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CN-118955387-B - Ganbao element-adipic acid eutectic crystal and preparation method thereof

CN118955387BCN 118955387 BCN118955387 BCN 118955387BCN-118955387-B

Abstract

The invention discloses a glycyrhizome-adipic acid eutectic crystal and a preparation method thereof, wherein the method comprises the steps of 1 dissolving glychizome solid in a solvent I, 2 adding adipic acid solid into a solution obtained in the step 1, 3 heating the solution obtained in the step 2 and keeping the temperature, continuously stirring, 4 filtering a clear solution obtained in the step 3, evaporating the obtained filtrate, 5 drying the crystal obtained in the step 5, and obtaining the glychizome-adipic acid eutectic after drying. The crystal of the gamboge-adipic acid eutectic is good in chemical stability, the water solubility of the gamboge-adipic acid eutectic is far better than that of the original crystal form, and the wet stability of the gamboge-adipic acid eutectic is better than that of the gamboge bulk drug crystal form.

Inventors

  • WANG NA
  • SONG WENXI
  • HAO HONGXUN
  • WANG TING
  • HUANG XIN
  • HOU BAOHONG
  • ZHOU LINA
  • XU ZHAO
  • XIE CHUANG

Assignees

  • 天津大学

Dates

Publication Date
20260512
Application Date
20240710

Claims (7)

  1. 1. A co-crystal of ganbaolin and adipic acid, wherein the crystal X-ray powder diffraction pattern is characterized by a characteristic peak at diffraction angle 2θ＝10.699±0.2°,12.638±0.2°,13.341±0.2°,13.738±0.2°,14.661±0.2°,16.460±0.2°,18.341±0.2°,18.581±0.2°,19.299±0.2°,19.780±0.2°,20.701±0.2°,21.480±0.2°,22.999±0.2°,23.481±0.2°,23.958±0.2°,24.401±0.2°,25.240±0.2°,25.420±0.2°,25.980±0.2°,27.700±0.2°,28.918±0.2°,31.581±0.2°,32.460±0.2°,34.779±0.2°.
  2. 2. The crystal of claim 1, wherein the crystal melting point is 76.64 ℃.
  3. 3. The crystal of claim 1, wherein the crystal decomposition temperature is 172.33 ℃.
  4. 4. A method of preparing a eutectic crystal according to any one of claims 1 to 3, comprising the steps of: step1, dissolving a solid of the ganbazole in a solvent I, wherein the solvent I is acetonitrile and/or ethanol; step 2, adding adipic acid solid into the solution obtained in the step 1; step 3, heating the solution obtained in the step 2 to 40-50 ℃ and keeping the temperature, and continuously stirring; Step 4, filtering the clarified solution obtained in the step 3, and evaporating the obtained filtrate, wherein the evaporation temperature of the solution is 0-15 ℃; And 5, drying the crystal obtained in the step 5, and obtaining the gamboge-adipic acid eutectic after drying.
  5. 5. The method of claim 4, wherein in step 1, the ratio of the solid of the glycal to the solvent I is 90mg/ml to 100mg/ml.
  6. 6. The method of claim 4, wherein in step 2, the molar ratio of adipic acid solids to the ganbazole solids of step 1 is 1:1.8 to 1:2.2.
  7. 7. The method according to claim 4, wherein in the step 3, the stirring rate is 100 to 200rpm.

Description

Ganbao element-adipic acid eutectic crystal and preparation method thereof Technical Field The invention belongs to the technical field of medicine separation, and particularly relates to a new Ganbaosu eutectic crystal and a crystallization preparation method thereof. Background Ganbao element (Climbazole, CAS number: 38083-17-9), also known as chloroetherketone, IUPAC name 1- (4-chlorophenoxy) -1- (1H-imidazol-1-yl) -3, 3-dimethyl-2-butanone, chemical formula C15H17ClN2O2, relative molecular weight 292.76, its structure is shown below. The appearance is white or off-white crystallization, is insoluble in water and in toluene and alcohol, the medicinal form is a raceme compound composed of R-and S-gamboge with equimolar quantity, The gamboge (Climbazole) is a classical imidazole antifungal agent, has broad-spectrum bactericidal performance, and has the bactericidal mechanism of inhibiting the biosynthesis of ergosterol by inhibiting the synthesis of lanosterol 14-alpha-demethylase in cytochrome P450 enzyme, thereby increasing the fluidity of fungal cell membranes and playing a role in inhibiting fungal growth. The shampoo is mainly used for itching relieving, dandruff removing and conditioning type shampoo, and can also be used for high-grade washing products such as antibacterial perfumed soap, bath foam, medicinal toothpaste, mouthwash and the like. Co-crystallization is an effective means of maintaining pharmacological properties and improving the physicochemical properties of the drug. The application range and the environmental friendliness of the glycal as a local broad-spectrum antifungal medicament with wide application prospect are limited by the poor water solubility of the glycal for a long time. Therefore, it is necessary to conduct a co-crystallization study on the glycal. Adipic acid (ADIPIC ACID) is mainly used as a key intermediate for synthesizing various medicines in the pharmaceutical industry, and has important application in the fields of producing antibiotics (such as penicillin G), local anesthetics (such as procaine), immunosuppressants (such as cyclosporin A) and the like. Disclosure of Invention The invention aims to provide a new co-crystal of the ganbaolin-adipic acid, which has higher water solubility and moisture absorption stability compared with the original crystal form of the ganbaolin. In order to achieve the above object, the present invention provides a glycyrhizosin-adipic acid eutectic crystal, wherein the X-ray powder diffraction pattern of the crystal is characterized by a characteristic peak at a diffraction angle 2θ＝10.699±0.2°,12.638±0.2°,13.341±0.2°,13.738±0.2°,14.661±0.2°,16.460±0.2°,18.341±0.2°,18.581±0.2°,19.299±0.2°,19.780±0.2°,20.701±0.2°,21.480±0.2°,22.999±0.2°,23.481±0.2°,23.958±0.2°,24.401±0.2°,25.240±0.2°,25.420±0.2°,25.980±0.2°,27.700±0.2°,28.918±0.2°,31.581±0.2°,32.460±0.2°,34.779±0.2°. Preferably, DSC-TG shows the melting point of the novel salt form at 76.64 ℃ Any of the above is preferred, the crystal decomposition temperature is 172.33 ℃. Preferably, any of the above, the crystal product is white in appearance as a powder. The invention also provides a preparation method of the gamboge-adipate eutectic, which comprises the following steps: Step 1, dissolving a solid of the gamboge in a solvent I; step 2, adding adipic acid solid into the solution obtained in the step 1; Step 3, heating the solution obtained in the step 2, maintaining the temperature, and continuously stirring; Step 4, filtering the clarified solution obtained in the step 3, and evaporating the obtained filtrate; And 5, drying the crystal obtained in the step 5, and obtaining the gamboge-adipic acid eutectic after drying. Preferably, in the method of the present invention, the crystallization mode is evaporative crystallization. Preferably, the ratio of the solid of the gamboge to the solvent I is 90 mg/ml-100 mg/ml. The starting reactant of the invention is a glycal product in the existing form in the prior art, and can be purchased commercially, and the solute-solvent ratio of the starting reactant in the technical scheme of the invention is converted into a glycal monomer form, namely the mass-volume ratio of glycal to solvent in the glycal solution obtained in the step 1 is 0.09 g:1-0.10 g:1ml. Further preferred is ,0.090g：1mL,0.091g：1mL,0.092g：1mL,0.093g：1mL,0.094g：1mL,0.095g：1mL,0.096g：1mL,0.097g：1mL,0.098g：1mL,0.099g：1mL,0.10g：1mL. Preferably, in step 1, the solvent I includes at least one of acetonitrile and ethanol, and more preferably acetonitrile. In any one of the above steps, preferably, in step 1, the temperature at which the solid of the glycal is dissolved in the solvent I is 40-50 ℃. Preferably 40, 45, 50C and ranges therebetween. Further preferably 45, 50 ℃ and ranges therebetween. In any one of the above steps, preferably, in step 2, the molar ratio of the adipic acid solid to the solid of the gamboge added in step 1 is 1:1.8 to 1:2.2. The adipic acid used as the