Production method of piperacillin sodium tazobactam sodium freeze-drying preparation for injection

A technology of piperacillin sodium and tazobactam sodium, applied in the field of medicine, can solve the problems of poor uniformity, high production cost, slow reaction speed and the like, and achieve the effects of improving stability, good product quality and fast reaction speed

Active Publication Date: 2013-08-14
山东安信制药有限公司
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0007] The existing production of piperacillin sodium and tazobactam sodium freeze-dried preparations for injection generally adopts piperacillin acid, tazobactam acid and sodium bicarbonate as reaction raw materials and auxiliary materials for production, but according to the observation from the actual production situation, the existing There are following 4 shortcomings in the production technology: (1) No matter the existing production method puts sodium bicarbonate into the mixed solution of piperacillin acid and tazobactam acid, or puts piperacillin acid into the sodium bicarbonate solution, A large amount of carbon dioxide foam will be generated during the reaction process, so when the feeding is too fast, it will easily lead to the phenomenon of flushing, and the method of continuous vacuuming must be used to remove the carbon dioxide generated during the reaction process, which is cumbersome to operate; (2) due to the large amount of carbon dioxide produced in the solution Carbon dioxide, it is difficult to observe whether the feed liquid has been clarified, which affects the judgment of the reaction end point; (3) due to certain errors in the judgment of the reaction end point, there is some unreacted piperacillin acid in the product, and piperacillin acid is unstable, so When doing the stability test, a part of impurities will be introduced due to the decomposition of piperacillin acid; (4) the sodium bicarbonate used for the reaction is weak in alkalinity, and the reaction speed in the feed-liquid reaction process is slow, the reaction cycle is long, and the production cost is relatively low. high
However, slow freezing can easily lead to "supercooling" during the freezing process. "Supercooling" will cause the dried product to be concentrated, resulting in poor uniformity and affecting the appearance of the freeze-dried product.

Method used

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  • Production method of piperacillin sodium tazobactam sodium freeze-drying preparation for injection
  • Production method of piperacillin sodium tazobactam sodium freeze-drying preparation for injection
  • Production method of piperacillin sodium tazobactam sodium freeze-drying preparation for injection

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Add 150ml of water, 80g of piperacillin acid monohydrate (molecular weight: 535.54, equivalent to 14.94cMol), and 10g of tazobactamic acid (molecular weight: 300.28, equivalent to 3.33cMol) in a 1L reactor. Dissolve 7.308g of sodium hydroxide (equivalent to 18.27cMol) in 350ml of water and slowly add to the reaction kettle with nitrogen at the bottom of the kettle and good stirring. During the alkali feeding process, the temperature of the reaction solution is controlled at ≤ 5°C, and the temperature of the feed liquid is controlled between 5-10°C after the feeding is completed. Finally adjust the pH to between 5.0-7.0, set the shelf temperature to -30°C, drop the shelf temperature to -40°C within 120 minutes, set the prefreeze temperature below -40°C, and stabilize 4- 8 hours. Vacuum to ≤-0.08MPa, heat up the plate layer to 55°C, and sublimation drying time is 6-12 hours. The vacuum degree of the second-stage drying of the product reaches ≤-0.05MPa, the temperature i...

Embodiment 2

[0027] Add 200ml of water, 160g of piperacillin acid monohydrate (equivalent to 29.88cMol), 20g of tazobactamic acid (equivalent to 6.66cMol) into a 2L reaction kettle, and pour nitrogen gas at the bottom of the reaction kettle under good stirring. Dissolve 14.62g of sodium hydroxide in 400ml of water (equivalent to 36.54cMol) and slowly add it to the reactor. During the alkali feeding process, the temperature of the reaction solution is controlled at ≤ 5°C, and the temperature of the feed liquid is controlled between 5-10°C after the feeding is completed. Finally adjust the pH to between 5.0-7.0, set the shelf temperature to -30°C, drop the shelf temperature to -40°C within 120 minutes, set the prefreeze temperature below -40°C, and stabilize 4- 8 hours; evacuate to ≤-0.08MPa, and the temperature of the plate layer rises from below -45°C to 55°C. The sublimation drying time is 6-12 hours, the vacuum degree of the second-stage drying of the product reaches ≤-0.05MPa, the temp...

Embodiment 3

[0029]Add 300ml of water, 200g of piperacillin acid monohydrate (equivalent to 37.35cMol), 25g of tazobactamic acid (equivalent to 8.33cMol) into a 2L reaction kettle, and pour nitrogen at the bottom of the reaction kettle under good stirring. Dissolve 18.272g of sodium hydroxide in 350ml of water (equivalent to 45.68cMol) and slowly add it to the reactor. During the alkali feeding process, the temperature of the reaction solution is controlled at ≤ 5°C, and the temperature of the feed liquid is controlled between 5-10°C after the feeding is completed. Finally adjust the pH to between 5.0-7.0, set the shelf temperature to -30°C, drop the shelf temperature to -40°C within 120 minutes, set the prefreeze temperature below -40°C, and stabilize 4- 8 hours; evacuate to ≤-0.08MPa, and the temperature of the plate layer rises from below -45°C to 55°C. The sublimation drying time is 6-12 hours, the vacuum degree of the second-stage drying of the product reaches ≤-0.05MPa, the temperat...

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Abstract

The invention discloses a production method of a piperacillin sodium tazobactam sodium freeze-drying preparation for injection and belongs to the technical field of medicines. The production method comprises the steps of reacting, prefreezing, sublimation drying, drying again and taking out of a box. According to the production method, in the step of reacting, sodium hydroxide is adopted for substituting sodium bicarbonate, so that no bubble is produced in a reaction process; and a sodium hydroxide solution is dropwise added into a turbid liquid containing piperacillin acid and tazobactam acid, reaction is carried out in a manner of adding nitrogen to the bottom of a reaction tank, and reaction speed of feed liquid can be increased while time that local concentration of sodium hydroxide is overhigh can be shortened, so that degradation effect of a high-concentration sodium hydroxide solution on piperacillin sodium tazobactam sodium is effectively avoided. According to the production method, mutual combination between quick freezing and slow cooling is realized on prefreezing of the piperacillin sodium tazobactam sodium freeze-drying preparation, so that a crystal form of the obtained piperacillin sodium tazobactam sodium freeze-drying preparation product, insoluble particles and related impurities of freeze-drying products are at the best level. The product piperacillin sodium tazobactam sodium freeze-drying preparation for injection prepared by using the production method disclosed by the invention is good in quality and low in impurity content.

Description

technical field [0001] The invention relates to a production method of a freeze-dried preparation of piperacillin sodium-tazobactam sodium for injection, which is suitable for all specifications of the freeze-dried preparation of piperacillin sodium-tazobactam sodium for injection (8:1) and for injection The freeze-dried preparation of all specifications of piperacillin sodium and tazobactam sodium (4:1) belongs to the technical field of medicine. Background technique [0002] Tazobactam sodium, molecular formula: C 10 h 11 N 4 NaO 5 S, molecular weight: 322.28, structural formula as shown below. Tazobactam is a new type of penicillane sulfone β-lactamase inhibitor developed by Japan Dapeng Pharmaceutical Co. Low toxicity, strong enzyme inhibitory activity and so on. [0003] [0004] Piperacillin sodium, molecular formula: C 23 h 26 N 5 NaO 7 S, molecular weight: 539.54, structural formula as shown below. It is an excellent variety of second-generation semi-sy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/496A61K9/19A61P31/00A61K31/431
Inventor 李素彬李保勇樊长莹李勇王峰寿俊华吴柯张兆珍朱绍万
Owner 山东安信制药有限公司
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