Wednesday, December 4, 2013

Process Wednesday: Merck's prep-scale safety review

From the Organic Process Research and Development ASAP stream, a overview of Merck's internal reviews for safety at prep scale [1] (as defined as 500 grams to 5 kilograms). It partially stemmed from an incident with a serious hand injury with a diazonium salt: 
In 2009, the decision was made to formalize this process to complement the Pilot Plant review and better ensure the safety of all chemists running reactions on prep lab scale. An additional element of the new review process was a formal Hazardous Reaction Review, which applied to a much smaller scale than that employed in the prep laboratories. The necessity of this component was realized when a senior-level scientist in the department incurred a serious hand injury upon isolating a diazonium salt on less than 5 g scale.1  
1. The published procedure he was following was somewhat ambiguous, only specifying not to use a metal spatula, with no indication of the serious hazards of isolating the diazonium salt. While scraping the material on the fritted funnel with a Teflon spatula, the material exploded, leaving the chemist with multiple lacerations requiring sutures to mend and nerve damage requiring surgery to fix.
The process to go to prep scale seems fairly methodical:
Prep lab scale is defined as reactions run in a vessel >5 L, even if the actual reaction volume is less. Note that the largest vessel size available for Merck prep lab use is 100 L. All prep lab scale experiments that involve a chemical reaction are covered by this policy. The policy requires the chemist to do the following prior to running the reaction: 
(a) Discuss with supervisor.
(b) Complete a “Paper Assessment”: Consult literature, Bretherick’s,3 MSDSs. Consider reaction type, functional group instabilities, known hazards.
(c) Chemistry Assessment: Complete probe reactions, documenting exotherms, addition times, cooling used,
workup procedures, etc.
(d) Acquire Differential Scanning Calorimeter (DSC) data on starting material(s) and product(s).4
(e) Submit completed “Reaction Review and Approval Form”.
(f) Obtain approval from both one SAC (Scientific Advisory Committee) designee and one EPSE (Environmental and Process Safety Engineering) designee before performing the experiment.
The authors note that they've found little delay using this process, with only one day's further testing on average. (They also note that more hazardous reactions have required longer turnaround times, which is understandable.)

The authors included some case studies with IBX, azide reactions and one (rather frightening-looking) decarboxylation, where an alternate route was found. Also, an example of a Blaise reaction, where the key to avoiding a runaway reaction was to look for reaction initiation, and not keep slowly adding starting material, if the chemist was not sure that the reaction had started:
A chemist experienced a runaway reaction at small scale when carrying out a Blaise reaction. EPSE found that this runaway can be easily reproduced if the bromoester is added rapidly. Calorimetry testing with slow addition showed that the decomposition was unusually vigorous, with an adiabatic ΔT of ∼200 K, and that there can be a delayed and autocatalytic initiation of the desired reaction. Approval was given to run this reaction on prep lab scale with the following provisions to prevent an overly vigorous delayed initiation: 
(1) After 3% of the acetate has been added, assay the batch for both consumption of starting material and formation of product (no quantitative assay was available for the intermediate). Do not add more acetate until confirming that the desired chemistry has been initiated.
(2) Repeat after the addition of acetate is 10% complete, and again after it is 40% complete.
(3) For deployment at pilot plant and manufacturing scale, investigate use of online instrumentation to monitor the reaction.
The last note I'll make about this paper is an interesting observation that I had not heard about aluminum pans in DSC measurements:
For safety screening, a special DSC cell that can withstand a significant amount of pressure is used. The standard crimped Al pan may leak at relatively low pressure, enabling the volatile components generated to escape the system. However, when a very rapid exothermic decomposition occurs at larger scale, the gases will often not have time to escape the system (even if it is not rated for pressure) before the remaining reaction mixture further reacts at higher temperature, which can lead to additional heat and pressure generation. In order to best balance resources and expertise, two to five chemists per research site were trained to run DSCs with the special cells. These cells are made of Hastelloy C rather than Al, as Al
reacts with many chemicals, thereby generating false positive or false negative results.
I don't think our pans are aluminum, but I had not heard that aluminum pans can deliver false positives or negative. Huh.

All in all, a worthwhile read.

1. Bassan, E.,Ruck, R.T.; Dienemann, E.; Emerson, K.M.; Humphrey, G.M.; Raheem, I.T.; Tschaen, D.M.; Vickery, T.P.; Wood, H.B.; Yasuda, N. "Merck’s Reaction Review Policy: An Exercise in Process Safety." Org. Process. Res. Dev., 2013, ASAP. doi:


  1. Diazonium salts are generally well behaved if the counterion is BF4, but with halogens you do tend to get the explosions and they are easier to explode on a larger scale. The BF4 counterion allows even for the measurement of melting points.

  2. Not having access to the article do they mention a time-frame when this Merck review process was instituted? I would be very surprised if this covers recent vintage work based on perceived strength of Merck Process (which has been greatly reduced in recent years so suspect this may be a "resume padding exercise" publication?).

    Pharma sometimes lags behind but I am aware traditional Chemical and Petroleum companies do this routinely. When I started in Pharma process over 25 years ago this type of fundamental safety assessment was pretty much SOP I believe at most large companies (where I worked or had friends) and often many small CMOs/Vendors (at least in US and EU that I dealt with). If DSC gave any hints of dramatic transitions there might be further experiments required before going into PP, fortunately we had access to a specialty lab that could do sophisticated experimentation (calorimetry bombs etc). This type mindset should always be the first and continuous lesson for Process Chemists.