Background/Objectives: Supramolecular hydrogels formed by low-molecular-weight gelators present a chemically heterogeneous transport environment whose molecularscale dynamics remain poorly understood. This study aimed to investigate how drug physicochemistry governs transport within a liquid-crystalline C18ADPA hydrogel at the molecular scale. Methods: Pulsed-field gradient NMR spectroscopy was used to measure self-diffusion coefficients of five model drugs (5-fluorouracil, acetylcholine, paracetamol, prednisolone, and amphotericin B) spanning a broad range of size, polarity, and charge state, in both free solution and the hydrogel matrix at pH 5.37. Results: Observed drug diffusion coefficients deviated substantially from classical obstruction theory predictions, demonstrating that transport is governed by host–guest chemical affinity rather than molecular size. The three water-soluble drugs exhibited bimodal diffusion, with relative amplitudes providing a direct estimate of bound and free drug fractions. Prednisolone co-diffused with the gelator scaffold, consistent with hydrophobic bilayer partitioning, while amphotericin B diffused at rates consistent with the structured interfacial water layer. The gel pH (5.37) emerged as an active determinant of transport: drug charge states at this pH from permanent cation (acetylcholine) to near-zwitterion (amphotericin B) correlated directly with the observed transport behavior. The near-zwitterionic character of amphotericin B at pH 5.37, arising from its carboxyl pKa (~5.5), suggests a previously unreported electrostatic interfacial trapping mechanism. Conclusions: The liquid-crystalline bilayer architecture creates chemically distinct microdomains that selectively recruit drugs based on hydrophobicity, hydrogen-bonding capacity, and pH-dependent charge state, providing a molecular-scale framework for rational formulation design in supramolecular drug delivery.
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