Identifying Chemical Process Stopping Points for Working in the Kilolab or Pilot Plant

It is not as if there is no planning in the laboratory. If a synthetic lab procedure is so long that the reaction and workup cannot be completed in a single day, chemists can use their experience to extrapolate from similar procedures and guess at what points manipulations can be stopped and under what conditions intermediate solutions or crude solids can be stored without damage. Occasionally there are misjudgments and surprises and a product will be prepared in lower than expected yield or poorer purity. But then even in the worst situation what is lost is no more than a couple of man-days of labor and the price of the starting materials consumed. Also, in the laboratory, because the capacities of refrigerators, freezers, and evaporators are so much greater than the quantities of material being transformed, there are do-able fixes at almost any stage for the situation where a stoppage is forced.

There is no room for such risk-taking on-scale. For advanced intermediates that are themselves the product of a series of sequential steps, one misstep can be economically disastrous. The more points in the process that have been verified as safe-to-stop, by actual test results, the more confidently the process team can be. Moreover, to be a safe stopping point it must be proven safe not just for the quantity and quality of the product but also for the protection of the processing equipment.

As a general rule once a reaction has been initiated, the kinetics must be allowed to run undisturbed to the proper end-point according to the batch sheet. The dynamic transformations cannot be expected to respond to any speed up or slow down without some quantity or quality deviation. After the endpoint condition has been reached and the reaction quenched then the mixture is likely more stable and various stopping points during the work-up can be tested by holding portions of a process mixture for given periods under controlled conditions and examining the mixtures and isolating the product to see whether an unacceptable deviation has occurred or not.

It is more difficult to demonstrate a good stopping point where the mixture in the process equipment is heterogeneous. The difficulty is taking a representative sample for analysis out of a heterogeneous mixture to show that no change affecting quantity, quality, or the protection of the reactor has occurred.  Since one cannot easily take a precise fraction of a heterogeneous mixture, working up that fraction after a pause will not accurately tell you whether the yield would have been different.

Finally, to fairly test the stability of an aliquot at a proposed stopping point the aliquot must be left in contact with a sample of the reactor material. In my experience, this is rarely ever done. At the very least it should be kept in mind where an aliquot might be corrosive to the reactor material.