| At present about two billion people are infected with tuberculosis in the world.Every year approximately8~10million new cases of TB are reported and2~3millionpeople die of it.China is not only one of the22TB prevalence countries in the world, butone of the world’s27MDR-TB prevalence countries. There are nearly1,300,000newcases of TB reported in China every year. China has the world’s second-largesttuberculosis patients, after India, and130,000people die of TB every year, more than thesum of other infectious disease death in China. So tuberculosis is one of critical illnessesto be controlled in China. The first-line treatment drugs of anti-tuberculosis are isoniazid,rifampicin, pyrazinamide, streptomycin and ethambutol hydrochloride, which mainlyused for the treatment of general initial TB patients and retreatment TB patients.Ethambutol hydrochloride is a kind of arabinose analogues, it was found in1961for its inhibition of Mycobacterium tuberculosis and Mycobacterium bovis. Ethambutol hydrochloride disrupts arabinogalactan synthesis by inhibiting the enzymearabinosyl transferase. It works by obstructing the formation of mycolyl-arabinogalactan-peptidoglycan complex in the cell wall. As a first-line treatment drug recommended by WHO, Ethambutol hydrochloride has an extremely important clinical significance in the field of anti-TB drugs.The chemical formula of Ethambutol hydrochloride is [2R,2[S-(R*，R*)]-R]-(+)-2,2’(1,2-Ethylenediimino)-di-1-butanol dihydrochloride,ethambutol is optical because ithas two chiral centers, It has L, D and meso isomers, only dextro isomer is clinicaleffective, its activity is200~500times higher than levo isomer and12times higher thanmesomer. Therefore, the optical purity of ethambutol hydrochloride make the clinicaleffect. By searching ethambutol synthesis approach in the literature, there is no report oncontrol and removal of the optical isomers of ethambutol. According to the need ofindustrial production, this paper selects a synthesis method, which is simple, low cost,high yield and the condition of reaction is mild in the research of synthesis process.Besides, it analyzes the sources of optical impurity and studied the removal methods ofoptical impurity. And the ultimate product has been confirmed by HPLC, IR, MS,1H-NMR and13C-NMR.In this paper, a method was established for the determination of ethambutolhydrochloride optical impurities by HPLC and the methodologicalvalidation has beendone. The sample solution was stable in4hours and ethambutol was also stable even inthe forced destructive condition. We studied the method of the optical impurities withlinear, responsible factors, reproducibility, recovery,limit of detection and quantitationlimit test. And the results meet the requirements of the technical guide of new drugs.Itshowed that the method established by HPLC can control the quality of the producteffectively.This paper has established a method for the determination of residual solvent ofethambutol hydrochloride by GC. Methanol, ethanol and1,2-dichloroethane were usedduring the synthesis of ethambutol hydrochloride, and the1,2-dichloroethane is belong toClass1solvent, methanol is belong to Class2solvent, ethanol is belong to Class3solvent. These three solvents were examined by headspace GC.The method are validated by linear, precision, reproducibility and recovery. And the results meet the requirementsof the guidance of new drugs.In this paper, the stability of ethambutol hydrochloride was investigated. Thecharacters,melting point,Specific Rotation,pH, loss on drying,related substances andcontents have been detected respectively by impact factors tests, accelerated stabilitytests and long-term stability tests. The results show that ethambutol hydrochloride isstable in storage conditions required.In summary, the method is provided to control the impurities of ethambutolhydrochloride in the process and quality research. It also provide a scientific guidance forthe packaging and storage through the stability tests of ethambutol hydrochloride. |
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