(2lx) Meet the Post-Doc Candidates Session: Process Intensification for Industrial Crystallizations Via Process Control and Design Strategies

Research Interests Crystallization is an essential process of solids manufacturing and is left inadequately designed in several fields, including energetics and 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.

Robust Crystallization of Energetic Materials First manufactured for use in World War II, nearly a century ago, Research Department/Royal Demolition Explosive (RDX) and High Melting Explosive (HMX), have been applied to military munitions, propellants, and general explosives and continue to be two of the largest manufactured energetic materials. Although researchers have extensively studied the solubility of the common energetic materials, RDX and HMX, little work has been completed on the process intensification of RDX and HMX crystallization.

In this work, we demonstrate the application of the Quality-by-Control (QbC) framework for the rapid design of the crystallization of energetic compounds. QbC allows for the minimization of experiments and experimental exposure by utilizing feedback control strategies for the critical quality attributes (CQAs) (Su et al., 2019). Using the QbC-based direct design approach a robust method for the industrial manufacturing of crystallized RDX and HMX could be suggested. Small-scale experiments completed with Crystalline showed that RDX and HMX have high solvent power (solubility) in Cyclohexanone and good temperature sensitivity which is desirable for crystallization control. The two applied direct design approaches are direct nucleation control (DNC) and supersaturation control (SSC) (Simone et al., 2015). DNC applies particle counts measurements collected with an in-situ focused beam reflectance measurement (FBRM) probe to a model-free closed feedback control loop which introduces temperature cycling to a saturated solution, stimulating controlled nucleation and crystal growth (Bakar et al., 2009). SSC applies solution concentration measurements collected with an in-situ infrared (IR) probe to a model-free closed feedback control loop which introduces temperature cycling to a saturated solution, stimulating controlled solution concentrations (Saleemi et al., 2012). In application with in-situ process analytical technology (PAT) tools, DNC and SSC allowed for the selection of crystallization design parameters that control the desired CQAs of RDX and HMX, including but not limited to polymorphic form and overall crystal quality, and the further optimization of the selected design parameters via model-based digital design. Further, we demonstrate the combination of mf-QbC and model-based digital design to develop a robust process intensification framework for the batch crystallization of energetic materials. This was completed by the development of a digital twin which enabled the in-silico design of experiments (DoE) and design space analysis of the system. Intensifying the industrial crystallization of common energetic materials, such as RDX and HMX, will improve the quality of manufactured energetic materials, and future process development for the manufacturing of energetic materials. Further applying this process intensification and system information to the continuous crystallization of energetic materials reduces manufacturing time and variability during the manufacturing of energetic materials.

Crystallization Control of a Polymorphic Agrochemical In this work, we demonstrate the multi-objective process control and design of an agrochemical crystallization by controlling the produced polymorphic form via combined cooling and antisolvent crystallization experimental and modeling-based strategies. Variations in combined cooling and antisolvent crystallization operating trajectory can have a dramatic impact on the generated polymorphic form (Kshirsagar et al., 2023). A polymorphic form design space was generated by a data-rich DoE enabled by the inclusion of in-situ PAT tools. This design space allowed for informed crystallization operating trajectory design. Using the polymorphic design space and targeted antisolvent and cooling crystallization operating trajectories, manufacturing in the presence of high AR morphology was improved.

All sectors of active ingredient and fine chemical processing face crystallization challenges, none of which have a catch-all solution, and as the complexity of molecules continues to increase as does the complexity of their unique challenges and eventual solutions. In my future research, I hope to utilize my skills in developing crystallization design and control strategies, my unique perspective and experience in building a lab safety culture, and my passion for mentorship, teaching, and leadership to answer the growing problems of modern crystallization challenges such as polymorphism phenomena, digital twin development, and other unique crystallization process design and control challenges.

References

1. Bakar, M. R. A., Nagy, Z. K., Saleemi, A. N., Rielly, C. D., 2009. The Impact of Direct Nucleation Control on Crystal Size Distribution in Pharmaceutical Crystallization Processes, Crystal Growth and Design, 9 (3): 1378–1384.
2. Saleemi, A. N., Rielly, C. D., Nagy, Z. K., 2012. Comparative Investigation of Supersaturation and Automated Direct Nucleation Control of Crystal Size Distributions Using ATR-UV/Vis Spectroscopy and FBRM, Crystal Growth and Design, 12 (4): 1792–1807.
3. Simone, E., Zhang, W., Nagy, Z.K., 2015. Application of PAT-based feedback control strategies to improve purity and size distribution in biopharmaceutical crystallization, Crystal Growth and Design, 15 (6): 2908–2919.
4. Su, Q.; Ganesh, S.; Moreno, M.; Bommireddy, Y.; Gonzalez, M.; Reklaitis, G. V.; Nagy, Z. K. A Perspective on Quality-by-Control (QbC) in Pharmaceutical Continuous Manufacturing. Chem. Eng. 2019, 125, 216–231.
5. Kshirsagar, S., Szilagyi, B., Nagy, Z.K., 2023. Experimental Design for the Efficient Determination of the Crystallization Kinetics of a Polymorphic System in Combined Cooling and Antisolvent Crystallization. Crystal Growth & Design.. doi:10.1021/acs.cgd.2c01075.