ESCAPE, Industrial Forum, May 28th 2002
Process Technology in Fine Chemical Industry:
A missing link for a sustainable future?
Alle Bruggink
Introduction
The fine chemical industry, in particular the segment supplying the pharmaceutical industry, is the main domain for applied organic synthesis. Traditionally the organic chemist is dominating the development process from route selection, process development, process optimization and scale-up. Process technology and Engineering are only getting involved in the end phases. Attempts to bring synthetic chemists, process technologists and engineers together are numerous but have not been very successful so far.
The challengeThe challenge to bring synthetic organic chemistry and process technology together has
been on the table during the last 10-15 years. Attempts to train and educate students in fine
chemical process technology have met with very limited success.
In fact, we were unable to define the subject properly on an academic level. Given the
limited economic impact of fine chemicals up to 1980 also the sense of urgency was rather
small. Later on it was anticipated that increased molecular insight and advanced computer
programs would allow us to construct reliable kinetic models for fine chemical processes. So
far, practical proof is very limited (ref. 1,2) and nowhere near the results in petrochemicals
and bulk chemical processes. In fact only rather simple 1 or 2 step processes can be
modeled whereas a simple functionality (from a synthetic chemist point of view) like an
amino acid in a dipeptide synthesis is already pushing us to the limits. The Zwitter-ionic
character of amino acids is posing too much problems to arrive at robust models for plant
scale. Only for established processes and products with a rather long lifetime of 10 years or
more, i.e. penicillin’s and related ß-lactam antibiotics, this approach has shown some
practical results (ref. 3).
In the meantime the dynamics of the fine chemical industry are causing larger changes in
the required products and processes than the developing process technology can cope with.
Important issues are:
So far, the fine chemical industry has managed to survive this turmoil, but at a price. Profits and rewards are rather small given the high added value of the products and the great risks of failure in new business development or even in maintaining existing business positions. At the same time it has become virtually impossible to define the outline of the production plant of the future. Several options are mentioned in the literature and many academic groups are developing clever devices: fume-hood plants, carrousel reactors, membranes, monoliths, micro reactors, processes on chips etc. etc. None of these, however, have reached maturity or are at a status of proven robustness that a fine chemical entrepreneur would invest its money in it. The result is a continuation of investments and improvisations in existing batch type equipment of 5.000 - 15.000 L. In fact, the investments needed to bring a cleverly designed laboratory process to a batch type production plant are often exceeding the process development costs 5-10 fold..... and the result is always a compromise.
The ultimate challenge thus is: can we design conditions wherein the first synthesis of a molecule is representative for the eventual production process? In other words: 'Can we do our design in one-time-right'.
Process architectureAn interesting approach to this challenge has been developed by Dr. Hulshof at Eindhoven University and DSM Fine Chemicals (ref. 5) Through careful analysis of over 100 wholly or partly failed scale-ups in fine chemical and pharmaceutical plants a pattern has been developed that can be used for new, more representative protocols for development at laboratory scale. It has been shown that reliable protocols can be drafted for all common unit operations (stirring, heating/cooling, extraction, filtering, crystallization, drying etc.). Practical results at DSM Fine Chemicals in Venlo have been reached in existing plants with limited investments in equipment changes. A very rewarding result was the direct introduction of a 5-step synthesis for a drug intermediate from laboratory to plant scale: no pilot plants experiments were done!
Based on these initial results a future can be envisaged in which laboratory protocols are
available for all unit operations and a range of important unit processes. These protocols are
On a long-term basis the introduction of process chips or related micro-devices can be foreseen in which these minireactors are used to run the laboratory protocols. Kinetics can be studied much more fast and reliable in these systems. Combined with HTE/MTE techniques several process variants can be studied in a short time. Automations and synthesis robots are coming in sight when reactor chips containing catalysts for most molecular conversions are becoming available. The option to use existing equipment (batch scale plants or pilot plants previously used for scale-up) for commercial production is still available. 'Reactor engineering' is substituted by 'reaction engineering'.
Further reading: