ALEKSANDAR MITIC, SØREN HEINTZ, ROLF H. RINGBORG, VIJAyA BODLA, JOHN M WOODLEy, KRIST V. GERNAEy*
*Corresponding author
1. Technical University of Denmark (DTU), Department of Chemical and Biochemical Engineering, Søltofts Plads, Building 229, 2800 Kgs. Lyngby, Denmark

Abstract

Organic synthesis (incorporating both chemo-catalysis and biocatalysis) is essential for the production of a wide range of small-molecule pharmaceuticals. However, traditional production processes are mainly based on batch and semi-batch operating modes, which have disadvantages from an economic, environmental and manufacturing perspective. A potential solution to resolve these issues is to use flow chemistry in such processes, preferably with applications of micro- and mini-sized equipment. In addition, Process Analytical Technology (PAT) may be implemented in a very efficient way in such equipment due to the high degree of automation and process controllability that can be achieved in small scale continuous equipment.

INTRODUCTION

Continuous production is often cited as both eco-friendly and economic, mainly due to the higher energy efficiency and reduced consumption of resources that can be achieved in comparison with traditional batch production (1-4). Furthermore, continuous production fulfills very well the requirements defined by the regulatory bodies, such as the Food and Drug Administration (FDA). More particularly, the FDA has clearly indicated that it favors such processes – including on-line measurement and control – with the publication of the Process Analytical Technology (PAT) guidance in 2004 (5). PAT defines the key Initiative of cGMP (6) and is incorporated into the International Conference on Harmonization (ICH) Q8 guidance (7). The Initiative has shown many advantages in modern organic synthesis and biotechnology, and has consequently been applied in other industry sectors, such as food, chemical and life sciences (8).
The objective of this manuscript is to briefly review applications of flow chemistry in modern organic synthesis. Furthermore, the focus will be on emphasizing the benefits of such processes and additionally on identifying ...