(700c) Investigation of Pre-Nucleation Phenomena for Strategic Process Design of an Industrial Agrochemical Antisolvent Crystallization Experiencing Unique Phase Separations

Crystallization is an essential process of solids manufacturing, governed by multiple mechanisms that dictate the formation and growth of crystals. Although these mechanisms are well studied, the principal mechanism of nucleation is poorly understood across the crystallization community. Primary nucleation, the stochastic formation of new nuclei from a clear solution, has been studied for decades, and as molecules continue to gain complexity with each discovery or clarification we add another facet to the story. Similarly, as a process trajectory moves through the phase diagram, away from solubility in an attempt to induce and/or encourage nucleation some phase diagrams add a layer of mechanistic competition between nucleation and alternate phase separations (Deneau et al. 2005 & Dixit et al. 2003). These phenomena add another challenge to understanding the already unclear correlation between process conditions and nucleation. Many industries circumvent these challenging gray areas by seeding crystallization processes, providing just enough energy to promote nucleation rather than depending on it to happen naturally. However, not enough work has been done to understand these phenomena at a deeper level to explore if there are unknown advantages to designing primary nucleation crystallizations rather than defaulting to seeded processes.

In this work, we investigate the phenomenological formation of liquid-liquid and solid-liquid phase separations in competition with nucleation, the resultant impact on the crystallization process, the crystallization product, and the process design through these phenomena. Our model compound, a polymorphic high aspect ratio agrochemical antisolvent/cooling crystallization, exhibits several unique types of phase separation phenomena before crystal nucleation is observed. Originally observed with the naked eye, these phenomena were later confirmed with Dynamic Light Scattering (DLS) techniques and proved to result from solvent-antisolvent interactions as well as active ingredient-solvent interactions. With multiple extensive factorial designs of experiments, it was further determined that the resultant phases of these phenomena have unique solution compositions when compared to the bulk recrystallization mother liquor. These unique compositional regions can further be divided into one that promotes primary nucleation, introducing the active ingredient to the other region via mixing where it behaves as a source for in-situ seeding, promoting secondary nucleation. As a result of the completion of this study aided by the implementation of nano-level light detection techniques, a mechanism for the prenucleation phenomena can be suggested and as a result, utilized for the design of primary nucleation-dependent crystallization processes for an industrial agrochemical previously believed to be dependent on seeding and high antisolvent concentrations.

References

1. Emilie Deneau and Gerry Steele, An In-Line Study of Oiling Out and Crystallization (2005). Organic Process Research & Development, 9 (6), 943-950, DOI: 10.1021/op050107c.
2. Narendra M. Dixit and Charles F. Zukoski, Competition between crystallization and gelation: A local description (2003). Phys. Rev. E 67, 061501.