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Cefamandole nafate new crystal form and crystallization preparing method thereof

A technology of cefamandole sodium and its crystal form, which is applied in the field of new crystal form of cefamandole sodium and its crystallization preparation, which can solve the problems of unfavorable product packaging and transportation, poor fluidity of needle-like crystals, and unsolved solubility, etc. , to achieve the effect of easy commercial industrialization scale implementation, good liquidity and low cost

Inactive Publication Date: 2015-08-19
TIANJIN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Publication numbers CN201010257886.X and CN201010199235.X are both prepared hydrates. Although their solubility is relatively large, due to the presence of crystal water, the defect of crystal water instability often occurs during the preparation process.
And the compound of cefamandole sodium disclosed in publication number CN201210284600.6 does not solve the problem of solubility, and there are many insoluble particles
At the same time, most of the crystal forms reported in the research are needle-shaped, and the fluidity of needle-shaped crystals is poor, and the bulk density is low, which is not conducive to product packaging and transportation

Method used

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  • Cefamandole nafate new crystal form and crystallization preparing method thereof
  • Cefamandole nafate new crystal form and crystallization preparing method thereof
  • Cefamandole nafate new crystal form and crystallization preparing method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 0.50 g of the dry cefamandole sodium solid into 10 mL of methanol and ammonium acetate to form a suspension, wherein the volume ratio of methanol to ammonium acetate is 1:4, and heat the suspension to 10 °C under stirring to make the solids completely Dissolve, keep the temperature constant, add 50mL of cyclohexane dropwise to the solution at a rate of 0.1ml / min to obtain a suspension, add 0.3mL of acetanilide with a concentration of 0.1mg / L as an additive to the suspension, and grow the crystal for 1h, The crystalline slurry was vacuum filtered, and the product was dried at 20° C. under normal pressure for 5 hours to constant weight to obtain a new crystalline product of cefamandole sodium. The X-ray powder diffraction pattern of the new crystal product is as follows: figure 1 As shown, at diffraction angles 2θ=4.2, 5.3, 6.3, 7.4, 8.6±0.2, 9.4, 10.2, 10.3, 14.5, 15.4, 16.3, 17.5, 18.2, 18.4, 19.3, 19.6, 20.4, 20.6, 21.5, 22.4 , There are characteristic peaks at 27...

Embodiment 2

[0026] Add 2.31 g of dry cefamandole sodium solids into 20 mL of methanol and sodium bicarbonate to form a suspension, wherein the volume ratio of methanol to sodium bicarbonate is 2:3, and the suspension is heated to 30° C. under stirring to make All the solids are dissolved, and at a constant temperature, 100 mL of n-pentane is added dropwise to the solution at a rate of 0.3 ml / min to obtain a suspension. Adding 3.0 ml of adipic acid with a concentration of 0.2 mg / L in the suspension is used as an additive. After crystallization for 2 hours, the crystal slurry was vacuum filtered, and the product was dried at 30° C. under normal pressure for 5 hours to constant weight to obtain a new crystal form of cefamandole sodium. The X-ray powder diffraction pattern of the product is at diffraction angle 2θ=4.2, 5.3, 6.3, 7.4, 8.6±0.2, 9.4, 10.2, 10.3, 14.5, 15.4, 16.3, 17.5, 18.2, 18.4, 19.3, 19.6, 20.4, 20.6 , There are characteristic peaks at 21.5, 22.4, 27.4, and 31.0 degrees, and ...

Embodiment 3

[0028]Add 2.00 g of dry cefamandole sodium solid into 40 ml of propionic acid to form a suspension, stir the suspension at 25°C to dissolve all the solids, and add 300 mL of it dropwise to the solution at a rate of 2.0 ml / min at a constant temperature Acetone was used to obtain a suspension, and 3.0ml of potassium hydrogen phthalate with a concentration of 0.1mg / L was added to the suspension as an additive, the crystal was grown for 2 hours, the crystal slurry was vacuum filtered, and the product was dried at 30°C and normal pressure for 6 hours To constant weight, obtain cefamandole sodium new crystal form product. The X-ray powder diffraction pattern of the product has characteristic peaks at diffraction angles 2θ = 4.7, 8.2, 13.1, 14.4, 17.2, 18.2, 19.1, 19.6, 21.2, 21.7, 22.1, 23.3, 25.2, and 31.0 degrees. DSC at 98 ° C There is a characteristic endothermic peak. The appearance of the new crystal form product obtained by the method is prismatic, its solubility is 5.1% hig...

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Abstract

The invention relates to a cefamandole nafate new crystal form and a crystallization preparing method thereof. The cefamandole nafate new crystal form is characterized by characterizing the characteristic peaks of a diffraction angle 2 theta degree and a DSC by using X-ray powder diffraction patterns, wherein the cefamandole nafate new crystal form is defined as VI. The preparing method comprises the following steps of adding the cefamandole nafate solid into the good solvent, and mixing at the temperature of 10-30 DEG C to enable the cefamandole nafate to dissolve completely, wherein the solution concentration is 0.05-0.4 g / ml; adding additives at different concentrations into the solution; adding a solventing-out agent into the solution, wherein the dosage of the solventing-out agent is 5-20 times the dosage of the good solvent; after cultivating the crystal, performing suction filtration on formed suspension liquid; drying to obtain a cefamandole nafate new crystal form product. The solubility of the new crystal form is improved by more than 5%; the new crystal form has higher solubility, so that the dissolution rate of a medicinal preparation can be improved. The traditional stable crystal form is of a needle shape, but the appearance of the new crystal form is of a prism shape, thus, the bulk density of products is improved by more than 8%, better mobility is realized, and accordingly convenience in package and transport of the products is improved.

Description

technical field [0001] The invention belongs to the technical field of medicine separation, and in particular relates to a new crystal form of cefamandole sodium and a crystallization preparation method thereof. Background technique [0002] The chemical name of Cefamandole Nafate is 7-D-(2-formyloxyphenylacetamide)-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl] -8-Oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, the molecular formula is C 19 h 18 N 6 NaO 6 S 2 , with a molecular weight of 512.50. The structural formula is as formula (I). [0003] [0004] Cefamandole sodium was developed by Lilly Company of the United States in 1972 and first listed in 1978. The trade name of injection is MANDOL. Cefamandole sodium is a second-generation semi-synthetic cephalosporin with strong bactericidal effect. It has some advantages of the first-generation and third-generation cephalosporins. It is relatively stable to β-lactamase and has low nephrotoxicity. ...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/12
CPCC07D501/36C07D501/12
Inventor 郝红勋陶灵刚何芳侯宝红吕军尹秋响王永莉龚俊波谢闯鲍颖
Owner TIANJIN UNIV
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