| Polymorphism is very common in solid organic drugs.Generally,different crystal forms of the same molecule often have different spatial lattice arrangement,which could lead to different physical and chemical properties,bioavailability,and even the efficacy of drugs.Therefore,researchers have paid more and more attention to the research of polymorphism in recent years.Among them,the nucleation of different crystal forms and the conditions for polymorphic transformation are particularly important.Typically,by controlling those processes,the efficiency of obtaining the target polymorph should be improved significantly.In this thisis,the preparation and transformation of azelaic acid polymorphs were studied in-depth,and the details were as followed.Two polymorphs of azelaic acid were sucessfully prepared by cooling crystallization in different solvents,and the effects of the solvents and the cooling rates on the two crystal forms were initially obtained.At the same time,the structures and morphologies of the two forms were characterized and identified by XRD,FT-IR and other instruments.In addition,the crystal habit of different polymorphs were predicted by using the BFDH model and AE model,which laid the foundation for subsequent crystal surface modeling and molecular simulation.The solubility of both polymorphs of azelaic acid in pure water,ethanol and propionic acid were measured by a gravimetric method,and the data were correlated by the Apelblat model.The results showed that the solubility of the two forms both increased with temperature,while both were the most soluble in ethanol and the least soluble in water.What’s more,the solubility of the alpha form of azelaic acid was greater than that of beta form in all solvents,which confirmed that the beta form was thermodynamically more stable than the alpha form under our experimental condition.In addition,the dissolution process of azelaic acid polymorphs in the above solvents were simulated using Materials Studio software.It was found that the discrepancy of diffusion rates of the two polymorphs in different solvents might be the reason for their solubility differences.The polymorphic transformation from the alpha to the beta form of azelaic acid was mainly studied.XRD and UV spectrophotometer were respectively used to quantitatively monitor the solid phase composition and liquid phase concentration during the transformation.As a result,it was concluded that the growth of the beta form should be the rate-controlling step in the entire polymorphic transformation process according to the concentration analysis.Specifically,the effect of temperature and solvents on the transformation rate were systematically studied.The experiments found that the effect of the solvent was the largest,and the transformation in ethanol was faster than that in propionic acid,while the conversion rate in water was the smallest.Based on the experiments and the molecular structures of different azelaic acid crystal forms,the polymorphic transformation in ethanol and propionic acid were further stimulated using Materials Studio software in order to reveal that how the solvent could affect the transformation process.First of all,it was found that the propionic acid molecules are more easily to be adsorbed on the crystal surface,which may competitively hinder the growth of solute molecules on the surface,resulting in a longer transition time.Then on the perspective of solute molecule diffusion,the calculation results indicated that the azelaic acid molecules in ethanol are more likely to diffuse in the solution,which make them effective growth units to promote the growth of stable beta forms so as to promote the transformation process.Finally,after the molecular dynamic calculation,it was found that the molecular conformation of azelaic acid in the ethanol solution was more similar to that in the beta lattice,which indicates that ethanol may be more advantageous solvent for the beta form than propionic acid under the experimental conditions. |
