Wednesday, June 26, 2013

Process Wednesday: Th'Gaussling speaks the truth

Th'Gaussling writes a really great summary of ways that you can get less expensive prices from chemical manufacturers if you decide to scale up your chemistry -- it is really worth your time:
To the greatest extent possible the raw materials for your product are preferably:
  1. existing items of commerce unencumbered by composition of matter or process claims.
  2. available in a grade suitable for direct use.
  3. unencumbered by import restrictions, law enforcement watch lists, and relevant EPA restriction lists.
  4. TSCA and REACH listed already.
  5. those free of problematic isomers.
  6. those not requiring tight fractional distillation to purify.
  7. free of explosaphors like azide or nitro esters.
Your costs are best contained if your product:
  1. does not require enantiomeric purity or is not subject to facile isomerism affecting the specification.
  2. does not require more than one protection/deprotection scheme.
  3. does not require tight fractional distillation for final purity.
  4. does not require bulk high pressure chemistry (shops that can do this are limited).
  5. is air stable.
  6. is soluble enough in process solvents to maximize space yields (if it is, say, < 10 wt %, batch costs will start to get high).
  7. does not require solvent changes in a process unit operation.
  8. is amenable to parallel synthetic strategy.
  9. does not require serious chilling of the reaction mixture (say, < -20°C).
  10. has been screened for real purity requirements rather than those based on the desire for tidiness.
  11. can be isolated by a simple Buchner filtration rather than, say, a centrifuge or other more elaborate solids isolation scheme.
  12. can be isolated by simple distillation.
Of the items that th'Gaussling mentions, #7 in the process/non-raw materials section is the one that I think makes the most sense, but is least discussed among chemists. I think he is referring to solvent swaps, which are relatively simple to do in the lab -- you just throw your flask on the rotovap, strip off the first solvent and dump in the 2nd. In the plant, though, solvent swaps take a lot of time (hours to distill off a solvent) and you can't really distill to dryness, so you're left attempting to chase away the remaining drops of the first solvent by adding in increasing portions of the 2nd and distilling further. It's not an ideal solution and it tends to tie up a reactor with processing that isn't really making any product.

He has additional comments, so go read the whole thing -- if you're ever interested in working with a CMO, they're handy tips. 


  1. You can also make it yourself and cost it out. Then you can perhaps press the price even more!

  2. This is really good information. I often wonder what the expensive parts of a scaled up process are, and it is difficult to get a list of reagents/processes that are cost prohibitive at greater than bench scale. This will be printed out and posted on my wall for future reference. Thanks CJ and especially th'Gaussling.


looks like Blogger doesn't work with anonymous comments from Chrome browsers at the moment - works in Microsoft Edge, or from Chrome with a Blogger account - sorry! CJ 3/21/20