| Hydrates form an integral part of many solid dosage forms. This thesis attempts to better understand the hydration-dehydration behavior of some pharmaceutical hydrates, including theophylline, ampicillin and nedocromil bivalent metal salts, and to link the crystal structures to the physical stability and ultimately to the physicochemical properties.;The influence of water activity in organic solvent + water mixtures on the hydration state of the crystallizing drug phase is examined. The fundamental hypothesis that, when a drug, which can form a hydrate, is crystallized from mixtures of organic solvent + water, the water activity in the mixture is the major factor determining the nature of the anhydrate or hydrate phase that crystallizes, is tested and found to be valid for theophylline and ampicillin.;Nedocromil magnesium, zinc or calcium form hydrates with the following water stoichiometries: Mg, 10, 7, 5; Zn, 8, 7, 5; Ca, 5, 8/3. The thermodynamically most stable hydrate is found to be associated with the lowest degree of hydration. In the absence of the crystal structures of metastable hydrates, thermal analysis, powder X-ray diffraction, solid-state nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, intrinsic dissolution rate and solubility measurements provide insight into the structural and energetic differences among the salt hydrates.;To study further the effect of ionic radius of the bivalent cation on the stoichiometry of hydration of their salt hydrates with nedocromil, a manganese pentahydrate, a cobalt heptahydrate and a nickel octahydrate were also prepared and their crystal structures solved. In general, the smaller the cationic radius the greater the water stoichiometry. However, there are major differences in the coordination environments of the cations and in the bonding environments of the water molecules among the bivalent salt hydrates of nedocromil.;The kinetics and activation energy for the dehydration of nedocromil magnesium pentahydrate were determined by isothermal TGA and temperature-ramp DSC analyzed by Kissinger's method. Nucleation controlled mechanisms are proposed for both dehydration steps. The activation energy decreased with decreasing particle size and increasing sample weight. The dehydration rate increased with decreasing water vapor pressure and with repetition of the dehydration-hydration cycle. |
