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Cefquinome crystal and preparation method thereof

A technology for cefquinoxime and crystals, applied in the field of cefquinoxime crystals and preparation thereof, can solve the problems of cefquinoxime amorphous state, thermodynamic instability, large drug consumption, etc. The effect of cheap and easy-to-obtain raw materials and simple preparation method

Active Publication Date: 2016-06-08
TIANJIN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One is that the solid dosage form is added to the feed for feeding, but the drug consumption is large, the effective utilization rate is low, the dosage is not easy to control, and the curative effect is slow
The second is injection administration of emulsion or suspension, but the absorption rate is slow and the bioavailability is low; and the micropowder is easy to block the needle, increasing the resistance of pushing the needle, which brings inconvenience to the injection
The third is to prepare a clear injection, but the resistance of pushing the needle is large, and the injection is still inconvenient.
The applicant’s previous research found that liquid-liquid phase separation often occurs during the preparation of cefquinome by the solution crystallization method—a second liquid phase appears in the original homogeneous solution, which is rich in cefquinoxime and viscous like an oily substance , firmly adhered to the bottom of the kettle, the crystallization process is unsustainable
And, even overcome the generation of oil precipitation phenomenon, the cefquinome that makes is also often amorphous state
Amorphous form is a thermodynamically unstable solid state with no fixed melting point, easy deliquescence, and low thermal decomposition temperature, so the shelf life of amorphous drugs is short, and even has potential safety hazards
These may be an important reason why there is no cefquinome crystal preparation method and there is still no cefquinome product on the market

Method used

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  • Cefquinome crystal and preparation method thereof
  • Cefquinome crystal and preparation method thereof
  • Cefquinome crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Step 1: At 3°C, add 0.088 g of activated carbon to the cefquinome solution containing 70 mL of water and 0.25 g / (mL of water), stirring for 30 minutes, and filtering. Step 2: Add the filtrate obtained in Step 1 to 490 mL of n-butanol within 60 minutes under stirring at 3°C ​​and 300 rpm. After adding, continue to stir for 2h. Then, filter out the milky white soft "mud" cake. A small amount of ethanol is added multiple times to wash the filter cake, then filtered, the filter cake is ground into a powder, and dried at 45° C. under vacuum for 10 hours to obtain the cefquinoxime crystals.

[0030] The X-ray powder diffraction pattern of the cefquinome crystal prepared in this example is at diffraction angle 2θ=7.49, 7.88, 9.62, 10.06, 11.94, 13.72, 14.42, 15.60, 16.00, 16.92, 18.43, 19.74, 20.52, 20.97, There are characteristic peaks at 22.64, 22.96, 23.66, 24.14, 25.24, 26.34, 28.72, 31.23 degrees. The TG-DSC curve has an endothermic weight loss of 5.3% at 40~110℃, and an ...

Embodiment 2

[0032] Step one: Dissolve 1.33 g of sodium carbonate in 30 mL of water. Weigh 5.24 g of cefquinome sulfate and add it to the sodium carbonate solution in small quantities under stirring at 30° C. and 300 rpm to perform acid-base neutralization reaction to generate cefquinome and sodium sulfate. After the reaction was completed, the system was clear and transparent, and the solution was golden yellow. Then, 45 mL of acetone was added to the solution, the flow acceleration rate was 3 mL / min, and sodium sulfate was precipitated. Filter and remove sodium sulfate to obtain a cefquinoxime solution with a concentration of 0.15 g / (mL water). At 30°C, add 0.055 g of activated carbon to the cefquinoxime solution, stir for 30 min, and filter.

[0033] Step 2: Add all the filtrate obtained in Step 1 to 300 mL of acetone within 10 minutes under stirring at 30°C and 300 rpm, and then stir for 12 hours. Then it was filtered and washed, and the filter cake was dried at 25° C. under vacuum for...

Embodiment 3

[0036] Step one: Dissolve 0.33 g of potassium carbonate in 20 mL of water. Weigh 1.18 g of the raw material Cefquinome Sulfate and slowly add it to the potassium carbonate solution under stirring at 17° C. and 300 rpm to carry out the acid-base neutralization reaction to generate Cefquinome and potassium sulfate. The reaction is complete after the system is clear and transparent, and the solution is golden yellow. Then, 60 mL of ethyl acetate was added to the solution at a flow rate of 3 mL / min to precipitate potassium sulfate. Filter to remove potassium sulfate to obtain a cefquinoxime solution with a concentration of 0.05 g / (mL water). At 17°C, add 0.02 g of activated carbon to the cefquinoxime solution, stir for 30 min, and filter.

[0037] Step two, prepare the crystal product of cefquinome: under the action of stirring at 17° C. and 300 rpm, all the filtrate obtained in step one is added to 170 mL of ethyl acetate within 35 minutes. Then, continue stirring for 7 hours. T...

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Abstract

The invention discloses a cefquinome crystal and a preparation method thereof. An X-ray powder diffraction spectrum of the cefquinome crystal has characteristic peaks at places where a diffraction angle 2theta is equal to 7.5 plus / minus 0.1, 7.9 plus / minus 0.1, 9.7 plus / minus 0.1, 10.1 plus / minus 0.1, 12.0 plus / minus 0.1, 13.8 plus / minus 0.1, 14.5 plus / minus 0.1, 15.5 plus / minus 0.1, 16.0 plus / minus 0.1, 17.0 plus / minus 0.1, 18.5 plus / minus 0.1, 19.8 plus / minus 0.1, 20.5 plus / minus 0.1, 20.9 plus / minus 0.1, 22.6 plus / minus 0.1, 22.9 plus / minus 0.1, 23.7 plus / minus 0.1, 24.2 plus / minus 0.1, 25.3 plus / minus 0.1, 26.3 plus / minus 0.1, 28.7 plus / minus 0.1, and 31.2 plus / minus 0.1. The preparation method comprises the steps of adding activated carbon in a cefquinome solution, stirring and filtering; adding filtrate into an organic solvent, thus obtaining the cefquinome crystal. The method is simple, high in yield and low in cost; safety is realized when the cefquinome crystal is used as a drug.

Description

Technical field [0001] The invention belongs to the technical field of chemical engineering crystallization, and specifically relates to a cefquinome crystal and a preparation method thereof. Background technique [0002] Cefquinome, also known as Cefquinol, Cefquinome, Molecular Formula C 23 H 24 N 6 O 5 S 2 , Molecular weight 528.69, CAS number 84957-30-2, chemical name: 1-(6R,7R)-7-[(2Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl Amino]-3-(5,6,7,8-tetrahydroquinolinyl-1-methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]octan-2- En-2-carboxy internal salt, the structural formula is shown in I. Since the development of Cefquinome by Hoechst AG in the 1980s, the raw materials used in the commercially available Cefquinome drugs, whether in solid preparations or injections, are their sulfuric acid addition salts-Cefquine Sulfate The solid form of oxime. Cefquinome Sulfate, molecular formula C 23 H 24 N 6 O 5 S 2 ·H 2 SO 4 , Molecular weight 626.69, CAS number 118443-89-3, chemical name:...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/46C07D501/12
CPCC07B2200/13C07D501/12C07D501/46
Inventor 鲍颖戚荣宝王利平李旭东郝红勋侯宝红刘爱玲王静康
Owner TIANJIN UNIV
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