(LONZA)
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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.
