Abstract

Background/Objectives: Cyclodextrin-based ternary systems are widely used to improve the solubility of poorly soluble drugs. Amino acids such as L-arginine may further increase dissolved drug concentrations and reduce precipitation under physiologically relevant conditions. In many systems, apparent solubility enhancement is influenced simultaneously by drug ionization, inclusion complex formation, multicomponent interactions, and solid–liquid equilibria. This study presents a physicochemical modeling approach for analyzing pH-dependent solubility enhancement and precipitation behavior in drug–cyclodextrin–L-arginine systems. Methods: The model combines acid–base equilibria, binary inclusion complexation, ternary association, and explicit solid-phase partitioning within a unified mass-balance treatment. The approach was applied to representative ternary systems containing repaglinide, sulfadiazine, cefixime, and meloxicam. Results: Quantitative comparison with published phase-solubility data for the repaglinide–HPβCD–L-arginine system confirmed the numerical consistency of the model. The calculated profiles showed that enhanced solubilization and reduced precipitation occur only within specific pH regions determined by coupled equilibrium effects. For cefixime and meloxicam, the calculations were interpreted as predictive applications because directly comparable validation datasets were not available. Outside the favorable pH regions, a substantial fraction of the drug remained in the solid phase. Conclusions: These observations support the importance of pH and multicomponent interactions in controlling formulation performance in cyclodextrin-containing systems. The obtained profiles may support preliminary optimization of formulation pH and excipient composition before experimental screening.

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