Investigation Of Oiling-out Phenomenon And Crystal Agglomeration Control In Solution Crystallization

Oiling-out phenomenon,also known as liquid-liquid phase separation,often occurs before nucleation event during the solution crystallization process.The occurrence of oiling-out not only makes the crystallization process more complicated and increases the difficulty of the precise control operation of the solution crystallization process,but also affects the quality of the final crystal product.Therefore,the thermodynamic analysis and kinetic characteristics of oiling-out phenomenon during the solution crystallization process are needed to be studied and analyzed.It is really important to understand the mechanism and key factors relate to oiling-out crystallization process,and the investigation of the effect of oiling-out on the solution crystallization process and product morphology are of great significance for the precise control of the solution crystallization process and the improvement of product quality.The main purpose of this work is to clarify the types of oiling-out by systematically studying the oiling-out crystallization processes and to explain the mechanism of different oiling-out phenomena from the perspective of thermodynamics,and to design appropriate oiling-out crystallization routes to precisely control and to improve the crystal morphology of the final crystalline product.This research provided guidance for the operation and control of the oiling-out crystallization process in industrial manufacturing process.The main research contents are as follows:1.The ethylvanillin-ethanol-water system was selected as an example to investigate the thermodynamic oiling-out process.Firstly,the ternary phase diagrams under different temperature were measured by dynamic method,and the single-phase crystallization operational area and the oiling-out operational area were determined;Then,by designing an appropriate crystallization trajectory,the oiling-out phenomenon and the agglomeration have been avoided successfully.This part of the research provides guidance for the control of the thermodynamic oiling-out crystallization process,and is beneficial to the optimization of the product properties.2.The cefquinome-acetone-water system was selected as example to investigate the dynamic oiling-out process.Firstly,the jelly-like phase were characterized,and it was found that the essence of the jelly-like phase is a viscous oil phase rather than a gel.Then,the ternary metastable phase diagram of cefquinome-acetone-water was determined by a dynamic method,and the jelly-like phase formation area and crystal formation area were determined.In addition,through the process analysis technology,the reverse antisolvent crystallization process was monitored,and the mechanism was clarified.The sticky jelly-like phase was successfully avoided by reverse antisolvent crystallization process,and the crystalline cefquinome was obtained for the first time.The crystalline cefquinome has a higher bioavailability than the commercial cefquinome sulfate,and has a bright market application prospects.3.The propylparaben-ethanol-water system was selected as an example to investigate the crystal agglomeration control and process mechanism in the oiling-out crystallization process.Through the design of different crystallization trajectories,the influence of different oil phase and water ratios on the crystal agglomeration in the oiling-out crystallization process was investigated,and unagglomerated crystals were successfully obtained under the condition of high oil phase ratio.At the same time,the process analysis technology was used to study the mechanism of crystal agglomeration under the condition of low oil phase ratio.Based on the analysis of the thermodynamic phase diagram,this study accurately controls the crystal agglomeration behavior during the oiling-out crystallization process,which is beneficial to other similar oiling-out systems.4.The propylparaben-ethanol-water system was selected to investigate the effect of wet milling on crystal agglomeration at different stages in the oiling-out crystallization process,and the effects of ultrasound and seeding were also analyzed and compared.It was found that wet milling can effectively reduce the particle size of the product,and the agglomeration.The nucleation-control technology provides a new direction for precise control agglomeration during the oiling-out crystallization process.