Crystallization method of ceftezole sodium

A technology of ceftizole sodium and ceftizole acid, applied in the field of medicine, can solve problems such as affecting the quality of finished products, high difficulty, small product particle size, etc., so as to reduce impurities and polymer content, improve stability and safety, and improve crystal The effect of uniform particle size distribution

Inactive Publication Date: 2012-11-14
天津新丰制药有限公司
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0010] In CN102286001A, step ceftezole acid crude product is added in the aqueous solution containing the sodium bicarbonate of equimolar amount and isopropanol, stir, evaporate part of solvent, stir and crystallize, filter and obtain ceftezole sodium, this method and It is not clear whether the crystals obtained are type I, type II or mixed type crystals, and their quality stability is in doubt
[0013] CN101229129A, on the basis of Mr. Hu Changqin's research, used a designated solvent, gradient cooling crystallization, and clearly studied and controlled the crystal form, but did not involve the problem of ceftezole sodium polymer removal, and the invention still uses the traditional solvent analysis. Crystallization method is used for production, crystals are prone to coalesce in the production process, resulting in the final product particle size is very small, difficult to filter, the product is mixed with a large amount of crystallization mother liquor, which affects the quality of the finished product, and the traditional method often adopts the addition of crystallization Seed method, but the particle size and adding time of the seed crystal have a certain influence on the final particle size distribution of the finished crystal, resulting in fluctuations in the quality of the finished product
This method is difficult to ensure the uniformity of crystal particles, the repeatability between different batches, and the crystallization of the mixed solution of isopropanol and ethanol is used. limit requirements
[0014] In summary, the existing sterile powder of ceftezole sodium has the disadvantages of poor stability, temperature and light instability, etc., which have great limitations on the production and clinical application of the drug.
In addition, the current preparation method of ceftezole sodium cannot effectively solve the problems of hygroscopicity, polymer and other impurity content and crystal form control of ceftezole sodium.

Method used

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  • Crystallization method of ceftezole sodium

Examples

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Embodiment 1

[0044] A crystallization method of Ceftezole Sodium, the steps are as follows:

[0045] ⑴ Dosing: Aseptically treat the reaction kettle, filter, and utensils used. Add 1950g (4.63mol) of ceftezole acid, 390g (4.63mol) of sodium bicarbonate and 20L of purified water into a 50L reactor, stir at room temperature to completely dissolve, flush into nitrogen protection, and adjust to 7.5 according to the actual pH value;

[0046] (2) Decolorization: Add 60g of activated carbon to the above solution, stir and absorb for 30 minutes, then decarbonize through titanium rod filtration, and obtain the filtrate through two-stage filtration with 0.22μm microporous membrane;

[0047] (3) Impurity removal: add 19.5 g each of sodium bisulfite and EDTA to the filtrate obtained in step (2);

[0048] (4) ultrafiltration: adopt step (3) gained solution to adopt the ultrafiltration membrane ultrafiltration that cut-off is 1000;

[0049] (5) Crystallization: Transfer the filtrate to a 50L crystalli...

Embodiment 2

[0053] A crystallization method of Ceftezole Sodium, the steps are as follows:

[0054] (1) Dosing: carry out aseptic treatment to the reaction kettle, filter and utensils used; add 2000g (4.54mol) ceftezole acid, 382g (4.54mol) sodium bicarbonate and 20L purified water into the 50L reaction kettle, and stir at room temperature Make it completely dissolved, rush into nitrogen protection, and adjust to 7.5 according to the actual pH value;

[0055] (2) Decolorization: Then add 62.4g of activated carbon, stir and absorb for 30 minutes, decarbonize by titanium rod filtration, and filter in two stages with 0.22μm microporous membrane;

[0056] (3) Impurity removal: add 20 g each of sodium bisulfite and EDTA to the filtrate obtained in step (2);

[0057] (4) ultrafiltration: step (3) gained solution is adopted to cut off the ultrafiltration membrane ultrafiltration of 1000;

[0058] (5) Crystallization: transfer the filtrate to a 50L crystallization tank in a local 10000-class cl...

Embodiment 3

[0060] A crystallization method of Ceftezole Sodium, the steps are as follows:

[0061] (1) Dosing: Aseptically treat the reaction kettle, filter and utensils used, add 2120g (4.81mol) ceftezole acid, 405g (4.81mol) sodium bicarbonate and 21L purified water into the 50L reaction kettle, and stir at room temperature Make it completely dissolved, rush into nitrogen protection, and adjust to 7.5 according to the actual pH value;

[0062] ⑵ Decolorization: Then add 62g of activated carbon, stir and absorb for 30 minutes. Titanium rod filtration decarbonization, 0.22μm microporous membrane two-stage filtration;

[0063] (3) Impurity removal: Add 21.2 g of sodium bisulfite and EDTA to the filtrate obtained in step (2);

[0064] (4) ultrafiltration: step (3) gained solution is adopted to cut off the ultrafiltration membrane ultrafiltration of 1000;

[0065] (5) Crystallization: transfer the filtrate to a 50L crystallization tank in a local 10000-class clean area, add 12L of asepti...

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Abstract

The invention relates to a crystallization method of ceftezole sodium. The crystallization method comprises the steps of: dissolving ceftezole acid in a solvent, carrying out nitrogen washing protection, adding a salifying agent to adjust pH until the solid is completely dissolved, adding activated carbon, carrying out titanium rod filtering, carrying out ultrafiltration, adding the solvent in filter liquor under the ultrasonic wave condition, carrying out gradient cooling to separate out crystals, filtering, washing, carrying out suction filtration, and carrying out vacuum drying to obtain the ceftezole sodium. The crystallization method adopts an ultrasound crystallographic orientation method to be combined with a gradient cooling solvent crystallization method to obtain the ceftezole sodium which obviously improves hygroscopicity, is high in purity, even in particles and good in batch repeatability and is a stable type I crystal form, and thus stability and safety of products are obviously improved.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a crystallization process for preparing ceftezole sodium from ceftezole acid, in particular to a crystallization method of ceftezole sodium. Background technique [0002] Ceftezole sodium is the first generation of cephalosporins for injection, developed by Fujisawa Company in Japan, and first listed in Japan, South Korea, Italy and other countries. In 1995, the ceftezole sodium raw materials and injections of South Korea Shinfeng Pharmaceutical Co., Ltd. were approved for import in China; in 2002, Tianjin Xinfeng Pharmaceutical Co., Ltd. and Harbin Pharmaceutical Group General Factory obtained production approval. At present, it has also become the leading product of Tianjin Xinfeng, and its product trademark has also become a famous trademark in Tianjin. Its English name is Ceftezole Sodium; its chemical name is: (6R,7R)-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-8-oxo-7-[2 -Sodium...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/12
Inventor 李章才许龙哲崔连泉苏秋菊张梦云
Owner 天津新丰制药有限公司
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