|Credit: Practical Process Research and Development|
With stress tests reaction mixtures are purposely exposed to more extreme conditions to assess the potential impact. For instance, a key reagent may be added in portions to determine wither higher level of impurities will form due to micromixing. Another example of a stress test is shown in figure 15.1 (CJ's note: above). Merck researchers anticipated that by using n-BuLi as base, small amounts of excess base could lead to metalation of one aryl ring, leading to a bis-aldehyde. When two equivalents of n-BuLi was charged in a stress test, 10% of this side product was indeed formed. Further screening showed that EtMgBr could be used as a base, even in 20% excess, avoiding the need to titrate and control the addition of the n-BuLi solution.Every once in a while, you have this terrible "what if" dream where the horrible "what if" scenario is "what if the operator makes a math error and adds twice as much as they should of a key reagent?" Performing these sorts of stress tests (and yes, math errors definitely happen) are a good idea and an important part of developing a plant process.
This section also talks about identifying a "normal operating range" and a "proven acceptable range" for operating parameters - I think part of the issue is that the temptation is to make the proven acceptable range to be the norm, and then mistakes happen, and then you're into "here be dragons and impurities and reworks" land.