The pharmaceutical industry continues to advance its technology and knowledge in both research and development (R&D) and manufacturing of active pharmaceutical ingredients (APIs). Process development for APIs has increasingly incorporated novel tools such as flow chemistry, process analytical technology (PAT), continuous crystallization, automation, and high-throughput screening. Despite these technological advancements, a disconnect often exists between synthesis and purification, with greater emphasis placed on synthetic process development, despite the critical role of purification in achieving desired product attributes. Crystallization is crucial in the pharmaceutical purification process, ensuring the production of pure, high-quality drug substances with consistent physical properties, such as particle size, morphology, and polymorphs.
Here, we discuss the successful technology transfer and integration of a 5-step nitrofurantoin synthesis process in flow chemistry, developed by CiTOS (University of Liège)1, and a continuous crystallization process developed by CDI (University of Puerto Rico) and MIT. We demonstrate the integration of the multi-step reaction process, reactive crystallization, continuous crystallization using biomass-derived building blocks and bio-based solvents. The results of critical product characterization methods, including powder X-ray diffraction, microscopy imaging, and assay purity analysis, are also discussed. This work, achieved through a multi-institutional collaboration, outlines the integrated workflow for synthesis and crystallization process development with the goal of attaining a high-purity API, which meets U.S. Pharmacopeia (USP) quality standards.
- Hellwig, H., Bovy, L., van Hecke, K., Vlaar, C., Romañach, R., Noor-E-Alam, Md., Myerson, A.S., Stelzer, T., Monbaliu, J.-C.: “A Continuous Flow Generator of Acetyl Nitrate for the Synthesis of Nitrofuran-based Pharmaceuticals”, 2025, https://doi.org/10.26434/chemrxiv-2025-dsx17
