Crystallization method of ceftezole sodium

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...

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.

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