Beyond solubility limits: end-to-end robust supersaturation for parenteral delivery via SBECD inclusion

Supersaturation induced by a pH shift in combination with sulfobutylether-β-cyclodextrin (SBECD) is a specialized solubilization strategy that has been reported for only a limited number of drug-cyclodextrin systems. Although this approach shows promise for injectable formulations, the mechanism by which supersaturation is maintained under manufacturing- and administration-related stresses remains unclear. In the present study, using the perampanel-SBECD system as a model, we demonstrate that pH shift in the presence of SBECD generates a kinetically stabilized supersaturated state that is maintained throughout the full process, from manufacturing operations to intravenous administration. Phase-solubility analysis showed pH-dependent inclusion complexation, with binding constants of 246.3 M^-1 at pH 2 and 3916.7 M^-1 at pH 7, indicating stronger hydrophobic association at neutral pH. The supersaturated solutions exhibited excellent physical stability during freeze-thaw cycling, high-shear mixing, lyophilization and reconstitution, dilution in infusion fluids, and 0.2 μm in-line filtration, without visible precipitation or notable drug loss. Molecular docking simulations and nuclear Overhauser effect spectroscopy suggested that inclusion complexes persisted under both acidic and neutral conditions, with electrostatic interactions contributing at acidic pH and hydrophobic interactions predominating at neutral pH. These findings provide a mechanistic basis for the stable supersaturation state in drug-cyclodextrin systems and support the feasibility of applying this strategy to injectable formulations.