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

Abstract

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-dihydroxybenzoic acid ( 26DHB ), were synthesized and structurally evaluated in order to study basic recognition patterns and crystal lattice energetic features. The literature-reported structures of this kind, i.e., N:24DHB, N:25DHB and N:26DHB (the last two were crystallized and remeasured by us at 100 K) and P:25DHB, completed the series. The analysis of interaction networks in the examined cocrystals reflects the relative affinity of the COOH and OH groups toward N-donor compounds. A major factor that governs the primary synthon formation is the basic character of the proton acceptors in the heterocyclic compounds. In a crystal lattice, the more rigid pyrazinamide tends to form its primary structural motifs, and hence is less influenced by the molecular surrounding than nicotinamide. Consequently, crystal lattice stabilization energy values for the cocrystals of nicotinamide are more advantageous, whereas the patterns created by pyrazinamide are more predictable. Nicotinamide cocrystals are also characterized by crystal lattices being more energetically uniform in all directions than the pyrazinamide equivalents. Importantly, cocrystal cohesive energies are more favorable than that of the respective single component crystal structures, which supports the cocrystal formation when both coformers are dissolved and mixed together. Although classical hydrogen bonds are majorly responsible for synthon formation, weak dispersive forces cannot be neglected either as far as the structure stabilization is concerned.