Picolinamide-Saccharin Cocrystal: Synthesis, Structure, Vibrational Spectra and Thermal Behavior

The design of pharmaceutical cocrystals has become an effective strategy for tailoring the solid-state properties of active molecules through predictable intermolecular interactions. Motivated by the complementary donor-acceptor functionalities of picolinamide (PIC) and saccharin (SAC), a new PIC-SAC cocrystal was synthesized and structurally, thermodynamically and vibrationally characterized. Single-crystal X-ray diffraction revealed a well-organized supramolecular architecture stabilized by reciprocal N–H···O hydrogen bonds between the amide group of PIC and the sulfonamide group of SAC. The crystal was found to be monoclinic, space group P21/c, with a = 7.4179(3) Å, b = 17.8483(8) Å, c = 10.5116(5) Å, β = 98.212(2) °, and V = 1377.43(11) Å3, with 4 PIC-SAC molecular units in the unit cell (Z = 4). Intermolecular interactions in the new crystalline material were examined in detail through Hirshfeld analysis and the energy decomposition method of Spackman and coworkers, providing a detailed picture of the cocrystal lattice energetics, also in comparison with those of the crystals of the pure components. Room temperature infrared (IR) and Raman spectra of the cocrystal were recorded and shown to display characteristic shifts compared to the spectra of the pure components, which are consistent with the new intermolecular interactions present in the cocrystal. The analysis of the experimental data received support from electronic structure calculations, within the Density Functional Theory (DFT) framework, which were performed on the isolated PIC-SAC structural unit and also using fully periodic calculations on the crystal. The thermal behavior of the cocrystal was examined using differential scanning calorimetry (DSC) which fully confirmed the formation of a distinct crystalline phase with melting point 122.8 ± 0.5 ºC and enthalpy of fusion of 35.1 ± 0.5 kJ mol–1 (of cocrystal PIC-SAC unit) The used combined experimental and computational approach demonstrates that SAC acts as an effective coformer for PIC, cocrystallization thus appearing as an appealing strategy to improve solubility of this latter compound and, by this way, improve its availability for therapeutic use.