Rosmeltirol crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of crystal form medicine molecules, and particularly relates to a rosmeltirol crystal form and a preparation method thereof. The invention provides two crystal forms of rosmeltirol, and the crystal forms of rosmeltirol-nicotinamide-methanol have characteristic peaks at least at the positions of 6.2 + / -0.2 degrees, 14.4 + / -0.2 degrees, 21.5 + / -0.2 degrees, 22.4 + / -0.2 degrees, 24.3 + / -0.2 degrees, 26.5 + / -0.2 degrees and 27.4 + / -0.2 degrees in an X-ray diffraction spectrum represented by 2 theta by using Cu-K alpha radiation; according to the crystal form, Cu-K alpha radiation is used, and an X-ray diffraction spectrum represented by 2 theta has characteristic peaks at least at the positions of 12.0 + / -0.2 degrees, 15.6 + / -0.2 degrees, 17.8 + / -0.2 degrees, 19.9 + / -0.2 degrees, 20.8 + / -0.2 degrees and 28.1 + / -0.2 degrees. The rosmeltirol crystal form is good in stability, almost free of hygroscopicity, high in solubility and high in medicinal value.

Description

Technical Field

[0001] This invention belongs to the field of crystal drug molecular technology, specifically relating to the crystal form of resimeltiro and its preparation method. Background Technology

[0002] Resmetirom (CAS: 920509-32-6), chemically named 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, has the following structural formula: .

[0003] Resmetiro is a THR (thyroid hormone receptor)-β agonist that regulates lipid metabolism by mimicking the effects of thyroid hormones in the liver, thereby reducing fat accumulation in the liver. On March 14, 2024, the U.S. FDA granted accelerated approval to resmetiro (brand name: Rezdiffra) in combination with diet and exercise for the treatment of adult patients with moderate to severe liver fibrosis (F2 to F3 stages) of noncirrhotic nonalcoholic steatohepatitis (NASH) / metabolic dysfunction-related steatohepatitis (MASH), making it the world's first marketed NASH / MASH treatment.

[0004] A crystal is a solid formed by the three-dimensional ordered arrangement of compound molecules in a lattice within a microscopic structure. Polymorphism refers to the phenomenon that a compound exists in multiple crystalline forms. A compound may exist in one or more crystal forms, but its specific existence and properties cannot be predicted. Different crystal forms of active pharmaceutical ingredients (APIs) have different physicochemical properties, which may lead to different dissolution and absorption rates in the body, thus affecting the clinical efficacy of the drug to some extent. This is especially true for some poorly soluble oral solid or semi-solid dosage forms, where crystal form is crucial to product performance. In addition, the physicochemical properties of crystal form are critical to the manufacturing process. Therefore, polymorphism is an important aspect of drug research and drug quality control.

[0005] CN105008335A discloses the marketable crystal form I of resimetidine, which requires sequential crystal transformation steps involving dimethylacetamide solvate, dihydrate, and methyl isobutyl ketone solvate. This process is complex, resulting in a purity of only 96.4%, low solubility (equilibrium solubility in FaSSGF medium at 1h and 24h of 1h), high hygroscopicity, and poor grinding stability (becoming amorphous). CN112638904A discloses various salt forms, solvates, and desolvates of resimetidine. However, methyl isobutyl ketone solvate, acetonitrile solvate, acetic acid solvate, and isopropyl acetate solvate all transform into desolvates at 30°C, exhibiting poor stability. Furthermore, the desolvates are mixed crystals composed of multiple crystal forms. Other solvates or salt forms disclosed in the patent also undergo crystal transformation under different temperatures and humidity levels, making them unsuitable for stable formulation development. WO2021129465A1, WO2021063367A1, WO2025011259A1, and CN116171275A disclose crystal forms CSIV, CSV, CSVI, CSI, and CSVII, respectively, which have improved physical and chemical properties to some extent compared to crystal form I.

[0006] Although numerous crystal forms have been disclosed in the aforementioned literature, systematic research on these crystal forms still needs improvement. A solid crystal form is still required to provide superior physicochemical properties (such as stability and solubility) without altering the pharmacological properties. This would provide better evidence for the application of resimeltiro in drug therapy, thereby maximizing its medicinal value. Summary of the Invention

[0007] In view of the shortcomings of the prior art, the present invention aims to provide new crystal forms of resmetrol, including resmetrol-nicotinamide-methanol crystal form and resmetrol-isonicotinamide-acetone crystal form. The resmetrol crystal forms of the present invention exhibit good stability, are almost non-hygroscopic, and have high solubility, thus possessing significant medicinal value.

[0008] In a first aspect, the present invention provides a resmetiro-nicotinamide-methanol crystal form, wherein the molar ratio of resmetiro, nicotinamide, and methanol in the crystal form is 1:1:1.

[0009] The described resmetrol-nicotinamide-methanol crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction spectrum (denoted as 2θ) at at least 6.2±0.2°, 14.4±0.2°, 21.5±0.2°, 22.4±0.2°, 24.3±0.2°, 26.5±0.2°, and 27.4±0.2°.

[0010] The described resimetiro-nicotinamide-methanol crystal form, when subjected to Cu-Kα radiation, exhibits X-ray diffraction characteristics expressed in 2θ as follows:Figure 1 The characteristic peaks shown are...

[0011] The crystallographic parameters of the resimetiro-nicotinamide-methanol crystal form are: monoclinic system, space group [missing information]. P2 1 / c The unit cell parameters are: a = 15.5769(2) Å, b = 13.55650(10) Å, c = 13.2628(2) Å, α = 90.00°, β = 108.578(2)°, γ = 90.00°, and the unit cell volume V = 2654.74(6) Å. 3 .

[0012] In a second aspect, the present invention also provides a method for preparing the resmetiro-nicotinamide-methanol crystal form, comprising the following steps: adding resmetiro and nicotinamide to a mixed solution of methanol and organic solvent A, heating and stirring, dissolving and reacting, cooling and crystallizing, filtering, and drying to obtain the final product.

[0013] The organic solvent A is selected from one or more of acetonitrile, ethanol, isopropanol, n-butanol, and acetone.

[0014] Preferably, the organic solvent A is one or a combination of ethanol, acetonitrile, or ethanol.

[0015] The volume ratio of methanol to organic solvent A is 1:1~3.

[0016] The mass-to-volume ratio of resmetrol and methanol is 43.5:0.5~3, where mass is expressed in mg and volume in ml.

[0017] Preferably, the mass-to-volume ratio of resmetiro to methanol is 43.5:2, where mass is expressed in mg and volume in ml.

[0018] The molar ratio of resmetiro to nicotinamide is 1:1 to 2.5.

[0019] Preferably, the molar ratio of resmetiro to nicotinamide is 1:1 to 2.

[0020] The heating temperature is 50~60℃.

[0021] The dissolution and reaction time is 2-5 hours.

[0022] The crystallization temperature is 5~25℃.

[0023] Preferably, the crystallization temperature is 5~10℃.

[0024] The crystallization time is 36-72 hours.

[0025] The drying temperature is 50~70℃.

[0026] The drying time is 8-12 hours.

[0027] In a third aspect, the present invention provides a resmetrol-isonicotinamide-acetone crystal form, wherein the molar ratio of resmetrol, isonicotinamide and acetone in the crystal form is 1:1:1.

[0028] The described resmetrol-isonicotinamide-acetone crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction spectrum (denoted as 2θ) at at least 12.0±0.2°, 15.6±0.2°, 17.8±0.2°, 19.9±0.2°, 20.8±0.2°, and 28.1±0.2°.

[0029] The described resmetrol-isonicotinamide-acetone crystal form, when subjected to Cu-Kα radiation, exhibits X-ray diffraction characteristics expressed in 2θ as follows: Figure 4 The characteristic peaks shown are...

[0030] The crystallographic parameters of the resmetiro-isonicotinamide-acetone crystal form are: monoclinic system, space group [missing information]. P2 1 / c The unit cell parameters are: a = 22.8739(3) Å, b = 8.89830(10) Å, c = 14.7273(2) Å, α = 90.00°, β = 105.3290(10)°, γ = 90.00°, and the unit cell volume V = 2890.93(6) Å. 3 .

[0031] In a fourth aspect, the present invention provides a method for preparing the resmetiro-isonicotinamide-acetone crystal form, comprising the following steps: adding resmetiro and isonicotinamide to a mixed solution of acetone and organic solvent B, heating and stirring, dissolving and reacting, cooling and crystallizing, filtering, and drying to obtain the crystal.

[0032] The organic solvent B is selected from one or more of methanol, acetonitrile, ethanol, isopropanol, and n-butanol.

[0033] Preferably, organic solvent B is one of methanol, ethanol, or a combination thereof.

[0034] The volume ratio of acetone to organic solvent B is 1:0.2~1.

[0035] The mass-to-volume ratio of resmetiro to acetone is 43.5:3~5, where mass is expressed in mg and volume in ml.

[0036] The molar ratio of resmetiro to isonicotinamide is 1:1.5~3.

[0037] The heating temperature is 40~60℃.

[0038] The dissolution and reaction time is 2-5 hours.

[0039] The crystallization temperature is 0~10℃.

[0040] Preferably, the crystallization temperature is 5~10℃.

[0041] The crystallization time is 36-72 hours.

[0042] The drying temperature is 50~70℃.

[0043] The drying time is 8-12 hours.

[0044] In a fifth aspect, the present invention provides a pharmaceutical composition comprising the resmetiro-nicotinamide-methanol crystal form / resmetiro-isonicotinamide-acetone crystal form and other pharmaceutically acceptable components.

[0045] The other components include other active ingredients, excipients, fillers, diluents, binders, disintegrants, lubricants, etc., that can be used in combination.

[0046] The pharmaceutical composition is prepared by using standard and conventional techniques to combine the resmetiro-nicotinamide-methanol crystal form / resmetiro-isonicotinamide-acetone crystal form of the present invention with other pharmaceutically acceptable components to prepare a usable dosage form.

[0047] The dosage forms of the pharmaceutical composition include, but are not limited to, tablets, capsules, granules, and pills.

[0048] Crystal structure confirmed:

[0049] (1) X-ray powder diffraction detection

[0050] X-ray powder diffraction testing instrument and conditions: X-ray powder diffractometer PANalytical E; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45 kV, current 40 mA; divergence slit: 1 / 4; anti-scattering slit: 1; Solar slit: 0.04 rad; step size: 0.5 s; scanning range: 3–50°. Specific results are shown in Tables 1 and 2.

[0051] Table 1. Main X-ray powder diffraction characteristic peaks of the resimetiro-nicotinamide-methanol crystal form

[0052] The resmetrol-nicotinamide-methanol crystal form samples prepared in the examples all have the same X-ray powder diffraction pattern.

[0053] Table 2. Main X-ray powder diffraction characteristic peaks of the resimetiro-isonicotinamide-acetone crystal form

[0054] The resmetrol-isonicotinamide-acetone crystal form samples prepared in the examples all have the same X-ray powder diffraction pattern.

[0055] (2) Single crystal diffraction detection

[0056] X-ray crystal data were collected on a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K using CuKa radiation and collected in an ω-scan manner. L p-correction. The crystal structure was calculated using the ShelXT program in the Olex-2 software, and the structure parameters and atom types were corrected using the least squares method in the ShelXL program. The positions of all hydrogen atoms were obtained using geometric calculations and the Fourier difference method. Specific crystallographic data are shown in Tables 3 and 4.

[0057] Table 3. Main crystallographic data of resimetiro-nicotinamide-methanol crystal forms

[0058] Crystallographic data of the resimetidine-nicotinamide-methanol crystal form prepared in this invention (Table 3): Monoclinic system, space group P2 1 / c The unit cell parameters are: a = 15.5769(2) Å, b = 13.55650(10) Å, c = 13.2628(2) Å, α = 90.00°, β = 108.578(2)°, γ = 90.00°, V = 2654.74(6) Å. 3 The molecular formula is: C 24 H 22 Cl2N8O6, molecular weight: 589.39. The ORTEP diagram and hydrogen bond diagram of the resimetidine-nicotinamide-methanol crystal form of this invention are attached. Figure 2 , 3 As shown.

[0059] Table 4. Main crystallographic data of resimetiro-isonicotinamide-acetone crystal forms

[0060] Crystallographic data of the resimetidine-isonicotinamide-acetone crystal form prepared in this invention (Table 4): Monoclinic system, space group P2 1 / cThe unit cell parameters are: a = 22.8739(3) Å, b = 8.89830(10) Å, c = 14.7273(2) Å, α = 90.00°, β = 105.3290(10)°, γ = 90.00°, V = 2890.93(6) Å. 3 Molecular formula: C 26 H 24 Cl2N8O6, molecular weight: 615.43. The ORTEP diagram and hydrogen bond diagram of the crystalline form of resmetidine-isonicotinamide-acetone of this invention are attached. Figure 5 , 6 As shown.

[0061] Compared with the prior art, the present invention has the following advantages: it provides for the first time the crystal forms of resmetiro-nicotinamide-methanol and resmetiro-isonicotinamide-acetone and their preparation methods; the obtained crystal forms have improved solubility, which helps to improve oral bioavailability; and they have good stability, almost no hygroscopicity, which makes them easy to apply to formulations and have strong pharmaceutical value; the preparation method is simple to operate, the crystallization process is easy to control, and the reproducibility is good. Attached Figure Description

[0062] Figure 1 X-ray powder diffraction pattern of the retrimetrol-nicotinamide-methanol crystal form;

[0063] Figure 2 ORTEP diagram of the crystal form of resimetirox-nicotinamide-methanol;

[0064] Figure 3 Hydrogen bond diagram of the retrimetiro-nicotinamide-methanol crystal form;

[0065] Figure 4 X-ray powder diffraction pattern of the retrimetrol-isonicotinamide-acetone crystal form;

[0066] Figure 5 ORTEP diagram of the crystalline form of resimetirox-isonicotinamide-acetone;

[0067] Figure 6 Hydrogen bond diagram of the retrimetiro-isonicotinamide-acetone crystal form. Detailed Implementation

[0068] The present invention will be further described below through specific embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0069] Example 1

[0070] 435 mg of resimetirox and 250 mg of nicotinamide were added to a mixed solution of 40 ml of ethanol and 20 ml of methanol. The mixture was heated to 60°C and stirred to dissolve and react for 3 hours. The temperature was then slowly lowered to 5-10°C, and the mixture was allowed to stand at the controlled temperature for 48 hours to crystallize. The crystals were then filtered and dried in an oven at 50°C for 12 hours to obtain the resimetirox-nicotinamide-methanol crystal form with a yield of 89.36% and a purity of 99.75%.

[0071] Example 2

[0072] 435 mg of resmetiro and 122 mg of nicotinamide were added to a mixed solution of 30 ml acetonitrile and 10 ml methanol. The mixture was heated to 50°C and stirred to dissolve and react for 5 h. The temperature was then slowly lowered to 5-10°C and allowed to stand for crystallization for 36 h. The crystals were then filtered and dried in an oven at 50°C for 10 h to obtain the resmetiro-nicotinamide-methanol crystal form with a yield of 86.54% and a purity of 99.52%.

[0073] Example 3

[0074] 435 mg of resmetiro and 183 mg of nicotinamide were added to a mixed solution of 20 ml acetonitrile and 20 ml methanol. The mixture was heated to 60°C and stirred to dissolve and react for 4 hours. The temperature was then slowly lowered to 5-10°C, and the mixture was allowed to stand at the controlled temperature for crystallization for 48 hours. The crystals were then filtered and dried in an oven at 50°C for 12 hours to obtain the resmetiro-nicotinamide-methanol crystal form, with a yield of 88.03% and a purity of 99.34%.

[0075] Example 4

[0076] 435 mg of resmetiro and 250 mg of nicotinamide were added to a mixed solution of 40 ml isopropanol and 20 ml methanol. The mixture was heated to 60°C and stirred to dissolve and react for 3 hours. The temperature was then slowly lowered to 5-10°C, and the mixture was allowed to stand at the controlled temperature for 48 hours to crystallize. The crystals were then filtered and dried in an oven at 50°C for 12 hours to obtain the resmetiro-nicotinamide-methanol crystal form, with a yield of 76.48% and a purity of 98.70%.

[0077] Example 5

[0078] 435 mg of resmetiro and 253 mg of isonicotinamide were added to a mixed solution of 20 ml methanol and 40 ml acetone. The mixture was heated to 50°C and stirred to dissolve and react for 3 hours. The temperature was then slowly lowered to 5-10°C, and the mixture was allowed to stand at the controlled temperature for 48 hours to crystallize. The crystals were then filtered and dried in an oven at 50°C for 10 hours to obtain the resmetiro-isonicotinamide-acetone crystal form, with a yield of 91.68% and a purity of 99.83%.

[0079] Example 6

[0080] 435 mg of resmetiro and 183 mg of isonicotinamide were added to a mixed solution of 30 ml ethanol and 30 ml acetone. The mixture was heated to 50°C and stirred to dissolve and react for 3 hours. The temperature was then slowly lowered to 5-10°C, and the mixture was allowed to stand at the controlled temperature for 48 hours to crystallize. The crystals were then filtered and dried in an oven at 50°C for 10 hours to obtain the resmetiro-isonicotinamide-acetone crystal form, with a yield of 88.72% and a purity of 99.47%.

[0081] Example 7

[0082] 435 mg of resmetiro and 365 mg of isonicotinamide were added to a mixed solution of 10 ml methanol and 50 ml acetone. The mixture was heated to 55°C and stirred to dissolve and react for 3 hours. The temperature was then slowly lowered to 5-10°C, and the mixture was allowed to stand at the controlled temperature for 48 hours to crystallize. The crystals were then filtered and dried in an oven at 50°C for 12 hours to obtain the resmetiro-isonicotinamide-acetone crystal form, with a yield of 89.83% and a purity of 99.52%.

[0083] Comparative Example 1

[0084] 500 mg of resimetiro was added to 2.5 ml of 2-methoxyethanol and stirred at 80°C for 30 min to completely dissolve the solid. Then, 140.5 mg of nicotinamide was added, and stirring was continued at 80°C for 30 min to completely dissolve the solid. The mixture was then vacuum dried at 45°C for 18 h. 5.12 ml of dichloromethane was added, and the resulting slurry was stirred at 25°C for 18 h. The solid was separated by centrifugation and vacuum dried at 45°C for 18 h to obtain resimetiro crystals with a purity of 99.52%.

[0085] Comparative Example 2

[0086] 200 mg of resmetiro was dissolved in 20 ml of acetone by sonication, filtered, and 54 ml of n-heptane was added with stirring to form a suspension. The suspension was stirred at room temperature for 3 hours, centrifuged, and vacuum dried at room temperature for 24 hours to obtain resmetiro crystal form with a purity of 99.73%.

[0087] Comparative Example 3

[0088] 435 mg of resimetiro was added to 6 ml of methanol to obtain a suspension. The suspension was stirred at room temperature for 2 days and then filtered to obtain resimetiro crystals with a purity of 98.95%.

[0089] Comparative Example 4

[0090] 435 mg of resimetirox and 250 mg of nicotinamide were added to a mixed solution of 40 ml of 2-methoxyethanol and 20 ml of methanol. The mixture was heated to 60°C with stirring, and after dissolution and reaction for 3 hours, the temperature was slowly lowered to 5-10°C. Crystallization was allowed to occur under controlled temperature for 48 hours, followed by filtration and drying in a 50°C oven for 12 hours. The desired crystals could not be obtained. Figure 1The X-ray powder diffraction pattern shown indicates the crystal form of resmetrol-nicotinamide-methanol.

[0091] Comparative Example 5

[0092] 435 mg of resmetiro and 253 mg of isonicotinamide were added to a mixed solution of 20 ml methanol and 40 ml acetone. The mixture was heated to 50°C and stirred to dissolve and react for 3 hours. The temperature was then slowly lowered to 20-25°C, and the mixture was allowed to stand for 48 hours to crystallize. After filtration, the crystals were dried in a 50°C oven for 10 hours. The desired crystals could not be obtained. Figure 4 The X-ray powder diffraction pattern shown indicates the crystal form of resmetrol-isonicotinamide-acetone.

[0093] Verification Example 1: Solubility Test

[0094] 1. Test materials: Resmetiro crystal forms of Examples 1, 6 and Comparative Examples 1-3.

[0095] 2. Experimental Method: Using water, FaSSGF, and FaSSIF as dissolving media, 5 mg of the crystal form was dispersed in 2.0 ml of each of the above media to prepare suspensions. After equilibration at 37℃ for 0.5 h, 1 h, and 24 h, the suspensions were filtered. The content of the sample in the solution (μg / ml, calculated as resmetiro) was determined by ultra-high performance liquid chromatography. Three parallel experiments were performed, and the average value was taken.

[0096] 3. Experimental results: The experimental results are shown in Table 5.

[0097] Table 5. Solubility test results (μg / ml)

[0098] Through experiments, the solubility of the resmetiro-nicotinamide-methanol crystal form and the resmetiro-isonicotinamide-acetone crystal form of the present invention in water, FaSSGF, and FaSSIF is significantly better than that of the comparative crystal form.

[0099] Verification Example 2: Hygroscopicity Test

[0100] 1. Test materials: Resmetiro crystal forms of Examples 1, 6 and Comparative Examples 1-3.

[0101] 2. Experimental Method: Take a dry, stoppered glass weighing bottle and place it in an artificial climate chamber at a temperature of 25±1℃ and a relative humidity of 80±2% one day before the experiment. Weigh a certain amount of crystal form and spread it evenly (1 mm thick) in the weighing bottle. After storing it open in the artificial climate chamber at 25±1℃ / 80±2%RH for 24 hours, weigh the solids and calculate the weight gain ratio. Perform three parallel experiments and take the average value of the results.

[0102] Description of hygroscopic characteristics and definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 9103 - Guidelines for Hygroscopicity Testing of Drugs, Experimental conditions: 25℃±1℃, 80%±2% relative humidity): Deliquescence: Absorbs sufficient water to form a liquid. Highly hygroscopic: Weight gain due to hygroscopic absorption is not less than 15%. Hygroscopic: Weight gain due to hygroscopic absorption is less than 15% but not less than 2%. Slightly hygroscopic: Weight gain due to hygroscopic absorption is less than 2% but not less than 0.2%. No or almost no hygroscopicity: Weight gain due to hygroscopic absorption is less than 0.2%.

[0103] 3. Test results: The test results are shown in Table 6.

[0104] Table 6 Results of Hygroscopicity Test

[0105] Through testing, both the resmetiro-nicotinamide-methanol crystal form and the resmetiro-isonicotinamide-acetone crystal form of this invention have almost no hygroscopic properties.

[0106] Verification Example 3: Influencing Factor Experiment

[0107] 1. Experimental materials: Resmetiro crystal forms prepared in Examples 1, 6 and Comparative Examples 1-3.

[0108] 2. Experimental Method: Appropriate amounts of the resimetidine crystals prepared in Example 1 and Comparative Examples 1 and 2 were placed in open containers under conditions of light (4500 Lux), high temperature (60℃), and high humidity (RH 90%). Samples were taken on days 10 and 30, and the purity (%) was determined by HPLC. The experiment was performed in triplicate, and the average value was taken.

[0109] 3. Test results: The test results are shown in Table 7.

[0110] Table 7. Results of the experiment on influencing factors

[0111] Through testing, the resmetrol-isonicotinamide-acetone crystal form of this invention exhibits good stability under light, high temperature, and high humidity conditions, with minimal change in purity.

Claims

1. A resimeltiro-nicotinamide-methanol crystal form, characterized in that, The molar ratio of resmetirox, nicotinamide, and methanol in the crystal form is 1:1:

1.

2. The resimeltiro-nicotinamide-methanol crystal form according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at least at 6.2±0.2°, 14.4±0.2°, 21.5±0.2°, 22.4±0.2°, 24.3±0.2°, 26.5±0.2°, and 27.4±0.2°.

3. The resimeltiro-nicotinamide-methanol crystal form according to claim 1, characterized in that, The crystallographic parameters of the crystal form are: monoclinic system, space group . P2 1 / c The unit cell parameters are: a = 15.5769(2) Å, b = 13.55650(10) Å, c = 13.2628(2) Å, α = 90.00°, β = 108.578(2)°, γ = 90.00°, and the unit cell volume V = 2654.74(6) Å. 3 .

4. The method for preparing the resimeltiro-nicotinamide-methanol crystal form according to any one of claims 1-3, characterized in that, The process includes the following steps: adding resmetiro and nicotinamide to a mixed solution of methanol and organic solvent A, heating and stirring to dissolve and react, then cooling to crystallize, filtering, and drying to obtain the final product.

5. The preparation method according to claim 4, characterized in that, The organic solvent A is selected from one or more of acetonitrile, ethanol, isopropanol, n-butanol, and acetone; preferably one or a combination of ethanol, acetonitrile, or acetone.

6. A crystalline form of resimeltiro-isonicotinamide-acetone, characterized in that, The molar ratio of resmetiro, isonicotinamide, and acetone in the crystal form is 1:1:

1.

7. The resimetiro-isonicotinamide-acetone crystal form according to claim 6, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at least at 12.0±0.2°, 15.6±0.2°, 17.8±0.2°, 19.9±0.2°, 20.8±0.2°, and 28.1±0.2°.

8. The resimetiro-isonicotinamide-acetone crystal form according to claim 6, characterized in that, The crystallographic parameters of the crystal form are: monoclinic system, space group . P2 1 / c The unit cell parameters are: a = 22.8739(3) Å, b = 8.89830(10) Å, c = 14.7273(2) Å, α = 90.00°, β = 105.3290(10)°, γ = 90.00°, and the unit cell volume V = 2890.93(6) Å. 3 .

9. The method for preparing the resimeltiro-isonicotinamide-acetone crystal form according to any one of claims 6-8, characterized in that, The process includes the following steps: adding resmetiro and isonicotinamide to a mixed solution of acetone and organic solvent B, heating and stirring to dissolve and react, then cooling to crystallize, filtering, and drying to obtain the final product.

10. The preparation method according to claim 9, characterized in that, The organic solvent B is selected from one or more of methanol, acetonitrile, ethanol, isopropanol, and n-butanol; preferably one or a combination of methanol, ethanol, or methanol.

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