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. The technique of Liquid Cell Electron Microscopy was used to probe the crystal growth of flufenamic acid; a current commercialised active pharmaceutical ingredient. This work demonstrates liquid phase electron microscopy analysis as an essential tool for assessing pharmaceutical crystal growth in their native environment while giving insight into polymorph identification of nano-crystals at their very inception. Possible mechanisms of crystal nucleation due to the electron beam with a focus on radiolysis are discussed along with the innovations this technique offers to the study of pharmaceutical crystals and other low contrast materials.
Highlights
The molecular crystalline state is prevalent in both natural and synthetic materials which are ubiquitously employed in industries ranging from electronics to agrochemicals.[1,2,3] Within the pharmaceutical industry, in particular, molecular crystalline solids are the dominant form of delivery of active pharmaceutical ingredients (APIs), forming the biologically active part of the commercial product,[4] they are prone to polymorphism
The electron density of these naturally occurring materials is low but due to the metal component in the molecules forming the crystals, they do not present the same challenges as low z-contrast materials such as API molecular crystals formed from aromatic organic molecules, in particular, regarding visualisation with transmission techniques such as Transmission Electron Microscopy (TEM)
Using the latest technologies in electron microscopy and advances in specialised specimen holders and detectors for the electron microscope, we report the first direct observations of the nucleation and subsequent crystal growth of a small organic molecule, FFA, in situ in organic solvent
Summary
The molecular crystalline state is prevalent in both natural and synthetic materials which are ubiquitously employed in industries ranging from electronics to agrochemicals.[1,2,3] Within the pharmaceutical industry, in particular, molecular crystalline solids are the dominant form of delivery of active pharmaceutical ingredients (APIs), forming the biologically active part of the commercial product,[4] they are prone to polymorphism. The progress gained from LCEM has been used for developing electrodeposition techniques of palladium,[7] improving lithium battery nanoscale processes[8] and directly uncovering new stages of nanoparticle growth processes of platinum,[9] and to pave the way for controllable nanocrystal synthesis and stability for materials such as lead sulfide.[10] Crystal growth of naturally occurring materials such as calcium carbonate,[11] calcium phosphate[12] and iron oxyhydroxide[13] has been studied using LCEM Nucleation events of these low z-contrast materials have been revealed through real-time data to compare to theorised nucleation mechanisms and growth theories e.g. classical nucleation theory (CNT) and multistep pathways.[14] The electron density of these naturally occurring materials is low but due to the metal component in the molecules forming the crystals, they do not present the same challenges as low z-contrast materials such as API molecular crystals formed from aromatic organic molecules, in particular, regarding visualisation with transmission techniques such as TEM. Advances in the crystallisation of proteins and polymers using LCEM have been reported exemplifying the possibility to observe dynamic processes of low z-contrast materials.[15,16]
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