Experimental design (Box, G. E. P.; Hunter, W. G.; Hunter, J. S. Statistics for Experimenters; Wiley: New York, 1978 and Carlson, R. Design and Optimisation in Organic Synthesis; Elsevier: Amsterdam, 1992) is an established and proven methodology for product and process improvement in the pharmaceutical industry. This paper presents a step-by-step approach to optimisation of a synthetic transformation using a central composite experimental design, in conjunction with automated on-line HPLC. Highly predictive models for the reaction were obtained using a commercially available software package. [There are many commercially available DOE packages. The software package we used was Design-Expert 5 (DX-5) (http://www.statease.com).] These mathematical models were interrogated to examine the effect on yield and quality under a variety of reaction conditions or constraints. The synergy of experimental design and automation is also discussed.
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Owen et al. (2001) studied this question.