Mechanistic Investigation into the Phase Separation Behavior of Soluplus in the Presence of Biorelevant Media.

Abstract

More than a decade since its introduction, the polymeric excipient Soluplus continues to receive considerable attention for its application in the development of amorphous solid dispersions (ASDs) and its utility as a solubilizer for drugs exhibiting solubility limited absorption. While it is well-recognized that Soluplus forms micelles, the impact of its lower critical solution temperature of approximately 40 °C remains an underexplored aspect. This study investigated the phase behavior of Soluplus in fasted-state simulated intestinal fluid (FaSSIF-V1). It was demonstrated that Soluplus forms a dispersed polymer-rich coacervate phase, which coexists with Soluplus micelles at 37 °C. This behavior was confirmed by cloud point measurements, visually discernible phases after centrifugation, as well as multi-angle dynamic light scattering (MADLS) measurements, and quantitative ¹H-nuclear magnetic resonance (NMR) spectroscopy of Soluplus concentrations in the supernatant pre- and post-centrifugation. The practical relevance of these findings was contextualized by solvent shift experiments and dissolution testing of spray-dried ASD. The results demonstrated that the poorly water-soluble drug RO6897779 resided in a polymer-rich coacervate phase and was spun down during centrifugation, which resulted in an amorphous pellet exhibiting the characteristics of a viscous liquid. The entrapment of the drug within the polymer-rich phase was further analyzed by temperature- and time-dependent MADLS experiments. The findings of this study are of particular relevance for a mechanistic understanding, relevant to comprehending in vitro-in vivo relationships of Soluplus-based ASDs. Low sampled drug concentrations in FaSSIF-V1 at 37 °C may originate not only from limited drug release and precipitation but also from the formation of a drug-containing, polymer-rich Soluplus phase. Therefore, a liquid-liquid phase separation occurring from Soluplus-based formulations in a biorelevant medium can be excipient-driven, which is different from the common perception that phase separation in the solution state is triggered primarily by high drug concentrations exceeding their amorphous solubility.