Preparation,Characterization And Properties Of Aripiprazole Polymorphs

Most of solid active pharmaceutical ingredients(APIs)have polymorphs,and different polymorphic forms might have quite different solubility and stability,which will affect the dissolution,bioavailability and even safety of medicament.Therefore,it is of great significance to comprehensively explore the polymorphism of APIs in drug development.In this thesis,the preparation,characterization,thermodynamic properties,interconversion and morphology of three polymorphs of aripiprazole have been studied.In addition,the corresponding in vitro evaluation model had been established to evaluate the influence of polymorphs on dissolution.This research provides the basis for the selection,storage,quality control and evaluation of aripiprazole crystal form which ensure the effectiveness,safety and quality control of drugs.The specific research contents are as follows:(1)Preparation and characterization of aripiprazole form: form I,form III and monohydrate of aripiprazole have been prepared and characterized by PXRD,TGA,DSC,IR,Raman and DVS.In addition,the crystal structures of form III and monohydrate have been determined and analyzed.The results show that there are obvious differences in structure and morphology among the three forms,but none of them has hygroscopicity.(2)Study on crystal habit of aripiprazole: crystal habits of aripiprazole have been investigated.Different crystal habit will bring different properties,such as wettability,specific surface area and even stability.The results show that the thermostability of flaky form III is better than that of rod form III.The hygroscopicity of form III is positively related to the specific surface area.(3)Study on crystal transformation of aripiprazole: the stability and transformation of form I,flaky form III and monohydrate of aripiprazole have been evaluated by simulating the preparation process,the storage environment of APIs and products.The results show that the energy barriers of the three forms are low,and they are stable for a long time at room temperature.The experimental results are also in accordance with the thermodynamic theory and the prediction of crystal structure.The three forms of aripiprazole can be transformed to other forms under different crystallization conditions and temperature and humidity conditions.(4)Study on in vitro dissolution of aripiprazole: through the experiments of equilibrium solubility and intrinsic dissolution rate,the properties of three forms are compared.The results show that the order of equilibrium solubility and intrinsic dissolution rate in p H4.5 medium is form III> form I> monohydrate.In addition,the dissolution evaluation method of different forms in aripiprazole tablets is established and verified.The results show that when the content of monohydrate reaches more than 30%,the dissolution curve similarity of aripiprazole tablets was different to that of anhydrous tablets.