Liquid-Liquid Phase Separation in Crystallization

Liquid-Liquid Phase Separation (LLPS) in crystallization, also known as oiling out or phase demixing, is a phenomenon is characterized by the formation of a dispersed phase (solute rich droplets) and a continuous phase (solute lean) from an initial single liquid phase. LLPS is often encountered during the development of an Active Pharmaceutical Ingredient (API). Liquid-Liquid Phase Separation can have signficant effects on crystal purity and scale-up.

This presentation describes a strategy employed to design and develop robust, scalable crystallization processes that avoids Liquid-Liquid Phase Separation (LLPS) or oiling out. 

Experimental and modeling approaches are presented for an intermediate and a final Active Pharmaceutical Ingredient (API) exhibiting Liquid-Liquid Phase Separation (LLPS). This webinar focuses specifically on examples where Liquid-Liquid Phase Separation (LLPS) occurs in a ternary system (solute/solvent/anti-solvent). The solvent and anti-solvent are fully miscible in the P,T phase diagram but the presence of the solute forces a spinodal decomposition that inhibits/delays the formation of crystals. A thermodynamic and kinetic development is proposed to explain why:

1. The rich and lean phases have the same supersaturation (i.e. same chemical potential/Gibbs free energy) once Liquid-Liquid Phase Separation (LLPS) occurs
2. The supersaturation level in each individual phase should be in theory similar (or lower) to the supersaturation of the original single phase (i.e. before the demixing)
3. The oil droplets should crystallize preferentially

Conclusions

• Relative Backscatter Index (RBI) trend of PVM is similiar to FBRM
• PVM with RBI is the most suitable tool for a molecule exhibiting Liquid-Liquid Phase Separation (LLPS)
  • Determine the phase diagram
  • Design, develop and monitor a crystallization process
• Compounds prone to Liquid-Liquid Phase Separation (LLPS) can be crystallized with seeding using the same approach applied for a typical molecule
• The supersaturation in the dispersed phase is similar to the supersaturation of the single phase
• Nucleation should occur first in the oil

Perspectives on Liquid-Liquid Phase Separation (LLPS) System: Particle Engineering Potential

• We can take advantage of natural behavior to design a spherical crystallization process to enable enhanced beneifts in terms of processability (filtration rate), physical properties (flowability, bulk and tapped density)
• Spherical crystals: towards the universal bulk
• No need to use surfactant (typical emulsion process) or mixture of immiscible solvent/ant-solvent/binder for spherical agglomeration
• Can use wet milling for droplets size distribution control
• Trigger nucleation in droplets with sonication
• Can be a continuous process
• Secondary nucleation zone versus Liquid-Liquid Phase Separation (LLPS) zone is key for spherical crystallization control (i.e. to get only crystallized droplets)