Theoretical analysis of the effects of counterions on the supramolecular arrangement of sulfamethoxazole

Active pharmaceutical ingredients are formulated as the salt form, aiming to modulate their physicochemical properties. In this regard, the optimization and choice of the salt former have a strong influence on toxicity, therapeutic efficiency, and bioavailability. Sulfamethoxazole (SMZ) salts with Na + , Cl − , and Br − counterions influence in the supramolecular arrangement as well as in their thermodynamic and kinetic parameters. Herein, we analyzed the interactions of the Na + , Cl − , and Br − counterions on the supramolecular arrangement of the sulfamethoxazole salts by Hirshfeld surfaces, fingerprint plots, and theoretical methods—quantum theory of atoms in molecules and natural bond orbitals. Moreover, we evaluated their electronic structure by density functional theory using calculation of the frontier molecular orbitals. Molecular electrostatic potential maps were also obtained to predict the interactions of the counterions along crystalline arrangements. We observed that the structures of [SMZ] + and [SMZ] − ions differ slightly from the SMZ. The chemical reactivity indices show that the SMZ is kinetically more stable than its respective ions, while its anion is more polarizable, and its cation has a higher global electrophilicity index. The molecular electrostatic potential maps show high charge density in the sulfonyl group (nucleophilic region) and the heterocyclic amino group (electrophilic region). Although the molecular skeleton is identical among the three SMZ species and the presence of different counterions in the formation of the crystalline structure of the salts results in supramolecular arrangements with different patterns of intermolecular interactions, despite being very similar in terms of intensities.