Solvent-Reconfigured Polymorphic Transition of Lamotrigine-Salicylic Acid Salts

Abstract Solvent-reconfigured hydrogen bonding governs the polymorphic landscape of lamotrigine-salicylic acid salts. Two anhydrous polymorphs (forms I/II) and three solvates (ethanol, acetonitrile, ethyl acetate) were designed and prepared, with crystal analysis confirming their distinct structural motifs: isolated site packing in ethanol and acetonitrile solvates versus channel type topology in the ethyl acetate solvate, whose 25.8% void volume drives rapid desolvation and instability. Molecular electrostatic potential and Hirshfeld surface analyses revealed solvent-specific hydrogen bonds. Solvent-mediated transition studies showed that, under the investigated conditions, form I was the phase ultimately obtained. This study elucidates the solvent driven hydrogen bond reconfiguration in polymorphism, establishing a mechanistic framework for the rational design of multicomponent pharmaceutical salts.