Structural and Energetic Analysis of Molecular Assemblies in a Series of Nicotinamide and Pyrazinamide Cocrystals with Dihydroxybenzoic Acids

Four new cocrystals of pharmaceutically active N-donor compounds,pyrazinamide (P) and nicotinamide (N), with a series of dihydroxybenzoic acids, i.e., 2,3-dihydroxybenzoic acid (23DHB), 2,4-dihydroxybenzoic acid (24DHB), and 2,6-dihydrox-ybenzoic acid (26DHB), were synthesized and structurally evaluated in order to study basicrecognition patterns and crystal lattice energetic features. The literature-reported structures ofthis kind, i.e.,N:24DHB,N:25DHBandN:26DHB(the last two were crystallized andremeasured by us at 100 K) andP:25DHB, completed the series. The analysis of interactionnetworks in the examined cocrystals reflects the relative affinity of the COOH and OH groupstoward N-donor compounds. A major factor that governs the primary synthon formation is thebasic character of the proton acceptors in the heterocyclic compounds. In a crystal lattice, themore rigid pyrazinamide tends to form its primary structural motifs, and hence is lessinfluenced by the molecular surrounding than nicotinamide. Consequently, crystal latticestabilization energy values for the cocrystals of nicotinamide are more advantageous, whereas the patterns created bypyrazinamide are more predictable. Nicotinamide cocrystals are also characterized by crystal lattices being more energeticallyuniform in all directions than the pyrazinamide equivalents. Importantly, cocrystal cohesive energies are more favorable than thatof the respective single component crystal structures, which supports the cocrystal formation when both coformers are dissolvedand mixed together. Although classical hydrogen bonds are majorly responsible for synthon formation, weak dispersive forcescannot be neglected either as far as the structure stabilization is concerned.