Non-Monotonic Glass Transition Behavior as a Molecular Signature of Strong Interactions in Co-Amorphous and Crystalline Celecoxib-Etoricoxib Systems

Co-amorphous API−API systems often exhibit improved physical stability compared to their neat amorphous counterparts. This effect, however, becomes less straightforward when both components possess nearly identical glass transition temperatures (Tg). In this work, we investigate a model celecoxib + etoricoxib (CEL + ETO) system, in which both APIs display comparable Tg and molecular dynamics, yet markedly different physical stability. Using differential scanning calorimetry (DSC), broadband dielectric spectroscopy (BDS), Fourier-transform infrared spectroscopy (FTIR), and solid-state Nuclear Magnetic Resonance spectroscopy (ssNMR), we demonstrate that CEL + ETO mixtures exhibit a rare, non-monotonic dependence of Tg on composition, with a maximum near the equimolar ratio. This behavior is consistently observed across independent techniques and deviates from conventional mixing rules. Despite only moderate changes in molecular mobility, co-amorphization with ETO leads to a pronounced suppression of CEL recrystallization, as confirmed by dielectric studies. Spectroscopic data reveal strong heteromolecular interactions, including hydrogen-bonded heterosynthons, which disrupt CEL self-association and hinder nucleation. Importantly, these interactions may also influence the crystalline phase, where deviations from ideal eutectic behavior and sensitivity to mechanical treatment indicate non-ideal, preparation-dependent crystalline-phase behavior and possible mechanically induced crystalline rearrangements. These findings suggest that non-monotonic Tg − composition dependence can serve as a signature of strong intermolecular interactions and provide a link between amorphous-phase behavior and crystalline-phase organization.