| The overall objectives of this thesis work are to (i) study the influence of thermal history and interaction with solvents on the properties of amorphous pharmaceuticals, and (ii) develop new approaches for the characterization of amorphous phases. The effect of thermal history (method of preparation and subsequent aging) on pharmaceutically relevant properties of amorphous trehalose were investigated. The history influenced not only the rate and extent of water sorption, but also the phase crystallized. Interestingly, water sorption could reverse the effects of physical aging, leading to an apparent removal of thermal history. Using an automated vapor sorption balance, the dehydration behavior of carbamazepine dihydrate, to yield amorphous anhydrous carbamazepine, was studied under a variety of conditions. It was possible to differentiate between the removal of physically bound water and the lattice water. Dehydration in the presence of the ethanol vapor was a two-step process and the fraction dehydrated at each step was a function of the ethanol vapor pressure. The crystallization behavior of amorphous anhydrous carbamazepine was a complex function of the solvent activity, kinetics and solid-solvent interaction. A new method was developed for in situ crystallinity determination. Using amorphous sucrose and sucrose-PVP mixtures as model systems, an inverse gas chromatographic method was developed for determination of the Tg of amorphous pharmaceuticals and extended to an in situ study of the plasticization effect of small molecules. The effect of experimental conditions on the enthalpic relaxation measurement by DSC was evaluated. It was observed that the enthalpic recovery at Tg may not reflect the state of the sample, and may be influenced by the experimental conditions. Finally, using an improved X-ray diffractometric method, it was possible to quantify very low levels of crystallinity (<2% w/w) in a substantially amorphous matrix. |
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