.1H NMR data of Form CSV are: .sup.1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.25 (s, 1H), 7.79 (s, 2H), 7.45 (s, 1H), 3.05 (m, 1H), 1.20 (d, J=6.9 Hz, 6H)

TABLE-US-00003 TABLE 3 Relative 2θ (°) d spacing (Å) intensity % 10.61 8.34 13.46 11.88 7.45 100.00 12.47 7.10 8.14 13.03 6.79 5.05 13.83 6.41 22.15 16.63 5.33 3.82 17.27 5.13 20.20 18.61 4.77 2.21 19.59 4.53 9.14 19.94 4.45 10.80 20.85 4.26 11.12 21.20 4.19 16.07 22.15 4.01 8.96 22.97 3.87 12.28 23.77 3.74 8.66 24.06 3.70 13.65 24.49 3.64 10.51 24.92 3.57 8.42 25.82 3.45 7.83 26.24 3.40 11.66 26.64 3.35 4.46 27.05 3.30 6.36 27.41 3.25 2.39 27.91 3.20 4.26 28.50 3.13 12.48 29.10 3.07 3.56 29.36 3.04 4.07 30.38 2.94 4.99 31.07 2.88 2.13 32.33 2.77 6.22 33.25 2.69 4.77 34.24 2.62 2.21 36.17 2.48 3.66 37.13 2.42 2.11 37.96 2.37 1.65 39.54 2.28 3.02

Example 4 Preparation of Form CSV

[0110] 498.8 mg of Compound I solid was weighed into a glass vial, 15 mL dimethyl carbonate was added, and then stirred at 5° C. for 17 hours to form a suspension. The suspension was centrifugated, and the separated solid was dried under vacuum at 50° C. for 3 hours to obtain a dry solid. 81.5 mg of the dry solid was weighed into a glass vial, 1 mL of isopropyl alcohol was added, and then stirred at room temperature for 14 hours to form a suspension. The formed suspension was centrifugated, and the separated solid was dried under vacuum at 40° C. for 4 hours to obtain Form CSV.

Example 5 Kinetic Solubility of Form CSIV, Form CSV and Form I

[0111] 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. SGF can be used to simulate the condition in vivo and predict the effects of eating, thus solubility in this medium is closer to that in vivo.

[0112] Approximately 5-20 mg of Form CSIV and 5-20 mg Form CSV of the present disclosure were suspended into 2.0 mL of SGF to get suspensions. After equilibrated for 1 h and 24 h, concentrations (μg/mL) of these solutions were measured by UPLC. The results are listed in Table 4. WO2020010068A1 disclosed that the solubility of Form A (Form I in U.S. Pat. No. 9,266,861B2) in SGF is 1.1 μg/mL for both 1 hour and 24 hours.

TABLE-US-00004 TABLE 4 1 hour 24 hours Crystalline Concentration Concentration form (μg/mL) (μg/mL) Form CSIV 11.7 5.5 Form CSV 7.8 9.6

[0113] According to the results in Table 4, in SGF, Form CSIV and Form CSV have higher solubility than that of Form I.

Example 6 Physical and Chemical Stability of Form CSIV and Form CSV

[0114] A certain amount of Form CSIV of the present disclosure was sealed up and 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 5, and the XRPD overlay is shown in FIG. 6.

TABLE-US-00005 TABLE 5 Conditions (sealed) Time Crystalline form Purity Initial — Form CSIV 99.80% 25° C./60% RH 6 months Form CSIV 99.79% 40° C./75% RH 6 months Form CSIV 99.76% 60° C./75% RH One month Form CSIV 99.76%

[0115] The results show that Form CSIV is stable for at least 6 months under 25° C./60% RH and 40° C./75% RH condition in sealed dish, and is stable for at least one month under 60° C./75% RH sealed condition. It can be seen that Form CSIV has good stability under long-term, accelerated and stress conditions.

[0116] A certain amount of Form CSV of the present disclosure was stored under different conditions of 40° C./75% RH and 60° C./75% RH in open and sealed dishes. Crystalline form and chemical purity were checked by XRPD and HPLC, respectively. The results are shown in Table 6, and the XRPD overlay are shown in FIG. 7 and FIG. 8.

TABLE-US-00006 TABLE 6 Conditions Time Crystalline form Purity Initial   Form CSV N/A 40° C./75% RH (open) One month Form CSV 99.81% 40° C./75% RH (sealed) Form CSV 99.85% 60° C./75% RH (open) One week Form CSV 99.86% 60° C./75% RH (sealed) Form CSV 99.87%

[0117] The results show that Form CSV is stable for at least one months under 40° C./75% RH with open and sealed dishes, and is stable for at least one week under 60° C./75% RH with open and sealed dishes. It can be seen that Form CSV has good stability under accelerated and stress conditions.

Example 7 Physical Stability of Form CSV and Form I Upon Grinding

[0118] Form CSV and Form I were 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 CSV does not change before and after grinding, while Form I almost transform into amorphous after grinding. Compared with Form I, Form CSV has better physical stability upon grinding.

Example 8 Hygroscopicity of Form CSIV and Form CSV

[0119] Dynamic vapor sorption (DVS) analyzer was applied to test hygroscopicity of Form CSIV and Form CSV with certain amount of samples. The weight gains at each relative humidity were recorded in a cycle of 0-95% RH. The results show that the weight gain of Form CSIV under 25° C./80% RH is 0.58%. Form CSIV is slightly hygroscopic, and the crystalline state remains unchanged before and after DVS. The weight gain of Form CSV under 25° C./80% RH is 0.13%. Form CSV is non hygroscopic or almost non-hygroscopic, and the crystalline state remains unchanged before and after DVS. The DVS curve of Form CSIV and Form CSV are shown in FIG. 9 and FIG. 10, respectively.

[0120] Description and definition of hygroscopicity (general notice 9103 drug hygroscopicity test guidelines in 2020 edition of Chinese Pharmacopoeia, test at 25° C.±1° C., 80% RH±2% RH. The definition of hygroscopicity in the 9th European Pharmacopoeia 5.11 is consistent with the Chinese Pharmacopoeia). [0121] deliquescent: Sufficient water is absorbed to form a solution; [0122] very hygroscopic: Increase in mass is equal to or greater than 15%; [0123] hygroscopic: Increase in mass is less than 15% and equal to or greater than 2%; [0124] slightly hygroscopic: Increase in mass is less than 2% and equal to or greater than 0.2%. [0125] non hygroscopic or almost non hygroscopic: Increase in mass is less than 0.2%.

Example 9 Compressibility of Form CSIV

[0126] ENERPAC manual tablet press was used for compression. 80 mg of Form CSIV and 80 mg of Form I were weighed and added into the dies of a φ6 mm round tooling, compressed at 10 kN manually, then stored at room temperature for 24 h. Diameter (D) and thickness (L) were tested with caliper. When elastic recovery is complete, hardness (H) was tested with an intelligent tablet hardness tester. Tensile strength of the powder was calculated with the following formula: T=2H/nDL. Under a certain force, the greater the tensile strength, the better the compressibility. The results are presented in Table 7. The XRPD pattern of Form CSIV before and after tableting is shown in FIG. 11.

TABLE-US-00007 TABLE 7 Form I Form CSIV 1 2 1 2 Thickness (mm) 2.11 2.00 2.12 2.12 Diameter (mm) 6.01 6.11 6.03 6.04 Hardness (kg) 8.7 7.9 28.3 27.7 Tensile strength (MPa) 0.44 0.41 1.41 1.38 Average tensile strength (MPa) 0.43 1.40

[0127] The results indicate that Form CSIV has better compressibility compared with Form I, and the crystalline state of Form CSIV remains unchanged before and after tableting.

[0128] Failure in hardness/friability test and tablet crack issue can be avoided due to better compressibility, making the preparation process more reliable, improving product appearance, promoting product quality. Better compressibility can increase the compression rate, thus further increases the efficiency of process. In addition, the crystalline form with good compressibility improves the feasibility of the process of direct compression and reduces the cost of research and production.

[0129] 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.