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. Picolinamide (PIC) and saccharin (SAC) are well-known substances receiving application in pharmaceutical industry as excipients (taste-masking agent in the case of SAC) and coformers. Motivated by the complementary donor-acceptor functionalities of picolinamide and saccharin, 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. 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 combined experimental and computational approach demonstrates that SAC acts as an effective coformer for PIC, highlighting cocrystallization as a promising strategy for tuning the physicochemical properties of PIC and potentially enhancing its suitability for therapeutic applications.