Abstract <p>Investigating the thermodynamics of intermolecular interactions between crown ethers and biomolecules—the foundation for modifying natural fibrous materials—represents a fundamental challenge. Crown ethers show considerable promise as modifiers for natural fibrous materials in medical applications owing to their selective binding affinity toward both organic and inorganic cations. Through targeted solvent selection, the stability of crown ether–biomolecule complexes and associates—as well as the thermodynamic parameters governing their formation—can be tuned by altering the solvation state of the reacting species. This approach enables precise control over the release kinetics of a bioactive compound as its crown ether complex dissociates within the matrix of a medical textile. Accordingly, this work reports the stability constant (log <i>K</i>⁰) and the associated thermodynamic functions (Δ_r<i>H</i>⁰, Δ_r<i>G</i>⁰, <i>T</i>Δ_r<i>S</i>⁰) for the formation of the molecular complex between 18-crown-6 (18C6) and β-alanine (β-Ala) in EtOH–H₂O mixed solvents across a range of compositions at <i>T</i> = 298.15 K. It has been established that during the transition from water to aqueous-ethanol solvents, the increase in the stability of the [β-Ala18C6] complex is due to a favorable enthalpy contribution to the change in the Gibbs energy of complex formation reactions. Using a solvation-based framework, we analyzed how solvent composition influences the thermodynamics of 18C6–β-Ala complexation and compared these findings with corresponding data for 18C6 complexes of amino acids bearing diverse functional substituents. The thermodynamic parameters of 18C6 complexation with β-Ala obtained in this work are necessary for predicting the reactivity of amino compounds of various structures with crown ethers in aqueous-ethanol solvents, which is relevant for pharmaceuticals and the development of technologies for creating medical nanomaterials based on them.</p>