Atomic-Level Drug Substance and Polymer Interaction in Posaconazole Amorphous Solid Dispersion from Solid-State NMR

Despite the wide utilization of amorphous solid dispersions (ASDs) for formulating poorly water-soluble drugs, fundamental understanding of the structural basis behind their stability and dissolution behavior is limited. This is largely due to the lack of high-resolution structural tools for investigating multicomponent and amorphous systems in the solid state. In this study, we present what is likely the first publication quantifying the molecular interaction between the drug and polymer in ASDs at an angstrom level by utilizing ¹⁹F magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. A variant of the ¹⁹F-¹³C rotational-echo and double-resonance (REDOR) technique was developed to quantify interatomic distances by implementing a supercycled symmetry-based recoupling schedule and synchronized simultaneous detection. We successfully deployed the technique to identify "head-to-head" and "head-to-tail" packing of crystalline posaconazole (POSA). To probe molecular interactions between POSA and hypromellose acetate succinate (HPMCAS) in the dispersion, as a major goal of this study, two-dimensional (2D) ¹H-¹⁹F correlation experiments were performed. The approach facilitated observation of intermolecular hydrogen-to-fluorine contacts between the hydroxyl group of the polymer and the difluorophenyl group of the drug substance. Atomic distance measurement, utilizing the developed ¹⁹F-¹³C REDOR technique, revealed the close proximity of ¹³C_OH-¹⁹F at 4.3 Å. Numerical modeling analysis suggested a possible hydrogen bonding interaction between the polymer O-H group as an acceptor and POSA fluorine (O-H···F) or difluorophenyl ring (O-H···Ph) as a donor. These ¹⁹F MAS NMR techniques, including 2D ¹⁹F-¹H heteronuclear correlation and ¹⁹F-¹³C atomic distance measurement, may shed light on the nature (i.e., type and strength) of drug-polymer interactions in ASDs and offer a new high-resolution analytical protocol for probing the microstructure of amorphous pharmaceutical materials.