(343b) API Synthesis in Flow Enabled By on-Line Proton NMR and UV-Vis Chemometrics

Active pharmaceutical ingredients (APIs) are traditionally synthesized via batch processing strategies as opposed to continuous manufacturing within flow reactors. While batch synthesis facilitates the production of APIs in bulk metric ton quantities, the iterative nature of this methodology often results in extensive hands-on labor, complicated logistics, and vulnerable supply chains. Continuous API manufacturing is emerging as a promising alternative to batch processing as it enables live, on-line monitoring of chemical species from starting materials to products using process analytical technologies (PAT) such as nuclear magnetic resonance (NMR) and UV-Vis spectroscopy. This talk examines the transfer of a traditionally batch API synthesis route to continuous flow manufacturing for the production of albuterol sulfate within a modular continuous API manufacturing system. Albuterol is a beta-agonist bronchodilator used for the treatment of asthma and frequently listed on the ASPR drug shortage list. Practical aspects related to appropriate synthon selection to enable flow chemistry, process intensification, and on-line analytical characterization will be discussed. Specifically, we will highlight the utilization of ¹H NMR and UV-Vis as powerful on-line PAT tools to assess S_N2 amination chemistry, catalytic hydrogenation, and purity assessment of the final API product in flow. Methods for improving ¹H NMR data quality and resolution via carbon satellite decoupling and solvent suppression will be demonstrated. Additionally, an overview of signal processing and chemometric modeling is used to establish a quantitative correlation between high performance liquid chromatography (HPLC) with both ¹H NMR and UV-Vis for on-line concentration monitoring (i.e., 1.0-50 mg/mL). Lastly, practical engineering design considerations related to the closed-loop integration of these systems into a continuous end-to-end manufacturing system will be discussed to help mitigate shortages of this critical lifesaving drug.