Research On A Simple Synthesis Method Of Retigabine And Quality Control Method For Pharmaceutics

Epilepsy is a common serious neurological disorders,and is featured with repeated epileptic seizure caused by abnormal discharge of brain neurons.There have been more than 50 million cases worldwide.Retigabine is a new antiepileptic drug,which was used as the partial treatment for refractory epilepsy and onset seizures in adults,and was approved for sale in the European Union and the United States in 2011.There are two main contents in this thesis.Part 1 is the synthetic technology research of Retigabine pharmaceuticals,to get Active Pharmaceutical Ingredients(APIs)to meet the registration requirements.Firstly the reported synthetic technologies were reviewed and analyzed.Targeted with getting final product with qualified impurities(less than millesimal for single impurity),it studied the reaction solution,reaction temperature,reaction time and material molar ratio and other key items,so as to confirm the optimal reaction conditions.Otherwise,the stability of final products was studied.In this thesis,the target compound was synthesized from5-Fluoro-2-nitroaniline,which reacted with 4-Fluorobenzylamine by nucleophilic substitution to give 2-amino-4-(4-fluorobenzylamino)nitrobenzene,with the following reduction reaction of nitro and selective acylation without separation.So the final product was got by refining.The synthesis method was suitable for industrial production for the simple process routes and feasible materials.The structure of the product retigabine was confirmed by ~1H-NMR and MS.Part 2 is the study on quality control method for retigabine preparations.The main purpose is establish a detection method through the methodology study and make clinical quality standard and limits.Through a lot of experiments,the feature,weight difference,inspection,related substances identification,content determination,dissolution test methods were confirmed,and the corresponding methodology verification was made.The test results showed that the detection methods used were conform to the corresponding validation index in quantitative limit,accuracy,precision,specificity,detection limit,linear,durability and other aspects,in order to control and assurance drug quality.On the basis of the research on the quality control method,the quality standards were normalized so as to make the quality standards comply with the Chinese pharmacopoeia(2015),and explain the basis for quality standards.