A Perspective on the Analytical Challenges Encountered in High-Throughput Experimentation

Abstract

High-throughput experimentation (HTE) is a well-established technique used in the pharmaceutical industry to accelerate compound synthesis and route optimization through automated chemical processes. A key part of any HTE workflow is the analytical component, through which the reaction outcome can be determined. The development of new analytical techniques capable of high-throughput data generation from nanoscale chemical reactions has been required to streamline the HTE process and address challenges generated through the recent move to miniaturize synthesis. In this Perspective, we review the currently available state-of-the-art analytical methods, discuss the challenges encountered in high-throughput analysiswith a particular focus on the analysis of nanoscale reactions, and provide a future outlook on potential developments in the field.

Automation isn't automatic

“…Increased throughput is a popular appeal of automation and no other area of chemistry automation has gained as much traction in recent years as HTE. 22 HTE platforms push the limit of what is humanly possible to somewhere between 96 and 1536 reactions per day. 7,13,23,24,25 HTE in 96-well plates is typically carried out in semi-automated fashion on micromole scale, leveraging chemical libraries dispensed through automation, with experimental execution carried out through manual pipetting.…”

“…An example is acoustic ejection pipetting, a technique capable of multiple single digit nanoliter volume dispensing steps per second. 22 Due to those restrictions most automated experiments are carried out on the micromole 7,13,23,24,26 or millimole scale . 8,29 One interesting concept would be to add "scale" as a factor to the multi-categorical screening, but in practice most automated experimentation equipment cannot handle both nanomole and millimole scale reactions.…”

“…13). 22,30,31 In process chemistry applications, chemists sometimes prefer to carry out automated experiments in larger scale automated reactors such as Mettler-Toledo Auto Chem EasyMax reactors in order to mimic pilot plant reactor geometries. These millimole-scale automated reactors allow for overhead stirring, which becomes especially important in reactions sensitive to mixing efficiency, such as heterogeneous reactions.…”

“…12 shows a comparison of the suitability of analytical techniques for high-throughput systems, and an in-depth discussion of automated sampling and analytics follows in Section 4. 22 …”

Rxn Rover: automation of chemical reactions with user-friendly, modular software

“…Indeed, the pharmaceutical industry has taken the lead in developing and applying high-throughput, automated hardware and software to advance drug discovery and synthesis. [7][8][9][10][11][12][13][14][15] While these advances have enabled significant improvements in time to solution, safety and reproducibility, the cost of this specialized instrumentation is well out of reach of most research groups. There is a need for delivering affordable and accessible automation solutions to these groups.…”