Relationships between Crystal Structures, Thermal Properties, and Solvate Stability of Dialkylhydroxypyridones and Their Formic Acid Solvates

Abstract

Four 1,2-dialkyl-3-hydroxy-4-pyridones (DAHPs), which are iron chelators potentially suitable for oral administration, and their formic acid solvates (DAHP-Fs) were examined in powder form by powder X-ray diffraction (PXD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and hot-stage microscopy (HSM). The experimental PXD pattern of each DAHP-F is different from that of the corresponding DAHP, indicating different crystalline phases. The PXD patterns calculated from the published crystal structures closely resemble the corresponding PXD patterns determined experimentally, indicating that the powdered materials studied are structurally identical with the single crystals previously examined. The DAHPs have similar DSC profiles consisting of melting followed by vaporization. The DSC profiles of the DAHP-Fs share five common features: melting and desolvation of the solvate, crystallization of the nonsolvate, vaporization of the released formic acid, melting of the nonsolvate, and vaporization of the nonsolvate. The weight loss steps in TGA indicate that each DAHP-F contains 1 mol of formic acid/mol of DAHP. The threshold temperature for desolvation of each DAHP increases with decreasing length of the hydrogen bond between the pyridone carbonyl oxygen and the formic acid carboxyl proton, corresponding to an increase in solvate stability. Thus, the relative stabilities of the solvates are delineated and are related to the length of the hydrogen bond between the DAHP and the formic acid molecules.