Aseptic grade filtration, washing and drying machine for cephalosporin raw materials

 Cefdiazine sodium was jointly developed by the German company Hirst and the French company Russell and was introduced to the Chinese market in 1994. Cefdiazine sodium has a broad antibacterial spectrum and can enhance the immune function of the human body. It has a good inhibitory effect on Streptococcus pneumoniae, Streptococcus, Klebsiella, Proteus vulgaris, Neisseria neisseri, Salmonella, Neisseria meningitidis, Escherichia coli, Haemophilus influenzae and Corynebacterium, etc. However, as a key intermediate in the synthesis of cefdiazine sodium, the purity of cefdiazine acid products sold on the market in the current technology is not high enough, which has a certain impact on the purity of its downstream product, cefdiazine sodium, and cannot meet the demands of cefdiazine sodium producers. Therefore, it is necessary to conduct further research on its purification methods.

At present, the preparation method of high-purity cephalosporin raw material cefdiazine sodium generally adopts the solvent method process, and the specific steps are as follows:

Dissolve sodium isooctanoate in an ethanol solution to obtain an ethanol solution of sodium isooctanoate.

(2) At 0 to 30℃, add ethanol, cefdiazine acid and triethylamine, mix and stir until clear, then decolorize to obtain cefdiazine acid solution.

(3) Mix the above-mentioned sodium anisotropic acid ethanol solution with cefdiazine acid solution to precipitate solid cefdiazine sodium.

(4) Wash the filter cake with anhydrous ethanol and acetone, then filter it by suction to obtain cefdiazin sodium wet material. Filtration and drying.

However, in the long-term production practice, it was found that the prepared cefdiazine sodium had the following problems: the particles were relatively small and in powder form; High static electricity, poor fluidity, and difficulty in aliquoting reagents; And it has disadvantages such as a large amount of ethanol residue. This process still needs further improvement.

A new refining process for high-purity cephalosporin raw material drug cefdiazine sodium

The new refining process for high-purity cephalosporin raw material cefdiazine sodium has the advantages of simple operation, high yield and high product purity compared with other existing technical solutions. The products prepared by the new process have the following advantages: cefdiazine sodium particles are uniform in size, have good fluidity, and are easy to be repackaged. The solvent residue is low, with the ethanol residue below 0.3% and the solvent residue reduced by 90.0%. The specific process steps are:

First, dissolve sodium isooctanoate in an ethanol solution and add a small amount of hydrochloric acid until the PH of the solution is 6.0 to 6.5, obtaining an ethanol solution of sodium isooctanoate.

(2) At room temperature, ethanol, cefdizinic acid, benzophenone hydrazone, sodium bisulfite and triethylamine were mixed in sequence and stirred until cefdizinic acid was dissolved to obtain cefdizinic acid solution. The cefdiazine acid solution was decolorized with injectable activated carbon at 0 to 30℃.

(3) Decolorize the cefdiazine acid solution obtained in step 2, then mix the decolorized cefdiazine acid solution with the ethanol solution of sodium isoocoocate obtained in step 1, stir, and add a small amount of hydrochloric acid until the PH of the solution is 6.5 to 7.0, to obtain the ethanol solution of cefdiazine sodium crystals.

(4) The sodium cefdiazine crystals were purified using ethanol solvent in a sterile filtration, washing and drying machine. Wash the filter cake with anhydrous ethanol for 15 to 20 minutes, then filter it by suction. Wash the filter cake with acetone for another 15 to 20 minutes, then filter it by suction to obtain cefdiazin sodium wet material.

(5) Use a sterile grade filtration, washing and drying machine to dry the wet cefdiazine sodium material. Vacuum drying is carried out in a three-in-one dryer for 1 hour, followed by hot water drying at 50-53℃ for 6-8 hours to obtain the finished product of cefdiazine sodium with a weight moisture content of less than 3.5%.

Process improvement of aseptic filtration, washing and drying machine for the refinement of high-purity cephalosporin raw material cefdiazine sodium

(1) The design and assembly of the equipment are strictly carried out in accordance with the requirements of national GMP and the US FDA, fully meeting the requirements of the pharmaceutical production process. The system is safe, stable and reliable.

(2) The materials of the equipment are strictly controlled. All components that come into direct contact with materials are made of non-toxic and corrosion-resistant SUS316L material, PTFE or EPDM sealing materials. The filter screen adopts SUS316L metal sintered mesh to avoid fiber generation.

(3) The inner surfaces of the equipment that come into direct contact with the materials are flat, smooth and free of dead corners, making them easy to clean and disinfect.

(4) The equipment does not cause pollution to the environment outside the device and proper measures such as dust prevention, leakage prevention, heat insulation and noise prevention are taken. The fully enclosed working state ensures that the motor, reducer and lifting device are protected by stainless steel covers. The jacketed return channel is insulated with thermal insulation felt, significantly reducing heat loss and the impact on the outside world.

(5) Strictly adopt safe and reliable explosion-proof electrical appliances, and be equipped with pulleys for eliminating static electricity and other safety interlock functions and safety devices.

(6) All pipelines for materials, solvents, nitrogen, etc. are designed without dead corners or blind pipes. The surfaces of the equipment are all mechanically and automatically finely polished or pitted polished. The Ra on the inner surface of the equipment is ≤0.4, and the Ra on the outer surface is ≤0.8.

(7) The stirring shaft and the side discharge valve stem are protected by metal bellows.

(8) Removable rotating cleaning spray balls for online cleaning;

(9) Dry double-end face mechanical seal, nitrogen protection and cooling, can be used for online leak detection.

(10) The dust collector can be CIP, and the rotary joint can be used for online leak detection.

Photos of the aseptic grade filtration, washing and drying machine for the refined cephalosporin raw material drug cefdiazine sodium