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Caroline Fatina, Pharmsci graduate student (Yu Lab), will be defending her PhD research thesis:

Amorphous Pharmaceutical Solids: Structural Characterization and Formulation Strategies for Molecular Glass-Formers

Abstract:

This dissertation examines how structure develops and evolves in molecular glass-formers, and how it can be manipulated to influence physical properties and pharmaceutical performance.

We first consider how molecular organization and mobility can be modified by intermolecular interactions. Thermotropic liquid crystals combine molecular order with the mobility of a liquid, providing useful systems for examining the relationship between structure and dynamics. In the liquid crystalline drug itraconazole, 5 wt% glycerol enhances smectic ordering while increasing fluidity, despite the usual tendency of impurities to disrupt order. X-ray scattering data support the idea that glycerol reduces molecular offsets within the smectic layers, producing more compact layers with nearly zero thermal expansion. This behavior is attributed to hydrogen bond mediated bridging of itraconazole molecules and demonstrates that increased mobility does not necessarily correspond to decreased structural order.

More generally, different aspects of structure and dynamics in glass-forming liquids can evolve independently, in 2-ethyl-1-hexanol (2E1H), the main scattering peak associated with alkyl chain packing evolves continuously until becoming arrested near the glass transition temperature, T_g. In contrast, the prepeak associated with hydroxyl group correlations undergoes a transition near 220 K and becomes nearly frozen well above T_g. This transition coincides with changes in orientational correlations of the OH dipoles and is attributed to increased hydrogen bonding and improved regularity of the alcohol bilayers.

T_g is a key descriptor of molecular mobility and physical stability in amorphous materials, making its control through composition and intermolecular interactions important for material design. When acidic and basic components ionize each other, the T_g of the mixture can exceed that of either neutral component, behavior not captured by conventional mixing models. We show that this effect can be quantitatively described by treating the ionized fraction as a new component with its own characteristic T_g in a modified Fox equation. Using experimentally measured degrees of ionization, the model accounts for T_g enhancement in pharmaceutically relevant acid-base mixtures and provides a framework for understanding the reduced mobility of salt-forming amorphous materials

The role of ionization is explored further in amorphous drug-polymer salts of bedaquiline (BDQ), a poorly soluble basic drug. The main goal of formulation development is to improve drug release while maintaining physical stability against crystallization. Poly(acrylic acid) (PAA) protonates BDQ more completely than the other polymers examined, and slurry conversion produces more complete salt formation and greater physical stability than melt quenching. PAA molecular weight has little effect on protonation but does affect drug release in biorelevant media, with an intermediate molecular weight giving the best performance. These results show that both salt formation and polymer properties influence drug release.

Understanding amorphous pharmaceuticals also requires knowing how their structure evolves with temperature and becomes arrested on cooling. Although the glass transition is often represented by a single temperature, different aspects of liquid structure can fall out of equilibrium separately. Temperature-dependent X-ray scattering of posaconazole, TPD, and DSA-Ph shows that the width, w, of the main scattering peak becomes frozen at a fictive temperature 8-14 K higher than its position, q_m. In other words, packing regularity falls out of equilibrium before molecular spacing. In the equilibrium liquid, w and q_m follow the relationship expected for a hard sphere liquid, whereas vitrification drives the structure away from this trajectory. The existence of multiple fictive temperatures demonstrate that a single structural transition temperature can be insufficient to describe the development of a molecular glass.