A Partition-Controlled Kinetic Model for Drug Release from Polymeric Nanocapsules: Resolving the Solubility Paradox.

Mathematical descriptions of drug release from polymeric nanocapsules are commonly based on first-order kinetics derived from the Noyes-Whitney equation. However, previous formulations implicitly predict that increasing drug solubility in the oily core accelerates release, which contradicts experimental evidence. In this work, we revisit the modeling framework and derive a physically consistent equation based on diffusion through the polymeric shell coupled with partition equilibrium at the oil-water interface. The resulting model shows that release kinetics are governed by the dimensionless partition-solubility group Π S = S 0 S where S 0 denotes the solubility of a reference formulation (S 0 = 1 mg mL-1) and S is the drug solubility (mg mL-1). Accordingly, k obs = kΠ S , so that the inverse-solubility effect emerges from relative partitioning behavior rather than from absolute solubility alone. This formulation resolves the apparent paradox, preserves the experimentally observed exponential saturation behavior, and collapses kinetic data into a single intrinsic parameter. We further demonstrate that the only prior model proposed specifically for nanocapsular systems also embeds the solubility paradox, and show that its own published validation data in fact confirm the inverse-solubility scaling derived here, with a deviation of only ∼9% between two independent formulations. Dimensional consistency, comparison with classical and nanoscale-specific models, and validation using published data support the robustness of the proposed approach.