Understanding properties and mechanisms that govern drug degradation in the solid state is of high importance to ensure drug stability and safety of solid dosage forms. In this study, we attempt to understand drug–excipient interac-tions in the solid state using both theoretical and experimental approaches. The model active pharmaceutical ingredi-ents (APIs) under study are Carvedilol (CAR) and Codeine Phosphate (COP), which are known to undergo esterifica-tion with citric acid (CA) in the solid state. Starting from the crystal structures of two different polymorphs of each compound, we calculated the exposure and accessibility of reactive hydroxyl groups for a number of relevant crystal surfaces, as well as descriptors that could be associated with surface stabilities using molecular simulations. Accelerated degradation experiments at elevated temperature and controlled humidity were conducted to assess the propensity of different solid forms of the model APIs to undergo chemical reactions with anhydrous CA or CA monohydrate. In addi-tion, for CAR, we studied the solid state degradation at varying humidity levels and also under mechano activation. Regarding the relative degradation propensities, we found that variations in the exposure and accessibility of molecules on the crystal surface play a minor role compared to the impact of molecular mobility due to different levels of mois-ture. We further studied drug–excipient interactions under mechano-activation (co-milling of API and CA) and found that the reaction proceeded even faster than in physical powder mixtures kept at accelerated storage conditions.