Wednesday, December 8, 2010

Process Wednesday: writing up for scaling up

It's time to face facts, if you haven't already -- that procedure you wrote up to scale up? It's probably not detailed enough. Once again, from our friend Neal Anderson, page 114 and 115:
Details of the specific conditions must be thoroughly described before a process can be safely and reproducibly scaled up, especially by someone who did not develop the original process. Few chemists are naturally inclined to describe in detail the conditions that they used. The nonspecific descriptors ("groaners") listed [below] in Table 5.1 are not sufficient to allow for ready scale-up of most processes: 
Added slowly, added dropwise (CJ's note: my personal favorite), to a dilute solution, added in portions, added to a cold solution, was run overnight, added at -78°C (was the temperature kept constant during the addition?*), with a slight exotherm, at room temperature (colder in England, hotter in the tropics*), excess reagent, vigorous agitation, worked up in the usual way, gave a white solid, sufficiently pure, yields given without consideration of product quality. 
Well, now you know -- so take a little more time writing up next time you throw it over the fence, hey?

*Anderson's comments, not CJ's. 


  1. It is probably a universal truth that we could all learn to write more descriptively. Imagine being passed a procedure written by someone who has not spent that time to describe what they see. I recall one experiment where there was no mention that the reaction should be homogeneous. I had no clue. When I noticed that the solid was not dissolving in the solvent, I had to re-trace that it was a different procedure that was used to make my starting material. It turns out 20% of the weight of my starting material was inorganic salts. Case in point.

  2. One needs to be more specific (whether overnight was 9 or 19 hours) although many reactions are run at RT overnight for convenience sake - and if the chemist is not a complete hack he will not leave a reaction that is nor robust enough to "over-react".

    Scale up safety issues like exotherms and runaway auto-catalytic processes have to be looked for by the scale up chemists anyway, and it is not advisable to scale up a reaction on the first run (unless the procedure is very thorough and the starting material cheap).

    I noticed that some of my medicinal chemistry colleagues write notebook entries that are brief and cryptic, and often they make a compound only once by a nonoptimized procedure - and when the time comes for putting together a writeup on how the compounds were made (for patent examples or supplementary of an article) they write a plausible procedure based on incomplete record and guesswork, a procedure that may have reproducibility issues

  3. As someone who spent all of grad and postdoc on 50 mg, and now does 50-L reactor chemistry, I can say that small scale DOES NOT even approximate large scale. "Trace" solvents are measured in grams, heat transfer is a nightmare.

    At this scale, descriptors such as appearance, stir rate, addition rate, and exact temperature are musts for reproducibility.