Visualising early-stage liquid phase organic crystal growthvialiquid cell electron microscopy

Abstract

Here, we show that the development of nuclei and subsequent growth of a molecular organic crystal system can be induced by electron beam irradiation by exploiting the radiation chemistry of the carrier solvent.

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

“…The oxyanion of FFA, as a result of radiolysis events, could partake in the DOLLOP formation, perhaps due to the anionic form of the FFA molecules as they attempt to restructure. Metastable DOLLOP formation could be why we do not observe, at this stage, defined hexagonal crystals indicative of form I FFA 16 .…”

“…The constant electron beam penetration contributes to the production of radiolytic products such as O 2 gas (causing oxidation), H + and H . (altering the pH) and other molecular products contributing to the local chemical environment of the events we report 16,30 .…”

“…Thus, acquisition of crystallinity confirmation through lattice resolution imaging or Selected Area Electron Diffraction (SAED) was not possible throughout the observed crystallisation process. The difficulties associated with resolution limitations in LPEM are discussed thoroughly by de Jonge et al and also highlighted in a previous paper by Cookman et al specifically when imaging FFA 16,29 .…”

“…In previous work by the authors, hexagonal FFA crystals were grown from a 50 mM solution of FFA in EtOH. It was hypothesised that radiolysis of the solvent by the electron beam played a vital part in allowing FFA to partake in nucleation in an undersaturated solution 16 . In the aforementioned experiments there were no preformed particles present to induce nucleation.…”

“…In these experiments, we consider radiolysis of the solvent to play a part in the crystallisation events where the reactive products can catalyse and accelerate the events. The resultant ionic species expected to be produced from continuous radiolysis events are cations, protons, anionic forms of FFA, along with other radical and molecular species 16,30 . An associated theory originating from reported results of ACC, describes the intermediate phase as a structural configuration called dynamically-ordered liquid-like oxyanion polymer, aka.…”