Optimization of physicochemical properties of theophylline by forming cocrystals with amino acids

This study presents the synthesis and characterization of novel cocrystal structures of theophylline (THE) with the amino acids gamma-aminobutyric acid (GABA) and l-arginine (ARG). Despite a large number of reports about THE cocrystals, no crystallographic parameters of cocrystals formed by THE and amino acids have been reported. THE is characterized by low solubility, while amino acids as cocrystal co-formers (CCFs) are increasingly recognized for their high solubility and safety. Consequently, the synthesis of cocrystals with amino acids has garnered considerable research interest. To optimize THE's physicochemical properties, amino acids were chosen as CCFs, resulting in the synthesis of two novel cocrystals: THE-GABA and THE-ARG-2H₂O. Comprehensive characterization, such as X-ray diffraction analysis, spectral analysis, thermal analysis, and dynamic vapor sorption were conducted for THE-GABA and THE-ARG-2H₂O, alongside stability and solubility assessments. To better explain the characterization and evaluation results, the theoretical calculation methods were adopted, including the molecular electrostatic potential (MESP), topological analysis, energy framework, Hirshfeld surface and crystal voids. The study's findings reveal that the solubility and permeability of THE in both novel cocrystals, THE-GABA and THE-ARG-2H₂O, have increased, especially in the latter. Meanwhile, the hygroscopicity of them was at a low level which was basically consistent with THE.