Modeling Bioactive Release from Cyclodextrin Complex-Loaded Polymeric Films: A Unified Theoretical Framework...

Bioactive release from polymeric films loaded with cyclodextrin (CD) inclusion complexes couples host-guest equilibrium to multi-species transport. This work establishes the Cyclodextrin-Polymer Film Interactive Release (CPFIR) model, integrating complexation thermodynamics with diffusion, swelling, and erosion. Its central element is the Thermodynamic Eigenrate Decomposition (TED), which reduces each mechanism to a first-order depletion rate in s^-1. Because the rates share a dimension, their normalized values are weights that sum to unity and remain non-negative by construction, not by imposed normalization. Flory-Huggins parameters computed from Hansen solubility parameters enter the rates directly and supply a thermodynamic gate that suppresses swelling in hydrophobic matrices. A structural identifiability analysis shows the weights cannot be recovered from release data, because the model depends on the weights and the transport rate constants only through their products; determining them a priori is therefore a logical necessity rather than a convenience, and it supplies a falsification test no empirical model possesses. Retrospective application to two published experimental systems, a β-cyclodextrin nanosponge hydrogel and cyclodextrin-citrate coatings, with the weights computed a priori and held fixed, reproduces the reported release behavior (R² = 0.9952) and the reported mechanistic classification without adjusting any weight. Synthetic case studies across five regimes confirm internal consistency (R² ≥ 0.9955) but test self-consistency, not predictive accuracy. The framework is accordingly semi-predictive: it predicts the mechanism balance and the qualitative form of the profile before any release measurement, whereas the transport constants D_eff,app, λ_relax, and k_e require independent measurement or fitting.