2025 AIChE Annual Meeting

(504a) Optimization of Continuous Reactive Crystallization with Impurity Purging Analysis for Nitrofurantoin

Authors

Yuma Miyai - Presenter, Virginia Commonwealth University
Nicole Torres, University of Puerto Rico at Mayaguez
Tianjie Zhu, Northeastern University
Nathaly Movilla, University of Puerto Rico
Aibolat Koishybay, Massachusetts Institute of Technology
Rodolfo Romañach, University of Puerto Rico, Mayaguez
Muhammad Noor Alam, Northeastern University
Cornelis Vlaar, University of Puerto Rico
Jean-Christophe Monbaliu, University of Liege
Nima Yazdanpanah, U.S. Food and Drug Administration
Allan Myerson, Massachusetts Institute of Technology
Torsten Stelzer, Crystallization Design Institute
Reactive crystallization is a process that combines chemical reactions and crystallization to form solid products from solutions. It involves the simultaneous or sequential occurrence of reaction, nucleation, and growth. Crystals form when reactants with higher solubility in a given solvent system react to produce a new compound that possesses lower solubility. This process is widely used in various industries, including pharmaceuticals and fine chemicals, to produce pure solid materials, control particle size, and enhance reaction efficiency. Key factors influencing reactive crystallization include supersaturation, temperature, concentration, and solvent systems. Understanding the mechanisms of reactive crystallization requires investigating both reaction and crystallization kinetics.

In this work, we discuss the investigation of the optimization of a reactive crystallization using the final reaction step of the 5-step nitrofurantoin synthesis process1. The reaction and crystallization kinetics were decoupled and studied to develop a process model aimed at optimizing yield, purity, and particle size. As the reaction progressed rapidly, vibrational spectroscopy was employed to monitor reaction progress, to overcome challenges with offline HPLC analysis. Additionally, purging efficiency was analyzed to optimize impurity rejection during the reactive crystallization process. This work advances the understanding of the reactive crystallization for nitrofurantoin by examining both the reaction and crystallization steps, with a particular focus on impurity rejection. The framework and methodologies can be used in other continuous reactive crystallization processes and across the industry.

  1. Miyai, Y., Lee, H.L., Koishybay. A., Hellwig, H., Bovy, L., Romañach, R., Noor-E-Alam, Md., K., Vlaar, C., Monbaliu, J.-C., Myerson, A.S., Stelzer, T.: “Integration of synthesis and crystallization of nitrofurantoin from bio-based building blocks and solvents”, 2025, AIChE