Stirred-tank reactors are used throughout the process industry. They are not only applied in the chemical industry, but also in newer industrial sectors, such as biologics, pharmaceuticals, nanotechnology, and regenerative medicine. Certain fea- tures have not changed for many years, but the understanding of the physical processes occurring within has greatly increased. Since knowledge of the interaction between the physics of mixing, single- or multiphase, and the underlying science is critical, the physical processes of mixing/stirring are considered as they developed over the last ~75 years.69479

Keywords: Computational fluid dynamics, Impellers, Kolmogorov theory, Single-phase systems, Two-phase systems

1 Introduction

The use of stirring and stirred tank reactors (STRs, includ- ing bioreactors) is ubiquitous throughout the process indus- tries; biologics, chemicals (heavy, specialty and pharmaceut- ical), cosmetics, food, oil, mineral, paints, paper, plastics, polymers, water, etc. Commercially used STRs start at the 15-mL scale, as the recently developed robotically operated ambr' [1], which is proving popular for the selection of the clones for therapeutic protein production from animal cell culture, up to tanks of many 100s of cubic meters, which have been available for many years. Somewhat sur- prisingly, they are rapidly becoming the configuration of choice for the growth on microcarriers of stem cells fol- lowed by their harvesting for allogeneic therapeutic pur- poses in regenerative medicine [2, 3]. They are used for fluid systems of low viscosity in which the flow is turbulent; and in very high viscosity and non-Newtonian fluids where the flow is deeply laminar. In many cases, there is more than one phase and mixing may be required to enhance a rate process taking place between the phases; or to produce a rheologically complex, stable product with a long shelf life. The possibilities are endless; and the range of applications is a measure of their inherent flexibility.

STRs have also been fabricated in a wide range of materi- als from carbon steel, and for cleanliness, sterility or corro- sion-resistance, more exotic steels and corrosion resistant metals and glass-lined equipment [4]. Recently, simple sealed sterile plastic bags placed in a metal container as sin- gle-use bioreactors for cell culture have also become popu- lar [5]. Most STRs are cylindrical in shape with a dished or

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Prof. Alvin W. Nienow (A.W.Nienow@bham.ac.uk), University of Birmingham, School of Chemical Engineering, Birmingham B15 2TT, UK.

hemispherical bottom as that shape is more able to handle pressure whether required for the process taking place or due to the static head. In others, especially for large vessels in minerals processing and oil storage, flat bottoms are used, occasionally square or rectangular in cross-section to maximize the number of vessels/unit area.

The first clear example of an STR was given in the book De Re Metallica (Latin for on the nature of metals) by Georg Bauer (pen name Agricola) on the art of mining and extracting metals published in 1556 [6] (Fig. 1). In many respects, the figure resembles a modern STR in that it has a prime mover (a water wheel in this case rather than an elec- tric motor), a gear box to provide an appropriate speed (in this case, increasing the rate of rotation of an impeller rather than slowing it down) and a paddle with six flat blades to provide the energy input into the reactor (each made of wood rather than any modern material as listed above) in order to achieve stirring. A major difference com- pared to current practice is the use of open reactors, each of which contains mercury amalgam being used to recover gold from an ore. It would not meet the current health and safety at work legislation.

Another difference between 1556 and today is the level of understanding of stirring, which is now available to help in designing STRs and that has led to a significant change in impeller and equipment design in recent years. Further on in this article, the development of that understanding will be outlined leading up to a brief assessment of the current state of the art. Some discussion of what is required to fur- ther increase understanding and equipment design will also be covered.