Microstructured Reactors for Rapid Process Development and Scale-Up

The authors discuss a continuous-flow reactor that avoids parallel channels and enables economic plant setup. This article is part of a special issue on API Development, Formulation, Synthesis and Manufacturing.
Sep 01, 2010

Pharmaceutical and fine-chemical production is dominated by batch processes, which enable many kinds of reactions and can handle multiphase systems in multipurpose plants. Operators can arrange vessels in various configurations to establish several reaction routes and even certain work-up steps such as distillation or extraction. Production quantities of pharmaceutical intermediates or active pharmaceutical ingredients (APIs) vary from a few grams in the first medicinal studies to several hundred tons per year for successful pharmaceutical products. This wide production range demands various manufacturing devices at several scales for process transfer.

The first laboratory studies work with just a few grams of reagents in glass flasks, but continuous-flow devices with integrated microchannels also produce these quantities (1). Process development leads from small-scale production, to sample production at pilot scale, to large-scale production (2). Often, during the scale-up of the chemical process, a wide range of stirred vessels is used to perform the reaction. Heat transfer and mixing rate, however, are often limited in stirred vessels, which need high dilution, long operation or dosing times, and sometimes do not permit highly exothermic reactions. One solution is to combine the versatility of batch vessels with the safety, reproducibility, and high transport capabilities of continuous-flow microstructured equipment.

Microstructured devices

Microstructured devices with small internal volumes and high surface-to-volume ratios offer transport capabilities for rapid mixing, enhanced heat transfer for good temperature control, and intensified mass transfer (3). The proper control of these often harsh conditions is not only essential for the safe operation of chemical equipment, but also necessary to enable an economical chemical process. Harsh conditions with an unusual range of temperature, pressure, concentration, mixing time, and residence time make new process windows and process routes available, and enable the manufacture of new chemical intermediates. These conditions and routes are not feasible in batch vessels or cannot be maintained during process scale-up (4–6). But harsh reaction conditions can be handled safely in closed systems with small internal volumes.

Microstructured devices operate under continuous flow conditions. Generally, continuous processes offer many advantages ranging from controlled process conditions to high flow rates and mass throughput. Continuous operation enables bulk-chemistry processes to have high production capacities. Fluid dynamics determine the characteristics of continuous-flow equipment such as pressure loss, residence time, heat-transfer characteristics, and mixing time. The combination of continuous-flow processes with microstructured devices brings benefits to the laboratory and production environments. This article discusses microreactors with a single rectangular channel, typical diameters from 0.2 to 2.0 mm and higher, moderate flow rates (e.g., 10–300 mL/min), and Reynolds numbers in the transitional regime (i.e., 100–3000) from straight laminar to turbulent flow. The authors describe process design and related issues with generic examples, as well as with real chemical examples from Lonza's (Basel) experience.