(241d) Design and Optimization of Continuous Crystallization Processes: Cascades of Mixed Suspension Mixed Product Removal Crystallizers

Vetter, T., ETH Zurich
Doherty, M. F., University of California

Crystallization processes in the pharmaceutical industry have been carried out for decades as batch processes. It is recognized that this type of operation suffers from product variability from batch-to-batch and comparably high manufacturing costs [1]. While continuous processing is a proven technique in many large scale industries for overcoming both these deficiencies, the pharmaceutical industry was reluctant to adopt such an approach in the rapid growth era of the twentieth century. However, competition and regulatory demands are ever-increasing and there is now more focus on reducing manufacturing costs while maintaining high product quality.

While the design and optimization methodology for batch crystallization processes are relatively well understood for various combinations of cooling, anti-solvent or reactive crystallization [2] and for different optimization objectives [3], there are yet relatively few studies targeted on the design and optimization of continuous crystallization processes that keep the specific challenges posed to the pharmaceutical industry in mind [4,5].

In this work we present a comprehensive investigation of cascades of mixed suspension mixed product removal (MSMPR) crystallizers based on population balance equation models. The influence of the number of stages, temperature and residence time in each crystallizer on the particle size distribution of the product is ellucidated. Specifically, we show that for any number of MSMPRs and a constant production rate, there exists a clearly defined attainable region in a diagram of mean particle size vs. total residence time in the MSMPR cascade. This attainable region can be entirely traversed by altering the temperature and residence time in each MSMPR. We further report the influence of constraints (such as limitations in the maximally tolerated supersaturation in the MSMPRs and yield constraints) on the attainable region. By rephrasing well-established batch operating policies in the context of the attainable regoins, we highlight the underlying similarities between MSMPR cascades and batch processes and report design heuristics that can be used even in the absence of kinetic data. The concept of the attainable region and the associated heuristics could evolve into a convenient design tool for the conceptual design of continuous crystallization processes in a cost- and time-efficient manner.

Since the above mentioned investigations are dependent on the kinetics of crystal nucleation and growth, we report several case studies that employ different kinetic models and different ways to induce crystallization; among them the cooling crystallization of paracetamol from ethanol and the combined anti-solvent/cooling crystallization of aspirin from ethanol (solvent)/water (anti-solvent).


[1]     Randolph, A. D., Larson, M. A., Theory of Particulate Process: Analysis and Techniques of Continuous Crystallization, 2nd ed.; Academic Press: Toronto, Canada, 1988.

[2]     Lindenberg, C., Krättli, M., Cornel, J., Mazzotti, M., Cryst. Growth. Des. 9, 1124-1136 (2009).

[3]     Ward, J.D., Mellichamp, D.A., Doherty, M.F., AIChE J. 52, 2046-2054 (2006).

[4]     Wong, S.E., Tatusko, A.P., Trout, B.L., Myerson, A.S., Cryst. Growth Des. 12, 5701-5707 (2012).

[5]     Zhang, H., Quon, J., Alvarez, A.J., Evans, J., Myerson, A.S., Trout, B.L., Org. Process Res. Dev. 16, 915-924 (2012).