Dissolution testing is a performance test for many dosage forms including tablets and capsules. The objective of this study was to evaluate if computer simulations can predict the in vitro dissolution of two model drugs for which different dissolution data were available. Published montelukast sodium and glyburide dissolution data was used for the simulations. Different pharmacopeial and biorelevant buffers, volumes, and rotations speeds were evaluated. Additionally, a pH change protocol was evaluated using these buffers. DDDPlus™ 3, Beta version (Simulation Plus, Inc.), was used to simulate the in vitro dissolution data. The simulated data were compared with the in vitro data. A regression coefficient between predicted and observed data was used to assess the simulations. The statistical analysis of Montelukast sodium showed that there was a significant correlation between the in vitro release data and the predicted data for all cases except for one buffer. For glyburide, there was also a significant correlation between the experimental data and the predicted data using single pH conditions. Using the dynamic pH protocol, a correlation was significant for one biorelevant media. The simulations showed that both in vitro drug releases were sensitive to solubility effects which confirmed their BCS class II category. Computer simulations of the in vitro release using DDDPlus™ have the potential to estimate the in vivo dissolution at an early stage in the drug development process. This might be used to choose the most appropriate dissolution condition to establish IVIVC and to develop biorelevant in vitro performance tests to capture critical product attributes for quality control procedures in quality by design environments.