The aim of the present study was to combine vibrational spectroscopy and chemometrics for investigating excipient-induced disproportionation of the calcium salt of atorvastatin into the corresponding free acid form in environments relevant to manufacturing and storage of solid dosage formulations. Of the excipients investigated, citric acid and polyacrylic acid were found to induce disproportionation. Moreover, it was also observed that exposure to high relative humidity, elevated temperatures, and milling all promoted disproportionation. The results suggest that disproportionation of drug salts in powders happens via a solution-mediated mechanism and that the choice of excipient has a considerable impact on the extent of disproportionation observed. Thus, careful attention must be paid to excipient selection during pharmaceutical development and exposure to stresses such as high humidity and mechanical activation should be minimized.