The Azithromycin'salts and its preparation

Release time:2014-12-02 15:16:32 viewed:
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1.Introduction of Product

      Azithromycin(C38H72N2O12,Mol:748.9) was a broad spectrum antibacterial compound derived from erythromycin A,and still the only marketed a 15-membered semi-synthetic macrolide antibiotic from the group of azalides,which systematic name was(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-1-3-O-methyl-alfa-L-ribo-hexopyranosyl)-oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14- heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamin)-beta-D-xylo-hexopyranosyl)oxy]-1-Oxa-6-azacyclopentadecan-15-one,It had the formula:
 
      Azithromycin showed an excellent antimicrobial activity against gram-positive and some cases of gram-negative bacteria,Clinical use of this macrolide was broadening its application to the treatment of various infections, particularly infections of the urinary tract, bronchial tract, lungs, sinuses and the middle ear.Compared to Erythromycin A,it was stability to acid,possessed high concentration in organic,effection lasted for a long time,broad antibacterial spectrum,side effect was too low,etc.when Azithromycin was administered in the dosage-form of an oral, the bioavailability was low(about 37%) it was a great waste in clinical,but it was same with the erythromycin, the solubility was very small in the water, and unable to prepare to the injection directly, Therefore,how  to make the stable salts to increase its solubility and application to clinic was the goal which the pharmacy researcher continuously diligently into studies.
 
2.The Related Research and Invention at China and Abroad
      In regarding to the preparation of Azithromycin'salts,We had found  large numbers of related reports at China,For example,CN1157824(Azrinomycin dihydric phosphate complex salt and its preparation),CN1123279(Azithmycin water-soluble salt, injection thereof and their usage),CN1205338(Synthetic method and medical application of azimycin water soluable salt),CN1259520(Adriamycin polybasic acid sodium salt complex salt),CN1344541(Water soluble Azithromycin salt and its eye drop),CN1493579(Injection preparation of arjimycin water soluble phosphate and its preparation method),CN1733789(Azithromycin tartrate preparation method),CN1775794(A preparation of Azrinomycin complex salt and its use),CN1789273(Azrinomycin dissoluble salt and its preparation use)and CN1798756(Azrinomycin citrate preparation method)etc,but they all reacted with organic acid or a weaker inorganic acid(or acid salt) to obtain Azithromycin'salts,it costed a lot,preparation technics was difficult and maneuverability was low,because the above process of form salts had carried out in water,it would make Azrinomycin decomposing,which was unable to guarantee the quality of the product;In overseas, the correlation report were very few, there were only statements in CZ288601(process for preparing Azrinomycin dihydrochloride),But the preparation was complex,and not easy to control.Therefore, we improved and innovated the preparation technics of Azithromycin'salts on the basis of  previous documents.
 
3.Technics Characteristic
      Our company studied one kind of water-soluble strong acid salt of Azrinomycin to be advantageous for the industrialization production and be able to use in the clinical treatment, its could inject in the muscle or the intravenous directly, it reacted with strong acid in a appropriate organic solvent, obtained the salt of Azrinomycin which could be used in the clinical treatment, the process as follows:
      Azrinomycin dissolved a suitable  organic solvent under the certain temperature condition, instigates and adds  sulfuric acid which dissolved in organic solvent in drops, in this process,the precipitated crystals were obtained, filters, obtained the crude of Azrinomycin, after the recrystallization,the high-purity Azrinomycin'salt were obtained.
      This technics was convenient operated, easy controlling,and the product with high purity. Its purity could reach 99.0% according to the analysis of High Performance Liquid Chromatography.
 
4.Synthesis Route
 
    m and n are 1 or 2,X halogen or sulphate(acid salt).
 
5. The Procedure of Research and Invention
      Our company had finished the Synthesis technics, structure certification and quality research of the medical material and its related dosage-forms of Azithromycin'salts. We gave a systematic research to the product's quality standard such as character,identification, inspectation, the related compounds and assay,the content in the light of CP2005 requirement for the quality of the medical material and related dosage-forms.So we made up the corresponding standard of quality controlling according to the experiment results. The results showed that the purity of the medical material from this technics could reach above 99.0%, related material less than 1.0%, and other standard of physics and chemistry being in line with the documents' reports. Besides, we were dealing with the research of the stability. So far we had finished the inspectation of stability for the product being tested as long as 24 months. The results showed us this product was stable under the room temperature condition, and the long-time experiment was proceeding. At the same time, the related patent application and administration protection were application.
 
6.the clinical research
      Confirmation result indicated that 60 patients treated with Azithromycin sulfuric acid injection,the clinical efficacy rate was 86.67%, the rate of bacterial elimination was 98.15%, The rate of ADR was 6.67%,other 60 patients were in the control group in which patients were treated by Lincomycin Injection in comparison,the clinical efficacy rate was 81.67%, the rate of bacterial elimination was 98.00%,The rate of ADR was 6.67%, which indicated no obvious differences in statistics.
      Azithromycin sulfuric acid injection which had reliable clinic effect was worthy of application on the treatment of infective diseases.