Rosemeltirome-aminopyridine monohydrate crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a rosmeltirome-aminopyridine monohydrate crystal form and a preparation method thereof. The rosemeltirol-aminopyridine monohydrate crystal form provided by the invention is high in solubility, and is beneficial to improving the bioavailability and clinical curative effect of drugs; and the preparation method is suitable for preparation and long-term storage of medicinal preparations, is simple and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of crystal drug molecule technology, specifically relating to a crystal form of resimetiro-aminopyridine monohydrate and its preparation method. Background Technology

[0002] Resmetirom, chemically named 2-[3,5-dioxo-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, is a white or off-white crystalline powder. CAS No.: 920509-32-6, molecular formula: C 17 H 12 Cl2N6O4 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] The original research company disclosed Resmetirom crystal form I and its preparation method in patent WO2014043706A (CN105008335A). However, using a solvate makes it difficult to directly obtain high-purity crystal form I. Instead, it often requires conversion to a MIBK solvate, followed by the preparation of crystal form I from the MIBK solvate, making the process complex. Furthermore, repeated characterization of its properties revealed that crystal form I has low solubility, poor grinding stability, and after grinding, it largely transforms into an amorphous form, exhibiting poor compressibility.

[0005] CN201980056826.0 discloses crystalline salts of resmetirom (wherein the counterion is selected from L-lysine, L-arginine, 2-hydroxy-N,N,N-trimethylethane-1-amine, diethylamine, ethanolamine, ethanol-2-diethylamine, Na). + Mg 2+ K + Ca 2 +Diethanolamine, triethanolamine, L-histidine, and meglumine), solvated / desolventized polymorphic forms of resmetirom, named as B, C, D, E, F, G, H, I, K, L, S+T, S, U, V, W, X, Y, Z, α, β, γ, δ, ε, φ, η, and λ forms, cocrystals of resmetirom with glutaric acid, and amorphous solid dispersions of resmetirom.

[0006] WO2021129465A1 discloses new crystal forms CSIV and CSV, while WO2021063367A1 provides crystal form CSI for resmetirom. These crystal forms offer advantages in physicochemical properties, formulation processing performance, and bioavailability. For example, they exhibit advantages in at least one aspect of melting point, solubility, hygroscopicity, purification, stability, adhesion, compressibility, flowability, in vitro and in vivo dissolution, and bioavailability. In particular, they possess high solubility, good physicochemical stability, low hygroscopicity, good mechanical stability, and good compressibility, thus addressing the problems existing in current crystal forms and holding significant importance for the development of drugs containing resmetirom.

[0007] WO2022052822A1 discloses a new crystalline form CSVI. Compared with the prior art, the crystalline form CSVI provided by this invention has higher solubility. In particular, in SGF, the solubility of crystalline form CSVI is approximately twice that of the prior art crystalline form I.

[0008] The resmetirom crystal form CSVII provided by WO2025011259A1 has high solubility and good physicochemical stability, which solves the problems existing in the current technology and is of great significance for the development of drugs containing resmetirom.

[0009] CN202210098713.0 provides a resmetirom crystal form 3. The new crystal form is easy to prepare, has good stability, low hygroscopicity, uniform particle size distribution, good solubility, high dissolution rate, and fast dissolution, which meets the requirements for pharmaceutical use, can be stored stably, has great development value, is conducive to the preparation of pharmaceutical products, and is suitable for large-scale industrial production.

[0010] CN202210388473.8 discloses new crystal forms of resmetirom, Form 4, Form 7, and Form 9, along with their preparation methods and applications. Compared to existing crystal forms, the resmetiroms provided exhibit good crystal stability, uniform particle size distribution, and simpler preparation processes, eliminating the need for expensive reagents and complex process conditions. Furthermore, the solvents used are highly safe, with low residue requirements, making them of great development value.

[0011] CN202311183195.3 discloses a solvate compound crystal formed by resmetiro and 1,4-dioxane solvent. The preparation process of this crystal form is simple and easy to operate. The quality indicators of the obtained crystal form remain basically unchanged in the accelerated stability test, which shows good stability. It is easy to preserve during the production and distribution process and provides a good option for the preparation of its drug formulations. This is of great significance for drug development.

[0012] CN202410767042.1 discloses a crystal form of a thyroid hormone receptor agonist and a method for its preparation. Crystal forms K1, K2, K3, K4, K5, K6, K7, K8, K9, K10, K11, and K12 are disclosed.

[0013] CN202410850621.2 provides a retrimetrol crystalline form BSI and its preparation method. The retrimetrol crystalline form BSI described herein exhibits good physical and chemical stability, high solubility, and low hygroscopicity.

[0014] CN202411110874.2 discloses a new crystalline form of resmetidine, crystalline form APTI-I. This crystalline form is easy to prepare, has high purity, good stability, and good solubility in water-based media, making it suitable for industrial-scale production and preparation of pharmaceutical formulations.

[0015] CN202510125733.6 discloses new crystalline forms of resimetidine and their preparation methods, namely crystalline forms APTI-II and APTI-III. These crystalline forms are easy to prepare and have high purity. In particular, crystalline form APTI-III exhibits good stability and high solubility in aqueous solutions, making it suitable for industrial-scale production and the preparation of pharmaceutical formulations.

[0016] WO2022086894A1 discloses crystalline resmetirom: nicotinamide, resmetirom: caffeine, resmetirom: 2-pyridinecarboxylic acid, and / or resmetirom: urea, and their solid forms. This invention also provides resmetirom N-methyl-morpholine salt, resmetirom piperazine salt, resmetirom benzathine salt, resmetirom: L-proline, and their crystalline forms. This disclosure also provides methods for their preparation and pharmaceutical compositions thereof. Resmetirom and its crystalline forms: nicotinamide, resmetirom: caffeine, resmetirom: 2-pyridinecarboxylic acid, and / or resmetirom: urea, or resmetirom N-methyl-morpholine salt, resmetirom piperazine salt, resmetirom benzathine, and resmetirom salt: L-proline, can be used to prepare other solid forms of resmetirom, resmetirom salts, or cocrystals and their solid forms.

[0017] US20240423993A1 relates to an amorphous form of resmetirom and a method for preparing the same, and also to a pharmaceutical composition comprising the amorphous form of resmetirom.

[0018] WO2025231587A1 provides a non-crystalline form of resimetidine (CH). The preparation process of this crystal form is simple and easy to operate. The new crystal form has good stability and is easy to preserve during the production and distribution process. When used to prepare tablet formulations, the product quality is stable and the dissolution rate has certain advantages compared with the original crystal form. It provides a good choice for the preparation of drug formulations and is of great significance to drug development.

[0019] The inventors, in their research on the crystallization forms of resimetiro and aminopyridine, unexpectedly developed a resimetiro-aminopyridine hydrate eutectic crystal, which to some extent solved the stability and dissolution problems of resimetiro. This provides better evidence for the application of resimetiro in drug therapy. Summary of the Invention

[0020] In view of the shortcomings of the prior art, this application provides a eutectic crystal of resmetiro-aminopyridine hydrate. The resmetiro crystal of this invention exhibits good stability, is almost non-hygroscopic, and has high solubility, thus possessing significant medicinal value.

[0021] In a first aspect, the present invention provides a crystalline form of resmetrol-aminopyridine monohydrate, wherein the molar ratio of resmetrol, aminopyridine and water is 1:1:1.

[0022] The described resmetrol-aminopyridine monohydrate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at 4.3±0.2°, 4.5±0.2°, 9.5±0.2°, 9.7±0.2°, 15.0±0.2°, 21.7±0.2°, and 22.6±0.2°.

[0023] Preferably, the resmetrol-aminopyridine monohydrate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 4.3±0.2°, 4.5±0.2°, 4.7±0.2°, 8.5±0.2°, 9.0±0.2°, 9.5±0.2°, 9.7±0.2°, 13.7±0.2°, 15.0±0.2°, 17.1±0.2°, 21.7±0.2°, 22.6±0.2°, 24.4±0.2°, 26.9±0.2°, 27.4±0.2°, and 28.0±0.2°.

[0024] Preferably, the resimetiro-aminopyridine monohydrate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks conforming to the following...Figure 1 The X-ray powder diffraction pattern shown is shown.

[0025] Preferably, the crystallographic parameters of the resmetiro-aminopyridine monohydrate are: monoclinic system, space group P21 / c; cell parameters are: a = 19.8326(9) Å, b = 11.3904(4) Å, c = 12.0660(6) Å, α = 90°, β = 95.066(4)°, γ = 90°, and cell volume V = 2715.1(2) Å. 3 The molecular formula is: C 22 H 20 Cl2N8O5 has a molecular weight of 547.34.

[0026] The second aspect of this application provides a method for preparing the crystal form of resmetrol-aminopyridine monohydrate, the specific preparation steps of which include: dissolving resmetrol and aminopyridine in a mixed solvent of organic solvent A and water, heating to dissolve, clarifying the solution, cooling to crystallize, filtering and drying to obtain the crystal form of resmetrol-aminopyridine monohydrate.

[0027] Preferably, the organic solvent A is one or more of acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, and acetone.

[0028] More preferably, the organic solvent A is one or two of methanol, ethanol, acetonitrile, and acetone.

[0029] Preferably, the molar ratio of resmetiro to aminopyridine is 1.0:1.0 to 1.1, and more preferably, the molar ratio of resmetiro to aminopyridine is 1.0:1.05.

[0030] Preferably, the mass-to-volume ratio of resmetiro to organic solvent A and water in the system is 30-20:1-2:0.12-0.5, where the mass is expressed in mg and the volume in ml.

[0031] Preferably, the melting and heating temperature is 45–60°C.

[0032] Preferably, the cooling crystallization temperature is 0-15℃, and more preferably, the cooling crystallization temperature is 5-10℃.

[0033] More preferably, the preparation method includes the following steps:

[0034] Resmetiro and aminopyridine were dissolved in a mixed solvent of organic solvent A and water at 45–60°C, stirred and refluxed, cooled to 5–10°C, and crystallized for 40–62 hours. The crystals were then filtered and dried to obtain a eutectic of resmetiro-aminopyridine monohydrate.

[0035] Preferably, the drying temperature is 50-70°C and the drying time is 8-12 hours.

[0036] A third aspect of this application provides a pharmaceutical composition comprising the resimetiro-aminopyridine monohydrate crystal form described in this invention, and mixed with other components.

[0037] Preferably, the pharmaceutical composition of the present invention is prepared as follows: using standard and conventional techniques, the compound of the present invention is combined with a pharmaceutically acceptable solid or liquid carrier, and optionally combined with pharmaceutically acceptable excipients and formulations to prepare a usable dosage form.

[0038] Preferably, the other components include other active ingredients, excipients, fillers, etc., that can be used in combination.

[0039] Preferably, the pharmaceutical composition is a spray, tablet, capsule, powder for injection, liquid for injection, etc.

[0040] The fourth aspect of this application provides a resmetrol-aminopyridine monohydrate crystal form as an active ingredient for the treatment of non-alcoholic steatohepatitis with liver fibrosis.

[0041] Confirmation of crystal structure 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 calculation and the Fourier difference method.

[0042] The crystallographic data obtained from testing and analyzing the crystal form of the resmetiro-aminopyridine monohydrate prepared in this invention are shown in Table 1. Its crystallographic parameters are: monoclinic system, space group P21 / c; cell parameters are: a = 19.8326(9) Å, b = 11.3904(4) Å, c = 12.0660(6) Å, α = 90°, β = 95.066(4)°, γ = 90°, cell volume V = 2715.1(2) Å. 3 The molecular formula is: C 22 H 20Cl2N8O5, with a molecular weight of 547.34. The ORTEP diagram of the resimetidine-aminopyridine monohydrate crystal form of this invention shows that resimetidine and aminopyridine are linked together by intramolecular hydrogen bonds. Specifically, the amino hydrogen atom of the resimetidine triazine ring forms a hydrogen bond with the carbonyl oxygen atom of aminopyridine. Furthermore, the amino hydrogen atom on aminopyridine forms an intramolecular hydrogen bond with the carbonyl oxygen atom of acetone. The hydrogen bond diagram of the resimetidine-aminopyridine monohydrate crystal form of this invention is attached. Figure 3 As shown.

[0043] Table 1. Main crystallographic data of resimetiro-aminopyridine monohydrate crystals

[0044] The X-ray powder diffraction testing instrument and testing conditions in this invention are as follows: X-ray powder diffractometer: PANalyticalEMPYREAN; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kV, current 40mA; divergence slit: 1 / 4; anti-scattering slit: 1; Solar slit: 0.04rad; step size: 0.5s; scanning range: 3~50°.

[0045] Based on crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1 And Table 2.

[0046] Table 2. Main PXRD peaks of resimemetiro-aminopyridine monohydrate crystal forms

[0047] All samples prepared in the examples conformed to X-ray powder diffraction patterns.

[0048] The method for preparing resimetiro-aminopyridine monohydrate crystals provided by this invention is simple to operate, yields crystals with high purity and high yield, and exhibits good grinding stability, as well as excellent stability under high temperature, high humidity, and light conditions. It also demonstrates good solubility in pH solubility assessments. This is crucial for the efficacy of resimetiro. Attached Figure Description

[0049] Figure 1 X-ray powder diffraction pattern of the crystal form of resimetiro-aminopyridine monohydrate.

[0050] Figure 2 ORTEP diagram of the crystal form of resimetiro-aminopyridine monohydrate.

[0051] Figure 3Hydrogen bond diagram of the crystal form of resimetiro-aminopyridine monohydrate. Detailed Implementation

[0052] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0053] Example 1

[0054] 290.1 ​​mg of resmetrol and 65.8 mg of aminopyridine were added to 5 ml of acetonitrile, 5 ml of acetone and 1.5 ml of water. The mixture was heated to 50 °C and stirred under reflux for 1 hour. After slowly cooling to 5-10 °C, the mixture was allowed to stand at a controlled temperature for 48 hours to crystallize. The crystals were then filtered and dried under vacuum at 50 °C for 10 hours to obtain a resmetrol-aminopyridine monohydrate eutectic. The yield was 92.33% and the purity was 99.93%.

[0055] Example 2

[0056] 290.1 ​​mg of resmetrol and 65.6 mg of aminopyridine were added to a mixed solvent of 5 ml acetone, 5 ml methanol and 1.5 ml water. The mixture was heated to 50 °C and refluxed with stirring for 1 hour. After slowly cooling to 5-10 °C, the mixture was allowed to stand at a controlled temperature for crystallization for 48 hours. The crystals were then filtered and dried under vacuum at 50 °C for 10 hours to obtain a resmetrol-aminopyridine monohydrate eutectic. The yield was 91.68% and the purity was 99.90%.

[0057] Example 3

[0058] 290.0 mg resmetrol and 65.2 mg aminopyridine were added to 10 ml acetone and 1.5 ml water, heated to 50 °C and stirred under reflux for 1 hour. The mixture was then slowly cooled to 5-10 °C and allowed to stand for crystallization for 48 hours. After filtration, the mixture was vacuum dried at 50 °C for 10 hours to obtain a resmetrol-aminopyridine monohydrate eutectic. The yield was 92.30% and the purity was 99.92%.

[0059] Verification experiment:

[0060] Verification Example 1: Solubility Test

[0061] 1. Experimental materials: The crystal form of resimetiro-aminopyridine monohydrate was prepared in Example 1.

[0062] 2. Experimental Method: Water, gastric juice FaSSGF and intestinal juice FaSSIF simulating a fasting state were used as dissolving media, and a pH 7.4 buffer solution was prepared by diluting 1.36 g of potassium dihydrogen phosphate with 79 ml of 0.1 mol / L sodium hydroxide solution and water to 200 ml. 5 mg of the crystalline form was dispersed in 2.0 ml of the above medium to prepare suspensions. After equilibration at 37°C for 1 hour and 24 hours, the suspensions were filtered. The content of the sample in the solution (mg / ml, calculated as resmetiro) was determined by ultra-high performance liquid chromatography. The experiment was performed in triplicate, and the average value was taken.

[0063] 3. Experimental results: The experimental results are shown in Table 3.

[0064] Table 3. Solubility test results (mg / ml)

[0065] Experiments have shown that the resmetrol-aminopyridine monohydrate crystal form obtained by this invention has higher solubility.

[0066] Verification Example 2: Hygroscopicity Test

[0067] 1. Experimental materials: The crystal form of resimetiro-aminopyridine monohydrate was prepared in Example 1.

[0068] 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.

[0069] Regarding the description of hygroscopic characteristics and the 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: The process of absorbing sufficient water to form a liquid.

[0070] Extremely hygroscopic: the weight gain due to moisture absorption is not less than 15%.

[0071] It has hygroscopic properties: the weight gain due to moisture absorption is less than 15% but not less than 2%.

[0072] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0073] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0074] 3. Experimental results: The experimental results are shown in Table 4.

[0075] Table 4 Results of Hygroscopicity Test

[0076] Through experiments, the crystal form of resmetrol-aminopyridine monohydrate obtained by this invention is almost non-hygroscopic, and the crystal form does not change.

[0077] Verification Example 3: High Temperature, High Humidity, and Light Irradiation Test

[0078] 1. Experimental materials: The crystal form of resimetiro-aminopyridine monohydrate was prepared in Example 1.

[0079] 2. Experimental Method: Appropriate amounts of 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.

[0080] 3. Experimental results: The experimental results are shown in Table 5.

[0081] Table 5. Experimental Results of Influencing Factors

[0082] Experiments have shown that the resmetrol-aminopyridine monohydrate crystal form prepared by this invention exhibits good stability under light, high temperature, and high humidity conditions, and the crystal form remains unchanged.

[0083] Verification of mechanical stability in Example 4

[0084] 1. Experimental materials: The crystal form of resimetiro-aminopyridine monohydrate was prepared in Example 1.

[0085] 2. Experimental method: The crystal form of resimetiro-aminopyridine monohydrate was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding.

[0086] 3. The results showed that the crystal form of resmetrol-aminopyridine monohydrate remained unchanged after grinding, and resmetrol-aminopyridine monohydrate had good mechanical stability.

[0087] In summary, the resmetrol-aminopyridine monohydrate crystal form obtained by this invention has good solubility and stability, which is beneficial for storage and transportation. The resmetrol-aminopyridine monohydrate crystal forms obtained in Examples 2 and 3 have the same properties as the resmetrol-aminopyridine monohydrate crystal form obtained in Example 1.

[0088] Verification Example 5: Effect of the crystal form of the present invention on a rat model of hypothyroidism-induced fatty liver.

[0089] Forty Wistar rats (SPF grade) were selected, with 10 rats serving as the control group. The control group was administered 10 mg / kg / day of physiological saline by gavage. The remaining 30 rats were administered 0.1% propylthiouracil (PTU) at 10 mg / kg / day by gavage. After 4 weeks of administration, a rat model of hypothyroidism-induced fatty liver was established. At the end of the 4-week period, blood was collected via the orbital vein for model evaluation. After successful model establishment, the 30 rats were divided into three groups: Group 1 (n=10) continued normal feeding for 8 weeks; Group 2 (n=10) was normally fed with galesmetiro compound (10 mg / kg in drinking water) for 8 weeks; and Group 3 (n=10) was normally fed with galesmetiro-aminopyridine monohydrate crystal form (Example 1) (same molar dosage, in drinking water) for 8 weeks. After administering the drug once daily for 8 consecutive weeks, blood samples were collected to measure serum levels of total thyroxine (TT4), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). All rats were sacrificed, and blood and organ tissues, including liver, intestines, heart, and kidneys, were collected to observe lesions. Serum levels of total cholesterol (TC) and low-density lipoprotein (LDL-C) in liver tissue were measured.

[0090] Table 6 Test Results

[0091] The experimental results above show that in rats successfully modeled with hypothyroidism, TT4 levels were significantly reduced, while TC, LDL, ALT, and AST levels were significantly increased. This demonstrates that low thyroid hormone levels lead to increased TC and LDL content in the liver, resulting in hepatic fat accumulation. After using resimetiro alone, serum TT4 levels significantly increased, while TC and LDL levels in liver tissue significantly decreased. The resimetiro-aminopyridine monohydrate significantly increased serum TT4 levels and decreased TC and TG levels in liver tissue, and also significantly reduced serum ALT and AST levels. Furthermore, no toxic reactions were observed in the rats during the experiment (no deaths occurred), and no obvious lesions were found in the liver, intestines, heart, and kidneys collected from dissected rats. Therefore, the combination of resimetiro and aminopyridine is safe and effective.

Claims

1. A crystalline form of resimeltiro-aminopyridine monohydrate, characterized in that, In the crystal form, the molar ratio of resmetrol, aminopyridine, and water is 1:1:

1.

2. The crystalline form of resimeltiro-aminopyridine monohydrate according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at 4.3±0.2°, 4.5±0.2°, 9.5±0.2°, 9.7±0.2°, 15.0±0.2°, 21.7±0.2°, and 22.6±0.2°.

3. The crystalline form of resimeltiro-aminopyridine monohydrate according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at 4.3±0.2°, 4.5±0.2°, 4.7±0.2°, 8.5±0.2°, 9.0±0.2°, 9.5±0.2°, 9.7±0.2°, 13.7±0.2°, 15.0±0.2°, 17.1±0.2°, 21.7±0.2°, 22.6±0.2°, 24.4±0.2°, 26.9±0.2°, 27.4±0.2°, and 28.0±0.2°.

4. The resimetiro-aminopyridine monohydrate crystal form according to claim 1, characterized in that, Using Cu-Kα radiation, its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1.

5. The crystalline form of resimeltiro-aminopyridine monohydrate according to claim 1, characterized in that, Its crystallographic parameters are: monoclinic system, space group P21 / c; cell parameters are: a = 19.8326(9) Å, b = 11.3904(4) Å, c = 12.0660(6) Å, α = 90°, β = 95.066(4)°, γ = 90°, cell volume V = 2715.1(2) Å. 3 .

6. The method for preparing the crystalline form of resimemetiro-aminopyridine monohydrate according to any one of claims 1-5, characterized in that, The process includes the following steps: dissolving resmetrol and aminopyridine in a mixed solvent of organic solvent A and water, heating to dissolve, clarifying the solution, cooling to crystallize, filtering and drying to obtain the resmetrol-aminopyridine monohydrate crystal form.

7. The preparation method according to claim 5, characterized in that, The organic solvent A is one or more of acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, and acetone.

8. The preparation method according to claim 5, characterized in that, The molar ratio of resmetiro to aminopyridine is 1.0:1.0 to 1.1, preferably 1.0:1.

05.

9. The preparation method according to claim 5, characterized in that, In the system, the mass-to-volume ratio of resmetiro to organic solvent A and water is 30–20:1–2:0.12–0.5, where mass is expressed in mg and volume in ml.

10. The preparation method according to claim 5, characterized in that, The melting and heating temperature is 45-60℃; the cooling and crystallization temperature is 0-15℃, preferably 5-10℃.

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