Automation Technologies to Enable Data-Rich Experimentation: Beyond Design of Experiments for Process Modeling in Late-Stage Process Development

Abstract

Automated reactor and sampling technologies were used in process characterization studies of a cyclization reaction using gaseous ammonia. These data-rich experiments were structured according to a 2 4 full factorial design of experiment, with each experiment having 12 reaction samples at equal time intervals. Data-driven models were established for key reaction responses to create a process fingerprint, to identify the optimal operating conditions under various constraints, and to evaluate the stability of the process. Leveraging these technologies in late-stage reaction characterization enabled significant improvements in efficiency and experimental reproducibility compared to conventional methods.

Comparative Evaluation of Light‐Driven Catalysis: A Framework for Standardized Reporting of Data**

“…In addition, concepts for autonomous reaction discovery are currently being developed and could become available for catalysis research. [125][126][127][128] In this context, the use of continuous reactors together with online and in situ analytics will be essential for implementing these approaches in catalytic laboratories. [12] A direct link between high-throughput experiments to databases will then allow the large number of data recorded to be harnessed, enabling comprehensive evaluation, comparison, and correlation.…”

Automation isn't automatic

“…11). 29 Here, the use of DoE reduced the experimental throughput, allowing for experimental execution via a Mettler-Toledo Auto Chem EasyMax reactor outfitted with an EasySampler module. The final consideration is analysis of experimental outcomes.…”

“…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. This is due to the different reactor volumes, as well as liquid and solid handling modules, that become inaccurate for small scales (1µL ± 5 µL) or take too much time for large scales (a 1 mL syringe dispensing 2 L solvent is simply unreasonable).…”

“…These millimole-scale automated reactors allow for overhead stirring, which becomes especially important in reactions sensitive to mixing efficiency, such as heterogeneous reactions. 29 3.…”

“…Some automated workflows mirror the set of operations familiar to bench chemists: dispensing of solids, followed by liquids, followed by specialty gas delivery, if applicable. 29,32,33 However, parallelized micromole-scale workflows typically involve the automated dispensing of stock mixtures. Boga and Christensen at Merck implemented the latter method in their automated strong base screening workflow (Fig.…”