Noncovalent Interaction Analysis of Montelukast With DMF, DMSO, Ethanol, and Water Using Density Functional Theory Reveals Site‐Selective Hydrogen Bonding

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Drug–solvent interactions play an important role in determining solubility, stability, and overall therapeutic efficacy, especially for compounds with limited aqueous solubility. In this study, the site‐selective 1:1 microsolvent noncovalent interactions between the drug montelukast (MK) and four solvents (DMF, DMSO, EtOH, and water) were investigated using the M06‐2X method and the cc‐pVDZ basis set to determine the most favorable solvation environment. Quantum chemical approaches, along with tools such as natural bond orbital (NBO), atoms in molecules (AIM), noncovalent interaction based on reduced density (NCI‐RDG), interaction region indicator (IRI), and independent gradient model based on Hirshfeld partition (IGMH) analyses, were used to characterize the electronic distributions and to visualize the spatial distribution of attractive and repulsive forces. Energy decomposition analysis (EDA) quantified the contributions of different physical and chemical forces to the overall stabilization of the drug–solvent systems. The results indicate that the interaction of all solvents is higher at the O 46 –H 47 site of MK (Type 1 systems) than at the O 76 –H 77 site (Type 2 systems), and that, among all solvents, DMSO and water showed the most stable interactions with MK across both interaction types. The study provides a molecular‐level insight into the solvent‐dependent stabilization mechanisms of MK and highlights the importance of integrating theoretical approaches for rational solvent selection.