Wednesday, July 31, 2013

Process Wednesday: extractions over filtrations

Another helpful tip from our mentor-by-literature Neal Anderson and his book Practical Process Research and Development:
Extractions are generally preferred over filtrations to remove impurities. Extractions can often be performed in the vessel where the reaction occurred, while filtration require additional equipment (filters, receivers and transfer lines) and more operations. Filter elements can also plug, causing delays in processing. For instance, it is more convenient to remove Et3N-HCl from a reaction run in toluene by extraction into water than by filtration; however, if large volumes are needed for extractions, filtration may be preferred. Solvents that dissolve small amounts of water may be preferred if the product is water-sensitive. For instance, i-PrOAc may be preferred over EtOAc. 
Perhaps the thing that separates laboratory-scale operations from plant-scale operations is the lack of a bottom valve on laboratory flasks*; the bottom valve is what allows a 2000-gallon reactor to serve as its own separatory funnel. Pump the water in, turn on the agitator for a while, let it settle, drain your aqueous layer away, Bob's your uncle.

*Although you can certainly purchase them with bottom valves!

10 comments:

  1. "the bottom valve is what allows a 2000-gallon reactor to serve as its own separatory funnel" This is true but shaking and flipping that sucker is sure a real b!tch. :0
    I think you have previously mentioned to do this a need for a sight glass hook up and if dealing with dark layers in not always trivial to see the boundary.

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  2. However the major problem with extractions is the formation of emulsions that never break-up or are very slow to separate delaying further processing. I have vivid memories of looking through a sight glass at 10pm; 11pm ...3am; 4am; ...7am... and seeing nothing but emulsion and cursing all night long. There are tricks of the trade to solve this problem, but they are hard to implement in the middle of a GMP run.

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    1. Oh, God. I'm right there with you (w/o the added stress of the GMP run, that is.)

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  3. Those flasks are handy, but a jacket version for heating and cooling of reactions would be preferable (http://www.chemglass.com/product_view.asp?pnr=CG-1539).

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  4. One of the more non-intuitive things I learned over the years is that the kinetics of many layer separations will improve as you move the temperature up. This is not something you can explore using only a sep funnel. A useful trick is to run your extraction in a cylindrical reactor with a bottom valve. Heat up your extraction, mix, settle, and then drain out the majority of the bottom layer. Drain the phase split into a sep funnel to do the last of the separation and voila - heated extraction.

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    1. You bring up a great point! I can attest to doing this with sep funnel and heat gun though. Not exactly temperature control but it gets the job done when you need it!

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  5. One trick, which can be done GMP, is to push your emulsion through an in-line filter into a second tank or reactor. This presumes that the batch has no rag layer or other pptt. Then settle and split times are much shorter. This is a good trick when your batch cannot be heated. Learned it from a terrific engineering colleague.

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  6. Yeah about 3am we tried the filter thing, but all those little charged particles just clogged it up and round two of cussing began at a higher decibel. The material was heat and pH sensitive, so our options kept getting narrower as the early morning hours rolled by.

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  7. Once you've seen a membrane separation work, you'll never want to use a sep funnel again.

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  8. On smale scale, ultrasonication sometimes breaks emulsions very fast and efficiently. (It can form emulsions as well, and you don't know until you try if it forms or breaks an emulsion.)

    ChristianPFC

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