Control of mixing in continuous crystallisation of pharmaceuticals

Crystallisation is widely used for purification of commodity and specialty chemicals and pharmaceuticals and for making advanced materials for catalysis, separations and sensing applications. One of main challenges in developing robust and efficient crystallisation processes is to control nucleation, especially in mixing controlled processes, such as antisolvent, reactive, salting out or pH shift crystallisation. Control of nucleation is a particular challenge for the development of continuous crystallisation processes where operation under steady state conditions stipulates a specific rate of nucleation of a desired solid form in order to achieve critical quality attributes such as particle size distribution, solid loading and polymorphism. Antisolvent crystallisation processes are commonly employed in manufacturing of pharmaceuticals and fine chemicals. In these processes, supersaturation is generated mixing two or more fluid streams to provide required solution composition. Mixing process inevitably generates concentration heterogeneities, and a complex interplay between the scale of these heterogeneities, corresponding mixing time scales, and nucleation timescales determines effects of mixing on nucleation kinetics of relevant solid forms. It is well known that nucleation in many antisolvent crystallisation processes is strongly dependent on how mixing of solutions with antisolvents is performed. However, there is very limited understanding of microscale and mesoscale mixing phenomena for thermodynamically miscible solvents (e.g., in antisolvent crystallisation), in contrast with mixing dilute solutions in common solvents (e.g., in reactive crystallisation). In practice, empirical approaches are often deployed to adjust mixing conditions by trial and error and this leads to difficulties with design and optimization of manufacturing processes, product consistency and efficiency of secondary processing.
The aim of this project is to develop a fundamental understanding of continuous mixing of miscible solvent pairs commonly used in antisolvent crystallisation, such as water-acetone and methanol-heptane, and to investigate effects of local concentration heterogeneities and corresponding mixing time scales on kinetics of crystal nucleation. This will provide insight into the role of solvents played in controlling nucleation in antisolvent crystallisation and rationalize solvent selection in development of industrial crystallisation processes.