The crystallization process is a significant stage in the pharmaceutical industry. During the process of crystallization with cooling, it is possible for a secondary liquid phase to appear before the formation of crystals. This phenomenon is called "oiling out" or liquid-liquid phase separation (LLPS). In this article, we explore the oiling-out phenomenon in a binary system of water and vanillin using stability analysis based on Gibbsian surface thermodynamics. To obtain the full picture of oiling out, we investigated three cases: droplet-solute-lean liquid equilibrium (), crystal-solute-rich liquid equilibrium (), and crystal-solute-lean liquid equilibrium (). The phase diagram of the system is plotted using the NRTL model for activity coefficients, along with considering the effect of the interfacial curvature on the phase diagram. From the phase boundaries and free-energy diagram of each case, we showed that the occurrence of the oiling-out phenomenon is justified based on the lower energy barrier of the droplet formation compared to that of the crystal formation. However, the energy level of a stable crystal is significantly lower and hence more stable than that of a stable droplet. Finally, we have determined different regions for droplet and crystal formation in the metastable phase diagram based on their supersaturation and provide insight for the oiling-out phenomenon.
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Article Synopsis
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- Monitoring LLPS is crucial, and various process analytical technologies (PATs) have been used to identify separation boundaries, although these methods can be slow and costly.
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December 2020
Department of Chemical Engineering, Tokyo University of Agriculture and Technology (TUAT).
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