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The objective of the research was to improve the process design of a combined antisolvent-cooling crystallization to reduce the degree of agglomeration of a real active pharmaceutical ingredient product, which was manufactured using a crystallization stage employing a methanol/water solvent system. Knowledge was gained from the use of process analytical technology (PAT) tools to monitor the process variables, allowing particle size, degree of agglomeration, solute concentration, and supersaturation to be tracked throughout the process. Based on knowledge of the solubility behavior and interpretation of the PAT histories, changes were made to the sequences of antisolvent addition and cooling within the crystallization process to reduce agglomeration in the final product. Different seed loadings and seeding addition points were also investigated to maintain operation within lower supersaturation regions of the phase diagram to limit agglomeration and avoid an undesired polymorphic transformation to an unstable form. The improved sequences of operations and seeding conditions did not provide sufficient improvement in the product quality and so were augmented by applying wet milling for further deagglomeration followed by temperature cycling to remove fine particles generated during milling. Open-loop heating and cooling cycles produced some limited improvements, whereas closed-loop direct nucleation control methods using FBRM as a feedback sensor for particle counts per second were much more successful at producing high-quality crystals of the desired polymorphic form. The work shows that understanding the trajectory of the process through the phase diagram to follow appropriate supersaturation profiles gives improved control of the various kinetic mechanisms and can be used to improve the quality of the final product. more...

This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation loop were investigated. It was found that all methodologies significantly improved the nucleation kinetics, and the effects of key process parameters (e.g., mill speed, temperature, and ultrasound intensity) on particle size were experimentally investigated. A minimum d50 of 27 and 36.8 μm was achieved when using the wet mill and ultrasound, respectively. The effectiveness of wet milling was demonstrated in a three-stage mixed suspension mixed product removal continuous crystallization of the API that was operated continuously for 12 h (eight residence times), achieving a steady state with minimal fouling. Strategies for improving the overall robustness of the setup in routine manufacturing are discussed. more...