Organic Process Research & Development 2001, 5, 652−658
Microreaction Technology as a Novel Approach to Drug Design, Process
Development and Reliability
Shahriyar Taghavi-Moghadam *, Axel Kleemann, and Klaus Georg Golbig
CPC-Cellular Process Chemistry Systems GmbH, Hanauer Landstrasse 526 G58 II, 60343 Frankfurt, Germany
Abstract:
specific process or simply on demonstration of the feasibility
for a particular task. The emphasis in any case was not on
creating a universal system that could be used for different
applications such as development as well as production of
pharmaceuticals and chemicals under manufacturing condi-
tions. Providing scientists with an integrated and “ready to
use” operating system has now been realized by CPC-
Cellular Process Chemistry Systems, an innovative company
involved in the design and fabrication of integrated microre-
action systems and their application to a wide range of
chemical reactions.
This paper focuses on the application of microreaction technol-
ogy in the life science industry. Certain features of microreac-
tion technology, for example, mixing, heat transfer, and
residence time distribution, are discussed. Important advantages
such as high operational safety and the possibility to transfer
the experimental results directly from laboratory to the produc-
tion of pilot-plant scales are mentioned. Potential application
fields in the drug discovery and development processes, from
research to production, by including chemical synthesis of
different targets in the case of the quinoline acid derivative
(ciprofloxacin) and the Paal-Knorr pyrrole synthesis are
presented.
2. Definition and Features of Microreaction Technology
At least two basic functions can be assigned to the
microreactor: initiate and facilitate a reaction through mixing
of the reactants, to provide or remove reaction heat (heat
transfer).
1. Introduction
The time and cost of developing drug compounds for the
pharmaceutical industry have increased dramatically over the
last three years.1 Combinatorial chemistry and high through-
put screening even speed up the identification of new lead
compounds. However, the fast preparation of the first
kilogram quantities of drug candidates and active ingredients
represents an immense pressure to keep pace with developing
processes for large amounts of drug substances. The increas-
ing need to reduce cost and time consumption, improve
process routes, and minimise environmental impact leads to
an enormous interest in developing new technologies to be
used as an alternative to or combined with conventional batch
processes. In the past decades, a wide variety of methods
have been developed for the realization of “state of the art”
chemical synthesis. One strategic approach is to simplify the
synthetic route by employing unique reactions such as
“domino” or cascade transformation. Another strategic
approach uses innovative technologies to improve the quality
of synthetic reactions. Microreaction technology belongs to
the latter one. Because of their reduced hold-up, high
throughput potential, and the elimination of the scale-up
process, microdevices have become of interest in chemistry,
particularly for hazardous reactions in the early 1970s.2
Microreactor devices are generally defined as miniaturised
reaction systems fabricated by microtechnology and precision
engineering. They are available today in different models
and designs, and most of these are meant for research or
have been designed for precisely defined applications.3 The
development of these microreactors was focused either on a
Microreactors usually consist of several stacked plates
containing the microstructures in the submillimeter range
(Figures 1 and 2). Because of flow structures with submil-
limeter dimensions in which the chemical processes occur,
excellent heat transfer and improved mixing of the reactants
compared to those for conventional systems can be achieved.
These features provide the system with an exact control of
the reaction temperature which significantly affects the
quality of chemistry and the reproducibility of syntheses.
2.1. Mixing. Provided the most common casesthe mixing
of two miscible liquids in a macroscopic reactor, mixing
occurs mainly due to the action of the following: (1) rather
large fluid aggregates are coarsely spread over the reactor
volume and (2) mixing proceeds via shear stress induced by
vortexes. These decay under the action of turbulent eddy
diffusion into smaller and smaller ones, which dissipate
energy primarily through viscous shear and influence chemi-
cal reactions strongly if they show reaction time constants
in the order of milliseconds. Examples are crystal nucleation
and growth or in reactions which are sensitive with respect
to stoichiometric ratio. To measure and characterise the
micromixing in chemical reactors, fast and stoichiometrically
sensitive reactions, such as described by Bourne et al.4 as
well as by Villermaux,5 have to be employed. This type of
reaction can be also used to optimise the mixer design as
reported by Hessel et al.6
(4) Bourne, J. R,; Oemer, M. K.; Lenzner, J. Ind. Eng. Chem. Res. 1992, 31,
949-958.
(5) Fournier, M.-C.; Falk, L.; Villermaux, J. Chem. Eng. Sci. 1996, 51(23),
5187-5192.
(1) Littlehales, C. The Price of a Pill. Mod. Drug DiscoVery 1999, 2, 21.
(2) U.S. Patent 3,701,619, 1970 and U.S. Patent 5,534,328, 1993.
(3) Top. Curr. Chem. 1998, 194.
(6) Ehrfeld, W.; Golbig, K.; Hessel, V.; Lo¨we, H.; Richter, T. Ind. Eng. Chem.
Res. 1999, 38, 1075-1082.
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Vol. 5, No. 6, 2001 / Organic Process Research & Development
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