Thermodynamics And Nucleation Mechanism Of Small Organic Molecule In Oiling Out Process

Oiling out is a phenomenon that often occurs during the crystallization of pharmaceutical organic small molecules,which often leads to the agglomeration of crystal,the reduction of purity,and even the formation of undesirable crystal habits and crystal forms.This thesis focuses on revealing the crystallization process in the case of thermodynamic and kinetic oiling out and nucleation pathway,and tries to further understand the oiling out crystallization process from micro and macro perspectives,so as to guide the oiling out crystallization process in the production practices.In this thesis,thermodynamic critical temperature of liquid-liquid phase separation,solubility and ternary phase diagram of ibuprofen under different solvent ratios were firstly determined at different temperatures.It is found that the liquid-liquid equilibrium curve changes very little with temperature.By combining the predecessors’ researches and analysis of phase law,it is found that the tie lines are not parallel to each other and do not intersect.Thus,we assume that thermodynamics liquid-liquid phase separation follows the principle that the water phase satisfies the optimal stable ratio and the oil phase satisfies the suboptimal stable ratio.Further,simulation was carried out according to the measured endpoints concentration data of tie lines,and it was found that the total energy of the liquid-liquid phase separation system was lower than that of the homogeneous system.Afterward,the effects of cooling rate and saturation temperature on the metastable zone width(MSZW)of oiling out and nucleation of ibuprofen in the ethanol-water system were investigated.It was found that at a lower cooling rate(below the critical cooling rate),the self-assembly behavior of ibuprofen solute molecules followed the classical nucleation theory.When the cooling rate of the system exceeds the critical cooling rate,the nucleation behavior of ibuprofen in the ethanol-water system follows a two-step nucleation mechanism.Interestingly,it was found that the oiling out temperature did not change with the cooling rate,which indicates that the first Gibbs free energy during two-step nucleation do independent on the driven force.At the same time,the modified Sangwal model is used to fit the nucleation metastable zone width(NMSZW),so as to realize the prediction of the critical cooling rate,which can be used to predict whether the system undergo one-step nucleation pathway or two-step nucleation.Then,the relationship between oiling out metastable zone width(OMSZW)and saturation temperature under different solvent ratios was investigated.It was found that with the increase of the saturation temperature,the OMSZW become narrowed and the critical temperature of liquid-liquid phase separation can be predicted in this way.Therefore,it provides a novel method for us to predict the critical temperature of liquid-liquid phase separation through OMSZW.Furthermore,by analyzing the crystal structure of the solute molecules,it is found that a weak π???π interaction and the hydrophobic effect may be the main murderer for the oiling out during nucleation process.Finally,by employing vanillin and ethyl vanillin as model substances,we further prove:1.The liquid-liquid phase equilibrium basically does not change with temperature.As the temperature increases,the liquid-liquid-solid equilibrium phase transitions to the liquidliquid equilibrium phase.The above phenomenon is consistent with that obtained from the ibuprofen-ethanol-water system,so we believe that the above phenomenon is universal.2.During the oiling out process,the cooling rate in the two-step nucleation path does not affect the OMSZW,which is most likely a universal phenomenon.3.As the saturation temperature increases,the OMSZW becomes narrower in the cooling process.Moreover,if the system is thermodynamically easy to liquid-liquid phase separation,it is also more favorable for oiling out kinetically.Finally,we propose two models to predict the thermodynamic critical temperature of liquid-liquid phase separation and the kinetic OMSZW based on the relationship between the saturation temperature and the OMSZW.