(159b) Process Control, Design, and Modeling of the Steady-State Continuous Crystallization of an Industrial Polymorphic Agrochemical

As the fine chemical processing industry continues to advance and introduce new molecules for modern problems the average molecular weight and complexity continue to increase and with it increasing the probability of polymorphic and high aspect ratio (AR) crystals (Leeson et al. 2015). Complications such as these introduce a plethora of problems ranging from manufacturing to regulatory. A majority of these problems need to be addressed at the separations stage/unit operation, the most common of which industrially is crystallization, representing 60% of all fine chemical solids and 90% of all pharmaceutical solids. Even with the ubiquity of crystallization as an essential process of solids manufacturing, it is left inadequately designed in several fields, including agrochemical manufacturing. Inadequately designed crystallization protocols can lead to particles with undesired physical or chemical characteristics, such as particle morphology, polymorphism, crystal size distribution/aspect ratio, manufacturability, and overall crystal quality.

In previous work, we started to address these shortcomings by demonstrating the multi-objective process control and design of an agrochemical crystallization by i) controlling the produced polymorphic form via combined cooling and antisolvent crystallization, and ii) intensifying the process by moving the system from batch to continuous for increased production rate with reduced footprint. A polymorphic form design space was generated by a data-rich design of experiments (DoE) enabled by the inclusion of in-situ process analytical technology (PAT) tools allowing for informed crystallization operating trajectory design for form isolation. Following the isolation of the singular polymorphic forms, concerns about manufacturability arose from the presence of a high AR morphology. Avoiding these manufacturability issues the metastable polymorph was given preference and was successfully and robustly isolated in batch without transformation. However, throughput requirements required that the crystallization process be upgraded to a continuous operation.

In this work, we consider the same material system of metastable polymorph isolation, now using continuous operation via steady-state mixed suspension mixed product removal (MSMPR) operation. The steady-state isolation of metastable-dominant polymorphic mixtures has previously been shown experimentally for enantiotropic systems (Lai et al., 2014 & 2015) and the feasibility of that observation was later validated mathematically (Farmer et al. 2016). However, in this work, we conducted a series of experiments using a factorial design to isolate kinetics for the formation of independent polymorphic forms. This experimental data was used to generate a digital design space of the continuous crystallization process. We then leveraged this digital design space to enable process optimization to reduce the processing time of the crystalline product. Through the application of steady-state bifurcation design space analysis, and polymorphic population balance modeling the design of a robust MSMPR process with polymorphic control of an industrial monotropic system was demonstrated. This framework demonstrates the potential for streamlining process design with automatic polymorphic control for industrial continuous processes, in particular for metastable-targeted polymorphic systems dictated by solvent-mediated transformations, a subset of products long avoided by the fine chemical manufacturing community.

References

1. Leeson PD, Young RJ. Molecular Property Design: Does Everyone Get It? (2015), ACS Med Chem Lett., 6(7):722-5. DOI: 10.1021 /acsmedchemlett.5b00157
2. Farmer, T.C., Carpenter, C.L. and Doherty, M.F. (2016), Polymorph selection by continuous crystallization. AIChE J., 62: 3505-3514. https://doi.org/10.1002/aic.15343
3. Lai, T-T.C., Ferguson, S., Palmer, L., Trout, B.L., and Myerson, A.S. (2014), Continuous Crystallization and Polymorph Dynamics in the l-Glutamic Acid System.Organic Process Research & Development, 18 (11), 1382-1390. DOI: 10.1021/op500171n
4. Lai, T-T.C., Cornevin, J., Ferguson, S., Li, N., Trout, B.L., and 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. DOI: 10.1021/acs.cgd.5b00466