Structural diversity and anomalous formation properties of nicotinamide co-crystals

Cocrystals provide an opportunity to improve the properties of pharmaceutical solids and other materials. Although many studies have focused on the discovery and structure of cocrystals, the work has been limited on the thermodynamic formation properties of cocrystals.;This thesis work reports a method for determining the formation enthalpies of cocrystals in which enthalpies of melting are measured for a cocrystal 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 cocrystal's formation enthalpy. For the system of nicotinamide (NIC) and R-mandelic acid (RMA), the formation enthalpy at 30 °C is -20 (3) J/g for the 1:2 cocrystal, -23 (3) J/g for the 1:1 cocrystal form 1, -18 (3) J/g for the 1:1 cocrystal form 2, and -8 (3) J/g for the 4:1 cocrystal. The thermodynamic relationship between two polymorphs of the 1:1 cocrystal is also reported.;A solid state screening method for discovering new cocrystal phases is also reported in this thesis. Through this method, a remarkable system of cocrystals was discovered containing NIC and RMA in numerous stoichiometric ratios (4:1, 1:1 with two polymorphs, and 1:2). These cocrystals have unusual formation properties: they have negative formation enthalpies but positive formation volumes, indicating that cocrystallization lowers energy but expands volume. Analysis of all cocrystals containing NIC (n = 40) found that most have larger volumes than their component crystals: +3.9 A3/molecule or +17 cm3/kg on average, corresponding to a 2 % expansion. A dispersion-corrected density functional theory (DFT-D) method has been used to calculate the formation energies and volumes of NIC cocrystals and a broad agreement is found between experimental and computed values. This volume expansion correlates with the shortening and strengthening of hydrogen bonds upon cocrystallization, in analogy with water freezing and other processes that exhibit anomalous enthalpy-volume correlations. NIC has two conformers 4 kJ/mole apart in energy and both can form cocrystals, with the resulting structures having comparable formation energies and volumes. These results are relevant for understanding the nature of cocrystallization and why NIC is a prolific cocrystal former.