In Situ Dynamics of the Microscopic Crystallographic Dehydration Pathway in a Model Channel Hydrate, Theophylline
Solid-state phase transformations in molecular crystal hydrates govern stability and functional performance across a range of applications, including pharmaceutical, agrochemical and coordination framework materials. During dehydration, these hydrates can undergo substantial structural reorganisation involving changes in molecular orientation, intermolecular interactions, and lattice symmetry. Despite extensive study, the microscopic crystallographic pathways by which such transformations proceed remain poorly understood. Here, we investigate the dynamics of solid-state dehydration of theophylline monohydrate as a model molecular hydrate using in situ low-dose scanning electron diffraction (SED). Simultaneous observations of changes in morphology and crystallographic phase and orientation mapped across single particles reveal how complete dehydration proceeds via a two-step, reconstructive topotactic solid-state transformation: anisotropic, surface-specific mass loss of material near water channel sides (suggesting the monohydrate adopts a non-centrosymmetric crystal structure) is followed by surface-localised nucleation and growth of anhydrous form II on the parent monohydrate while preserving similar molecular orientations at a common plane. By providing direct, local crystallographic insight into hydrate dehydration, this work demonstrates how surface-controlled mass loss, morphological changes, and lattice orientation jointly govern solid-state transformations in molecular hydrates. More broadly, it establishes low-dose SED as an effective approach for probing dynamic phase transformations in beam-sensitive molecular crystals.