Crystal form of resmetirom, and preparation method therefor and use thereof

Abstract

The present invention relates to a new crystal form of Resmetirom and a preparation method therefor, a pharmaceutical composition containing the crystal form, and a use of the crystal form in preparation of a THR-β selective agonist pharmaceutical formulation and a pharmaceutical formulation for treating MASH and HeFH.

Description

Crystal form of resmetirole, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of crystal chemistry, and more particularly to a crystal form of resmetirole, a preparation method thereof, and uses thereof. Background Art

[0002] Heterozygous familial hypercholesterolemia (HeFH) is the most severe of lipid metabolism diseases and can lead to a variety of life-threatening cardiovascular complications. Non-alcoholic steatohepatitis (MASH) is a serious liver disease with fatty degeneration accompanied by inflammation and liver cell damage. Resmetirom, a thyroid hormone receptor THR-β selective agonist, can stimulate liver mitochondrial biogenesis in MASH individuals by reducing low-density lipoprotein cholesterol, triglycerides, and liver fat levels, thereby improving the symptoms of MASH and HeFH. Resmetirom has been approved in the United States for the treatment of MASH.

[0003] The chemical name of resmetiro is 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (hereinafter referred to as "Compound I"), and its structural formula is as follows:

[0004] A crystal is a solid formed by the orderly three-dimensional arrangement of compound molecules within a microscopic structure, forming a lattice. Polymorphism refers to the phenomenon of a single compound existing in multiple crystalline forms. A compound may exist in one or more crystalline forms, but their existence and properties cannot be precisely predicted. APIs in different crystalline forms have varying physicochemical properties, potentially leading to varying dissolution and absorption in the body, which in turn may affect the drug's clinical efficacy. This is particularly true for poorly soluble oral solid or semisolid dosage forms, where the crystalline form is crucial to product performance. Therefore, polymorphism is a crucial aspect of pharmaceutical research and quality control.

[0005] US9266861B2 discloses hydrates, anhydrous crystal form I, methyl isobutyl ketone solvate, and dimethylacetamide solvate of Compound I. WO2020010068A1 discloses various salt forms of Compound I, including free form, calcium salt, magnesium salt, sodium salt, potassium salt, and ethanolamine salt, including various free solvate forms and multiple desolvated forms. WO2022086894A1, WO2022171200A1, and CN115124515A disclose multiple crystalline forms of Compound I, primarily solvates and cocrystals.

[0006] Form I is a known solid form of Compound I with relatively good properties. The inventors of the present application repeated the preparation method disclosed in US Pat. No. 9,266,861 B2 to obtain Form I. Characterization of Form I revealed low solubility. The inventors of the present application unexpectedly discovered Form CSVII of Compound I, provided herein, which exhibits high solubility and excellent physicochemical stability. This solves the problems of the prior art and is of great significance for the development of pharmaceuticals containing Compound I.

[0007] Summary of the Invention

[0008] The present invention provides a new crystal form of Compound I, a preparation method thereof, and a pharmaceutical composition comprising the crystal form.

[0009] According to the purpose of the present invention, the present invention provides the crystalline form CSVII of Compound I (hereinafter referred to as "crystalline form CSVII").

[0010] In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 6.5°±0.2°, 7.7°±0.2°, and 23.4°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2θ of 6.5°±0.2°, 7.7°±0.2°, and 23.4°±0.2°.

[0011] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one or two of the diffraction angles 2θ of 12.2°±0.2° and 19.7°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2θ of 12.2°±0.2° and 19.7°±0.2°.

[0012] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9 of the diffraction angle 2θ values ​​of 6.5°±0.2°, 7.7°±0.2°, 23.4°±0.2°, 19.7°±0.2°, 24.2°±0.2°, 22.7°±0.2°, 25.4°±0.2°, 12.2°±0.2°, and 21.1°±0.2°.

[0013] Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII is substantially as shown in FIG1 .

[0014] Without limitation, Form CSVII is an anhydrate.

[0015] Without limitation, Form CSVII loses about 0.5% weight upon heating to 100°C.

[0016] According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSVII, which comprises: placing the solid of Compound I in methyl tert-butyl ether and stirring, separating the solid, and heating the obtained solid to obtain the crystalline form CSVII.

[0017] Furthermore, the heating end point temperature is 100°C-170°C, more preferably 140°C.

[0018] According to the purpose of the present invention, the crystal form CSVII of the present invention is used to prepare other crystal forms or salts or co-crystals of compound I.

[0019] According to the purpose of the present invention, the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of crystalline form CSVII and pharmaceutically acceptable excipients.

[0020] According to the purpose of the present invention, the present invention provides the use of the crystalline form CSVII in the preparation of a THR-β selective agonist pharmaceutical preparation.

[0021] According to the purpose of the present invention, the present invention provides the use of the crystalline form CSVII in the preparation of pharmaceutical preparations for treating MASH and HeFH. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the XRPD pattern of Form CSVII

[0023] Figure 2 is the TGA diagram of Form CSVII

[0024] Figure 3 is the DSC diagram of Form CSVII

[0025] Figure 4 is a comparison of the solubility of Form CSVII and Form I

[0026] FIG5 is a comparison of XRPD patterns of Form CSVII before and after storage under different conditions (from top to bottom: before storage, storage at 25°C / 60% RH for 6 months, storage at 40°C / 75% for 6 months, and storage at 60°C / 75% for 3 months)

[0027] Figure 6 is the XRPD pattern of Type K65

[0028] Figure 7 is the XRPD pattern of Type K65

[0029] Figure 8 is the XRPD pattern of Type K65 desolvate DETAILED DESCRIPTION

[0030] The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many variations in both materials and methods may be made without departing from the scope of the present invention.

[0031] The abbreviations used in the present invention are explained as follows:

[0032] XRPD: X-ray powder diffraction

[0033] TGA: Thermogravimetric analysis

[0034] DSC: Differential Scanning Calorimetry

[0035] HPLC: High Performance Liquid Chromatography

[0036] 1 H NMR: liquid hydrogen nuclear magnetic spectroscopy

[0037] RH: relative humidity

[0038] Instruments and methods used to collect data:

[0039] The X-ray powder diffraction patterns of the present invention were collected on a Bruker D8 ADVANCE X-ray powder diffractometer. The X-ray powder diffraction method parameters of the present invention are as follows:

[0040] X-ray source: Cu, Kα

[0041] Kα1 :1.54060;Kα2 :1.54439

[0042] Kα2 / Kα1 intensity ratio: 0.50

[0043] Voltage: 40kV

[0044] Current: 40mA

[0045] Scanning range: from 4.0 to 40.0 degrees

[0046] The TGA images of the present invention were collected on a TA Q500. The method parameters of the TGA of the present invention are as follows:

[0047] Scan rate: 10℃ / min

[0048] Shielding gas: N2

[0049] The DSC patterns of the present invention were collected on a METTLER TOLEDO DSC 3. The DSC method parameters of the present invention are as follows:

[0050] Scan rate: 10℃ / min

[0051] Shielding gas: N2

[0052] 1 H NMR data were collected on 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 prepare a 2-10 mg / mL solution.

[0053] The solubility detection method of the present invention is shown in Table 1.

[0054] Table 1

[0055] In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.

[0056] The separation is accomplished by conventional methods in the art, such as centrifugation or filtration. The centrifugation operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all solids settle to the bottom of the centrifuge tube.

[0057] The drying process is accomplished using conventional methods in the art, such as vacuum drying, forced air drying, or air drying. The drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2-48 hours, or overnight. Drying is performed in a fume hood, forced air oven, or vacuum oven.

[0058] The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

[0059] The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When tested using Cu-Kα radiation, the peak position can usually have an error of ±0.2°.

[0060] In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that X-ray powder diffraction patterns can vary depending on instrument conditions, sample preparation, and sample purity. The relative intensities of diffraction peaks in an X-ray powder diffraction pattern may also vary with experimental conditions, so the diffraction peak intensities cannot be the sole or decisive factor in determining a crystal form. In fact, the relative intensities of diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown herein are illustrative and not intended for absolute comparison. Therefore, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed by the present invention do not necessarily have to be identical to those in the Examples described herein; any crystal form having an X-ray powder diffraction pattern with characteristic peaks identical or similar to those in these patterns falls within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction patterns listed herein with those of an unknown crystal form to determine whether the two patterns reflect the same or different crystal forms.

[0061] In some embodiments, the crystalline form CSVII of the present invention is pure and substantially free of any other crystalline form. As used herein, "substantially free" when referring to a new crystalline form means that the crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more particularly less than 5% (by weight) of other crystalline forms, and even more particularly less than 1% (by weight) of other crystalline forms.

[0062] The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0063] Unless otherwise specified, the following examples were all performed at room temperature.

[0064] According to the present invention, the compound I and / or its salt as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I as a raw material is in solid form.

[0065] Compound I and / or its salts used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2020010068A1.

[0066] Example 1: Preparation of Crystalline Form CSVII

[0067] 527.6 mg of Compound I solid was weighed into a glass bottle, and 15 mL of methyl tert-butyl ether was added. After stirring at room temperature for 1 day, the solid was isolated by filtration and dried under vacuum at 25°C for 0.5 hour to obtain a dry solid. A portion of the dried solid was heated to 140°C at 10°C / min under nitrogen and held for 60 minutes. The resulting solid was cooled to room temperature to obtain Form CSVII. The resulting solid was ground in a mortar for 1 minute, retaining Form CSVII. Its XRPD pattern is shown in Figure 1, and the XRPD data are shown in Table 2.

[0068] The crystal form CSVII of the present invention was subjected to TGA, DSC and 1 H NMR test, its TGA graph is shown in Figure 2, when it is heated to 100 ° C, there is a mass loss of about 0.5%; its DSC graph is shown in Figure 3, it has an exothermic peak near 264 ° C and an endothermic peak near 333 ° C; the NMR data are: 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 7.79 (s, 2H), 7.44 (d, J = 0.7 Hz, 1H), 3.13–2.97 (m, 1H), 1.19 (d, J = 6.9 Hz, 6H), one of the active hydrogen peaks was absent.

[0069] Table 2

[0070] Example 2: Dynamic Solubility of Form CSVII

[0071] When conducting a drug solubility test to predict the in vivo performance of a drug, it is very important to simulate the in vivo conditions as much as possible. FaSSIF is a simulated intestinal fluid in the fasting state, and the solubility tested in FaSSIF is closer to the solubility in the human body environment. Take an appropriate amount of the crystal form CSVII of the present invention and the prior art crystal form I and disperse them in FaSSIF to prepare a suspension. After balancing for 5 minutes, 15 minutes and 30 minutes, filter to obtain a saturated solution, and use high performance liquid chromatography to test the concentration (mg / mL) of the sample in the saturated solution. The results are shown in Table 3 and Figure 4. The results show that the crystal form CSVII has a higher solubility in FaSSIF.

[0072] Table 3

[0073] Compound I is a poorly water-soluble drug. The crystalline form CSVII provided by the present invention has higher solubility, which helps improve drug absorption in the human body and enhances bioavailability. Furthermore, higher solubility can reduce drug dosage while maintaining drug efficacy, thereby reducing drug side effects and improving drug safety.

[0074] Example 3: Stability of Form CSVII

[0075] Appropriate amounts of the crystalline form CSVII prepared according to the present invention were placed under 25°C / 60% RH, 40°C / 75% RH, and 60°C / 75% RH, respectively. HPLC and XRPD were used to determine the purity and crystalline form. The results are shown in Table 4, and a comparative XRPD diagram is shown in Figure 5. The results demonstrate that crystalline form CSVII is stable for at least six months at 25°C / 60% RH and 40°C / 75% RH, and for at least three months at 60°C / 75% RH. This demonstrates that crystalline form CSVII maintains good stability under long-term conditions, accelerated conditions, and even more stringent conditions.

[0076] Table 4

[0077] Packaging conditions: sealed (with desiccant)

[0078] High temperatures and humidity caused by seasonal variations, regional climate differences, and environmental factors can impact the storage, transportation, and production of APIs and drug products. Therefore, the stability of APIs and drug products under accelerated and even more stringent conditions is crucial. The crystalline CSVII API exhibits excellent stability under these harsh conditions, helping to prevent degradation of drug quality due to crystal transformation or purity loss during storage.

[0079] Example 4: Preparation of Crystalline Form Type K65

[0080] 51.2 mg of Compound I solid was weighed into a vial, and 1.0 mL of a 7:1 volume ratio of acetonitrile and methanol was added. The mixture was suspended and stirred overnight at room temperature, and then centrifuged to obtain a solid. Testing confirmed that the resulting solid was Form K65 of the present invention. Its XRPD data are shown in Table 5, and the XRPD pattern is shown in Figure 6.

[0081] Table 5

[0082] Example 5: Preparation of Crystalline Form Type K65

[0083] Weigh 10.1 mg of Compound I solid into a vial, add 0.2 mL of acetonitrile, sonicate at room temperature for approximately 1 minute, and centrifuge to obtain a solid. Testing confirmed the resulting solid to be Form K65, as described herein. Its XRPD data are shown in Table 6, and the XRPD pattern is shown in Figure 7.

[0084] Table 6

[0085] Example 6: Preparation of Type K65 Desolvate

[0086] After the Type K65 obtained in Example 4 was placed at room temperature for about 5 hours, the obtained solid was detected to be the Type K65 desolvate of the present invention. Its XRPD data is shown in Table 7, and the XRPD pattern is shown in Figure 8.

[0087] Table 7

[0088] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be covered by the scope of protection of the present invention.

Claims

1. A crystalline form of compound I, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 7.7°±0.2°, and 23.4°±0.2°.

2. The crystal form according to claim 1, characterized in that Using Cu—Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of 2θ values ​​of 19.7°±0.2° and 12.2°±0.2°.

3. The crystal form according to claim 1, characterized in that Using Cu-Kα radiation, its X-ray powder diffraction pattern is basically as shown in Figure 1.

4. The method for preparing the crystal form according to claim 1, characterized in that: The method comprises: placing the solid of compound I in methyl tert-butyl ether, stirring, separating the solid, and heating to obtain the compound I.

5. A pharmaceutical composition comprising an effective therapeutic amount of the crystalline form of Compound I according to claim 1 and a pharmaceutically acceptable excipient.

6. Use of the crystalline form of Compound I described in claim 1 in the preparation of THR-β selective agonist drugs.

7. Use of the crystalline form of Compound I as claimed in claim 1 in the preparation of drugs for treating MASH and HeFH.

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