<p dir="ltr">The dissolution profile is one of the most important critical quality attributes (CQAs) for pharmaceutical solid oral dosage forms, as failure to meet the dissolution specification can impact bioavailability. Dissolution tests are essential to assess lot-to-lot product quality and guide the development of new formulations. Therefore, predictive dissolution reduced-order models (ROM) are crucial for the successful implementation of any real-time release testing (RTRT) strategy. Mechanistic and semi-mechanistic ROMs of tablet dissolution for realizing quality by control (QbC) and RTRT frameworks in continuous manufacturing are still scarce or nonexistent. Moreover, realizing the underlying coupled mechanics of wetting, swelling, disintegration, and dissolution is still an open question. This dissertation contributes to developing a mechanistic ROM of pharmaceutical tablet dissolution for the design, optimization, and control of manufacturing processes. We follow several steps towards the progression of the mechanistic model development. First, we develop a semi-mechanistic ROM to capture the relationship between critical process parameters (CPPs), critical material attributes (CMAs), and dissolution profiles. We demonstrate the versatility and the capability of the semi-mechanistic ROM to estimate changes in dissolution due to process disturbances in tablet porosity, lubrication conditions, and moisture content in the powder blend. Next, to understand the underlying coupled mechanism of wetting, swelling, disintegration, and dissolution, we use dynamic micro-computed tomography (micro-CT) with a high temporal resolution to visualize water penetration through the porous network of immediate-release tablets. We couple liquid penetration due to capillary pressure described by the Lucas-Washburn theory with the first-order swelling kinetics of the excipients to provide a physical interpretation of the experimental observations. From the mechanistic understanding of the water penetration kinetics using the micro-CT tests, we propose a two-stage mechanistic ROM, which is comprised of (i) a mechanistic dissolution model of the active pharmaceutical ingredient (API) that solves a population balance model (PBM) for a given API crystal size distribution and dissolution rate coefficient, and (ii) a tablet wetting function that estimates the rate at which the API is exposed to the buffer solution. These two sub-models are coupled by means of convolution in time to capture the start time of the API dissolution process as water uptake, swelling, and disintegration take place. Finally, we demonstrate the versatility and the capability of the mechanistic API dissolution model and the two-stage tablet dissolution ROM to represent the dissolution profile of different pharmaceutical formulations and its connection with CMAs, CPPs, and other CQAs, namely initial API crystal size distribution, porosity, composition, and dimensions of the tablet. In all of the cases considered in this work, the estimations of the model are in good agreement with experimental data. </p>