(287e) Mechanistic Investigation of Spherical Crystallization of Active Pharmaceutical Ingredients Using in-Situ PAT and Mathematical Models

With increasing R&D costs for drug companies, the focus on Pharmaceutical Manufacturing (PM) cost has gained centerfold. Process Intensification (PI) is one of the most widely used strategies to reduce the cost of PM. Spherical Crystallization is an innovative PI strategy which leads to the formation of spherical crystalline agglomerates, thereby enabling control over manufacturability and bioavailability in a single unit operation. Spherical Crystallization also enables formulation of drug-excipient co-agglomerates, which can potentially lead to direct compounding of drug products leading to complete elimination of Drug Product Manufacturing. However, controlling the size of the primary particles that form the agglomerates, along with the agglomerate size remains a challenging task. In this work, mechanistic mathematical models are first constructed for the SC process which gives the time course evolution of the droplet population and crystal population within the droplets. It is found that there are major differences in primary crystal size distribution for two different agglomerate sizes, which ultimately would lead to differences in bioavailability of the product agglomerates. Experiments are also carried out in the laboratory using Process Analytical Technology tools (FBRM) to find the evolution of the droplet population within the crystallizer. It is found that from the dynamical evolution of the FBRM data, the fundamental rate processes of crystal nucleation and growth within individual droplets could be deduced. This work would ultimately provide a framework for implementation of Quality By Design for PI in PM involving multi-scale rate processes.