Study On Polymorphs And Crystallization Process Of Theophylline

Theophylline is a kind of methyl steroids,which has been mainly used for the treatment of bronchial asthma,emphysema,bronchitis,and cardiac dyspnea.However,there still exists many problems in the production of theophylline,such as low purity,small crystal size,impure crystal form,and poor fluidity.In this work,the polymorphs and crystallization process are systematically studied for the existing problems of theophylline and theophylline monohydrate.Firstly,the crystal morphology,crystal structure and thermodynamic stability of theophylline Form I,Form II and theophylline monohydrate were studied by XRD,SEM,TGA and Raman spectroscopy.The characteristic peaks of XRD,crystal habits,melting points and characteristic peaks of Raman spectra about them were determined,which provided a theoretical basis for studying the crystal form and crystal habit of theophylline.Secondly,in the thermodynamic study of theophylline,the solubility data of theophylline Form I,Form II in pure solvent system(methanol,ethanol,isopropanol)and theophylline monohydrate in pure solvent A were measured by a dynamic method.The Modefied Apelblat equation,the Van’t Hoff equation and the NRTL equation were used to fit the experimental data,and the related thermodynamic properties were calculated by Van’t Hoff equation,which provided a theoretical basis for the study of crystal transformation process and process design.Thirdly,the solution-mediated transformation of theophylline from form I to form II was studied by using in-situ Raman and UV spectra method.The effects of different system temperatures and different solvents on crystal transformation process were investigated.The dissolution-precipitation model of the crystal transformation process was established,and the transformation process was simulated by the model.The simulation results were ideal.Lastly,on the basis of above studies,the processes of theophylline Form II and theophylline monohydrate were optimized by studying the effects of crystallization method,initial concentration,stirring intensity and cooling rate on the quality of the final product.According to above experimental results,the optimized operating conditions of them were determined.The products prepared by the optimal process are superior to the original process in terms of purity and particle size.The results in this paper provide a theoretical support on the industrialization and industrial scale-up of the theophylline crystallization process.