A Rational Approach to the Impact of Solids in the Synthesis of Active Pharmaceutical Ingredients

The development to industrial scale of production processes in the pharmaceutical industry consists of a series of scale-ups, starting from small amounts of material for early safety or clinical studies all the way to scaling up to a manufacturing plant, to make commercial supplies. Because of this, process development relies mostly on empirical and experience-based procedures that lead to high energy consumption and large waste production. A major contributor, among others, to the elevated waste production is the presence of solid phases at various steps of the process. Solid phases impact also the API synthesis. Specifically, during drug synthesis, solids may be present as heterogeneous catalyst, reagents, products, or a combination of these, and this may be true for several of the steps required to produce the final molecule. The presence of solids in a reactive environment always implies the coexistence of physical phenomena, such as dissolution, precipitation, and mass transfer between phases, in addition to reaction kinetics. This inherently introduces additional challenges in the development, optimization, and scale-up of processes. Several are the issues to be faced with when working with reaction involving solid phases, such as mixing of solid-liquid suspensions, fluid dynamic modeling, mass and heat transfer quantification, structural changes over time, fouling and clogging. These issues vary depending on the type of process, whether batch or continuous, and can be classified in operational and modelling challenges. Given this plethora of challenges, the objective of this thesis is to apply a science-based approach grounded in the principles of chemical engineering, to tackle some of these issues. The aim of this work is to provide guidance, tools, and a methodology for address similar processes, rather than focusing on a single reaction. In fact, a collection of case studies was discussed, each with its own specific goals and issues. The common thread connecting them, aside from the presence of solid phases and the intertwining between physical phenomena and reaction kinetics, is the approach used for the analysis of each process.