Adhesion problems during tablet manufacturing have been observed to be dependent on many formulation and process factors including the run time on the tablet press. Consequently, problems due to sticking may only become apparent towards the end of the development process when a prolonged run on the tablet press is attempted for the first time. It would be beneficial to predict in a relative sense if a formulation or new chemical entity has the potential for adhesion problems early in the development process. It was hypothesized that favorable intermolecular interaction between the drug molecules and the punch face is the first step or criterion in the adhesion process. Therefore, the rank order of adhesion during tablet compression should follow the rank order of these energies of interaction. The adhesion phenomenon was investigated using molecular simulations and contact mode atomic force microscopy (AFM). Three model compounds were chosen from a family of "profen" compounds. Silicon nitride AFM tips were modified by coating a 20-nm iron layer on the surfaces by sputter coating. Profen flat surfaces were made by melting and recrystallization. The modified AFM probe and each profen surface were immersed in the corresponding profen saturated water during force measurements using AFM. The work of adhesion between iron and ibuprofen, ketoprofen, and flurbiprofen in vacuum were determined to be -184.1, -2469.3, -17.3 mJ. m(-2), respectively. The rank order of the work of adhesion between iron and profen compounds decreased in the order: ketoprofen > ibuprofen > flurbiprofen. The rank order of interaction between the drug molecules and the iron superlattice as predicted by molecular simulation using Cerius(2) is in agreement with the AFM measurements. It has been demonstrated that Atomic Force Microscopy is a powerful tool in studying the adhesion phenomena between organic drug compounds and metal surface. The study has provided insight into the adhesion problems occurring during tablet compression and a direction for continued study.