Anhydrous crystal form ch of resmetirom and preparation method therefor

Abstract

Provided in the present invention is an anhydrous crystal form CH of resmetirom. The preparation process of the crystal form is simple, and is easy and convenient to operate. The new crystal form has good stability, is easy to store during the production and circulation process, has a stable quality when used for preparing a tablet formulation, and has a certain advantage in dissolution rate compared with the original crystal form, thereby providing a good selection for the preparation of a pharmaceutical formulation thereof, and having a very important significance on drug development.

Description

A method for preparing resimetirol amorphous CH4 Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical engineering, specifically relating to Resmetirom, a drug for the treatment of non-alcoholic steatohepatitis, in its amorphous CH form and its preparation method. Background Technology

[0002] Nonalcoholic steatohepatitis (NASH), also known as metabolic steatohepatitis, is a clinical syndrome with pathological changes similar to alcoholic hepatitis but without a history of excessive alcohol consumption. It commonly affects middle-aged individuals, especially overweight and obese individuals. NASH is closely related to metabolic disorders such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia. Its main characteristic is macrovesicular steatosis of hepatocellular cells accompanied by hepatocellular damage and inflammation. In severe cases, it can develop into cirrhosis and even liver cancer, seriously affecting health and even threatening life. Currently, there are still no effective treatments available.

[0003] Resmetirom, an investigational thyroid hormone receptor beta (THR-β) agonist developed by the US biotechnology company Madrigal, can improve symptoms of NASH and HeFH (heterozygous familial hypercholesterolemia) by stimulating mitochondrial biosynthesis in individuals with non-alcoholic fatty liver disease (NAFLD) by lowering triglyceride, liver fat levels, and low-density lipoprotein cholesterol. In March 2024, the FDA announced accelerated approval for resmetirom, making it the first successful treatment for NASH.

[0004] Resmetiro's chemical name 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-triazin-6-carboxynitrile, and its structural formula is shown in Figure 1.

[0005] Figure 1. Resmetirom structure

[0006] US Patent 9266861B2 discloses the hydrate, amorphous form I, and other solvate crystal forms of resimetidine; PCT Patent WO2021063367A1 discloses other hydrate crystal forms of resimetidine, CSI. The crystal form I reported in US Patent 9266861B2 requires a complex process involving recrystallization of a dimethylacetamide solvent compound to convert it to a hydrate crystal form, followed by two subsequent crystallizations. The CSI crystal form disclosed in PCT Patent WO2021063367A1 exhibits approximately 7.6% weight loss upon heating to 150 degrees Celsius, indicating that this crystal form is a hydrate, which presents a challenge for formulation development.

[0007] Summary of the Invention

[0008] To provide more options for the formulation application of resimetiro, the present invention provides a new crystal form of resimetiro, amorphous CH. Compared with the previously reported crystal forms, the preparation method of this crystal form is simpler, more reproducible, and more suitable for scale-up production. Furthermore, compared with crystal form I, it has better dissolution for tablet preparation, giving it an advantage in the formulation application of resimetiro.

[0009] To achieve the objective of the invention, the technical solution of the present invention is as follows:

[0010] A crystalline CH-type resimemetiro has characteristic peaks at 5.62, 11.36, 17.20, 18.78, 21.48, and 23.16 in its X-ray powder diffraction pattern obtained using Cu-Kα radiation, with an error range of ±0.2° for the 2Theta value.

[0011] Furthermore, the retimetirol amorphous CH, as measured by Cu-Kα radiation, exhibits characteristic peaks at 9.42, 14.76, 15.34, 16.58, 25.54, and 27.38 in its X-ray powder diffraction pattern, with an error range of ±0.2°.

[0012] Furthermore, the retimetilol amorphous CH, as measured by Cu-Kα radiation, contains six or more characteristic peaks at 5.62, 9.42, 11.36, 14.76, 16.58, 17.20, 18.78, 21.48, 23.1, 25.54, and 27.38 in its X-ray powder diffraction pattern, with the 2Theta value having an error range of ±0.2°.

[0013] This invention also provides a method for preparing resimetidine amorphous CH, which adopts the following technical solution:

[0014] A method for preparing resmetiro amorphous CH involves using crude resmetiro as a starting material. An alkali or carbonate is added to water or a mixed solvent containing an organic solvent and water to dissolve the resmetiro. The solution is filtered, and the filtrate is collected. Then, an acid equivalent to 0.3–3.0 molar amounts of resmetiro is added to the filtrate to precipitate a solid. Crystallization is carried out under stirring within a specific temperature range. The wet product is separated by centrifugation or filtration and dried to obtain resmetiro amorphous CH. The molar amount of acid used is 0.3–3.0 molar amounts of crude resmetiro.

[0015] Furthermore, in the mixed solvent formed by the organic solvent and water, the organic solvent is selected from methanol, ethanol, isopropanol, acetone, tetrahydrofuran, or acetonitrile; the base or carbonate is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, or sodium carbonate; the acid is selected from hydrochloric acid, acetic acid, or citric acid; and the recrystallization temperature range is 100 to -20°C.

[0016] The non-crystalline CH form of resimetidine provided by this invention has a simple preparation process and is easy to operate. The quality indicators of the obtained crystal form remain basically unchanged in the accelerated stability test, which indicates that the new crystal form of the product has good stability and is easy to preserve during the production and distribution process. It is used to prepare tablet formulations with stable product quality and has a certain advantage in dissolution rate compared with the original crystal form, providing a good choice for the preparation of drug formulations and having great significance for drug development. Attached Figure Description

[0017] Figure 1 shows the PXRD pattern of the CH crystal form;

[0018] Figure 2 shows the TGA diagram of the CH crystal form;

[0019] Figure 3 shows the PXRD patterns of the stability of crystalline CH under light and high temperature conditions. Detailed Implementation

[0020] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0021] In the following embodiments, the test methods are generally carried out under conventional conditions or conditions recommended by the manufacturer. The crude resimeltiro was prepared according to existing technology, and its preparation method can be found in PCT patent WO2014043706A. Other raw materials and solvents were obtained commercially available.

[0022] The X-ray powder diffraction pattern described in this invention was acquired using a D8 ADVANCE X-ray powder diffractometer at room temperature (approximately 25°C). The detection method parameters are as follows:

[0023] The differential scanning calorimetry (DSC) images described in this invention are acquired on a TAQ2000, and the detection method parameters are as follows:

[0024] The thermogravimetric analysis (TGA) chart described in this invention is acquired on a TAQ5000, and the detection method parameters are as follows:

[0025] Example 1

[0026] Add crude resmetiro (45.71 g, 95.20% purity, 100.0 mmol) to a three-necked flask, add 457 mL of water and sodium hydroxide (4.40 g, 110 mmol), stir to dissolve, filter to remove trace amounts of insoluble matter, collect the filtrate, heat to 55–60 °C, add 5% dilute hydrochloric acid (87.5 g, 120 mmol), keep warm and stir for 1 hour, slowly cool to 0–10 °C to crystallize, keep warm and stir for 1 hour, centrifuge, collect the solid and dry to obtain resmetiro amorphous form CH (40.47 g, purity 99.90%, yield 92.9%).

[0027] The X-ray powder diffraction data of the new crystal form obtained in this embodiment are shown in Table 1, its PXRD pattern is shown in Figure 1, and its TGA pattern is shown in Figure 2.

[0028] Table 1. X-ray powder diffraction data of crystal type A obtained in Example 1.

[0029] In Example 1, sodium hydroxide can be replaced by potassium hydroxide, lithium hydroxide, potassium carbonate or sodium carbonate, and hydrochloric acid can be replaced by acetic acid or citric acid.

[0030] Example 2

[0031] Add crude resmetiro (45.71 g, 95.20% purity, 100.0 mmol) to a three-necked flask, along with 45.7 mL of anhydrous methanol, 457 mL of water, and 15.20 g (110 mmol) of potassium carbonate. After stirring to dissolve, filter to remove trace amounts of insoluble matter. Collect the filtrate, heat it to 55–60 °C, and slowly add acetic acid (12.01 g, 200 mmol) to acidify it. Keep it warm and stir for 1 hour, then slowly cool it to 0–10 °C to crystallize. Keep it warm and stir for 1 hour, centrifuge, collect the solid, and dry it to obtain resmetiro crystalline form CH (38.27 g, 99.95% purity, 87.9% yield).

[0032] In Example 2, methanol can be replaced by ethanol, isopropanol, acetone, tetrahydrofuran, or acetonitrile.

[0033] Examples 3 to 9

[0034] The experiment was conducted with varying feed amounts according to Example 2, and the results are as follows:

[0035] The products of Examples 2-9 were tested by XRPD, and the results were consistent with those of Example 1, all of which were resimetiro non-crystalline CH.

[0036] Stability evaluation of crystalline CH

[0037] The crystal stability of CH in Example 1 was evaluated. The stability experiment showed that the crystal form of CH remained basically unchanged under high temperature and light conditions.

[0038] Light stability: The stability of the samples was evaluated by placing them under light conditions of 4500±500 lux. Samples were taken at 7 days and 14 days to test PXRD, purity and moisture.

[0039] High temperature stability: The samples were placed at 60℃ to evaluate their high temperature stability. Samples were taken at 7 days and 14 days to test PXRD, purity and moisture content.

[0040] The PXRD patterns of the stability of crystalline CH under light and high temperature conditions are shown in Figure 3.

[0041] Experimental results show that crystal form A is stable under light and high temperature conditions, and its quality indicators such as chemical purity and moisture content are basically stable.

[0042] Table 2. Stability of A-type crystal under high temperature light irradiation obtained in Example 1

[0043] Comparative test

[0044] The crystalline CH and crystalline I samples prepared in Example 1 were mixed with FaSSIF (simulating intestinal fluid under fasting conditions) to prepare saturated solutions (FaSSIF preparation: add 3 mmol of sodium taurocholate, 0.75 mmol of lecithin, 3.9 g of potassium dihydrogen phosphate, and 7.7 g of potassium chloride to 1 L of water, and adjust the pH to approximately 6.5 with sodium hydroxide). Samples were taken at fixed time points, and the content of the samples in the saturated solutions was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 3.

[0045] Table 3: Solubility in simulated intestinal fluid

[0046] The results showed that in FaSSIF, crystalline form CH exhibited significantly superior solubility compared to crystalline form I, with a 75% increase in solubility, producing unexpected effects. The intestine is the primary site of drug absorption; the significant increase in the solubility of crystalline form CH in FaSSIF is beneficial for improving intestinal absorption and increasing the bioavailability of resimeltiro.

Claims

1. A retrimetrol amorphous CH, characterized in that... The X-ray powder diffraction pattern obtained using Cu-Kα rays shows characteristic peaks at 5.62, 11.36, 17.20, 18.78, 21.48, and 23.16, with an error range of ±0.2°.

2. The resimelotirone amorphous CH according to claim 1, characterized in that... The X-ray powder diffraction pattern obtained using Cu-Kα rays shows characteristic peaks at 9.42, 14.76, 15.34, 16.58, 25.54, and 27.38, with an error range of ±0.2°.

3. The resimelotirol amorphous CH according to claim 2, characterized in that... The X-ray powder diffraction pattern obtained using Cu-Kα rays contains six or more characteristic peaks at 5.62, 9.42, 11.36, 14.76, 16.58, 17.20, 18.78, 21.48, 23.1, 25.54, and 27.38, with an error range of ±0.2°.

4. A method for preparing resimeltiro amorphous CH, characterized in that... Using crude resmetiro as the starting material, an alkali or carbonate is added to water or a mixed solvent containing an organic solvent and water to dissolve it. The mixture is then filtered, and the filtrate is collected. Acid is added to the filtrate to precipitate a solid. The solid is stirred and crystallized within a certain temperature range. The wet product is separated by centrifugation or filtration and dried to obtain amorphous resmetiro CH. The molar amount of acid used is 0.3 to 3.0 equivalents of the molar amount of crude resmetiro.

5. The method for preparing retrimetrol amorphous CH according to claim 4, characterized in that... The solvent is a mixture of an organic solvent and water, wherein the organic solvent is selected from methanol, ethanol, isopropanol, acetone, tetrahydrofuran or acetonitrile; the base or carbonate is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or sodium carbonate; and the acid is selected from hydrochloric acid, acetic acid or citric acid.

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