Effects of Scale, Equipment, and Operation on Agglomeration during a Reactive Crystallization

Developing processes to deliver formulation-ready active pharmaceutical ingredients (APIs) in a robust and consistent manner comes with challenges. An important challenge relates to particle properties, and one of the representative particle properties that can be measured is the particle size distribution. In the absence of further processing such as particle size reduction, it is paramount to understand and control the particle size of the API within the final crystallization stage. The example presented here is a salt formation in which the introduction of the salt forming agent into the solution of the ionized form of the API enables the new salt entity to crystallize. It is important to evaluate the risks associated with changes in equipment and scale on particle size and shape, to ensure that any appropriate mitigation activities can be implemented. Here, the approach was divided in two steps: first, the establishment of the crystallization mechanisms involved in the process and, second, the modeling of the mixing profiles applied at the production scale. This study enabled understanding of how the particles were formed in the reactor at production scale and identification of key manufacturing criteria to control and reduce the particle size to achieve the current specifications. A regime map is proposed to understand the risk of agglomeration based on shear rates and mesomixing scale time.