INTEGRATED PROCESS MODELING AND EXPERIMENTAL ANALYSIS FOR OPTIMIZING CONTINUOUS MANUFACTURE OF DRUG SUBSTANCE CARBAMAZEPINE

Abstract

This dissertation presents a comprehensive study on the continuous manufacture (CM) of the drug substance (DS) carbamazepine (CBZ), a widely used anti-epileptic medication, aimed at enhancing process efficiency and product quality. The research progresses through a series of investigations, beginning with the development of kinetic models for CBZ synthesis from iminostilbene via two different synthetic routes using urea and potassium cyanate across various reactor setups, including batch and continuous flow systems. Discrepancies between batch and continuous models, particularly in yield prediction and impurity formation, are thoroughly examined and addressed through adjustments in reactant addition methods and system designs. This demonstrates the value of mechanistic modeling, a tool that has been undervalued in recent research particularly for its ability to compare between batch and continuous systems. Subsequently, the research delves into the crystallization processes, employing a population balance model (PBM) to study CBZ polymorph form III crystal formation, highlighting the influence of seed crystal size distribution on product crystal quality. It also provides novel strategies for modeling the evolution of crystal size distribution (CSD) due to nucleation and growth and evaluates the robustness of these strategies as seed CSD varies. Lastly, the scope is expanded to a holistic view of the integrated synthesis and crystallization process presenting one of the first studies of a complete DS CM system and emphasizing the development of a robust Quality-by-Control (QbC) framework. This includes the implementation of in-line Raman spectroscopy for real-time concentration monitoring, an active feedback level control system, dynamic modeling of impurity partitioning for enhancing disturbance mitigation across the CM process, and a retrograde design strategy that optimizes the upstream synthesis based on downstream purification capabilities/limitations. Through all these contributions, the dissertation aims to advance the modernization of continuous manufacturing practices in the pharmaceutical industry and promotes a shift towards more adaptive and controlled production environments.