(542f) Evaluation of Liquid-Liquid Phase Separation and Spinodal Boundaries Using a Continuous-Flow Microfluidic Mixer

Liquid-liquid phase separation (LLPS), also known as oiling out, refers to the process where the liquid droplets with high concentration of solute phase separate in a supersaturated solution. Oiling-out is a common phenomenon among hydrophobic pharmaceutical compounds. The spontaneous nature of the transformation of oil droplets into solids makes LLPS very hard to measure. As a result, it is considered an undesired phenomenon and is typically avoided during the crystallization. Therefore, the most critical step in process development is to obtain the phase diagram to ensure the crystallization does not occur within the LLPS zone. Here, we have used the previously designed continuous-flow microfluidic mixer to evaluate the LLPS phenomena of Beta-Alanine. In this study, we present the isothermal ternary phase diagram of beta-alanine in water and isopropyl alcohol (IPA) or ethanol.

All the following experiments are performed using an optical microscope to track and record the appearance and disappearance of oil droplets. The microfluidic mixer consists of four tangential inlets. Two of them are streams of a concentrated beta-alanine solution in water, one is pure solvent (water), and the last one is pure anti-solvent (IPA or Ethanol). The procedure will start by fixing the ratio of the anti-solvent to solvent stream. Then we will start with the highest flowrate for the pure solvent stream at a fixed ratio of anti-solvent. After that, the flow rate of beta-alanine streams is gradually increased while that for the pure solvent is gradually decreased. The composition at which the droplets appear in the mixture is considered the spinodal point. Once the oil droplets appear, the flowrate of solvent stream is gradually increased until the droplets disappear. This composition indicates the binode. Finally, these spinodal and binodal points are used to plot the ternary phase diagram to highlight the LLPS zone.