Anomalous formation properties of nicotinamide Co-Crystals

Abstract

Co-Crystals provide an opportunity to improve the properties of organic materials. We report that Co-Crystals containing nicotinamide (NIC) are anomalous as their formation generally decreases energy but expands volume. This conclusion is demonstrated first for an extraordinary system of Co-Crystals of NIC and (R)-mandelic acid (RMA) and then for all NIC Co-Crystals in general. The volume expansion is evaluated using the crystallographic densities of the cocrystals and their component crystals. The energy decrease upon co-crystallization is demonstrated using experimental data on four Co-Crystals of NIC and RMA and then generalized for all NIC Co-Crystals using computed values from a dispersion-corrected DFT model, after validating the model on the experiment. The anticorrelation between energy and volume on the formation of NIC Co-Crystals is in contrast to most physical processes, but similar to water freezing. As in the case of water freezing, the Co-Crystallization with NIC leads to stronger hydrogen bonds and looser molecular packing, a combination that is likely responsible for the anomalous formation properties. NIC has two conformers 4 kJ/mol apart in energy and both can form co-crystals, with the resulting structures having comparable formation energies and volumes. These results are relevant for understanding the nature of Co-Crystallization and why NIC is a prolific Co-Crystal former.