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Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof

A technology of tazobactam sodium and piperacillin sodium, which is applied in the field of medicine and chemical industry, can solve the problems of poor stability and no co-amorphous matter in the preparation process, and achieve the effect of good product stability

Active Publication Date: 2021-02-26
山东安信制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 1. Whether it is piperacillin (sodium) or other bactam (sodium), in the process of freeze-drying ingredients and freeze-drying heating, it is easy to cause product degradation to generate corresponding impurities;
[0008] 2. During the freeze-drying process, amorphous piperacillin sodium and amorphous tazobactam sodium are produced, and the product has poor stability
[0010] Piperacillin sodium and tazobactam sodium preparations have good clinical application value, but there is no research report on co-amorphous substances in its preparation process

Method used

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  • Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof
  • Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof
  • Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof

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Experimental program
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Effect test

Embodiment 1

[0040]Weigh 10.0g of tazobactam and 80.0g of piperacillin, add 1200ml of acetone to dissolve, slowly add ethyl acetate solution of sodium isooctanoate (34.3g of sodium isooctanoate in 275ml of ethyl acetate) dropwise at 20-25°C, drop After the addition, stir for 2-2.5 hours, filter, and vacuum-dry at 40-50°C for 4-5 hours to obtain 85.2 g of piperacillin sodium and tazobactam sodium co-amorphous substance, yield 93.29%, HPLC: 99.77% . Residual solvent: acetone 320ppm, ethyl acetate 879ppm. The product is analyzed by powder X-ray diffraction, infrared, and DSC, and the results are as follows: figure 1 , 2 and 5.

[0041] Such as figure 1 As shown, using Cu-Ka radiation, there is no sharp diffraction peak in the X-ray powder diffraction (XRPD) figure represented by 2θ angle, indicating that it is not a crystalline state, but an amorphous state.

[0042] Such as figure 2 As shown, using an aluminum crucible, under flowing nitrogen, in a closed cup with pinholes, at a heati...

Embodiment 2

[0046] Weigh 10.0g tazobactam and 80.0g piperacillin, add 1000ml methyl ethyl ketone to dissolve, slowly add sodium formate butyl acetate solution (13.2g sodium formate dissolved in 105ml butyl acetate) dropwise at 20~25°C, after the dropwise addition is completed, Stir for 2-3 hours, filter, and vacuum-dry at 40-50°C for 4-5 hours to obtain 84.5 g of piperacillin sodium and tazobactam sodium co-amorphous substance, yield 92.52%, HPLC: 99.61%. Residual solvent: butanone 89ppm, butyl acetate 680ppm.

Embodiment 3

[0048] Weigh 10.0g tazobactam and 80.0g piperacillin, add 900ml cyclohexanone to dissolve, slowly add sodium acetate methyl acetate solution (18.2g sodium acetate dissolved in 150ml methyl acetate) dropwise at 25-30°C, drop After the addition, stir for 2-3 hours, filter, and vacuum-dry at 40-50°C for 4-6 hours to obtain 84.8 g of piperacillin sodium and tazobactam sodium co-amorphous substance, yield 92.85%, HPLC: 99.72% . Residual solvent: cyclohexanone 320ppm, methyl acetate 620ppm.

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Abstract

The invention discloses a piperacillin sodium and tazobactam sodium co-amorphous substance and a preparation method thereof. The preparation method comprises the steps of dissolving piperacillin and tazobactam into an organic solvent in proportion, dropwise adding dissolved organic sodium salt (or inorganic sodium salt) in an anhydrous state, and separating out piperacillin sodium and tazobactam sodium mixed powder after reaction. The mixed powder is determined as a hydrogen bond bonded co-amorphous substance of piperacillin sodium and tazobactam sodium through powder X diffraction, infrared spectroscopy and DSC analysis. Compared with the traditional generation mode, the piperacillin sodium and tazobactam sodium co-amorphous substance prepared by the method has the advantages of low impurity content and good stability, the medication safety can be better improved, and the generation of adverse reactions is reduced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a piperacillin sodium-tazobactam sodium co-amorphous substance and a preparation method thereof. Background technique [0002] Piperacillin sodium is a ureidopenicillin antibiotic with broad-spectrum and high activity, but the problem of drug resistance is becoming more and more serious. Most of the drug-resistant rates of Escherichia coli and other Enterobacteriaceae bacteria have exceeded 50%. The main reason for this is due to Gram-positive (G + ) cocci and Gram-negative (G - ) bacteria can produce β-lactamases. The combined application of piperacillin sodium and β-lactamase inhibitor tazobactam sodium can make piperacillin play its antibacterial effect well through the enzyme inhibitory effect of tazobactam sodium. The antibacterial activity of piperacillin sodium and tazobactam sodium on various medium and heavy bacterial infections is similar to ...

Claims

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Application Information

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IPC IPC(8): C07D499/68C07D499/87
CPCC07D499/68C07D499/87
Inventor 陈中南周显峰杨庆坤侯传山李卓华秦春霞李洪云
Owner 山东安信制药有限公司
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