Wednesday, March 16, 2011

Process Wednesday: filtration

Continuing on Kilomentor's list of questions for scale-up, let's face his questions on filtration:
Does the process have a filtration process step? If so:
  1. Has the rate of filtration been checked?
  2. Does the solid shrink in diameter size on the filter after removing solvent or does the filter cake crack?
  3. Do your instructions make provision to prevent shrinking or cracking to facilitate washing?
  4. Have you done a split run (reaction mixture is worked in several parts) to assess the effect of inadequate washing of the crystalline mass?
  5. If the filtration uses charcoal or filter-aid- has the substrate been completely removed from the filter material? Do you have an in-process control to assess the quantity in filtrate and the quantity caught in the adsorbant?
Having confronted filtration on a not very large scale, I can't answer these questions very well for myself. The cracking of the filter cake is something that happens on a regular basis, even on small scale. I presume that this is not a good thing, as it promotes a easier channel for air and wash solvent to proceed through (rather than through the cake itself.) I'll be honest, I'm not quite sure how to prevent it -- I hope there's a reader who has more experience than I.

Question 4 is something that I note about process chemists; they want to find out what happens when something doesn't go as planned. While the protocol is written (I imagine) to ensure adequate washing, what happens if it doesn't happen and the material goes on to the next step? Planning for things to go wrong (and knowing in advance what might happen) is a good idea.

Readers, any comments on these questions?

1 comment:

  1. In answer to Q4: during process development you typically do a fate and purge analysis of the impurities you'd anticipate making in the process. You could do this by running the reaction with dirty material or synthesising impurities and spiking them in. You'd then check in advance the sort of upgrade you get during the reaction workup, and explore reslurry/recrys/other options to potentially remove them.

    You'd also take un-purified material through the rest of the synthesis in the lab to determine whether you could purge them at a later stage (so although the material on plant may not meet the desired spec, there may be a contingency to not worry about reworking as you're confident you can get rid of the impurity later).

    All this said, having a good analytical method is key to spotting the impurities, often at very low (<0.1%) levels.


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