Drug instability in solid dosage forms includes chemical or physical processes involving covalent or polymorphic transformations wherein different polymorphs possess crystal structure differences. Gabapentin chemically degrades by intramolecular cyclization to gabapentin-lactam (lactam) in the solid-state. Additionally, gabapentin undergoes polymorphic solid-state transformations. A kinetic model was developed to describe the environmental and excipient effects on chemical and physical instability associated with milling induced stress and subsequent storage under controlled temperature and humidity conditions. Reaction mixtures were generated by co-milling gabapentin Form II with various excipients. The effects of environmental conditions were studied by storing reaction mixtures at 40-60 ºC and 5-50 %RH. The chemical and polymorphic compositions of the reaction mixtures were measured as a function of time using a combination of chromatographic method, 13C ssNMR and XRPD. Degradation models that describe the relationship between polymorphs and degradation product in a series of sequential or parallel steps were devised based on analysis of the resultant concentration time profiles. Model parameters were estimated using non-linear regression and Bayesian methods and evaluated in terms of their quantitative relationship to compositional and conditional variations. In reaction mixtures composed of co-milled gabapentin and excipients, gabapentin was found to exist in three forms: anhydrous polymorph II and III and gabapentin-lactam. A fourth form (II*) was observed based on initial degradation kinetics and was hypothesized to be a crystal-disordered form generated by mechanical stress. The effect of environment moisture was to decrease the net rate of lactam formation by facilitating polymorphic transformation kinetics and crystal annealing. However, excipient blocked the catalytic moisture effect on polymorphic transformations. The key features of our model are first-order physical state transitions of II* and III to II, first-order degradation of II* to lactam and autocatalytic lactamization of II and III. For chemical transitions, no humidity effect was present but the catalytic effects of excipients on the conversion of II and III → lactam were observed. For physical transitions, excipient primarily influenced the physical state transitions of II*and III → II through its ability to interact with humidity and the degree of contact between excipient and substrate.