Polymer Type Impacts Amorphous Solubility and Drug-Rich Phase Colloidal Stability: A Mechanistic Study Using Nuclear Magnetic Resonance Spectroscopy.

The polymer used in an amorphous solid dispersion (ASD) formulation plays a critical role in dosage form performance. Herein, drug-polymer interactions in aqueous solution were evaluated in order to better understand the dispersion stability of the colloidal drug-rich phase generated when the amorphous solubility is exceeded. The amorphous solubility (Sa,IBP) of ibuprofen (IBP) decreased when hypromellose (HPMC) or polyvinylpyrrolidone/vinyl acetate (PVP-VA) were present in solution. Solution nuclear magnetic resonance (NMR) spectroscopy revealed that a large amount of HPMC and PVP-VA distributed into the IBP-rich phase. The mixing of HPMC and PVP-VA with the IBP-rich phase led to the decreased Sa,IBP. In contrast, the charged amino methacrylate copolymer (Eudragit E PO, EUD-E) showed minimal mixing with the IBP-rich phase; however, this polymer did lead to solubilization of IBP in the bulk aqueous phase. Although the IBP-rich phase generated by dissolving IBP at concentrations above Sa,IBP rapidly coarsened followed by creaming in the absence of polymer, all of the polymers stabilized the IBP dispersion to some extent. The droplet size of the IBP-rich phase immediately after formation was around 300 nm in HPMC and PVP-VA solutions, and around 800 nm in the EUD-E solution. The mixing of the former two polymers with the drug-rich phase is thought to account for the smaller droplet size. Despite a smaller initial size, the dispersion stability of the IBP-rich droplets was relatively poor in the presence of PVP-VA. In contrast, the coalescence of the IBP-rich droplets was effectively suppressed by the steric repulsion and electrostatic repulsion derived from adsorbed HPMC and EUD-E, respectively. The present study highlights the complex effects of a polymer on the drug amorphous solubility and colloidal stability, which should be considered when optimizing ASD formulations with the goal of maximizing drug absorption.