(713b) Polymorph Selection By Continuous Crystallization

Polymorphic solids are ubiquitous in both nature and industry and generally exhibit unique mechanical, electrical, and physicochemical properties, as well as unique solubility curves in solution. Polymorph selective processing is necessary in these systems due to the typical material and pharmacokinetic property variation among polymorphs of the same chemical composition. The study of polymorphism in batch systems has a long history that has led to deep understanding of the concepts of solvent-mediated phase transformations and Ostwaldâ??s rule of stages. These fundamental ideas are applied in many papers and processes to steer batch processes towards a desired polymorph. Here, we discuss the implications of continuous processing on polymorphism, and outline a methodology that enables polymorph selection and simplifies the necessary process control strategies in applicable systems.

It is well known in batch crystallizer design that the polymorph distribution is governed by the induction time of the most stable form, and that in the limit of very long batch times the most stable polymorph is obtained. Continuous devices do not operate under a similar constraint. After an initial start-up phase, a continuous device can operate at a dynamically stable operating point indefinitely, regardless of the thermodynamic stability of the effluent crystals. Interestingly, essentially pure, thermodynamically metastable steady-states exist in systems in which the thermodynamically stable solid cannot nucleate and grow on the time scale of the crystallizer residence time. These conditions depend on design choices (such as solvent choice, temperature, residence time, feed supersaturation, etc.), and are therefore accessible in many systems. This concept has been formalized with the use of a bi-polymorph population balance model, the method of moments, and a linear stability analysis. The analysis gives simple functions of parameters (dimensionless groups) for which one can continuously produce thermodynamically metastable products based only on the relative polymorph dynamics.

This work was motivated by the remarkable experiments recently reported by Lai, Trout, and Myerson et al [1] on continuous crystallization in the L-glutamic acid system. We demonstrate agreement with their L-glutamic acid results as well as another set of data describing the continuous crystallization of p-aminobenzoic acid [2]. For many polymorphic compounds, engineering a process to produce a desired polymorph is as simple as finding a reasonable operating point for the continuous mixed-suspension mixed-product removal crystallization process (temperature, residence time, initial supersaturation, etc.).

References

[1] Lai, T. T. C., Ferguson, S., Palmer, L., Trout, B. L., & Myerson, A. S. (2014). Continuous Crystallization and Polymorph Dynamics in the l-Glutamic Acid System. Organic Process Research & Development, 18(11), 1382-1390.

[2] Lai, T. T. C., Cornevin, J., Ferguson, S., Li, N., Trout, B. L., & Myerson, A. S. (2015). Control of Polymorphism in Continuous Crystallization via Mixed Suspension Mixed Product Removal Systems Cascade Design. Crystal Growth & Design, 15(7), 3374-3382.