Cefodizime sodium has a wide antibacterial spectrum and can enhance the immune function of the human body. Cocci, Escherichia coli, Haemophilus influenzae and coryneform bacteria all have good inhibitory effect. But, cefodizime acid is as the key intermediate of synthetic cefodizime sodium, in the prior art, the purity of the cefodizime acid product sold on the market is not high enough, and the purity of its downstream product cefodizime sodium has certain limitation Therefore, it is necessary to carry out further research on its purification method.
At present, the preparation method of high-purity cephalosporin bulk drug cefodizime sodium generally adopts the solvent method process, and the specific steps are:
(1) sodium isooctanoate is dissolved in ethanol solution to obtain the ethanol solution of sodium isooctanoate;
(2) At 0-30°C, add ethanol, cefodizime acid, and triethylamine, mix and stir to dissolve, decolorize, and obtain cefodizime acid solution;
(3) Mix the above-mentioned ethanol solution of sodium isosulfate with the solution of cefodizime acid to separate out the solid of cefodizime sodium.
(4) Wash the filter cake with absolute ethanol and acetone, and filter with suction to obtain the wet material of cefodizime sodium; filter and dry.
However, in the long-term production practice, it was found that the prepared cefodizime sodium existed: the particles were relatively small and powdery; the static electricity was large, the fluidity was not good, and it was difficult to pack when making reagents; and the ethanol residue was large. The process still needs further improvement.
New refining process of high-purity cephalosporins raw material drug cefodizime sodium
Compared with other prior art schemes, the new process for refining the high-purity cephalosporin bulk drug cefodizime sodium has the advantages of simple operation, high yield and high product purity. The product prepared by the new process has the following advantages: the particle size of cefodizime sodium is uniform, the fluidity is good, and the packaging is easy; the solvent residue is low, the ethanol residue is below 0.3%, and the solvent residue is reduced by 90.0%. Concrete process steps are:
(1) First dissolve sodium isooctanoate in ethanol solution, add a small amount of hydrochloric acid until the pH of the solution is 6.0 to 6.5, and obtain an ethanol solution of sodium isooctanoate;
(2) At room temperature, sequentially mix ethanol, cefodizime acid, benzophenone hydrazone, sodium metabisulfite, and triethylamine, and stir until the cefodizime acid dissolves to obtain a cefodizime acid solution.
Use activated carbon for injection to decolorize the cefodizime acid solution at 0-30°C.
(3) decolorize the cefodizime acid solution obtained in step 2, then mix the decolorized cefodizime acid solution with the ethanol solution of sodium isooctanoate obtained in step 1, stir, add a small amount of hydrochloric acid, until the pH of the solution is 6.5～ 7.0, obtain the ethanol solution of cefodizime sodium crystal;
(4) The cefodizime sodium crystals are purified in a sterile-grade filter washing and drying machine using an ethanol solvent. Wash the filter cake with absolute ethanol for 15-20 minutes, and then filter with suction, then wash the filter cake with acetone for 15-20 minutes, and filter with suction to obtain the wet material of cefodizime sodium;
(5) Dry the cefodizime sodium wet material by using a sterile filter washing and drying machine.
Vacuum drying in a three-in-one drier for 1 hour, followed by hot water drying at 50-53° C. for 6-8 hours, to obtain a finished product of cefodizime sodium with a water content within 3.5% by weight.
Process Improvement of Sterile Grade Filtration Washing and Drying Machine for High-purity Cefodizime Sodium Raw Material Drug
(1) The design and assembly of the equipment are strictly in accordance with the requirements of the national GMP and the US FDA, fully complying with the requirements of the pharmaceutical production process, and the system is safe, stable and reliable;
(2) Equipment materials are strictly controlled. The parts in direct contact with the material are made of non-toxic, corrosion-resistant SUS316L material, PTFE or EPDM sealing material.
The filter uses SUS316L metal sintered mesh to avoid fiber generation;
(3) The inner surface of the equipment in direct contact with the material is flat, smooth, free of dead angles, and easy to clean and disinfect;
(4) The equipment does not pollute the environment outside the device, and measures such as dustproof, leakproof, heat insulation, and noise prevention are properly taken. Fully enclosed working state, the motor, reducer, and lifting device are protected by stainless steel covers, and the return channel of the jacket is insulated with thermal insulation felt, which greatly reduces heat loss and the impact on the outside world;
(5) Strictly adopt safe and reliable explosion-proof electrical appliances, and are equipped with pulleys for eliminating static electricity and other safety interlocking functions and safety devices.
(6) All pipelines for materials, solvents, nitrogen, etc. are designed without dead ends and blind pipes. The surface of the equipment is mechanically and automatically finely polished or spot-polished. The inner surface of the equipment is Ra≤0.4 and the outer surface Ra≤0.8;
(7) The stirring shaft and the side discharge valve stem are protected by metal bellows;
(8) Removable rotating cleaning spray ball for online cleaning;
(9) Dry-process double-end mechanical seal, nitrogen protection and cooling, and online leak detection.
(10) The dust collector can be CIP, and the rotary joint can be leak detected online.