Wednesday, October 12, 2011

Process Wednesday: "The Safe Use of Sodium Hydride on Scale"

A recent Organic Process Research and Development paper from Merck Process [1] talks about something that I've heard about, but never had the opportunity to use: metal hydride reagents contained in sealed bags. The bags dissolve in solution, allowing the material to be handled in a relatively safe matter. To wit:
The risk of ignition during the addition of NaH to the reactor was eliminated by using NaH in dissolvable bag packaging (SecuBags) from Chemetall Foote Corp. The risks associated with waste disposal of unused NaH were also eliminated since the bags were purchased in premeasured quantities; the entire bag was used in the reaction. 
The authors describe a chloropyrimidine displacement using an unnamed alcohol with the bagged sodium hydride (60% in an oil dispersion) and MeTHF at reflux; they used a mass spectrometer in line with the reactor to monitor hydrogen off-gassing. The authors also cover the quenching of the sodium hydride with 4% wet MeTHF, analysis of the product and analysis for remnants of the bag in the product:
The SecuBag is made of styrene-butadiene-styrene (SBS) block copolymers. To ensure the SecuBag was sufficiently removed during the filtration, analytical methods were developed to rest for residual SecuBag and styrene in the isolated product. An analytical method that was developed to monitor residual SecuBads polymer used size exclusion chromatography with UV detection at 215 nm... The batch samples contained SecuBags polymer in the range of 120-250 ppm with respect to total weight of the sample analyzed, which was well below the ICH recommended level of 1000 ppm.  
...[regards to potential styrene in the product] Analysis of a concentration of 0.1 g/mL for pyrimidine 3 with a detection limit of 5 ppm styrene demonstrated that styrene was not detectable in any of the four batches produced by the described process. 
I suppose I'm a little bit surprised that there's still a little bit of the polymer from the bag in the product, but apparently there's not much harm and it's still well within regulatory specifications. [Presumably, downstream processing would take care of it?]

Sounds neat -- now I want to try it.

[1] McCabe Dunn, J.M.; Duran-Capece, A.; Meehan, B.; Ulis, J.; Iwama, T.; Gloor, G.; Wong, G.; Bekos, E. Org. Process. Res. Dev. ASAP. DOI: 10.1021/op200114t


  1. Ummm....why not switch to PLGA/PLA and a basic wash??
    SBS is not something I want just "hanging around."

    This might be why regular people hate chemistry.

  2. @anon: polyesters might not have sufficient stability to withstand NaH, LAH and their hydrolysis products on long-term storage. I know for example that plexiglass (PMM) rapidly degrades by gaseous NH3. If residual polystyrene-co-butadiene carries over into the product they can incorporate filtration through charcoal or C18 silica cartridge to take care of the problem. But my guess is that a crystallization one step further along the synthetic route will remove it too

  3. It is neat technology especially doing at plant scale which did about 20 years ago at 1.5 kg NaH. I don't recall that we did a check for styrene in final product because was very early in the process and believe was a limit established on an intermediate. Converse to comment 1 we had an acid group in the intermediate so took product into aqueous layer and back washed (EtOAc?) which appeared to effectively extract out bag polymer by-product. I also saw used with LAH and tBuOK as means to introduce in large scale reactors. These were good lessons on how different doing things on the bench verses in pilot or manufacturing realms.

  4. Handling NaH in bags is a very wise precaution, especially on scale. Twice in my career I've had sodium hydride inflame spontaneously on me. The form doesn't seem to matter - the second time the reagent was as a 60% dispersion in mineral oil, which is normally considered safe.

  5. milkshake: In my limited experience with these bags, yes crystallization from an organic solvent is usually enough to get the polymer impurity level to something reasonable. And as Anonymous 2 said, if the step is early, it's pretty reasonable to expect the polymer to be completely gone after another couple of crystallizations downstream.

  6. Polyester's electrophilic carbonyl groups would likely show cross reactivity with the types of reactions you would use NaH for, i.e. deprotonating some species to generate a more powerful nucleophile.

    I'm a little confused by that first comment. Why would the use of SBS be a big issue if you can show that it is removed sufficiently in this and/or downstream steps? Why would its mere use engender "hatred" of chemistry from regular people?

    I would bet if you go through any manufacturing process for any pharmaceutical it is littered with "toxic" substances (solvents, reagents, etc.) that someone not versed in the art of chemistry would freak out about.

    Knowledge of process controls coupled with analytical analysis are extremely powerful tools for ensuring paient safety (when applied correctly). As mentioned in above comments, I would expect this to be no different for SBS.

  7. I want to really thank every one of the commenters here; it's really a great way to learn process chemistry.

    Any advice/requests for me to make this better?