Weak Interactions Cause Packing Polymorphism in Pharmaceutical Two-Component Crystals. the Case Study of the Salicylamide Cocrystal

Two polymorphs of the salicylamide cocrystal with oxalic acid have been obtained and described. Form I of the cocrystal was prepared by three alternative methods in various solvents, while formation of form II was achieved only by a special crystallization procedure. Single-crystal X-ray analysis has revealed that polymorphs consist of conformationally identical salicylamide and oxalic acid molecules, which are assembled into supramolecular units connected via a network of very similar hydrogen bonds. The packing arrangements of the cocrystal polymorphs, however, were found to be different, suggesting a rare example of packing polymorphism. The stability relationship between the polymorphs has been rationalized by using a number of experimental methods, including thermochemical analysis, solubility, and solution calorimetry measurements. Similarities and differences in intermolecular contacts across two polymorphs have been visualized using the Hirshfeld surface analysis. The Bader analysis of the theoret...