Analysis and Control of Polymorphism Transformation Process of Drug

Author:Wu Song Gu

Supervisor:gong jun bo


Degree Year:2017





To obtain desired properties of pharmaceuticals or other solid state products,crystallization is playing a more and more important role in chemical process.Different crystal forms possess diverse physicochemical characteristics.The target crystal form can be prepared by synthetically controlling these process parameters.In addition to the intrinsic nature,particle characteristics are the most important factor on powder performance.Many products(e.g.stable forms,solvates)are not prepared directly from nucleation and growth in solution,but obtained from phase transformation.From this point of view,this project is deal with the relationship between phase transformation and powder performance.In this work,we employed sulfadiazine,gabapentin and azithromycin as our model compounds to show that how to control the powder properties through the phase transformation process and gain more insights into the phase transformation mechanismFirstly,we attempt to solve the problems of low bulk density and poor flowability of sulfadiazine in industrial.Generally,sulfadiazine is obtained by reaction and precipitation which always generate extreme huge supersaturation thus leading to the phenomenon of spontaneous nucleation.Consequently,the particles are needle-like shape and very small.The powder has poor tableting performance.In this case,we proposed that phase transformation may be a way to improve the powder performance of sulfadiazine.We designed and prepared N-,ethyl-pyrrolidone solvate,1,4-dioxane solvate and tetrahydrofuran solvate.The flowability and particle size distribution of solvate are better than that of sulfadiazine.Secondly,the phase behavior between sulfadiazine and solvate was studied and we found that sulfadiazine can transform into these solvates in corresponding solvents.The mechanism of transformation is traditional solvent mediated phase transformation.Interestingly,these solvates could transform into sulfadiazine immediately when suspended in water or alcohols.The product particles can retain the original shape and size of the solvate particles.The dissolution,nucleation and growth were done in a limited space of the original particles during the phase transformation process.We propose a new mechanism call solvent penetration mediated phase transformation according to the experimental phenomena and theoretical analysis.Thirdly,we compared the phase transformation difference between gabapentin and sulfadiazine.Then the phase transformation of gabapentin from form I to form II and the effect of solvent on the phase transformation were researched.And the phase transformation mechanism belongs to the classical solvent mediated phase transformation in alcohols.However,there is no obvious dissolution process in the whole transformation process in acetone,acetonitrile and ethyl acetate.But the product particles retain the shape and size of original particles in these solvents.There exist a dehydration and self-cleaving phenomenon in this process.So we proposed solvent-mediated non-oriented self-aggregation transformation.Finally,we compared the agglomeration caused by phase transformation mentioned above and the agglomeration of azithromycin.The research was focused on the reasons of agglomeration.It was found that there is a phase transformation in the anti-solvent crystallization process.Due to surface nucleation and hydrate transformation,the agglomerated particles present bad flowability and bulk density.According to the thermodynamic data the solution of inhibiting and avoiding phase transformation was proposed to obtain the products which can meet the requirements.We propsed the mechanism of solvent penetration mediated phase transformation and solvent-mediated non-oriented self-aggregation transformation.They can designe and prepare the well-defined shape and size of particles.The quality of the product is improved.