From Host–Guest to Crystal Interactions: Proposing Crystallization Mechanisms for a Novel β-CD/TTA-H Structure and Related Cyclodextrin Inclusion Complexes

Abstract Cyclodextrin inclusion complexes (ICs) have been extensively studied for their capacity to modulate the physicochemical properties of guest molecules, albeit their solid-state organization has been comparatively less explored. In particular, the relationship between host–guest interactions and crystallization mechanisms remains incompletely understood. Therefore, we investigated the crystallization mechanisms of cyclodextrin (CD) ICs and evaluated how different guest molecules influence nucleation and crystal growth, using a supramolecular cluster and retrocrystallization approach to reconstruct possible sequential crystallization stages. A series of nine ICs, including a newly reported β-CD/TTA-H structure as the study’s starting point, were analyzed as molecular models. Single-crystal X-ray diffraction data provided structural references, while energetic and contact area were used to characterize intermolecular interactions and identify the nucleation pathways. Hydrogen bonding and cumulative CH•••HC contacts were found to contribute significantly in stabilizing supramolecular organization. Our findings showed distinct crystallization mechanisms governed by the balance between interaction energy and contact area. Depending on the guest molecule, three behaviors were observed for β-CD complexes: preservation of the hydrated β-CD crystallization mechanism, slight modulation of early nuclei, or guest-influenced nucleation. Conversely, permethylated-β-CD (PM-β-CD) ICs did not present well-defined early nuclei, suggesting crystallization involves competing, less readily resolved pathways. Overall, these findings provide new insight into how host–guest interactions influence crystallization in CD systems and advance understanding of their solid-state behavior.