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CN-122010909-A - Ruimepiride-aminopyridine monohydrate crystal form and preparation method thereof

CN122010909ACN 122010909 ACN122010909 ACN 122010909ACN-122010909-A

Abstract

The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a crystalline form of a reletidine-aminopyridine monohydrate and a preparation method thereof. The crystalline form of the risperidone-fampridine monohydrate provided by the invention has high solubility, is favorable for improving the bioavailability and clinical curative effect of the medicament, has good stability, is suitable for manufacturing and long-term storage of a medicinal preparation, has a simple preparation method, and is suitable for industrial production.

Inventors

  • ZHAI LIHAI
  • XIA XIANGLAI
  • ZHANG MINGMING
  • LIU YUTING

Assignees

  • 山东新时代药业有限公司

Dates

Publication Date
20260512
Application Date
20260320

Claims (10)

  1. 1. A crystalline form of oseltamiol-fampridine monohydrate, characterized in that the mole ratio of oseltamiol, fampridine and water in the crystalline form is 1:1:1.
  2. 2. The crystalline form of oseltamiol-fampridine monohydrate according to claim 1, characterized in that the X-ray diffraction pattern expressed in 2Θ has a characteristic peak 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°,22.6±0.2° using Cu-ka radiation.
  3. 3. The crystalline form of oseltamiol-fampridine monohydrate according to claim 1, characterized by an X-ray diffraction pattern expressed in 2Θ with a characteristic peak 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°,28.0±0.2° using Cu-ka radiation.
  4. 4. The crystalline form of oseltamiol-fampridine monohydrate according to claim 1, characterized by the use of Cu-ka radiation, whose characteristic peaks conform to the X-ray powder diffraction pattern as shown in figure 1.
  5. 5. The crystalline form of oseltamiol-fampridine monohydrate according to claim 1, wherein the crystallographic parameters are monoclinic system, the space group is P21/c, the unit cell parameters are a= 19.8326 (9) a, b= 11.3904 (4) a, c= 12.0660 (6) a, α=90°, β= 95.066 (4) °, γ=90°, and the unit cell volume v= 2715.1 (2) a 3 .
  6. 6. The preparation method of the crystalline form of the oseltamizole-fampridine according to any one of claims 1 to 5, which is characterized by comprising the steps of dissolving the oseltamizole and the fampridine in a mixed solvent of an organic solvent A and water, heating and dissolving, cooling and crystallizing after clarifying the solution, and filtering and drying to obtain the crystalline form of the oseltamizole-fampridine.
  7. 7. The preparation method of claim 5, wherein the organic solvent A is one or more of acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol and acetone.
  8. 8. The preparation method according to claim 5, wherein the molar ratio of the risperidone to the fampridine is 1.0:1.0-1.1, preferably the molar ratio of the risperidone to the fampridine is 1.0:1.05.
  9. 9. The preparation method according to claim 5, wherein the mass-to-volume ratio of the risperidone to the organic solvent A to the water in the system is 30-20:1-2:0.12-0.5, wherein the mass is in mg and the volume is in ml.
  10. 10. The preparation method according to claim 5, wherein the temperature of dissolution and heating is 45-60 ℃, the temperature of cooling and crystallization is 0-15 ℃, and preferably the temperature of cooling and crystallization is 5-10 ℃.

Description

Ruimepiride-aminopyridine monohydrate crystal form and preparation method thereof Technical Field The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a crystalline form of a reletidine-aminopyridine monohydrate and a preparation method thereof. Background Resimetirol (Resmetirom), chemical name 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-triazine-6-carbonitrile, is white or off-white crystalline powder. CAS number 920509-32-6, molecular formula C 17H12Cl2N6O4, its structural formula is shown below. : 。 Resimitinol is a THR (thyroid hormone receptor) -beta agonist that regulates lipid metabolism by mimicking the action of thyroid hormone in the liver, thereby reducing fat accumulation in the liver. For day 3 and 14 of 2024, the U.S. FDA accelerated approval of Rasemet (trade name: rezdiffra) for joint diet and exercise, for the treatment of non-cirrhosis non-alcoholic steatohepatitis (NASH)/metabolic dysfunction-related steatohepatitis (MASH) adult patients suffering from moderate to severe liver fibrosis (stages F2 to F3), became the first-marketed NASH/MASH therapeutic drug worldwide. The original research company disclosed in patent WO2014043706a (CN 105008335A) a Resmetirom form I and a preparation method thereof, wherein the solvate is not easy to directly prepare the high-purity form I, but the solvate is often required to be converted into MIBK solvate, and then the MIBK solvate is used to prepare the form I, so that the operation is complex. In addition, the property of the crystal form I is repeatedly characterized, and the result shows that the crystal form I has low solubility and poor grinding stability, and most of the crystal form I is converted into amorphous after grinding and has poor compressibility. CN201980056826.0 discloses crystalline salts of resmetirom (wherein the counterion is selected from the group consisting of L-lysine, L-arginine, 2-hydroxy-N, N-trimethylethane-1-amine, diethylamine, ethanolamine, ethanol-2-diethylamine, na +、Mg2+、K+、Ca2+, diethanolamine, triethanolamine. L-histidine and meglumine), solvated/desolvated polymorphic forms, B, C, D, E, F, G, H, I, K, L, S + T, S, U, V, W, X, Y, Z, α, β, γ, δ, epsilon, phi, eta and lambda forms named resmetirom, co-crystals of resmetirom with glutaric acid and amorphous solid dispersions of resmetirom. WO2021129465A1 discloses new crystalline forms CSIV and CSV, WO2021063367A1 providing resmetirom of crystalline CSI. The preparation has advantages in aspects of physicochemical property, preparation processability, bioavailability and the like, such as at least one aspect of melting point, solubility, hygroscopicity, purification effect, stability, adhesiveness, compressibility, fluidity, in-vivo and in-vitro dissolution, bioavailability and the like, and particularly has the advantages of high solubility, good physicochemical stability, low hygroscopicity, good mechanical stability and good compressibility, solves the problems existing in the crystal forms in the prior art, and has very important significance for drug development containing resmetirom. WO2022052822A1 discloses that the novel crystalline form CSVI has a higher solubility of the crystalline form CSVI provided by the present invention compared to the prior art. Especially in SGF, form CSVI has a solubility of about 2 times that of prior art form I. The resmetirom crystal form CSVII provided by WO2025011259A1 has large solubility and good physicochemical stability, solves the problems existing in the prior art, and has very important significance for drug development containing resmetirom. CN202210098713.0 provides a resmetirom form 3. The new crystal form has the advantages of simple preparation mode, good stability, low hygroscopicity, uniform particle size distribution, good solubility, high dissolution rate, quick dissolution, stable storage, great development value and suitability for industrial mass production, and is suitable for pharmaceutical requirements. CN202210388473.8 provides the new crystal forms Form 4, form 7 and Form 9 of resmetirom and their preparation methods and uses. Compared with the existing crystal forms, the resmetirom provided by the preparation method has the advantages of good crystal form stability, uniform particle size distribution, simpler and more convenient crystal form preparation process, no need of expensive reagents and complex process conditions, high safety of solvents, low requirement on solvent residue and great development value. CN202311183195.3 provides a solvent compound crystal formed by the rismiterol and the 1, 4-dioxane solvent, the preparation process of the crystal form is simple, the operation is simple, the quality index of the obtained crystal form is basically unchanged in a stability acceleration experiment, the crystal form has good stability, the crystal form is easy to store i