Enhanced Performance of Blended Polymer Excipients in Delivering a Hydrophobic Drug through the Synergistic Action of Micelles and HPMCAS

Blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and dodecyl (C-12)-tailed poly(Nisopropylacrylamide) (PNIPAm) were systematically explored as a model system to dispense the active ingredient phenytoin by rapid dissolution, followed by the suppression of drug crystallization for an extended period. Dynamic and static light scattering revealed that C-12-PNIPAm polymers, synthesized by reversible addition fragmentation chain-transfer polymerization, self-assembled into micelles with dodecyl cores in phosphate-buffered saline (PBS, pH 6.5). A synergistic effect on drug supersaturation was documented during in vitro dissolution tests by varying the :blending ratio, with HPMACS primarily aiding in rapid dissolution and PNIPAm maintaining supersaturation. Polarized light and cryogenic transmission electron microscopy experiments revealed that C-12-PNIPAin micelles maintain drug supersaturation by inhibiting both crystal nucleation and growth. Cross-peaks between the phenyl group of phenytoin and the isopropyl group of C-12-PNIPAm in 2D H-1 nuclear Overhauser effect (NOESY) spectra confirmed the existence of drug polymer intermolecular interactions in solution. Plienytoiri and polymer diffusion coefficients, measured by diffusion-Ordered NMR spectroscopy (DOSY), demonstrated that the drug-polymer association constant increased with increasing local density of the corona chains, coincident with a reduction in C-12-PNIPAm molecular weight. These findings demonstrate a new strategy for exploiting the versatility of polymer blends through the use of self-assembled micelles in the design of advanced excipients.