New Insights into the Structure and Thermodynamic Stability of Polymorphs I and II of the Nicotinamide:Adipic Acid Co-Crystal: A BEST-CSP Study.

The polymorphism of the 1:1 nicotinamide:adipic acid (NIC:AA) cocrystal system was re-examined by combining structural and thermodynamic approaches. Differential scanning calorimetry (DSC), solid-state NMR (ssNMR), and variable-temperature powder X-ray diffraction (VT-PXRD) confirmed an enantiotropic relationship between the two polymorphs, evidenced by a direct solid-solid transformation from triclinic form I to monoclinic form II at ∼ 370 K. Solubility data subsequently indicated that this temperature is ∼78 K higher than the equilibrium transition temperature (289.2 ± 0.7 K), consistent with a phase transition hindered by a substantial activation barrier. This also explained why the reverse process was not detected on cooling within the time scale of the DSC, ssNMR, and VT-PXRD experiments. The relative stabilities of forms I and II, as well as their stability relative to dissociation into the coformers, at 298 K, were quantitatively established based on Gibbs energy, enthalpy, and entropy data obtained from solution calorimetry and solubility measurements. The results indicated that at 298 K: (i) form II is thermodynamically more stable than form I, despite having a lower lattice enthalpy; (ii) this is consistent with the conclusion that the equilibrium transition temperature (289.2 ± 0.7 K) is lower than 298 K and suggests that the stabilization of form II (the high-temperature polymorph) versus form I (low-temperature polymorph) under ambient conditions is of an entropic nature; (iii) both polymorphs are stable with respect to dissociation into the coformers nicotinamide and adipic acid; and (iv) the stability gain upon cocrystallization is primarily of an enthalpic rather than entropic nature, reflecting a lattice enthalpy advantage relative to the pure components. Single-crystal X-ray diffraction further showed that at ∼298 K form I exhibits an ∼3% higher density and packing index than form II, in line with the observed lattice enthalpy difference Δlat H m o(crI) > Δlat H m o(crII). Finally, although cocrystallization is frequently used to produce solid forms with enhanced solubility or stability relative to the individual coformers, the formation of the NIC:AA cocrystal does lead to improved solid-state stability but not to solubility enhancement, at least when acetonitrile is used as solvent.