Multiphase Bioreactor Design

increases too, which means that the crystalliser is operated at a lower supersaturation.
Increasing the hold-up also implicates that the size increase of the seed crystals becomes
smaller at constant residence time in the crystalliser. However, for appropriate
downstream processing, a large product crystal size is required. The latter demand limits
the increase in the crystal hold-up. So, an optimum crystal hold-up, and corresponding
optimum supersaturation (∆Copt), exist in the crystalliser. The optimum supersaturation
must be determined experimentally. In selecting the optimum supersaturation not only the
desired median crystal size, but also other desired product characteristics (that depend
more or less on the supersaturation) must be taken into account, like a small coefficient of
variation of the crystal size, a regular and compact shape, and a high purity.
The main advantage of continuously operated crystallisers is that they are superior to
batch crystallisers with respect to maintaining a constant optimal supersaturation and low
nucleation rate (Mersmann, 1995a). As a result, more homogeneous product crystals are
formed than in a batch crystalliser, which makes downstream processing cheaper (see
below).
The current status of biocatalyst immobilisation and of continuous reaction
crystallisation is reported shortly in relation to its relevance for solid-to-solid
bioconversions. This is used as a basis for a reactor design. Note that some features are
also applicable to batch systems. Finally, downstream processing of solids is discussed in
order to emphasize the need for a large crystal size. It should be stressed that this work
only focuses on systems in which dissolution, bioconversion, and crystallisation are
coupled directly, in order to fully profit from the benefits of multi-phase systems.

Biocatalyst Immobilisation

For continuous operation, biocatalysts are often immobilised, because immobilisation is
generally associated with increased efficiency and it makes different system
configurations possible; note, however, that with these profits the costs of immobilisation
must be earned back.
Kasche and Galunsky (1995) pointed out that, in reaction crystallisations involving
immobilised enzymes, small crystalline particles may be formed in the pores of the
support of the enzyme. If so, the accessibility of the immobilised enzyme decreases,
resulting in decreased reaction rates and in limited reuse of the immobilised enzyme.
Their study revealed that it is essential to use supports with small pores in order to avoid
intraparticle crystallisation; they reported a critical pore size range of 10–100 nm. The
latter implicates that in their experiments the critical cluster size—the size a cluster of
molecules in solution must have to grow spontaneously, so that a crystal is formed—was
larger than 10–100 nm.
For application in a continuous reaction crystalliser, the support materials for
immobilisation should have other characteristics too: insolubility, high mechanical
stability, high diffusivity, simple immobilisation procedure, high biocatalyst retention,
well separable from the product crystals, and preferably a low price. Leenen et al. (1996)
studied the characteristics of natural gels as carrageenan, Ca-alginate, and Ba-Ca-
alginate, and gels as polyvinyl alcohol (PVA), polycarbamoylsulphonate (PCS), and
polyethylene glycol (PEG), for application in wastewater-treatment systems, and found
that PVA, PCS, and PEG were more promising materials than natural gels. These

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