Organic Nucleation: Water Rearrangement Reveals the Pathway of Ibuprofen

Area of Science:

• Physical Chemistry
• Materials Science
• Chemical Engineering

Background:

• Organic nucleation is crucial for pharmaceutical crystallization and formulation.
• Understanding the early stages of nucleation, including prenucleation clusters, is key to controlling crystal growth.
• The role of solvent, particularly water, in organic nucleation is often complex and not fully elucidated.

Purpose of the Study:

• To investigate the organic nucleation of ibuprofen triggered by protonation of its sodium salt.
• To characterize the size, hydration, and aggregation of nanoscale species during ibuprofen nucleation.
• To explore the dynamic changes in water structure at the air-water interface during ibuprofen nucleation.

Main Methods:

• Analytical Ultracentrifugation (AUC) to track growth and aggregation of nanoscale species.
• Molecular Dynamics (MD) simulations to model solvated molecules, oligomers, and prenucleation clusters.
• Surface-specific vibrational spectroscopy combined with MD simulations to probe water-ibuprofen interactions at the air-water interface.

Main Results:

• AUC and MD simulations identified solvated molecules, oligomers, and prenucleation clusters of ibuprofen.
• Water structure changes significantly upon ibuprofen protonation and charge neutralization.
• Water rearrangement continues even after ibuprofen saturation, correlating with late-stage aggregate formation.

Conclusions:

• Ibuprofen nucleation involves protonation and hydrophobic assembly, accompanied by substantial water reorganization.
• The study highlights the critical and dynamic role of water in organic nucleation processes.
• These findings may be relevant for understanding organic nucleation in general aqueous environments.