Non-classical crystallisation pathway directly observed for a pharmaceutical crystal via liquid phase electron...

Area of Science:

• Materials Science
• Crystallography
• Chemical Engineering

Background:

• Non-classical crystallization (NCC) pathways are accepted, but intermediate stages remain poorly understood, especially for small organic molecules.
• Direct observation of these low-electron dense pre-crystalline entities is challenging due to signal-to-noise and contrast limitations in conventional methods.

Purpose of the Study:

• To capture and characterize the intermediate pre-crystalline stages of a small organic molecule using advanced imaging techniques.
• To elucidate the nucleation pathway of flufenamic acid (FFA) in its native organic solvent environment.

Main Methods:

• Liquid Phase Electron Microscopy (LPEM) was employed for high temporospatial imaging.
• The study focused on flufenamic acid (FFA), a pharmaceutical compound, in an organic solvent.

Main Results:

• LPEM successfully captured the intermediate pre-crystalline stages of FFA.
• The observed nucleation pathway for FFA involved Pre-Nucleation Clusters (PNCs) and exhibited two-step nucleation.

Conclusions:

• The findings support the hypothesis that nucleation pathways are often a combination of multiple non-classical theories.
• In situ techniques like LPEM are essential for providing direct evidence of crystallization intermediates.