Structural analysis and properties of three novel sulfonic acid-based pharmaceutical salts of paliperidone

Abstract

Three novel paliperidone sulfonate salts, including salt 1 (paliperidone methanesulfate), salt 2 (paliperidone benzenesulfate), and salt 3 (paliperidone p-toluenesulfate), were successfully designed and synthesized using a slow solvent evaporation method. Through TGA-DSC (thermogravimetric analysis-differential scanning calorimetry) testing, it was observed that the decomposition temperatures of these newly developed pharmaceutical salts were increased by 90 K, highlighting their enhanced thermal stability compared with paliperidone. The formation of these salts was primarily attributed to intermolecular hydrogen bonding interactions, as revealed by single-crystal structure analyses. Furthermore, the analyses of 3D dnorm Hirshfeld surface and 2D fingerprint plots demonstrated that the molecular stability was further enhanced by the interactions of H···H and H···O. Salt 1 showed a 10-fold increase in solubility and an approximately 200-fold increase in dissolution rate in a variety of simulated human body fluid environments. The confirmation of the formation of paliperidone drug salts and the high purity of the synthesized salts were further supported by PXRD (powder X-ray diffraction) and IR (infrared spectroscopy) analysis. Notably, this study represents the first reported investigation of paliperidone sulfonate salts, potentially providing valuable insights for the improvement of paliperidone pharmaceutical formulations.