In this work, a previously validated Computational Fluid Dynamics (CFD) approach was used to investigate the hydrodynamics in the USP Dissolution Testing Apparatus 2 vessel when the impeller was placed at different locations, all within the limits specified in the USP, i.e., in its reference location (centrally mounted and 25 mm off the vessel bottom), 2 mm off center, 2 mm higher and 2 mm lower than then reference location. Velocity profiles, energy dissipation rates, and strain rates inside the vessel were obtained and compared. In addition, simulations were conducted in which a virtual tablet was placed at different locations on the bottom of the vessel. It was found that small changes in the impeller locations, and especially those introduced when the shaft is placed in an off-center location, produced extensive changes in the velocity profiles. Predictions of the shear effects in this regions lead to the conclusion that the exact location of a dissolving table on the tank bottom could have a profound effect on the local power dissipation and solid-liquid mass transfer, and, as a result, on the tablet dissolution rate. The results of this work indicate that the hydrodynamics of dissolution testing is a strong function of the geometry of the system and the operating conditions under which the test is conducted. These results could have significant implications for the reliability of the dissolution test as it is currently conducted.