Understanding Molecular Interactions in Rafoxanide-Povidone Amorphous Solid Dispersions from Ultrafast Magic Angle Spinning NMR

摘要

In solid dosage formulations, probing intermolecular interactions between active pharmaceutical ingredients (APIs) and polymeric excipients, which have a mechanistic impact on physical stability as well as bioavailability, remains a challenge. In recent years, solid-state NMR spectroscopy has been demonstrated to be a powerful tool to provide structural details with an atomic resolution of therapeutic organic compounds and formulation products. However, conventional C-13-detected techniques often suffer from poor resolution and low sensitivity due to the disordered structure of certain materials such as amorphous pharmaceuticals and C-13 natural abundance, hindering in-depth investigations. In this study, we utilize the magic angle spinning (MAS) technique with ultrafast speeds (UF-MAS: nu(R) = 60 and 110 kHz) and demonstrate the enabled methods with H-1 detection to study the amorphous molecular complex of rafoxanide and povidone in the solid state. The downfield shift of the RAF amide proton, resolved under UF-MAS, and its correlations with aliphatic protons of PVP, serve as strong evidence of the existence of intermolecular hydrogen bonding. Two-dimensional (2D) H-1-detected H-1{C-13} and H-1-H-1 correlation experiments, interestingly, exhibit distinct API-polymer interactions in the spray-dried amorphous solid dispersions (ASDs), utilizing aqueous and organic cosolvents and organic solvents mixtures. The rich intermolecular interactions in the aqueously prepared ASDs presumably contribute to the physical stability, and the interactions are retained in the solution state to maintain supersaturation for an enhanced dissolution profile. This study presents the first application of UF-MAS NMR characterization of therapeutic solid dosages at a spinning frequency of 110 kHz and uncovers the molecular mechanisms of solvent-mediated pharmaceutical dispersions.