Study On Molecular Self-assembly Of Benzoic Acid Derivative Systems

Nucleation from solution is a key process affecting crystal design and controlled preparation,so understanding the crystal nucleation mechanism and studying the molecular self-assembly process in solution have been paid more and more attention.In this paper,benzoic acid derivatives are chose as the research object to study the nucleation process in solution systematically.The details are as following:Searched the crystal database,the crystal forms of the three selected substances,p-nitrobenzoic acid(PNBA),p-chlorobenzoic acid(PCBA)and p-methoxybenzoic acid(PMBA),were determined and prepared,and crystal structures were characterized and analyzed by differential scanning calorimetry,infrared spectroscopy and powder XRD diffractometer and so on.The result suggest PNBA have two forms and the relationship of two polymorphs are enantiotropically form.The solubility data of three model drugs in ethanol.2-propanol.ethyl acetate and acetonitrile were determined by static method.The solubility data were fitted and analyzed by empirical equation,such as λh equation,Apelblat equation and Van’t Hoff equation to establish the corresponding solubility model.The solubility data are the basic data of crystallization thermodynamics,which further paves the way for the nucleation process research.In addition,different concentrations of solution were prepared according to solubility data,and the aggregation of solute molecules in solution were analyzed by solution infrared spectroscopy.It was found that there were solvation monomers and hydrogen bond dimers of the benzoic acid derivatives in alcohol solvents and mainly in ethyl acetate and acetonitrile with solvation monomers.According to the measured solubility data,the nucleation induction time of three drugs with different solvents,temperature and supersaturation ratios was determined via cooling crystallization experiments.The relationship of induction time against different experimental conditions was analyzed,according to the classical nucleation theory,and the solid-liquid surface tension was calculated to analyze the factors influencing nucleation.And the effect of different crystallization conditions on polymorphism of p-nitrobenzoic acid was also studied.In order to further explore the molecular assembly process,the solution chemistry analysis,nucleation phenomenon and simulate calculation were combined.The desolvation is the key process during the nucleation pathway,from the view of intermolecular interaction.Finally,the process of solution mediated polymorphic transformation of p-nitrobenzoic acid was measured by in situ Raman spectroscopy.The impact of temperature and solvent on the transformation process were investigated and the rate-determining step was determined.And the heterogeneous nucleation of the transformation was also analyzed.The nucleation rate in 2-propanol,ethanol,ethyl acetate and acetonitrile increased in turn and it is revealed that solvent has significant influence on the transformation.