Loop-Configuration for Plug Flow Crystallization Process Development

Continuous crystallization plays a pivotal role in the transition to continuous manufacturing that the pharmaceutical industry is currently undertaking. Alas, the development of a continuous crystallization process using data from continuous operation is prohibitively material-intensive. Given the state of control nature of the continuous formalism, experimental design spaces entail several experiments, in which up to ten residence times are required to assess an experimental condition at steady state. Furthermore, transferring batch kinetics determined from batch experiments to a continuous crystallizer, despite being common practice, adds undesirable uncertainty to the development endeavors due to equipment-dependent mass and heat transfer. In this work, we present a novel configuration of a tubular crystallizer, capable of characterizing a system with a few experiments, curbing the reactor footprint, and abating the development's raw material requirements. A stream of crystallizing material, flowing inside a tubular crystallizer equipped with Kenics static mixers, was fully recirculated, implementing a looped plug flow configuration, and its evolution was monitored in-line continuously by means of in situ Process Analytical Technologies. This allows effective mimicking of long residence times (which correspond to large process volumes) in a short plug flow crystallizer while maintaining plug flow conditions and screening a process from nucleation to equilibrium. Computational fluid dynamics simulations supported the assumption of negligible back mixing and aided the comparison of the mixing with that of a cascade of continuous stirred tank reactors. The use of the novel configuration is showcased for the antisolvent crystallizations of ketoconazole, azithromycin, and glycine. Using this approach, we show reductions in raw material requirements from 50 to 98%, compared with an equivalent standard plug flow crystallizer. Naturally, the configuration can also be employed for manufacturing in a semicontinuous manner.