Relaxation of Nateglinide-Pyridinecarboxamide Coamorphous Systems to Cocrystals: Synthon Competition with Acid, Amide, and Pyridine Groups

Amide-amide, acid-amide, and acid-pyridine synthons are among the most effective hydrogen-bonded building blocks in multicomponent drug systems. In this work, a conformationally flexible compound with prolific polymorphism was chosen as a carboxylic acid model drug, combined with three pyridinecarboxamide positional isomers as co-formers─picolinamide, nicotinamide, and isonicotinamide. Quench-cooling molten mixtures with different molar ratios produced binary coamorphous systems. Their thermal stability was dependent on the heating rate, relaxing to equimolar cocrystals with picolinamide and isonicotinamide, also obtained by mechanochemistry. Contrarily, both methods could only produce physical mixtures with nicotinamide. Thermal analysis and X-ray diffraction were used to characterize the crystalline phases. Furthermore, the molecular dynamics of the pure compounds and binary phases were studied by dielectric spectroscopy, while the main intermolecular interactions were investigated by FTIR-ATR and computational methods based on DFT calculations─molecular electrostatic potential, NBO, and IGM-δg analyses. The acid hydroxyl group was the strongest hydrogen bond donor, and the amide carbonyl group was the best acceptor. However, the synthon competition outcome was found to depend on the pyridinecarboxamide isomer, with picolinamide having a more different behavior because of electronic and steric effects. Experimental and computational results suggest an acid-amide synthon in the nateglinide-picolinamide cocrystal, which was fully confirmed by single-crystal X-ray diffraction.