Synthesis Of Alogliptin Preparation Of Tables

Nesina（Alogliptin Benzoate）is developed by Takeda Pharmaceutical Company Limited,Osaka Plant.It is allowed to go pubic by Food and Drug Administration in January 2013.It is a dipeptidyl peptidase-IV inhibitor for the treatment of type 2diabetes.This experiment synthesizes alogliptin benzoate API.Orthogonal test is used to optimize the technology of alogliptin benzoate tables.The dissolution behavior of prepared tablets is similar to that of original tables and it is suitable for industrial expansion.The research contents of this paper were as follows:1.The synthesis of alogliptin benzoate.Firstly 3-methyl-6-chloro-uracil react with2-bromomethyl-benzonitriletoget2-（6-methylchloride-3-2,4-dichloro generation-3,4-dihydro-2H-pyrimidine-1-methyl）-benzonitrile,Andthenreactwith（R）-3-Boc-aminoperidine to eliminate Boc.At last salified with benzoic acid to obtain alogliptin benzoate.The API is white powder and the yield is 70%.According to the¹H-NMR and HLPC-MS to ensure the construction and purity of alogliptin benzoate.2.The preparation study of alogliptin benzoate tables.According to the prescription pre-design,single factor affecting test results,the prescription and production processes of alogliptin benzoate tables are determined by orthogonal test.To optimize zhe ratio of mannitol to microcrystalline cellulose,the amount of 3%HPMC water solution,the amount of croscarmellose sodium and its ratio of the inside to outside.The optimized prescription is alogliptin 34 g,mannitol 50 g,microcrystalline cellulose 50 g,3%HPMC water solution 62g,microcrystalline cellulose inner-added 20 g,microcrystalline cellulose external-added 10g,magnesium stearate 1.6 g（1000 pieces）.To smash the API、microcrystalline cellulose,mannitol,croscarmellose sodium and through 100 mesh screen.Mix zhe API,microcrystalline cellulose,mannitol and two thirds of croscarmellose sodium evenly.To configuration the 3%HPMC water solution and put into the raw material.Pass the product through 20 mesh screen to give the particles.To the product dry at 70℃.Put the magnesium stearate and a third microcrystalline cellulose into the particles.Mixing the particles and put them become tables.3.The quality standard study of alogliptin benzoate tables.Using f₂ factor method to compare dissolution curves of original alogliptin benzoate tables with different concentrations in four different medium,which showed that the dissolution curves of self-produced tables and original research alogliptin benzoate tables are similar.To check the content,brittleness and hardness of the self-produced tables.The results show that they are in accordance with the requirements of the Chinese Pharmacopoeia（2015）.To check the loose density,real density and rest angle of the particles.The results show that the liquidity and compressibility of the particles is good.4.The stability experiment.The results show that the appearance,content and dissolution do not process a significant change during the test.However the moisture absorption is obvious when put in the high humid environment.But the content and dissolution do not process a significant change.So suggesting that this tablet need to be keep in dry environment.