Controlling Complex Crystal Systems
Controlling meta-stable crystallization processes and understanding why crystallization control is so difficult. What keeps going wrong?
In each of the past five years more than 2,000 papers have been published on crystallization control. The motivation is clear, every major pharmaceutical company has dealt with unexpected forms. Avoiding nucleation of off-target forms is paramount; designing and controlling a robust process is challenging. Rather than develop new control algorithms, my group will investigate where these process often go wrong, what are the conditions that lead to off-target nucleation, and what are the tools available to prevent it.
Milling breaks crystals, exposing more fast growing faces and consuming supersaturation. Could it also be used to produce a metastable form?
The tools available to physically manipulate evolving populations of crystals remain poorly understood and underutilized despite years of access. The framework to explain, analyze, and design systems with evolving populations of solids are being developed alongside new tools to control, manipulate, and observe those systems. Techniques such as wet-milling, sonication, and gas-sparging have been shown to change nucleation rate, predominant form, and even crystal purity; how exactly these techniques exert their (potentially beneficial) influence is a matter of continued debate. Likewise, the hydrodynamics of suspensions lead to undesirable phenomena which can promote potentially ruinous phase transitions, nucleation, or product quality. My group will investigate how to use tools such as enhanced attrition and crystal size classification to enable difficult separations, such as polymorph selection and deracemization. We will also develop tools to predict, avoid, and control the nonidealities that often derail said difficult separations. Advanced population balance models (PBMs) will be one of our first deliverables and will provide the scaffold from which to analyze and engineer better processes.