Further Understanding of Agglomeration Mechanisms in Spherical Crystallization Systems: Benzoic Acid Case Study

Spherical crystallization is a particle size enlargement technique that can provide significant process and micromeritic benefits to the production of active pharmaceutical ingredients. To this point, mechanistic studies of spherical crystallization systems have not used process analytical technologies to assist in developing an understanding of the complex mechanisms occurring in a spherical crystallization technique. In this contribution, process analytical technologies are used to elucidate the underlying mechanisms of spherical crystallization. Moreover, since there are multiple operating modes of spherical crystallization, this study focuses on a subset referred to as spherical agglomeration or agglomeration in suspension. Spherical agglomeration uses a bridging liquid to agglomerate fine crystals into spherical particles. This study evaluates how different methods of incorporating the bridging liquid affect the mechanisms that ultimately lead to the formation of agglomerates. Results show that the most robust method of incorporating the bridging liquid is post crystallization. The study then further evaluates how the properties of the constituent particles and their interaction with the bridging liquid droplet affect agglomerate size and powder flow properties. The results indicate that there is a critical relationship between bridging liquid droplet size and crystal size that determines whether the agglomeration mechanism is immersive or distributive. The difference in mechanism leads to vastly different particle sizes, powder flows, and powder compression properties.