Molecular theory of oiling-out during crystallization

Area of Science:

• Chemical Engineering
• Physical Chemistry
• Crystallization Science

Background:

• Oiling-out, a liquid-liquid phase separation (LLPS) during pharmaceutical crystallization, reduces purity and yield.
• The molecular drivers of oiling-out and its impact on crystallization kinetics are poorly understood.

Purpose of the Study:

• To elucidate the molecular mechanism of crystallization during oiling-out.
• To investigate the role of antisolvent-induced changes in solvation structure.
• To quantify the kinetic barriers associated with oiling-out.

Main Methods:

• Atomistic molecular dynamics (MD) simulations were used to study the beta-alanine/water/isopropanol system.
• Analysis of radial and spatial distribution functions identified changes in solvation networks.
• Double-well potential analysis quantified crystallization activation barriers.

Main Results:

• Liquid-liquid phase separation (LLPS) is driven by antisolvent disrupting the water hydration network, creating solvation voids.
• These voids lead to partial desolvation and promote solute clustering.
• Oiling-out conditions significantly lower the desolvation and structural reorganization energy barriers for crystallization.

Conclusions:

• Oiling-out is initiated by antisolvent-induced disruption of solvation, not direct solvent displacement.
• Solute-rich droplets in oiling-out act as kinetically favored precursors, supporting two-step nucleation theory.
• This study provides a molecular framework for controlling crystallization in complex solvent mixtures.