TY - JOUR
T1 - Non-classical crystallisation pathway directly observed for a pharmaceutical crystal via liquid phase electron microscopy
AU - Cookman, J.
AU - Hamilton, V.
AU - Hall, S. R.
AU - Bangert, U.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85095134418&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-75937-2
DO - 10.1038/s41598-020-75937-2
M3 - Article
C2 - 33154480
AN - SCOPUS:85095134418
SN - 2045-2322
VL - 10
SP - 19156
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 19156
ER -