Study On Kinetic Prediction Of Ampicillin Crystal Morphology

Crystal morphology is one of the most important indicators of product quality in crystallization process and always has a great effect on the industrial application of crystal products.In this paper,ampicillin was selected as the model drug.The morphology of ampicillin in aqueous solution was studied experimentally.Then several classic theories were used to predict the crystal morphology of ampicillin and the research towards kinetic prediction of ampicillin was carried out.In this work,ampicillin crystals were prepared in aqueous solution.It’s found that ampicillin grew as a long-rod shape,with {100} and {0 11} faces exposed as the main faces.The crystal structure was optimized and the intermolecular interactions were calculated by the density functional theory(DFT).The Hirshfeld surface was used to analyze the interactions and the packing modes of ampicillin crystal.The crystal morphology of ampicillin was predicted by BFDH model,AE model,equilibrium model and spiral growth model.Neither the BFDH nor AE model could correctly predict the crystal habit of ampicillin.The prediction result of equilibrium model also deviates from the morphology observed.Considering the solvent effect and the kinetic factors in the crystal growth process,spiral growth model gives the best result.A kinetic Monte Carlo model was developed to predict the morphology with twonucleation mechanism and spiral growth mechanism.The effects of surface diffusion and simulation times on crystal growth were investigated,and then the model parameters were determined.The correctness of the Monte Carlo model was verified by Kossel crystal model,and the effects of input parameters,such as crystal growth mechanisms and intermolecular forces,on the relative growth rate of crystal plane were studied.On the basis of the theoretical model,another kinetic Monte Carlo model for the morphology prediction of actual crystals was developed,with the distribution of interactions and the types of growth units reconsidered.The crystal habit of ampicillin in aqueous solution was predicted.With the kinetic factors of crystal growth considered,the Monte Carlo model using tow-dimension nucleation mechanism yields similar results to AE model.A new simulation method for spiral growth model was developed and the Monte Carlo model using spiral growth mechanism could accurately predict the crystal habit within a certain range.