Abstract
Non-classical crystallisation (NCC) pathways are widely accepted, however there is conflicting evidence regarding the intermediate stages of crystallisation, how they manifest and further develop into crystals. Evidence from direct observations is especially lacking for small organic molecules, as distinguishing these low-electron dense entities from their similar liquid-phase surroundings presents signal-to-noise ratio and contrast challenges. Here, Liquid Phase Electron Microscopy (LPEM) captures the intermediate pre-crystalline stages of a small organic molecule, flufenamic acid (FFA), a common pharmaceutical. High temporospatial imaging of FFA in its native environment, an organic solvent, suggests that in this system a Pre-Nucleation Cluster (PNC) pathway is followed by features exhibiting two-step nucleation. This work adds to the growing body of evidence that suggests nucleation pathways are likely an amalgamation of multiple existing non-classical theories and highlights the need for the direct evidence presented by in situ techniques such as LPEM.
Highlights
Non-classical crystallisation (NCC) pathways are widely accepted, there is conflicting evidence regarding the intermediate stages of crystallisation, how they manifest and further develop into crystals
We report that the nanoscale crystallisation of flufenamic acid (FFA) occurs initially through Pre-Nucleation Cluster (PNC) pathway evidenced by the existence of pre-formed particles of ~ 8 nm
These PNCs were a result of unmonitored nucleation that was suspected to have occurred due to the introduction of an anti-solvent, water, which subsequently carried the pre-formed particles to the area of view
Summary
Non-classical crystallisation (NCC) pathways are widely accepted, there is conflicting evidence regarding the intermediate stages of crystallisation, how they manifest and further develop into crystals. Crystallisation is a fundamental, natural phenomenon that occurs to produce some of the most important materials in everyday life, including agrichemicals, semiconductors, geomaterials and Active Pharmaceutical Ingredients (APIs)[1,2,3,4]. The manifestation of such crystalline forms is subject to precise nucleation and growth pathways that give rise to their use in these vital applications. Instead theories associated with NCC include precursor particles larger than the atomic or molecular building blocks assumed in CNT, e.g. nanoparticles, crystalline or disordered[7] Such novel theories conforming to NCC include the Pre-Nucleation Cluster (PNC) pathway and two-step nucleation. Gebauer et al outlined that a liquid droplet intermediate forms before solidifying into a crystalline entity[10], and the appearance of the densified nucleus is described for protein crystallisation undergoing two-step nucleation[11]
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