Modeling the Structure of Ketoprofen-Poly(vinylpyrrolidone) Amorphous Solid Dispersions with Empirical Potential Structure Refinements of X-ray Scattering Data.

The metastability of amorphous formulations poses barriers to their safe and widespread commercialization. The propensity of amorphous solid dispersions (ASDs) to crystallize is directly linked to their molecular structure. Amorphous structures are inherently complex and thus difficult to fully characterize by experiments, which makes structural simulations an attractive route for investigating which structural characteristics correlate with ASD stability. In this study, we use empirical potential structure refinement (EPSR) to create molecular models of ketoprofen-poly(vinylpyrrolidone) (KTP/PVP) ASDs with 0-75 wt % drug loading. The EPSR technique uses X-ray total scattering measurements as constraints, yielding models that are consistent with the X-ray data. We perform several simulations to assess the sensitivity of the EPSR approach to input parameters such as intramolecular bond rotations, PVP molecule length, and PVP tacticity. Even at low drug loading (25 wt %), ∼40% of KTP molecules participate in KTP-KTP hydrogen bonding. The extent of KTP-PVP hydrogen bonding does not decrease significantly at higher drug loadings. However, the models' relative uncertainties are too large to conclude whether ASDs' lower stabilities at high drug loadings are due to changes in drug-excipient hydrogen bonding or a decrease in steric hindrance of KTP molecules. This study illustrates how EPSR, combined with total scattering measurements, can be a powerful tool for investigating structural characteristics in amorphous formulations and developing ASDs with improved stability.

Microgravity effects on nonequilibrium melt processing of neodymium titanate: thermophysical properties, atomic structure, glass formation and crystallization.

The relationships between materials processing and structure can vary between terrestrial and reduced gravity environments. As one case study, we compare the nonequilibrium melt processing of a rare-earth titanate, nominally 83TiO2-17Nd2O3, and the structure of its glassy and crystalline products. Density and thermal expansion for the liquid, supercooled liquid, and glass are measured over 300-1850 °C using the Electrostatic Levitation Furnace (ELF) in microgravity, and two replicate density measurements were reproducible to within 0.4%. Cooling rates in ELF are 40-110 °C s-1 lower than those in a terrestrial aerodynamic levitator due to the absence of forced convection. X-ray/neutron total scattering and Raman spectroscopy indicate that glasses processed on Earth and in microgravity exhibit similar atomic structures, with only subtle differences that are consistent with compositional variations of ~2 mol. % Nd2O3. The glass atomic network contains a mixture of corner- and edge-sharing Ti-O polyhedra, and the fraction of edge-sharing arrangements decreases with increasing Nd2O3 content. X-ray tomography and electron microscopy of crystalline products reveal substantial differences in microstructure, grain size, and crystalline phases, which arise from differences in the melt processes.