Crystal engineering and electrostatic properties of co-crystals of pyrimethamine with benzoic acid and gallic acid

Abstract

Crystal structures of co-crystal salt forms of anti-malarial drug pyrimethamine with benzoic acid in water solvent (I) and gallic acid in ethanol solvent (II) have been studied using X-ray diffraction data collected at room temperature. Refinement of crystal structures were carried out by independent atomic model (IAM), while the electrostatic properties were studied by transferring electron density parameters from an electron density database. Theoretically optimized hydrogen bond distances were used in the refinement procedures as they were found superior to the neutron diffraction distances. Results of both refinements were compared. Three dimensional Hirshfeld surface analysis and two dimensional fingerprint maps of individual molecules are dominated by H⋯H and O⋯H/H⋯O contacts. Topological analysis was carried out using Bader’s theory of Atoms In Molecules (AIM). Electrostatic properties such as dipole moment and electrostatic potential were calculated. Results of this study reveal that the co-crystal formation takes place due to N–H⋯O/N–H⋯O homosynthon. Quantitative and qualitative analysis shows that the synthon is robust one. Density functional theory (DFT) based calculations used to elucidate the factors which drive the co-crystallization, complement the experimental findings. The study highlights the significance of using multipolar parameters to understand the phenomena involved in crystal engineering.