Study On The Crystallization Process Of Paroxetine Hydrochloride

Paroxetine hydrochloride (PXH) is a potent and selective 5-hydroxytryptaminereuptake inhibitor and is useful as a therapeutic agent for various diseases such asdepression and Parkinson's diseases. Four crystal forms of paroxetine hydrochlorideanhydrate (PXHA) are known as A, B, C and D respectively. There are some seriousproblems in the production process of form A of paroxetine hydrochloride anhydrate(PXHAA), such as complicated procedure, poor quality and high content of residualsolvent. In this thesis, a better manufacturing scheme for PXHAA was presentedbased on a systematic study of crystallization processes.By indexing the PXHAA power X-ray diffraction data, the most possible crystalspace groups of PXHAA were determined. According to these data, the crystal spacelattice of PXHAA was determined by running Polymorph Predictor in commercialsoftware Cerius2. The theoretical crystal habit of PXHAA was predicted by BFDHmodel and AE model respectively. The results of model prediction resemble theobserved crystal morphology of experiment. Base upon the predicted crystal structureof PXHAA, the relative stability of paroxetine hydrochloride hemihydrate (PXHH),PXHAA and propan-2-ol solvate of PXH has been studied and the rule of thepolymorphic transformation has also been detected.Crystal yield is determined by crystallization thermodynamics. The solubility ofPXHH at different temperature and solvents was measured with dynamic method. Sixmodels and artifical neural networks approach were used to predict the solubility. Themetastable zone of PXH crystallization was also studied by laser method. The effectsof operation temperature, agitation speed and cooling rate on the width of metastablezone were observed and examined, which are necessary information for design andcontrol of crystallization process.Using FBRM, PVM, Malvern Mastersizer, AFM, TEM, DSC and SEM, thecrystallization process of PXHAA had been analyzed in detail. And the breakageproblem of secondary process had been especially studied. The data of CSD show thatthere is breakage problem in crystallization procedure of PXHAA. The minimumparticle size and metastable zone of breakage process had been proposed for the firsttime in this thesis.The experiential equations for secondary nucleation and crystal growth kineticswere determined by moment method. By linear regression analysis, and basing onexperimental data of crystal growth kinetics, experiential equations of minimumparticle size, maximum particle size, number of daughters produced in one breakageprocess, width of metastable zone of breakage process, breakage rate kernel anddaughter distribution were obtained.Base on population balance and mass balance equation, as well as analysis dataof crystallization process, the mathematical model for crystallization of PXHAA wasestablished. According to the simulation results, the optimum schedule for preparingPXHHA was discovered and high quality products were produced under the optimumschedule in a factory.No similar report to above study results has been published in literature up todate.