Method for preparing piperacillin sodium and tazobactam sodium freeze-dried powder by microreactor

Abstract

The invention discloses a method for preparing piperacillin sodium and tazobactam sodium freeze-dried powder by a microreactor. According to the method, an inorganic alkali solution and a piperacillinand tazobactam suspension solution enter a mixer to be mixed together by controlling a certain flow rate and enter a microreactor to react, the mixture is taken out of the microreactor after the reaction is completed, and piperacillin sodium and tazobactam sodium freeze-dried powder is obtained after filtration, sterilization and freeze-drying. According to the method, rapid reaction of the microreactor is utilized, so that degradation impurity increase caused by too high local concentration of alkali liquor is avoided, nitrogen does not need to be introduced in the reaction process, carbon dioxide generated in the reaction process does not need to be removed by vacuumizing and is directly discharged into the air; and due to short residence time in a micro-reaction unit and rapid reaction, the spraying phenomenon caused by carbon dioxide is avoided, so that the reaction steps are greatly simplified, the production period is short, the degradation impurities are few, the product stability is good, and the production cost is low.

Description

technical field [0001] The invention relates to a method for preparing piperacillin sodium-tazobactam sodium freeze-dried powder with a microreactor, and belongs to the technical field of medicine. Background technique [0002] Piperacillin sodium and tazobactam sodium are a compound antibiotic developed by Japan Dapeng Pharmaceutical Co., Ltd. In the compound preparation, piperacillin sodium is a broad-spectrum semi-synthetic penicillin antibiotic, and tazobactam sodium is a β- Lactamase inhibitors, when the two are used in combination, can produce obvious synergistic effects, clinically suitable for Staphylococcus, Escherichia coli, Citrobacter, Klebsiella, Enterobacter, which are sensitive to this product Genus, Providencia, Pseudomonas aeruginosa caused moderate to severe infection. Due to the excellent clinical performance of piperacillin sodium and tazobactam sodium, it has been widely used clinically at home and abroad, and the market demand is very large. [0003] ...

AI Technical Summary

Problems solved by technology

[0008] 2. A large amount of carbon dioxide is produced during the solution process. It is difficult to observe whether the feed liquid is clear, which affects the judgment of the reaction end point. If the feed liquid is not fully reacted, it will easily lead to increased impurities in the finished product;

[0009] 3. Sodium bicarbonate is used for the reaction, the reaction of the feed liquid is slow, and the reaction is generally completed in 6-8 hours, the reaction cycle is long, the degradation impurities are many, and the production cost is high

[0010] Patent CN103239454A has reported a kind of production method of piperacillin sodium tazobactam sodium freeze-dried preparation for injection, this method adopts sodium hydroxide to replace sodium bicarbonate, and sodium hydroxide solution is suspended in piperacillin and tazobactam Dropping in turbid liquid, and need to pass nitrogen gas in the reaction tank, the operation is cumbersome, and the dropping process may easily lead to excessive local alkalinity, resulting in degradation impurities

[0011] Patent CN105616415A discloses a method for preparing piperacillin sodium and tazobactam sodium. This method needs to firstly put citric acid and sodium bicarbonate into the reaction tank, and after adjusting the pH, add piperacillin and tazobactam At the same time, sodium bicarbonate solution is added dropwise, and the vacuum reaction is performed after feeding. Although the product obtained by this method has good stability, increasing the citric acid and sodium bicarbonate used to stabilize the pH of the feed liquid increases the reaction cost, and there are also some problems in the reaction. A large amount of carbon dioxide is produced, easy to flush

Images