Itraconazole (ITR) and posaconazole (POS) exhibit closely related molecular structures but differ significantly in their ability to form liquid crystalline (LC) phases. This makes them an attractive model system to investigate how subtle structural differences influence molecular organization in the amorphous state. In this work, we investigate coamorphous systems composed of ITR and POS prepared via melt-quenching, focusing on the interplay between molecular dynamics, physical stability, and LC ordering. Differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) reveal that the glass transition temperature remains nearly unchanged over a wide compositional range, indicating comparable molecular mobility of all investigated systems. Despite this similarity, a pronounced, nonmonotonic dependence of crystallization kinetics on composition is observed, with a clear stability maximum at the eutectic ratio. Strikingly, this specific composition is also associated with the complete disappearance of the LC ordering characteristic of neat ITR. While ITR-rich mixtures close to the eutectic point still exhibit residual LC transitions, the eutectic composition yields a fully disordered amorphous phase. These results demonstrate, for the first time, that coamorphization at the eutectic composition might suppress LC ordering. The findings highlight the critical role of composition in governing both molecular organization and stability in amorphous pharmaceuticals.

Background/Objectives: Bisoprolol fumarate (BF) is a cardioselective beta-blocker used to treat pediatric heart failure and certain tachyarrhythmias. Currently, it is administered mainly as extemporaneously prepared suspensions from crushed tablets, which may cause issues with dose accuracy, stability, and palatability. Orodispersible minitablets (MODTs) may facilitate administration and individualized dosing, while prolonged release could potentially reduce peak-to-trough fluctuations and, thus, minimize adverse effects such as hypotension or bradycardia. This proof-of-concept study aimed to develop spray-dried prolonged-release microparticles containing BF, incorporate them into MODTs, and evaluate the effect of compression on drug release. Methods: Microparticles were prepared by spray drying ethanolic solutions of BF and ethylcellulose at 40 °C, 50 °C, and 60 °C. Their characterization included scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and dissolution studies. Selected microparticles were compressed into 3 mm MODTs, which were evaluated for mechanical properties, disintegration, and BF release. Results: Formulations containing 10% BF and 90% ethylcellulose released from 52.6% to 73% of BF after 2 h, increasing to 84.8–90.0% after 8 h and reaching 96% after 24 h. Solid-state analyses indicated complete amorphization of the drug in these microparticles. The spray-drying temperature affected process efficiency but did not significantly impacted morphology or dissolution behavior. The optimized MODTs disintegrated in less than 30 s and had a tensile strength of up to 2.62 MPa. Importantly, compression increased the initial BF release from 26.4% for the microparticles to 43.9% for the MODTs at 0.5 h, resulting in f₂ values of 45.04–48.46. Despite the higher initial BF release, the moderately prolonged-release profile was maintained in the case of MODTs. Conclusions: These findings demonstrate the feasibility of combining prolonged-release microparticles with orodispersible minitablets as a proof-of-concept for a pediatric drug delivery approach.

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.