Understanding Molecular-Level Interactions Between the Soluplus–Bile Salts Mixed Micellar System

In this work, we report the micellization behavior of graft copolymer Soluplus that remains insufficiently explored, particularly in the presence of bile salts, which are biologically relevant surface-active agents. The unique amphiphilic architecture allows Soluplus to self-assemble into micelles above its critical micelle concentration (CMC ∼7.6 mg/L or 0.0003 mM at 25 °C), with the hydrophobic (poly(vinyl acetate) and thermoresponsive poly(vinyl caprolactam) blocks forming the core and poly(ethylene glycol) forming the hydrophilic corona, with an average hydrodynamic diameter size between ∼70 and 90 nm. The core radius is observed to be ∼14.5 nm at ambient temperature. However, its relatively low cloud point (CP) of ∼28-34 °C limits its applicability in temperature-sensitive and other formulations. To address this gap, we investigate the mixed micellar system of Soluplus in the presence of essential bile salts: sodium cholate (NaC) and sodium deoxycholate (NaDC) in an aqueous solution environment. Their influence on the micellization of the Soluplus was examined using a combined experimental and computational approach to characterize the mixed micelles formulation and explore their molecular interactions. Clouding studies demonstrated that NaC and NaDC increase the CP of Soluplus following the order: NaDC > NaC due to the former having a lower CMC (∼6 mM at 25 °C) and greater hydrophobicity, which promotes forming smaller and more compact micelles than NaC with a higher CMC (∼16 mM at 25 °C). Dynamic light scattering (DLS) data provided a concentration-dependent transition from Soluplus-rich to bile salt-rich micelles at different temperatures. Meanwhile, the analysis of small-angle neutron scattering (SANS) further confirmed their defined micellar morphologies. Additionally, density functional theory calculations at the B3LYP/3-21G level of theory were used to explore the electronic structure and energy of Soluplus, bile salts, and their mixed systems. At the same time, quantum mechanical descriptors provided further insights into the stability and interaction. Furthermore, noncovalent interaction and reduced density gradient analyses inferred weak intermolecular interactions within the mixed micellar systems. Fourier transform infrared spectral profile and theoretical infrared analyses assessed the compatibility between the Soluplus and the bile salts.