Co-crystal polymorphism: five colourful forms of prothionamide-saccharin co-crystal

Polymorphism in pharmaceutical co-crystals strongly influences solid-state properties and ultimately drug performance, yet the presence of multiple polymorphs within a co-crystal system remains uncommon, and it is very challenging to simultaneously isolate them. Herein, we report five distinct salt polymorphs (Forms I-V) of a 1 : 1 pharmaceutical co-crystal composed of an antituberculosis drug, prothionamide (PA), and the GRAS co-former saccharin (SA); they are obtained through solution-based crystallization by the controlled variation of the solvent and temperature. These forms show distinct morphologies (plate, block, hexagonal and rods) and vibrant colours (red, orange and yellow), as perceived by optical images. Single-crystal and powder X-ray diffraction analyses establish identical stoichiometry across all forms but reveal distinct unit cell parameters and packing motifs. Conformational analysis demonstrates that the inherent structural flexibility of a PA molecule plays a decisive role in enabling polymorphic diversity. Thermal characterization by differential scanning calorimetry (DSC) and variable-temperature powder X-ray diffraction (VTPXRD) shows that all the forms are stable and remain intact even under non-ambient conditions (for example, at high temperature), except Form III, which transforms into Form V upon heating. Furthermore, the stability of the polymorphs and the strength of their intermolecular interactions are evaluated by performing lattice energy and Hirshfeld surface analysis. Also, the distinct colours are substantiated with UV-visible and photoluminescence spectroscopic measurements, as well as computational studies.