Although the real revolution in high-throughput screening happened only one decade ago, some of the underlying ideas and strategies are as old as the science of chemistry itself.

For example, parallelization can be traced back to the sixteenth century, when G. Agricola, in the first book on industrial chemistry in modern times, describes how 700 pairs of pots were placed in an ''array'' of rows and were used for the preparation of mercury from its ores (see Fig. 30.1) [1].

Fig. 30.1. Parallel working in the sixteenth century [1]. A, The burning hearth; B, the timbers; C, the unlit hearth, into which the pots are put; D, the rocks; E, the rows of the pots; F, the upper pots; G, the lower pots. We thank the Agricola foundation for kind permission to reprint this figure.

The pioneering work on spot test plates was performed in the 1920s and 1930s by F. Feigl [2], who began preparing materials on spot test plates to analyze specific properties afterwards. Impressive examples of fast quantitative analysis of heavy metals are given in the journals of that time [3].

Also, parallel catalyst screening was used by Mittasch in the development of the ammonia process during the first 20 years of the twentieth century [4]. The use of parallel reactors for the testing of heterogeneous catalysts was described in the 1950s [5]. However, parallelization was limited, as, for example, Dowden and Bridger stated in 1957: ''a test apparatus ... can advantageously be multiplied to give a greater rate of testing, providing the temptation to overtax both observer and supervisor is avoided'' [6].

Obviously, this limit could not be overcome until the era of computers and process automation. Therefore, just recently, numerous articles and books have been published covering the topic of automated synthesis in process development. The main emphasis has been on chemical process development in the pharmaceutical industry.

An excellent review was published in 1999 by Harre et al. describing automated chemistry in organic process research and development [7]. Describing the pioneering work that started during the 1980s, they revealed that most published examples were based on a Zymark robot system. Second, owing to the lack of other commercially available solutions some companies launched programs with in-house developments such as the DART (development automated reaction toolkit) system of Glaxo Wellcome [8], or the ATLAS (assessing technologies for laboratory automation in synthesis) initiative by SmithKline Beecham [9].

Nowadays, the user has the choice between several commercially available systems with different degrees of automation and features. Harre et al. presented a table with a dozen systems available as at summer 1999 [7]. In mid-2001, the boom for parallelization in process development is continuing, leading to a greater variety of apparatus available on the market (see Tables 30.1 and 30.2).

Since 1996, numerous examples of the optimization of organic reactions by parallel process development have covered almost the whole area of organic chemistry. Recommended literature in this respect is by Hird [10], Orita et al. [11, 12], Zhang et al. [13], Gooding et al. [14], Kirchhoff et al. [15], and Emiabata-Smith et al. [8]. In addition, there are two books covering special aspects of parallel process development. The book Automated Synthetic Methods for Specialty Chemicals, edited by William Hoyle, includes a number of papers presented at a Royal Society of Chemistry symposium in 1999 [16]. For process development especially, the contributions by Evens [17] and by Armitage and Smith [18] are relevant, describing their experience with the Anachem SK233 workstation and the HEL AutoMate system. Owen and Dewitt wrote about ''Laboratory automation in chemical development'' in Process Chemistry in the Pharmaceutical Industry, edited by Gadamasetti [19]. They predict a shift of paradigm, where simply the emulation of manual methods with automation is not enough, but the chemists must develop techniques that are suited to automation, e.g. statistical experimental strategies.

834 | 30 Concepts of Combinatorial Chemistry in Process Development 30.2

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