Date: 19 February 2026 | Category: News
Authors: Kimberly E. Penzer, Daniel G. Gregory, Samantha G. Kohn, Kaitlin E. Kay, Justin T. Turnage, James K. Ferri*
James Ferri and co-workers from the Virginia Commonwealth University in Richmond, have devised a method using continuous flow chemistry to synthesize a key intermediate required for production of albuterol sulfate, a key medicine for treatment of asthma.[1] Their new approach, which uses the Vapourtec E-Series flow chemistry system, allows on-line monitoring of reaction progress and purity, as well as facile scale-up that could help alleviate shortages of this important drug, Figure 1.
![Amination of 2-Bromo-1-[4–hydroxy–3-(hydroxymethyl) phenyl]ethan-1-one with tert-butyl amine in flow.](https://www.vapourtec.com/wp-content/uploads/2026/02/Amination-of-2-Bromo-1-4–hydroxy–3-hydroxymethyl-phenylethan-1-one-with-tert-butyl-amine-in-flow.jpg)
Figure 1: Amination of 2-Bromo-1-[4–hydroxy–3-(hydroxymethyl) phenyl]ethan-1-one with tert-butyl amine in flow.
Flow chemistry: utility beyond facile scale-up
One of the most commonly cited benefits of flow chemistry is the efficiency, with excellent mass and heat transfer that can result in more efficient reactions through higher yields and/or fewer side products, alongside reduced waste streams and improved scalability and reproducibility. However, flow chemistry also offers the opportunity for incorporation of on-line process analytical technologies (PAT), financial savings – in some cases reducing production costs by up to 76% [2] – and the use of environmentally-considerate chemistry. Within pharmaceutical manufacture and development, these advantages are not going un-noticed, and in recent years there has been a drive toward development of continuous flow approaches for drug synthesis to combat supply bottlenecks and maximise efficiency. [1]
Albuterol sulfate: Plagued by shortages
Albuterol sulfate is a short-acting bronchodilator used extensively in the treatment of asthmatic patients. However, shortages in the supply of nebulized albuterol sulfate solution (the drug product) have impacted patient access. The traditional approach to this important drug uses a SN2 amination reaction for production of a key intermediate, but this reaction is usually performed using batch conditions where formation of side-products, including dimers, is common. These issues lead to reduced efficiency and an increase in the requirement for extensive purification and processing.
Continuous flow with the Vapourtec E-Series System allows simple inclusion of on-line line process analytical technologies (PAT)
The use of a continuous flow chemistry approach allowed rapid reaction optimization through varying residence time, solvents and temperature. An advantage of a continuous flow approach was the opportunity to use on-line 1H NMR technologies for identifying species formed within the process stream and confirming that the significant oligomeric by-product formation (particularly dimers) was suppressed. The real-time feedback and insight into reaction kinetics and product to byproducts ratios, as well as rapid adjustment of conditions, proved a critical part of the optimized process and a step towards advanced manufacturing technology for API production.
Overall, the use of continuous flow manufacture allowed:
- Use of a less toxic solvent
- Higher conversion and higher yields than in batch
- The opportunity for rapid scale-up to remove processing bottlenecks
References:
[1] Advances in Continuous Manufacturing of Albuterol Sulfate: Optimization of an Amination Reaction in Flow (K. E. Penzer, D. G. Gregory, S. G. Kohn, K. E. Kay, J. T. Turnage, J. K. Ferri, React. Chem. Eng., 2026). https://doi.org/10.1039/D5RE00465A
[2] Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study (S. D. Schaber, D. I. Gerogiorgis, R. Ramachandran, J. James M. B. Evans, P.l I. Barton, B. L. Trout, Ind. Eng. Chem. Res., 2011, 50 (17), 10083–10092). https://doi.org/10.1021/ie2006752