Wednesday, March 23, 2011

Process Wednesday: a quick poll on scaling up

Imagine a scenario where a trusted colleague has come to you and said, "I have run a 1 gram (starting material) reaction. Please run this reaction at the same conditions at 100 gram scale." Would you expect the purity, yield and time to completion to be basically the same?

Personally, I would not. So a quick poll for the process chemists out there -- if a colleague has run a reaction at 1 gram scale, what is the largest scale at which you expect the major parameters of the reaction (product yield, purity, time, temperature) to be basically similar?

My answer in the comments.


  1. 10 grams is the largest scale for which I would expect the results to be the same. 20 grams, 50 grams? If you're lucky, maybe. 100 grams and up? No way.

  2. I'd say 10 grams too - but it would depend on the purification.

    Crystallization, I'd say the yield may well increase going from 1-100g (probably SHOULD!)

    Chromatography on 10g is probably about the limit that I'd think feasible as a non-process person.

  3. I would say it might be similar at 20 g, depending on temperature profile and solubility. 100g is completely out, though. I never scale anything more than 5x at a time.

    There's a process we're looking to do on 2 kg right now, and the largest pilot we have to base ordering off of is...wait for it....50 g.

  4. The general rule for production scale is 3x but that's for larger lots at the pilot plant stage. For something as small as 1 g, I think you could go up 5x or even 10x. The larger you go, the more likely it is that you'll run into mixing problems, uneven heating, etc.

  5. 10g is the highest I'd go before reevaluating.

  6. Depends: My first reaction is if the person is a typical med chemist jock I'd doubt would scale all that well. If the person is an experienced process chemist then more of a chance to be similar and likely results turn out better.

    In reality answers mostly a function of the chemistry/reactions involved and what you know from literature or lab. I have done routine development at 100mg-10g scales then jumped with confidence immediately to 1-25kg scales. More often than not its play outs the targeted amount/time demand, COGs/availability of materials and facility constraints that dictate how transitions implemented and the process chemists struggle to keep up.

  7. Not a chance. The scale up conditions will probably vary greatly, especially with a mass change with that many orders of magnitude of difference...its going to take some brain waves to figure this one out.

  8. I'd never expect a 100% success rate for anyone repeating anything I've done no matter what the scale unless they do everything EXACTLY as I did it. Just because you got something to work once does not mean that you have any clue about the identity of or degree to which you need to control all the variables associated with your process.

    In my experience it is variation of one or more seemingly unimportant variables that ends up being the cause of a disparate result. Allowing that disparate result to guide further experimentation into determining the most important variables you need to control is actually the crux of development of a robust and repeatable process.

  9. When it comes to scaling up high pressure hydrogenation reactions, my experience is definitely not. The surface/volume ratio and thus the size of the gas/liquid interphase differs too much when scaling up by a factor of 100.

    In general, I am more confident about the reproducibility of a scale-up from 100 g to 10 kg than scaling up from 1 to 100 grams.


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