Solid State Properties of an Oral Iron Chelator, 1,2-Dimethyl-3-hydroxy-4-pyridone, and Its Acetic Acid Solvate. I: Physicochemical Characterization, Intrinsic Dissolution Rate, and Solution Thermodynamics

Abstract

1,2-Dimethyl-3-hydroxy-4-pyridone (1), a crystalline oral iron chelator, forms an acetic acid solvate (2) on recrystallization from acetic acid and carbon tetrachloride. Compound 2 forms compact prisms, and 1 forms needles from water (mp 274 °C). The X-ray powder diffraction patterns of 1 and 2 differ, indicating distinct solid phases. Compound 2 has an extra DSC endotherm at 82 °C that is accompanied by a weight loss of 29% in TGA, corresponding to the desolvation of a 1:1 acetic acid solvate. Comparison of the solid-state 13C NMR of 1 and 2 revealed two additional peaks for 2 at 20.3 and 175.6 ppm, characteristic of —CH3 and —COOH, respectively, of acetic acid. The integrated intensities confirmed the 1:1 stoichiometry between 1 and acetic acid. However, 2 underwent desolvation in air at 25 °C as suggested by a change in its appearance to opaque crystals and as confirmed by X-ray powder diffraction, DSC, and TGA. Desolvation of 2 at 25 °C was a zero-order process with a rate constant of 6.9 μmol · h−1. X-ray powder diffraction showed that crystals or compacted discs of 1 are converted to 2 in contact with glacial acetic acid (A), whereas crystals or discs of 2 are converted to 1 in contact with water. The intrinsic dissolution rate (J) and the apparent solubility (Cs) of compacted discs of 1 and 2 were measured in water at 25 °C, and the following relations were determined: J(2)/J(1) = 1.39 and Cs(2)/Cs(1) = 1.70. From solubility measurements, the standard Gibbs free energy of transfer (ΔG° kcal · mol−1) at 25 °C with respect to the molar concentration scale are as follows: 1 to H2O, 5.40; 2 to H2O, <8.18; 1 to A, estimated; 2 to A, −1.40; A to H2O, −10.48 (from literature data). Using solution calorimetry, the corresponding enthalpy changes (ΔG°, kcal · mol−1) at 25 °C were measured: 1 to H2O, 18.7; 2 to H2O, 30.2; 1 to A, 17.3; 2 to A, 29.4; A to H2O, − 1.1. A thermodynamic cycle shows that these values are self-consistent. The positive enthalpy changes indicate that the dissolution of 1 and 2 in water or A is entropy driven. Furthermore, the dissolution of 2 in water or A is more endothermic than that of 1 by only ~ 1 kJ · mol−1. Use of isotonic phosphate buffered saline (pH 7.4) instead of water gave similar thermodynamic values (within 5%), and the main conclusions were unaltered.