Abstract: This paper reports an advanced statistical physics modeling to elucidate the adsorption process of two relevant pharmaceuticals, namely amoxicillin (AMOX) and imipramine (IMP), on aluminum-pillared clay. A double-layer model was used to interpret the adsorption mechanism of these pharmaceuticals at 298–318. This model indicated the presence of molecular aggregation for IMP adsorption via the formation of dimers or trimers, and a monomolecular AMOX separation process. The removal of both compounds was endothermic, showing better adsorption capacity for IMP (82 mg/g) than for AMOX (37 mg/g). Calculated adsorption energies (∆E1, ∆E2 < 40 kJ/mol) confirmed a physisorption mechanism, which may be governed by hydrogen bonding due to the adsorbent chemistry and adsorbate molecular structure. Configurational entropy and free enthalpy were calculated to analyze the thermodynamics of AMOX and IMP adsorption equilibria. These thermodynamic functions confirmed the molecular disorder during adsorption and system’s spontaneity. This study contributes with new theoretical findings for unraveling complex
adsorption mechanisms, at the molecular level, of pharmaceutical molecules, with the aim of intensifying water depollution systems.