| Amorphous pharmaceuticals, because of their potential to confer superior biopharmaceutical properties, are attracting increasing attention in the pharmaceutical community. However, their inherent physical and chemical instability pose major challenges in their use. This study aims to understand, characterize and quantify the instability and develop guidelines for excipient selection so as to yield amorphous pharmaceuticals with increased physical and chemical stability. While the currently used approaches require a high excipient concentration (typically >20% w/w), our objective was to identify additives effective at low concentrations (< 5% w/w). Using differential scanning calorimetry as the analytical technique, we evaluated the inhibitory strength of additives. Urea was shown to be a very strong crystallization inhibitor of amorphous tolbutamide (TB). The mechanism of stabilization was the specific interaction between urea and TB. Based on this mechanism, amino acids were used to stabilize amorphous sugars, and their effectiveness increased with a decrease in molecular size. Chemical stabilization can be brought about by the excipient through several different mechanisms including the physical form of drug, the matrix molecular mobility, medium effects and the drug-excipient reaction. Using sucrose inversion as a model reaction, we attempted to understand the effects of matrix and salt on the chemical stability of lyophiles. The chemical composition of the matrix can profoundly influence the chemical stability of amorphous sucrose. There was a very good correlation between the Hammett acidity function and the reaction rate. In presence of neutral salt, the chemical stability decreased and there was no longer any correlation between 'solid state' acidity and chemical stability. The knowledge gained from this thesis should aid in the rational selection of excipients which can physically and chemically stabilize amorphous pharmaceuticals. |
