Mechanistic investigation into the phase separation behavior of soluplus in the presence of biorelevant media

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.

Keywords

Amorphous solid dispersions, Bioenabling formulations, Formulation, Liquid−liquid phase separation, Phase separation, Solubility, Soluplus, Supersaturation

Subject (DDC)

610 - Medizin und Gesundheit

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ISBN

ISSN

1543-8384
1543-8392

Language

English

Created during FHNW affiliation

Yes

Strategic action fields FHNW

Publication status

Published

Review

Peer review of the complete publication

Open access category

Hybrid

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Citation

Lange, J. J., Senniksen, M. B., Wyttenbach, N., Page, S., Bateman, L. M., O’Dwyer, P. J., Saal, W., Kuentz, M., & Griffin, B. T. (2025). Mechanistic investigation into the phase separation behavior of soluplus in the presence of biorelevant media. Molecular Pharmaceutics, 22(4), 1958–1972. https://doi.org/10.1021/acs.molpharmaceut.4c01140

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