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

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 (S_a,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 S_a,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 S_a,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.