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CN-118955388-B - Ganbaosu-succinic acid eutectic crystal and preparation method thereof

CN118955388BCN 118955388 BCN118955388 BCN 118955388BCN-118955388-B

Abstract

The invention discloses a novel ganbaolin-succinic acid eutectic crystal and a preparation method thereof, wherein the method comprises the steps of dissolving ganbaolin solid in a solvent I, adding succinic acid solid into a solution obtained in the step 1, heating the solution obtained in the step 2 and keeping the temperature, continuously stirring, filtering a clear solution obtained in the step 3, evaporating the obtained filtrate, and drying the crystal obtained in the step 5 to obtain the ganbaolin-succinic acid eutectic crystal. The solubility of the obtained Ganbao extract-succinic acid eutectic crystal in water is 0.487mg/mL, which is 10 times of that of the bulk drug, and the water solubility of the Ganbao extract-succinic acid eutectic crystal is far better than that of the original crystal form.

Inventors

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

Assignees

  • 天津大学

Dates

Publication Date
20260512
Application Date
20240710

Claims (7)

  1. 1. A new co-crystal of ganbaolin-succinic acid, characterized in that the crystal X-ray powder diffraction pattern is characterized by a characteristic peak at diffraction angle 2θ＝6.860±0.2°,11.581±0.2°,13.581±0.2°,14.419±0.2°,16.118±0.2°,18.078±0.2°,19.160±0.2°,20.602±0.2°,21.339±0.2°,21.739±0.2°,22.140±0.2°,22.820±0.2°,23.059±0.2°,23.281±0.2°,25.920±0.2°,26.420±0.2°,27.139±0.2°,27.360±0.2°,28.600±0.2°,29.079±0.2°,29.299±0.2°,30.241±0.2°,32.319±0.2°,33.018±0.2°,34.539±0.2°.
  2. 2. The crystal of claim 1, wherein the crystal melting point is 107.07 ℃.
  3. 3. A method of producing a crystal according to claim 1 or 2, comprising the steps of: step 1, dissolving a solid of the gamboge in a solvent I, wherein the solvent I is ethanol and/or methanol; step 2, adding succinic acid solid into the solution obtained in the step 1; step 3, heating the solution obtained in the step 2 to 30-50 ℃ 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 the evaporation time is 3-7 days; And 5, drying the crystal obtained in the step 5, and obtaining the gamboge-succinic acid eutectic after drying.
  4. 4. The preparation method according to claim 3, wherein in the step 1, the mass-volume ratio of the solid of the glycyrhizate to the solvent I is 90mg/ml to 100mg/ml.
  5. 5. The method according to claim 4, wherein in step 1, the temperature at which the solid of the ganbazole is dissolved in the solvent I is 30-50 ℃.
  6. 6. The method of claim 3, wherein in step 2, the molar ratio of the succinic acid solid to the ganbazole solid in step 1 is 1:1.8-1:2.2.
  7. 7. The method of claim 3, wherein in step 5, the temperature of drying the crystals is 40-50 ℃.

Description

Ganbaosu-succinic 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. Succinic acid (succinic acid ) is mainly used as a precursor and intermediate of various drugs in the pharmaceutical industry, and plays a key role in the production of antibiotics, vitamins and drugs for treating multiple sclerosis such as triamterene and the like. Disclosure of Invention The invention aims to prepare a new co-crystal of the ganbaolin-succinic acid, which has higher water solubility and thermal stability compared with the original crystal form of the ganbaolin. In order to achieve the above purpose, the invention provides a novel co-crystal of ganbaotou. The crystalline X-ray powder diffraction pattern is a characteristic peak at diffraction angle 2θ＝6.860±0.2°,11.581±0.2°,13.581±0.2°,14.419±0.2°,16.118±0.2°,18.078±0.2°,19.160±0.2°,20.602±0.2°,21.339±0.2°,21.739±0.2°,22.140±0.2°,22.820±0.2°,23.059±0.2°,23.281±0.2°,25.920±0.2°,26.420±0.2°,27.139±0.2°,27.360±0.2°,28.600±0.2°,29.079±0.2°,29.299±0.2°,30.241±0.2°,32.319±0.2°,33.018±0.2°,34.539±0.2°. Preferably, DSC-TG shows a melting point of 107.07 ℃for the new salt form. Any of the above is preferred to have a decomposition temperature of 170.16 ℃. Any of the above is preferred in that the product is white in appearance as a powder. The invention also provides a preparation method of the gamboge-succinate eutectic, which comprises the following steps: Step 1, dissolving a solid of the gamboge in a solvent I; step 2, adding succinic 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-succinic acid eutectic after drying. 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 ethanol and methanol, and more preferably ethanol. 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 30-50 ℃. Preferably 30, 35, 40, 45, 50 ℃ and ranges therebetween, and more preferably 35, 40 ℃ and ranges therebetween. In any one of the above preferred embodiments, in step 2, the molar ratio of the succinic acid solid to the ganbazole solid is 1:1.8-1:2.2. The succinic acid used by the initial reactant of the invention is a succinic acid product in a form existing in the prior art, and can be obtained through commercial purchase. Preferably, 1:1.8, 1:2.0, 1:2.1, 1:2.2 and ranges therebetween. It is further p