The Strategy of using Split Runs in Chemical Process Development

Split run does not appear to be a widely understood term; however, in my personal chemical process development experience it is a common term with a well defined meaning. Split runs are experiments done to test different work-up/isolation and/or purification procedures starting with equal portions from a single large reaction mixture. As a consequence, even if a reaction mixture is both complicated and uncharacterized, a chemist can compare different follow-on procedures for working it up without being concerned about reaction differences that may still exist from batch to batch because the reaction process itself has not yet been finalized and critic parameters completely controlled.

In the general case, the isolated yield fraction, (which when expressed as a percentage is often called simply the percentage yield), is the product of the reaction yield fraction (determined by an assay of the crude reaction mixture before work-up)  multiplied by the isolation yield fraction (the fraction representing the effectiveness of the recovery of pure product from the crude reaction mixture). In the case of comparing split runs, the ratio of isolated split run  yields is proportional to the ratio of the isolation yields because the pure reaction yield is the same for each, since they come from the same reaction batch. Thus, in comparing the recovered product from split runs, the difference represents only the effectiveness of the isolation protocols….it is independent of and not confounded by the exact details of the reaction conditions. In this way, even at an early stage in developing the particular reaction step, the development chemist can get some idea of the comparative effectiveness of different treatments of the crude reaction mixture.

Of course it is not just the best isolation yield that is of interest and of importance to the process development chemist but also the relative purities of the two products and the amounts of different impurities within each.

The benefit in using split runs results because the optimization of the reaction conditions and the screening of potential isolation methodologies can proceed in parallel. It is not necessary to wait until the optimized processing conditions have been selected to work on the best isolation/purification means. The work can proceed more quickly and an earlier completion date can be set for some project milestones. 

This does not mean that reaction optimization and isolation optimization can be completely decoupled. This can be seen to be intuitively obvious if one realizes that in an extreme case, if the assay yield in the reaction becomes 100%, there will be no residual starting material and no by-products formed and so this could simplify the work-up beyond all normal proportion and perhaps allow the most mundane isolation to give a fine outcome.