Formation Enthalpies and Polymorphs of Nicotinamide–R‑Mandelic Acid Co-Crystals

Co-crystals provide an opportunity to improve the properties of pharmaceuticals and other materials. We report a method for determining the formation enthalpies of co-crystals in which enthalpies of melting are measured for a co-crystal and the physical mixture of its component crystals. Because the two melting processes arrive at the same liquid, the difference of their enthalpy changes is the co-crystal’s formation enthalpy. For the system of nicotinamide (NIC) and R-mandelic acid (RMA), the formation enthalpy at 30 °C is −23 (3) J/g for polymorph 1 and −18 (3) J/g for polymorph 2. These values are comparable with the enthalpy of mixing for NIC and RMA liquids [−49 (4) J/g at 160 °C], indicating the need for correcting for nonideal mixing in calculating formation enthalpies of co-crystals via thermodynamic cycles. This correction is made automatically in our method by performing measurements with physical mixtures of component crystals, as opposed to pure component crystals. One of the NIC-RMA polymorphs (2) was discovered in this work, and its structure and thermodynamic relation to polymorph 1 are reported.