Piperacillin impurity and preparation method thereof

A piperacillin and impurity technology, applied in the field of medicine, can solve problems such as non-compliance, unknown impurity content cannot be effectively controlled, and product quality is affected

Inactive Publication Date: 2018-07-13
QILU TIANHE PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The unknown impurity content of RRT = 1.75 in piperacillin obtained from industrial production cannot be effectively controlled, and it does not meet the requirements of the ICH guidelines for unknown impurities ≤ 0.05%, which affects product quality

Method used

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  • Piperacillin impurity and preparation method thereof
  • Piperacillin impurity and preparation method thereof
  • Piperacillin impurity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Add 10g of finished piperacillin, 100ml of ethanol, 100ml of water, and 1.8g of sodium bicarbonate into a 500ml three-necked bottle, place the three-necked bottle in a water bath, control the temperature of the solution at 25-30°C, stir for 15 minutes, and the pH=7.97 solution Clear, no solids. After stirring for 25 hours, T=27°C, pH=8.67, start to add 2N HCl solution dropwise, control the dropping speed, after the dropwise addition is completed, T=28°C, pH=1.96, stir for 1 hour and then filter with suction, add 250ml of the solid into three ports In the bottle, add 100ml of water and raise the temperature to 80°C, stir for 30 minutes, cool down at 0°C and stir for 1 hour, then perform suction filtration and dry treatment. The impurity purity obtained by liquid phase detection of the obtained solid was 28.5%.

Embodiment 2

[0043] Add 10g of finished piperacillin, 100ml of ethanol, 100ml of water, and 2.0g of sodium bicarbonate into a 500ml three-necked bottle, place the three-necked bottle in a water bath, control the temperature of the solution at 30-35°C, stir for 15 minutes, and the pH=7.28 solution Clear, no solids. Under the condition of T=30-35°C, after stirring for 30 hours, T=31°C, pH=7.24, start to add 2N HCl solution dropwise, control the drop rate, after the dropwise addition, pH=2.48, stir for 1 hour and then suction filter , the obtained solid was added to a 250ml three-neck flask, 100ml of water was added and the temperature was raised to 80°C, and after stirring for 30 minutes, the temperature was lowered at 0°C and cooled and stirred for 1 hour, then dried by suction filtration. The impurity purity obtained by liquid phase detection of the obtained solid was 20%.

Embodiment 3

[0045] Add 10g of finished piperacillin, 100ml of ethanol, 100ml of water, and 1.8g of sodium bicarbonate into a 500ml three-necked bottle, place the three-necked bottle in a water bath, control the temperature of the solution at 25-30°C, stir for 15 minutes, and the pH=7.62 solution Clear, no solids. After stirring for 26 hours, T = 28°C, pH = 8.76, start to add 2N HCl solution dropwise, control the dropping speed, after the dropwise addition, T = 28°C, pH = 1.96, stir for 1 hour and then filter with suction, add the obtained solid to 250ml three ports In the bottle, add 100ml of water and stir at room temperature for 30 minutes, then cool and stir at about 0°C for one hour, then filter with suction for drying. The impurity purity obtained by liquid phase detection of the obtained solid was 25.6%.

[0046] 2. Separation of impurities with RRT=1.75

[0047] The liquid chromatography conditions are as follows:

[0048] Chromatographic column: Agient ZORBAX SB-C18 liquid chroma...

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Abstract

The invention discloses a piperacillin impurity and a preparation method thereof. The piperacillin impurity is shown as a formula (I); the piperacillin impurity is used as an impurity in a piperacillin synthesis process and appears in a piperacillin product. The preparation method of the piperacillin impurity comprises the following steps: taking piperacillin as a raw material; after dissolving with water and sodium bicarbonate, adding ethanol and reacting; after reaction is finished, dropwise adding an acid solution to adjust the pH (Potential of Hydrogen) to be equal to 1.5 to 3.0; filteringa separated-out product; adding water into a filter cake and dissolving; then cooling and separating out to obtain a piperacillin impurity crude product; then carrying out liquid chromatography separation and organic solvent extraction to obtain an impurity solution with the purity which is greater than or equal to 99 percent. According to the piperacillin impurity disclosed by the invention, anunknown impurity in the piperacillin RRT equal to 1.75 is synthesized and purified and an obtained impurity pure product is analyzed to determine the structure of the impurity; the impurity is a product obtained by carrying out opening ring ester formation on the piperacillin and ethanol and has no toxicity. The structure confirmation of the impurity and the preparation of the impurity pure product play an important role in quality control of the piperacillin. The formula (I) is shown in the description.

Description

technical field [0001] The invention relates to a piperacillin impurity and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] Piperacillin, chemical name: (2S,5R,6R)-3,3-dimethyl-6-[(R)-2-(4ethyl-2,3dioxo-1-piper (oxazicarboxamido)-2-phenylacetamido]-7-oxo-4-thia-1-nitrogen. Molecular weight: 517.55, molecular formula: C 23 h 27 N 5 o 7 S, the structural formula is as follows: [0003] [0004] Piperacillin is a semisynthetic semicarbazide benzyl antipseudomonal penicillin. It has strong antibacterial effect on some Gram-positive bacteria (such as Enterococcus, etc.) and most Gram-negative bacteria (Escherichia coli, Aerobacter, Neisseria Neisseria, etc.). There are many antibiotics with strong antibacterial effect on Pseudomonas aeruginosa, so they are used more. Because piperacillin has a strong bactericidal effect on bacteria in the breeding period, but has almost no effect on bacteria in the quiescent per...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 鄂德林杨家豪潘广鹏吕德帅孙政军张小勇
Owner QILU TIANHE PHARMA
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