Automated chemical synthesis. Part 2: Interfacing strategies

Research focused largely on developing new, highly automated tools for the process development laboratory is carried out in the authors' laboratory. The ability to evaluate, characterize and optimize synthetic routes, both quickly and comprehensively, is especially important in the pharmaceutical process development laboratory, where typically in a complex synthetic sequence many reaction parameters must be examined. Furthermore, the rapid elucidation of process routes details and idiosyncrasies will allow the synthesis of new materials intended for extensive preclinical and clinical testing to proceed by 'final. chemistry', where even slight changes in process conditions can affect trace impurity profiles. Increasing attention is being given to the opportunities generated by computers to enhance the productivity of these laboratories [1-2]. On the pilot and production scale, batch-reaction automation instrumentation and technology employing fully and semi-distributed control schemes are widely available [3-6]. On the laboratory scale, however, most researchers have pursued automation of continuous-flow techniques [7-9]. The automated chemical synthesis project described here entails designing and constructing a computer-controlled, bench-scale batch-type reactor, which is capable of self-directing experimentation and optimization [9-15]. Such a system would permit extensive, and often tedious, examination of chemical reactions in quite early stages of their development. Experimentation on the bench-scale in batch-type reactors will allow chemical reaction and process control data to be obtained, subsequently this will be directly applicable to the pilot and production scales. Further, by minimizing the size of the vessel, scarce developmental quantities of chemical intermediates can be conserved as automation technology is applied at the very earliest stages of process development programmes. A prototype unit was constructed to permit a close evaluation of various automation parameters: reactor design, temperature control, reagent delivery, chemical analysis.and computer interfacing. The unit consisted of a 100ml glass (jacketed) vessel with ports for a condenser, stirrer bearing, temperature sensor, reagent inlet, reaction sampling and a drain. Reagent and solvent were introduced into the vessel by positive displacement pumps; temperature was controlled by mixing hot and cold fluids and circulating the mixture through the vessel jacket; samples were removed and diluted (using a Technicon AutoAnalyser pumping system) for subsequent on-line analysis by HPLC. A timeshare computing system (a Digital Equipment Corporation PDP11/34 RSTS)was used to calculate the various operational parameters (stoichiometry, temperature, reaction time) according to a simplex experimental design. The chemical analysis results were reported back to the RSTS resident program which then calculated new reaction parameters. For a detailed …