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| Credit: Org. Process Res. Dev., |
The initial problem statement related to a substantial increase increase in the amount of agglomeration, which was observed following the isolation of compound A during recent manufacturing campaigns. This observation was in contrast with examination of previous isolated batches, which showed substantially less agglomeration. The difference in the extent of agglomeration between older and more recent batches is shown in Figure 1, which includes both scanning electron micrographs and photos of the material held on a sieve following equivalent sieving protocols for the two samples.
...As solubility measurements revealed that the solubility of compound A in 2-MeTHF at the wash temperature was over 7 times higher than that measured in the acetone/water mixture, this was considered a likely cause for the rise in agglomeration for recent batches.What I think is interesting about this paper (other than the incredibly awesome picture of compound A eggs forming in their agitated filter-dryer (AFD)) is that they were able to develop a measurement of the "agglomerate hardness" (i.e. how hard are the compound A eggs, anyway?) using sieving/shaking techniques and they tracked the effect of different washes of the wetcake and its stickiness (using rheological measurements). Perhaps somewhat unsurprisingly, they found that washes where compound A was more soluble would be more likely to develop agglomerates. The authors used a nitrogen "blow-through" step (i.e. blowing N2 through the wetcake) to remove solvent to a concentration below "the sticky point" (direct quote), which ultimately solved the agglomeration problem. All in all, an interesting read.
1. Birch, M.; Marziano, I. "Understanding and Avoidance of Agglomeration During Drying Processes: A Case Study." Org. Process Res. Dev. ASAP DOI: 10.1021/op4000972
Stewie Griffin
ReplyDeleteSo how does the operator assess when the solvent concentration is below the "sticky point"? LOD, TGA, or perhaps something simpler?
From the article: "In practice, the level of solvent removed with this blowthrough protocol is beyond the agglomeration derisking needs,
Deleteand a blow-through at 2000 mbar for 1 h was sufficient to remove residual solvent levels to <5% as measured for a number of subsequent plant batches."
Residual solvent -- that sounds like GC or LOD to me.