Drug uptake by polymer was modeled using a molecular dynamics (MD) simulation technique. Three drugs-doxorubicin (water soluble), silymarin (sparingly water soluble) and gliclazide (water insoluble)-and six polymers with varied functional groups-alginic acid, sodium alginate, chitosan, Gantrez AN119 (methyl-vinyl-ether-co-malic acid based), Eudragit L100 and Eudragit RSPO (both acrylic acid based)-were selected for the study. The structures were modeled and minimized using molecular mechanics force field (MM+). MD simulation (Gromacs-forcefield, 300 ps, 300 K) of the drug in the vicinity of the polymer molecule in the presence of water molecules was performed, and the interaction energy (IE) between them was calculated. This energy was evaluated with respect to electric-dipole, van der Waals and hydrogen bond forces. A good linear correlation was observed between IE and our own previous data on drug uptake* [R 2=0.65, Radj2 = 0.65,R pre2 = 0.56, and a F ratio of 30.25, P<0.001; Devarajan et al. (2005) J Biomed Nanotechnol 1:1-9]. Maximum drug uptake by the polymeric nanoparticles (NP) was achieved in water as the solvent environment. Hydrophilic interaction between NP and water was inversely correlated with drug uptake. The MD simulation method provides a reasonable approximation of drug uptake that will be useful in developing polymer-based drug delivery systems. © 2010 Springer-Verlag.