The overarching objective of this thesis is to demonstrate a systematic approach for addressing the instability issues associated with low limit degradants by developing quantitative degradation models that incorporate key instability determinants into predictive equations. Chlorhexidine was used as model compound in aqueous solution to demonstrate the application of the predictive models to issues of formulation design and manufacturing. Chorhexidine degrades to p-chloroaniline, a well-established toxicant, by various pH-dependent pathways. In acidic conditions, the direct formation of p-chloroaniline from chlorhexidine is the major pathway whereas the indirect formation of p-chloroaniline via p-chlorophenylurea is the main alkaline pathway. Rate laws and mechanisms for each pathway were presented. Shelf life predictions equations for chlorhexidine formulations were derived based on the kinetics of p-chloroaniline appearance as a function of formulation strength, solution pH, bulk chlorhexidine purity and storage temperature. The pH range for optimal shelf-life was 5.0 to 5.5. Simple extraction procedures used during formulation preparation were identified to improve bulk chlorhexidine purity and thereby extend product shelf-life. Gabapentin degrades directly to gabapentin-lactam in the solid-state. The established limit on gabapentin-lactam in gabapentin pharmaceutical formulations is <0.5% w/w thus gabapentin instability was studied as a model compound for solid state formulation applications. Mechanical stress associated with drug product manufacturing in unit operations such as milling increased the subsequent lactamization rate upon storage due to increased gabapentin crystal disorder. The effect of environment moisture was to decrease the rate of gabapentin-lactam formation due to competitive recovery of gabapentin crystallinity which was accelerated by humidity. A degradation model that combined both physical and chemical instability pathways including autocatalytic branching, spontaneous intra-molecular cyclization and moisture-induced physical transformation steps was shown to be consistent with lactamization kinetics as a function of both environmental (temperature and humidity) and manufacturing-related effects. This kinetic model was used to predict the shelf-life of gabapentin tablets prepared under various exemplary manufacturing conditions thereby demonstrating the ability of the model to link manufacturing variation and shelf-life stability in for solid-state drug formulations.