A well-written experimental protocol is one of the hallmarks of good process chemistry that we teach at Scientific Update in our Chemical Development course, so in this blog I thought I’d highlight an excellent example recently published in an open-access article by Nicholas Isley and Fabrice Gallou from Novartis (Helv. Chim. Acta 2023, 106, e202300143, doi.org/10.1002/hlca.20230143).
The paper describes a kilogram-scale Suzuki-Miyaura cross-coupling using micellar catalysis initially discovered by Bruce Lipshutz, and further refined and scaled-up by the team at Novartis to enable the implementation of more sustainable pharmaceutical manufacturing practices. The first half of the paper provides a clear summary of the benefits of the micellar catalytic technology which is performed predominantly in water, compared to conventional techniques that typically use either reproptoxic polar aprotic solvents, or ozone depleting chlorinated solvents. Many excellent references are cited in the paper for those who wish to learn more about the industrial implementation of the micellar approach. The concluding section of the paper is on environmental process metrics and just how superior the micellar approach is to the conventional approach when measured in terms of total mass of waste relative to the amount of desire product and also total carbon dioxide release, however I will focus this blog on the experimental write-up.
The first excellent feature of the experimental write-up is that it is for a kilogram-scale procedure. Depending on our perspective the terms ‘large-scale’ or ‘scale-up’ can mean different things, but as I was told by one of the kilo lab operators early in my industrial career: “it’s not scaled-up until you’ve put your chemistry in here”. The reason for this is that scale-dependent heat flow and mixing effects clearly start to manifest themselves once this scale is reached. We typically see these scale-up effects as negative or a challenge to be overcome, but they can be positive too. Indeed, in the paper the authors note “Advantage was taken of the superior mixing effect in production vessels which leads to improved and faster partitioning”.
I also learned quickly in my early industrial career that my academic style experimental write-ups were also completely inadequate in terms of detail and precision, especially when I used vague terms like “stir rapidly” or “add slowly”, so it’s great to see a published experimental write-up where these details are spelled out. For example, the authors provide details of the stirrer type (anchor) and stirrer rate throughout the reaction, especially that the rate needs to increase while adding the base to start the cross-coupling reaction. They specifically note “Deviation on the stirring rate could give rise to the formation of a less stable emulsion that will result in less performant exchanges and hence outcome of the reaction, or into longer time to demulsify the system during the work-up”. It is these types of notes that help the person implementing the process know where to focus their troubleshooting efforts if they encounter problems.
The experimental procedure in the main paper and the experimental procedure in the Supporting Information also include a number of observation notes that would be very helpful for someone performing the reaction for the first time. For example, the authors note how the appearance of the mixture changes from a slurry to a milk-like consistency as the reaction progresses, the different colors of the organic phases during the work-up, and that the residual surfactant after the reaction is predominately in the organic layers (not the aqueous layers, as I would have probably guessed). With the current global supply chain, it is these sorts of details that can help an operator on the other side of the world know whether the reaction is performing as expected, or if not, when in the process to start troubleshooting.
Finally, the procedure in the paper gives a level of detail about the work-up and product isolation that is unfortunately lacking in many published papers. Indeed, the work-up section is 50% longer than the section describing the reaction. Specific details include what temperature and pressure to remove the solvent, how much solvent needs to be removed before crystallization is expected, cooling rates for the crystallization, and the temperature and pressure in the vacuum oven to dry the final product.
That said, I still have some questions about the procedure, such as the ratio of activated charcoal/silica gel and Cellflock 40 that the crude product mixture is filtered through. However, my experience of handing over any procedure to the engineers and operators in the kilo lab or pilot plant was that they would have questions about details that I had glossed over, and that these questions ultimately made the procedure better and my experimental write-ups better too. Hopefully this paper from the Novartis team will help you too write better experimental procedures.
