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CN-118439976-B - Nafamostat mesylate crystal form and preparation method thereof

CN118439976BCN 118439976 BCN118439976 BCN 118439976BCN-118439976-B

Abstract

The invention provides the nafamostat mesylate crystal form and the preparation method thereof, which strictly control the types, the temperatures and the crystallization modes of crystallization solvents, solve the problem that the existing nafamostat mesylate crystal form is unqualified in turbidity in water, have good stability and can form regular crystal forms, thereby being beneficial to the technical treatment of medicines, the improvement of physical and chemical properties and the improvement of the properties of patent medicines, and also being beneficial to the transportation, the storage and the development and the utilization of pharmaceutical preparations, and being qualified in turbidity in water, good in medicinal property, high in yield and simple to operate. In the preparation process, the adopted crystallization mode is standing crystallization, so that the temozolomide mesylate crystals can be uniformly separated out, the purification of the crystals is facilitated, and the method is suitable for industrial production. In addition, in the operations of dissolution, mixing and the like when the nafamostat mesylate crystal form is prepared into an injection preparation, the qualified turbidity is beneficial to improving the quality of the nafamostat mesylate, and the method provides important guiding significance for the research of the nafamostat mesylate preparation.

Inventors

  • YU CHAOYANG
  • ZHOU DONGYAN
  • XIN NI

Assignees

  • 南京海纳医药科技股份有限公司
  • 南京海纳制药有限公司
  • 南京一诺医药科技有限公司
  • 南京泛海医药科技有限公司

Dates

Publication Date
20260512
Application Date
20240425

Claims (5)

  1. 1. A nafamostat mesylate crystal form is characterized in that the reflection angle 2 theta of an X-ray powder diffraction pattern has characteristic absorption peaks at 7.95+/-0.2, 16.93+/-0.2, 18.34 +/-0.2, 19.17 +/-0.2, 19.75+/-0.2, 20.17+/-0.2, 22.16+/-0.2 and 24.19+/-0.2 and an endothermic peak at 257.86 ℃, Stirring a nafamostat mesylate crude product and water at 50-60 ℃ until the nafamostat mesylate crude product and water are dissolved, filtering, heating the obtained filtrate to 50-65 ℃, adding a solvent, carrying out heat preservation and stirring for 30min, cooling to 20-30 ℃ for standing crystallization, standing crystallization for 6 hours, filtering, washing and drying to obtain the nafamostat mesylate crystal form; The solvent is dioxane or acetonitrile, the mass-volume ratio of the nafamostat mesylate crude product to the solvent is 1:24-25g/ml, and the mass-volume ratio of the nafamostat mesylate crude product to water is 1:4-5g/ml.
  2. 2. The crystalline form of nafamostat mesylate according to claim 1, wherein the crystalline form has an X-ray powder diffraction pattern as shown in figure 1.
  3. 3. The method for preparing the nafamostat mesylate crystal form is characterized by comprising the following steps of stirring a nafamostat mesylate crude product and water at 50-60 ℃ until the crude product and water are dissolved, filtering, heating the obtained filtrate to 50-65 ℃, adding a solvent, carrying out heat preservation and stirring, cooling to 20-30 ℃ for 30min, carrying out standing crystallization, standing crystallization for 6 hours, filtering, washing and drying to obtain the nafamostat mesylate crystal form; The solvent is dioxane or acetonitrile, the mass-volume ratio of the nafamostat mesylate crude product to the solvent is 1:24-25g/ml, and the mass-volume ratio of the nafamostat mesylate crude product to water is 1:4-5g/ml.
  4. 4. A pharmaceutical composition, characterized in that it comprises as active ingredient or main active ingredient the crystalline form of nafamostat mesylate according to claim 1, together with pharmaceutically acceptable excipients.
  5. 5. A formulation comprising an effective amount of the crystalline form of nafamostat mesylate according to claim 1.

Description

Nafamostat mesylate crystal form and preparation method thereof Technical Field The invention belongs to the technical field of medical biology, and particularly relates to a nafamostat mesylate crystal form and a preparation method thereof. Background Nafamostat mesylate (Nafamostat mesilate) is a synthesized serine protease inhibitor, has strong inhibition effect on a blood coagulation fibrinolysis system (thrombin, XIIa, xa, vila, plasmin), a kallikrein-kallikrein system (kallikrein), a complement system (C1 r-, C1 s-, B, D-) and pancreatin (trypsin, kallikrein), phospholipase A2 and the like, and can prolong the blood coagulation time and inhibit platelet aggregation and complement hemolysis reaction. The common dosage forms in the medical aspect are injection (powder) and the like, and are used for treating acute pancreatitis, acute exacerbation chronic pancreatitis, postoperative acute pancreatitis, acute pancreatitis after pancreatic duct imaging and acute traumatic pancreatitis. The structural formula of nafamostat mesylate is shown below, and is developed by Japanese bird house pharmaceutical Co., ltd, and is first marketed in Japan 10 months in 1986. The product has definite curative effect, good safety, small toxic and side effects, and has good protective effect on liver cells. Patent JP3796481B2 reports that nafamostat mesylate was refined with different solvents to obtain three different crystal forms. Wherein acetone/water is adopted for refining to obtain a crystal form I, III, water is adopted for recrystallization to obtain a crystal form I, II, and water, isopropanol, ethanol and methanol are adopted for recrystallization to obtain a crystal form III. Patent KR101595747B1 reports a naphthalene mesylate Mo Sijing type, refined with isopropanol/water to obtain a crystal form, and reports a powder diffraction pattern, which is consistent with that of japanese patent form III. The refining method in the prior art is repeated, and the problem that the obtained naphthalene mesylate Mo Sijing type product, including related substances, content, solvent residue, moisture, inorganic salt and the like, meets the standards, but the turbidity in water is not qualified, is found in the experimental process. The reasons for influencing the disqualification of the turbidity may be that foreign matters or insoluble impurities are out of standard, raw materials are degraded or different crystal forms have different solubilities. The detection of naphthalene mesylate Mo Sijing products obtained by different refining methods shows that related substances, content, solvent residues, moisture, inorganic salts and the like have no obvious influence on turbidity, and the influence of different crystal forms on turbidity is obvious. When reference JP3796481B2 is refined by using a mixed solvent of acetone and water, mixed crystal products of crystal form I and crystal form III are easily obtained, and turbidity is not qualified. When water is used as solvent for refining, the obtained solid cannot be filtered, and the product of the crystal form II is not obtained. When nafamostat mesylate is prepared into injection, the unqualified turbidity can affect the medication safety, so the turbidity of raw materials is important to the turbidity of the preparation. Therefore, the method for obtaining the raw materials with qualified turbidity has important guiding significance for the research of the preparation. Disclosure of Invention The invention aims to provide a nafamostat mesylate crystal form on the basis of the prior art, and provides important guiding significance for the research of nafamostat mesylate preparations. The invention also aims to provide a preparation method of the nafamostat mesylate crystal form. The crystalline form of nafamostat mesylate has characteristic absorption peaks at reflection angles 2 theta of 7.95+/-0.2, 16.93+/-0.2, 18.34 +/-0.2, 19.17 +/-0.2, 19.75+/-0.2, 20.17+/-0.2, 22.16+/-0.2 degrees and 24.19+/-0.2 of an X-ray powder diffraction spectrum. In a preferred embodiment, the present invention provides a naphthalene mesylate form Mo Sijing having an X-ray powder diffraction pattern as shown in figure 1. For example, the X-ray powder diffraction pattern has characteristic absorption peaks at reflection angles 2 theta of 7.95+ -0.2, 16.93+ -0.2, 18.34 + -0.2, 19.17 + -0.2, 19.75+ -0.2, 20.17+ -0.2, 22.16+ -0.2 DEG, 24.19 DEG+ -0.2. The nafamostat mesylate crystal form provided by the invention has an endothermic peak at 257-258 ℃. In a preferred scheme, the DSC spectrum of the nafamostat mesylate crystal form provided by the invention is shown in figure 2, and has an endothermic peak at 257.86 ℃. The invention provides a preparation method of a nafamostat mesylate crystal form, which comprises the following steps of stirring a nafamostat mesylate crude product and water at 50-60 ℃ until the crude product and water are dissolved, filtering, heating the obtained filtrate to 50-65 ℃,