Real-time optimization (RTO) is a supervisory strategy in the hierarchical industrial process automation architecture in which economically optimal set-point targets are computed for the lower level advanced control system, which is typically model predictive control (MPC). Due to highly volatile market conditions, recent developments have considered transforming the conventional steady-state RTO to dynamic RTO (DRTO) to permit economic optimization during transient operation. Published DRTO literature optimizes plant input trajectories without taking into account the presence of the plant control system, constituting an open-loop DRTO (OL-DRTO) approach. The goal of this research is to develop a design framework for a DRTO system that optimizes process economics based on a closed-loop response prediction. We focus, in particular, on DRTO applied to a continuous process operation regulated under constrained MPC. We follow a two-layer DRTO/MPC configuration due to its close tie to the industrial process automation architecture. We first analyze the effects of optimizing MPC closed-loop response dynamics at the DRTO level. A rigorous DRTO problem structure proposed in this thesis is in the form of a multilevel dynamic optimization problem, as it embeds a sequence of MPC optimization subproblems to be solved in order to generate the closed-loop prediction in the DRTO formulation, denoted here as a closed-loop DRTO (CL-DRTO) strategy. A simultaneous solution approach is applied in which the convex MPC optimization subproblems are replaced by their necessary and sufficient, Karush-Kuhn-Tucker (KKT) optimality conditions, resulting in the reformulation of the original multilevel problem as a single-level mathematical program with complementarity constraints (MPCC) with the complementarities handled using an exact penalty formulation. Performance analysis is carried out, and process conditions under which the CL-DRTO strategy significantly outperforms the traditional open-loop counterpart are identified. The multilevel DRTO problem with a rigorous inclusion of the future MPC calculations significantly increases the size and solution time of the economic optimization problem. Next, we identify and analyze multiple closed-loop approximation techniques, namely, a hybrid formulation, a bilevel programming formulation, and an input clipping formulation applied to an unconstrained MPC algorithm. Performance analysis based on a linear dynamic system shows that the proposed approximation techniques are able to substantially reduce the size and solution time of the rigorous CL-DRTO problem, while largely retaining its original performance. Application to an industrially-based case study of a polystyrene production described by a nonlinear differential-algebraic equation (DAE) system is also presented. Often large-scale industrial systems comprise multi-unit subsystems regulated under multiple local controllers that require systematic coordination between them. Utilization of closed-loop prediction in the CL-DRTO formulation is extended for application as a higher-level, centralized supervisory control strategy for coordination of a distributed MPC system. The advantage of the CL-DRTO coordination formulation is that it naturally considers interaction between the underlying MPC subsystems due to the embedded controller optimization subproblems while optimizing the overall process dynamics. In this case, we take advantage of the bilevel formulation to perform closed-loop prediction in two DRTO coordination schemes, with variations in the coordinator objective function based on dynamic economics and target tracking. Case study simulations demonstrate excellent performance in which the proposed coordination schemes minimize the impact of disturbance propagation originating from the upstream subsystem dynamics, and also reduce the magnitude of constraint violation through appropriate adjustment of the controller set-point trajectories. / Thesis / Doctor of Philosophy (PhD)