Relationships between solution thermodynamics and hydrogen-bond patterns of crystalline dialkylhydroxypyridone iron...

1,2-Dialkyl-3-hydroxy-4-pyridones (DAHPs) are iron chelators that are being considered for oral administration for the treatment of anemias. They form 1:1 solvates with formic acid (DAHP-F). The lower DAHP homologues, differing in the alkyl chain length in the 1- and/or 2-positions, have known crystal structures and hydrogen-bond patterns. The main objective of this work is to investigate the influences of the hydrogen-bond patterns and the position and chain length of the alkyl groups on the free energies, enthalpies and entropies of solvation of the nonsolvates in formic acid, and of desolvation of the solvates in water at 25 degrees C. The standard free energy changes for desolvation of the solvates in water and for solvation of the nonsolvates in formic acid differed for different alkyl chain lengths at the 2-position but not at the 1-position. In contrast, the calorimetric enthalpies and entropies of solvation fell into two distinct classes, depending on the hydrogen-bond patterns of the solvates: that is, compounds which form 18-membered hydrogen-bonded rings, and a compound that forms a 10-membered hydrogen-bonded ring. The equilibrium constants for solid-state solvation indicated an approximately twofold greater solvating tendency for the 2-ethyl DAHPs than for the 2-methyl DAHPs. The mass transfer coefficient for the aqueous dissolution of each solvate was usually lower than that for the corresponding nonsolvate. The results provide links between molecular structure, crystal structure, and solution properties among the DAHP series.