The synthetic route to an active pharmaceutical ingredient (API) used during discovery chemistry efforts is almost never the route used when larger quantities of material are required, such as when used to facilitate investigational new drug (IND)-enabling studies, supporting ongoing clinical trial work, etc. This is in no small part due to the pressures to synthesize novel, druggable molecules in a timely manner even if it means using expensive catalysts, complex chemical transformations unsuitable for larger scale, and using solvents that may remain in drug substances in unwanted concentrations. When the time comes, process chemistry teams must revisit the established synthetic route that was able to generate research quantities of API (i.e. grams) and reevaluate every step to result in a shorter, more robust synthesis that can generate multi-kilogram quantities. Typical goals are a synthetic route with fewer steps, increased overall yield, minimizing or eliminating chromatography steps and finding substitutes for expensive reagents among others. Process teams are increasingly relying on a high-throughput experimentation (HTE) approach for this task.
HTE can be generally thought of as performing multiple reactions in parallel in order to determine an optimal set of reaction conditions for a given chemical transformation. As more and more process groups within the pharmaceutical industry turn to HTE methodology, a set of latest “best practices and equipment” are becoming apparent and are the focus of this blog.
Recently, Steven Mennen (Drug Substance Technologies, Amgen) et al. published a review article in Organic Process Research and Development (https://pubs.acs.org/doi/10.1021/acs.oprd.9b00140) detailing how HTE is being used to answer chemistry questions surrounding key chemical transformations that are intended for scale up. Additionally, Mennen and coauthors provide an overview of equipment and consumables regularly found in process chemistry laboratories. When asked about reaction agitation/heating equipment found in HTE labs, a survey of 7 ‘Big Pharma’ groups and the HTE team at the University of Pennsylvania responded with V&P’s patented tumble stirring and specifically the VP 710E5X tumble stirrers used on many robotic systems as well as the Chemspeed VP 710CS-1 and the VP 710XC used in the Unchained/Freeslate Core Module. Tumble stirring of reaction blocks loaded with 1mL glass shell vials is the go-to methodology for HTE labs. The large and powerful rotating magnetic field of a V&P tumble stirrer ensures that mixing/agitation of all 96 wells is both uniform and strong. This is especially critical when reactions are heterogeneous and require robust mixing. Taking on the daunting task of optimizing a chemical reaction with say, 4 reactants and elevated temperature quickly becomes a series of literally hundreds of reactions that keep 1 variable constant while varying the others. The use of disposable glass shell vials (VP 580) as well as disposable stir elements make this task faster and more streamlined. The following is the body of an e-mail sent to us by a very satisfied Tumble Stirring customer.“Patrick-There is a long, official process (read: involves Legal department) for allowing endorsements of products with _______’s and/or my name. However, I would be happy to share my personal feedback to you. If you would like to refer this to anyone as unofficial information (i.e., “It came from someone in Process R&D in major Pharma.”), that would be great. At the least, you’ll see exactly why I love these stirrers.
Feedback for the Tumble Stirrers is this: enabling technology. I am now enabled to create reaction blocks and customize them to robotic systems with great ease. Why? The narrow deck height of the Tumble stirrers (even my larger strength units) combined with flexibility of alignment for the stirrers to the reaction vessels means I can use them almost anywhere.
The fact that I can use the same stirrer deck with any type/size of reactor simply by changing a mounting plate atop the stirrer deck gives me the kind of flexibility I require for parallel synthetic development of processes. That flexibility enables access to a wider range of projects (smaller scale) and a wider range of reaction conditions. I get more reactions per gram of starting material for evaluation of more diverse conditions, and I generate results faster because I run more of the experiments in parallel using the same amount of starting material. In one word, Tumble Stirring is enabling.
Oh, and the quality of agitation is fantastic for liquid-liquid mixes, slurries, or even oil suspensions.
Thanks again for this terrific product. D____.”
One of the case studies highlighted in the OPRD paper focused on the optimization of metalophotoredox catalysis. Therein, researchers screened 23 inorganic bases, 2 lewis acids and 2 solvents en route to optimizing an important chemical transformation. The use of 96-well Para-dox photoredox optimization blocks with 1mL glass vial inserts, VP 711D-1 stir bars and the associated drop dispenser, VP 711A-96-AS-1 greatly facilitated their reaction screening. The inexpensive VP 711D-1 Parylene coated stir element has quickly become the stir element of choice.
In a second case study, another V&P Scientific stir bar, the VP 775-20 was showcased and specifically highlighted as the optimal stir bar that afforded the best results. According to the authors:
The choice of stir bar was determined after mixing studies carried out in our laboratory that focused on a Bourne reaction as an example of mixing-sensitive reaction. On the basis of the outcome of those studies, we decided to employ this stir bar [VP 775-20] in all future project work carried out on our Freeslate Junior platform
Indeed, this testament is a great example of not only optimizing reagents and reaction conditions but also determining the stir bar that affords the best mixing. Given that researchers were running reactions in 8mL capacity vials filled to 4mL it became clear that a stir stick that stands upright in the vial and spans the length of the reaction solvent gave superior mixing when compared to a much smaller bar style stir element that stayed at the bottom of the vial.
As more and more HTE groups continue to use these important reaction throughput-facilitating methodologies, a set of best practices and indeed a gold standard is beginning to emerge. V&P Scientific tumble stirring, stir elements, heat blocks and related equipment are an integral part of that gold standard.
How can V&P Scientific help increase efficiencies and overcome obstacles in your lab?
