Sunday, August 23, 2009

Interview: what's it like to handle lots of nBuLi?

Commenter extraordinaire CMC guy recently commented on his experience performing larger-scale reactions with nBuLi. I asked CMC guy to answer a few questions about these reactions and he kindly agreed; his answers to my questions were lightly edited for clarity.

CMC guy's disclaimer: Observations from (former?) Process Chemist who’s been away for the bench for several years yet still directly oversees API R&D and Manufacturing (so on occasion I can pretend I still am a Chemist). The usage of BuLi mentioned was at least 15 years ago so certain details are lost to memory, or perhaps would be confidential even if I did fully recall, yet I can speak to some elements and trust will answer/illustrate features of larger scale chemistry (in context mainly of Pilot Plant).

CJ: What did you do different than a typical run in a lab?

Scale was 50-100x of largest lab runs so were many both direct and subtle differences typical of such efforts. Everything was “planned” in detail from lab experiments, available reagents (10N nBuLi) and multiple pre-campaign meetings to discuss and refine, particularly how to execute most safely. Procedure was codified and captured stepwise in Batch records, not recorded after the fact. Because usually reactors have only a sight glass port did not always have visual clues normally used in lab but had alternative monitoring (internal temp, pressure, sample testing) to reaction. We also had at least 2-4 people involved during operations, mostly lost PhDs and Chemical Operators who knew their stuff, particularly during hazardous portions. Weight of materials was used to measure quantities rather than doing by volume.

CJ: How'd you get the BuLi into the reaction?

Method analogous of “cannulation” commonly used in lab with the BuLi coming in canisters with valve ports, like heavy duty propane tanks, and used N2 pressure to push transfer (10N nBuLi a viscous solution whose behavior reminded me of tBuLi/Et2O which is more intense flammability than 1-2.5 N BuLi most people familiar with). The connections/plumbing not too different from gas cylinders with Teflon lined stainless steel flex transfer tubing (<1/2> 5L run went directly into reaction in stop/go pulses based on maintaining temperature control (keep between -40 to -20°C). The 20L amounts was placed in a drop tank, thinned with solvent (THF or DME) then added “dropwise” for smoother operation (and worked better since less manipulation of BuLi. N2 Purges were enhanced to assure continuous inert atmosphere. Post reaction we did breakdown and clean externally with CO2 saturated solvent (IPA?) wipes and tubing was sealed in bags then treated in same fashion in a lab hood.

CJ: What kind of PPE is needed for that scale?

Pilot Plant normally has many established Engineering controls for safety with alarms, suppression systems and hand extinguishers readily available. Clothing worn was not drastically different with lab coats or uniforms except hardhats/safety glasses were all mandated (and was strictly enforced well beyond lab). Gloves (nitrile-type mainly) and maybe rubber aprons, then face shields were used when connecting or adjusting values and the BuLi cylinders were placed behind a blast shield (lab type). One person always stood at distant watching and holding a fire extinguisher when handling the BuLi directly..

CMC guy's concluding comments:

A general remark, although it would seem obvious, in that Process Development/Scale-up pretty much always has inherent dangers because of the larger amounts involved and when utilize particularly hazardous agents this increases dramatically, therefore if some thing were to go wrong the potential damage would be much greater (however seen many new PhDs who have to be educated in this aspect because of bad habits picked up in grad school.)

Note that Costs correlates this same way as mistakes during scale-up can be extremely expensive so reinforces the overall awareness necessary. One hopes because of this risk factor process chemists become highly safety conscious in everything that they do but as it typically pertains to Pilot Plant Operations requirements create a very different environment from Labs. The basics distinctions between Lab vs. Scale-up arenas I would summarize as fall into Planning, Equipment, Personnel and Enforcement (of Policies).


  1. My workplace kilo lab has in the recent past worked with methyl lithium on very large scale. They closed off that end of the building to authorized personnel only. Multiple CO2 extinguishers lined the hallway and all personnel were in Tyvec suits and full respirators.

    All the chemists not involved in the transfer were peering into the room from adjacent rooms' windows waiting for fireworks while all the office staff took a long lunch. ;-) At least chemists can't complain their job is boring.

  2. Mad Chemist I had used/considered MeLi for a different project from the account above. Think we scaled to about 200-300g lab preps (probably your kilo lab equivelant) with MeLi (2-3x 1L bottles) but knew we could not implement in the Pilot Plant. Recall was not only issues of Safety (Et20 solvent in particular) but difficulty obtaining the MeLi in adequate quantity sizes/containers (no source in tanks) for operations as discussed above. Either the project died or we came up with alternate as it never went beyond the lab preps.