Grupo de Química Teórica e Estrutural de Anápolis, Universidade Estadual de Goiás, GO, Anápolis, Brazil.
Laboratório de Novos Materiais, Universidade Evangélica de Goiás, Anápolis, GO, Brazil.
J Mol Model. 2022 Oct 1;28(10):338. doi: 10.1007/s00894-022-05300-x.
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.
活性药物成分被制成盐的形式，旨在调节其物理化学性质。在这方面，盐前体的优化和选择对毒性、治疗效率和生物利用度有很大的影响。具有 Na、Cl 和 Br 反离子的磺胺甲恶唑 (SMZ) 盐会影响超分子排列以及热力学和动力学参数。在这里，我们通过 Hirshfeld 表面、指纹图和理论方法——原子在分子中的量子理论和自然键轨道，分析了 Na、Cl 和 Br 反离子对磺胺甲恶唑盐超分子排列的相互作用。此外，我们通过计算前沿分子轨道来评估它们的电子结构。还获得了分子静电势图，以预测沿晶体排列的反离子相互作用。我们观察到[SMZ]和[SMZ]离子的结构与 SMZ 略有不同。化学反应性指数表明，SMZ 在动力学上比其相应的离子更稳定，而其阴离子更具极化性，其阳离子具有更高的全局电负性指数。分子静电势图显示磺酰基（亲核区域）和杂环氨基（亲电区域）具有高电荷密度。尽管三种 SMZ 物种的分子骨架相同，并且在盐的晶体结构形成过程中存在不同的反离子，但导致超分子排列的分子间相互作用模式不同，尽管在强度上非常相似。
