Enzyme and Microbial Technology 34 (2004) 642–650
Process modeling and simulation can guide process
development: case study -cyclodextrin
Arno Biwer, Elmar Heinzle
∗
Department of Biochemical Engineering, Saarland University, P.O. Box 15 11 50, 66041 Saarbruecken, Germany
Received 18 March 2003; accepted 5 February 2004
Abstract
Modeling and simulation of biotechnological processes enables the quantification of possible process variations. In this way it provides
a tool for guiding research towards the most promising directions. The method is shown on the basis of the case study of -cyclodextrin
production. The production process was modeled and the model is used to evaluate the potential impact of CGTases with new properties.
Sensitivity analyses show that yield and selectivity are the crucial parameters. Reaction time has only limited impact and substrate
concentration has to be above 20%. The use of thermostable enzymes provides some energy savings. Furthermore, the effect of new
CGTases leading to a modified downstream processing was assessed.
© 2004 Elsevier Inc. All rights reserved.
Keywords: Modeling; Simulation; Cyclodextrins; CGTase; Downstream processing; Process development
1. Introduction
Modeling and simulation of biotechnological processes
allow the comparison of different process alternatives and
the quantification of potential process improvements. Thus,
research activities can be directed towards the most promis-
ing approach, and decision-making on a sound basis is
possible. This procedure is shown in the case study of
-cyclodextrin production.
Cyclodextrins (CD) are cyclic oligosaccharides composed
of -1,4-glycosidic linked glucosyl residues. There are three
different types of CDs, according to the number of gluco-
syl residues in the molecule: -, - and -CDs consisting of
6, 7 or 8 glucose units, respectively. Each type is produced
industrially today. In 1998, global consumption was around
6000 metric tons, with a high annual growth rate [1]. -CD
is more expensive than -CD (3–4 $/kg) and costs around
20–25 $/kg for industrial application [2]. CDs have a wide
range of applications in food, chemical, pharmaceutical and
textile industry. An extensive overview of possible and ex-
isting applications is given by Atwoods et al. [3] and Biwer
et al. [2].
-CD is produced from starch using cyclodextrin gly-
cosyl transferase [1,4--d-glucan 4--d-(1,4--d-glucano)-
∗
Corresponding author. Tel.: +49-681-302-2905;
fax: +49-681-302-4572.
E-mail address: e.heinzle@mx.uni-saarland.de (E. Heinzle).
transferase, EC 2.4.1.19, CGTase]. Today, research is focus-
ing on the discovery of new CGTases and on the genetic
modification of known enzymes to improve their properties.
The effect of these existing or potential new CGTases on
the production process is estimated in this work by model-
ing and simulation. Various process schemes are modeled
using the software SuperPro Designer and the impact of rel-
evant process variables in the reaction and in downstream
processing is studied.
2. Production process
At industrial scale, -CD is mainly produced in the
so-called “solvent process”. There, decanol is used as a
complexing agent and precipitates the -CD selectively and
such directs the enzyme reaction to produce mainly -CD
(see Fig. 1). Small amounts of -CD and partly -CD are
also precipitated. The exact ratio of CDs produced depends
on the CGTase and the complexing agent used and on re-
action conditions. A typical ratio -CD:-CD:-CD in the
precipitate is 96.5 : 3.5 : 0 [4], which is used in the model
(see Chapter 3).
Starch is the starting material for -CD production.
First, it has to be liquefied and partly hydrolyzed using
-amylase. After liquefaction, -amylase is inactivated by
heat. Afterwards the dextrin solution is cooled down to the
reaction temperature of the CGTase. CGTase and decanol
0141-0229/$ – see front matter © 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.enzmictec.2004.02.006