CAPE challenges
ESCAPE, Industrial Forum, May 28th 2002


Process Technology in Fine Chemical Industry:
A missing link for a sustainable future?

Alle Bruggink

  1. DSM Research: Life Sciences R&D
    P.O. Box 18, 6160 MD Geleen, The Netherlands
    E-mail: alle.bruggink@dsm.com
  2. Department of Organic Chemistry University of Nijmegen
    Toernooiveld 1, 6525 ED Nijmegen, The Netherlands

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 challenge

The 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 architecture

An 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 representative for existing plants because they have been developed through downscaling based on the existing equipment. Combined with HTE-MTE (high and medium throughput experimentations) techniques efficient process development using laboratory scale only can be envisaged, considerably shortening the 'time to market'.

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:

  1. M.B. Diender, A.J.J. Straathof and J.J.Heijnen, 'Predicting enzyme catalyzed reaction equilibria in cosolvent-water mixtures as a function up pH and solvent competition', Biocat. Biotransf. 16 (1998) 275-289.
  2. C.G.P.H. Schroën, V.A. Nierstrasz, H. Moody, M.J. Hoogschagen, P.J. Kroon, R. Bosma, H.H. Beeftink, A.E.M. Janssen and J. Tramper, 'Modelling of the enzymatic kinetic synthesis of Cephalexin', Biotechnology and Bio-engineering, 73 (3) 171-178 (2001).
  3. A. Bruggink (ed.), 'Synthesis of ß-lactam antibiotics, Chemistry, Biocatalysis and Process Integration', Kluwer Academic Publishers, May 2001.
  4. IBOS: Integration of Biosynthesis and Organic Synthesis (an ACTS Research Program, the Netherlands, 2002 - 2008, launched March 22, 2002)
  5. L.A. Hulshof, 'Challenges in Fine Chemical Scale-up', Proceedings 5th Industrial Conference on Org. Proc. Res. Dev., New Orleans, USA, Nov. 2001.

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