Machine Learning-Derived Correlations for Scale-Up and Technology Transfer of Primary Nucleation Kinetics.

Scaling up and technology transfer of crystallization processes have been and continue to be a challenge. This is often due to the stochastic nature of primary nucleation, various scale dependencies of nucleation mechanisms, and the multitude of scale-up approaches. To better understand these dependencies, a series of isothermal induction time studies were performed across a range of vessel volumes, impeller types, and impeller speeds.

Use of Wet Milling Combined with Temperature Cycling to Minimize Crystal Agglomeration in a Sequential Antisolvent-Cooling Crystallization.

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.

Templated nucleation of acetaminophen on spherical excipient agglomerates.

We investigated the effect of spherical agglomeration of heterogeneous crystalline substrates on the nucleation of acetaminophen (AAP). Optical and electron microscopy showed that the surface morphologies of single crystal triclinic lactose and D-mannitol differed significantly from their counterparts formed via spherical agglomeration. Spherical agglomerates of lactose were shown to enhance the nucleation rate of acetaminophen (AAP) by a factor of 11 compared to single crystal lactose; however, no such enhancement was observed for D-mannitol.