(92b) Process Control and Design of the Continuous Crystallization of a Polymorphic Agrochemical

Crystallization is an essential process of solids manufacturing and is left inadequately designed in several fields, including agrochemical manufacturing. Inadequately designed crystallization protocols can lead to particles with undesired physical or chemical characteristics, such as particle morphology, polymorphism, crystal size distribution/aspect ratio, manufacturability, and overall crystal quality.

In this work, we demonstrate the multi-objective process control and design of an agrochemical crystallization by i) controlling the produced polymorphic form via combined cooling and antisolvent crystallization, ii) controlling the final crystal size distribution (CSD) and resultant manufacturability with wet milling, and iii) designing the continuous crystallization for industrial manufacturing of the model system. Variations in combined cooling and antisolvent crystallization operating trajectory can have a dramatic impact on the generated polymorphic form (Kshirsagar et al., 2023). A polymorphic form design space was generated by a data-rich design of experiments (DoE) enabled by the inclusion of in-situ process analytical technology (PAT) tools. This design space allowed for informed crystallization operating trajectory design. Following the isolation of the singular polymorphic forms, concerns about manufacturability arose from the presence of a high aspect ratio (AR) morphology. High AR crystals are challenging to industrial processes in terms of poor mixing and filtration time, the inclusion of wet milling with specific crystallization operating trajectories improved both product CSD and AR regarding manufacturability (Eren et al., 2021). Using the polymorphic design space, wet milling, and targeted antisolvent and cooling crystallization operating trajectories, manufacturing in the presence of high AR morphology was greatly improved. Further applying this process control, design, and system information to the continuous crystallization of the model system reduces manufacturing time and variability during industrial manufacturing.

References

1. Kshirsagar, S., Szilagyi, B., Nagy, Z.K., 2023. Experimental Design for the Efficient Determination of the Crystallization Kinetics of a Polymorphic System in Combined Cooling and Antisolvent Crystallization. Crystal Growth & Design.. doi:10.1021/acs.cgd.2c01075.
2. Eren, A., Szilagyi, B., Quon, J.L., Papageorgiou, C.D., Nagy, Z.K., 2021. Experimental Investigation of an Integrated Crystallization and Wet-Milling System with Temperature Cycling to Control the Size and Aspect Ratio of Needle-Shaped Pharmaceutical Crystals. Crystal Growth & Design 21, 3981–3993.. doi:10.1021/acs.cgd.1c00308.