Automated Sampling for Chemical Reactions

Automated sampling enables increased productivity by addressing challenges associated with manual sampling tools such as pipettes and syringes. Automated sampling with EasySampler is the intuitive and seamless extension that streamlines the experimental workflow for every chemist while liberating personnel from the tedium of manual sampling.

EasySampler is an automated and unattended sampling solution – delivering high-quality samples day and night for standard offline analysis, such as HPLC. This unique, patented probe-based technology has a micro-pocket, which:

• Samples and quenches in-situ and at reaction conditions
• Takes samples at scheduled intervals
• Dilutes the sample in preparation for offline analysis
• Does not require expert knowledge to operate

The obligations of the workday (or night) often do not allow sampling of reactions as often as required. This leads to lost or missing data. Frequently, these missing data points omit optimum end-point and important understanding of impurity formation. EasySampler executes representative and reproducible sampling including in-situ quench and dilution – providing LC-ready samples at any time.

Automated sampling with EasySampler enables scientists to optimize their workflow and productivity by enabling increased reaction understanding while eliminating tedious manual sample practices. For even further productivity gains, sampling can be automatically scheduled or triggered as a function of varying process parameters including temperature, stirring, dosing, pH or other real-time process information.

EasySampler's intuitive touchscreen allows scientists to preprogram sampling and dilution sequences to track reaction progression over time – without manual intervention. This allows every scientist to reproducibly capture a representative sample for offline analysis such as HPLC or NMR to understand reaction pathways, kinetics, intermediates and impurity profiles.

Automated sampling with EasySampler can be used in round bottom flasks, jacketed lab reactors or seamlessly integrated with automated chemical reactors, such as EasyMax and OptiMax. This allows straightforward identification of the impact of varying process conditions on reaction performance. 

Manual sampling does not always provide precise and reproducible samples, especially in heterogeneous and multiphase reactions or reactions at sub-ambient or elevated temperatures and pressures. Delays in quenching typically lead to variable results and inaccurate analytical information. EasySampler provides an automated and robust inline method of capturing and quenching samples from reactions – even under difficult conditions.

The flexible nature of EasySampler allows scientists to obtain high-quality samples from a variety of processes from vial- to kilo-scale equipment including pressure vessels.

Automated sampling is a key enabler for reaction understanding as it eliminates sampling error and ensures that offline analytical results truly represent the reaction as it exists under process conditions.

Representative, reproducible results are achieved by:

• Sampling from the same position in the reactor, at reaction conditions
• Samples are time stamped which circumvents errors caused by variances in recordkeeping. Data can be easily combined with results from inline PAT-based analytical methods.
• Increased number of samples and data quality through automatic and seamless data collection supports data-rich experimentation

When working in the laboratory, scientists are potentially exposed to hazardous chemicals and are at risk of injury. When taking samples manually using traditional sampling tools, the operator needs to open the reactor and can be exposed to toxic materials at elevated temperatures or pressures. EasySampler reduces the need for manual handling and exposure to hazardous chemicals, reducing risks and improving user safety.

This paper reviews the advantages of automated sampling and four case studies testing the application of EasySampler at Pfizer for impurity and kinetics profiling as follows:

1. Impurity and kinetics profiling in an Ullman reaction
2. Measuring the effect of process parameters on an imidazolide reaction
3. Endpoint detection in a C-H activation reaction
4. Scale-up of an amination reaction

EasySampler combines three sampling steps into one single automated operation, sampling the same way every time to provide reproducible and accurate samples.

• Accurate sampling starts when the micro-pocket moves out and is immersed within the reaction mixture to ensure a representative sample is taken
• In-situ quench immediately stops the reaction and ensures the time point is representative
• Subsequent dilution and dispensing in the vial prepares samples for offline analysis  

These steps allow samples to be highly reproducible and provide representative analytical results. Above all, automated samples can be taken at preprogrammed or scheduled times. 

Continued automated sampling with the EasySampler supports reaction and impurity profiling studies. A list of publications from peer-reviewed journals focuses on exciting and novel applications of EasySampler by researchers in both academia and industry to support data-rich experimentation to advance their research.

• Lomont, J. P., Ralbovsky, N. M., Guza, C., Saha-Shah, A., Burzynski, J., Konietzko, J., Wang, S.-C., McHugh, P. M., Mangion, I., & Smith, J. P. (2022). Process monitoring of polysaccharide deketalization for vaccine bioconjugation development using in situ analytical methodology. Journal of Pharmaceutical and Biomedical Analysis, 209, 114533. https://doi.org/10.1016/j.jpba.2021.114533
• Ashworth, I. W., Frodsham, L., Moore, P., & Ronson, T. O. (2021). Evidence of Rate Limiting Proton Transfer in an SNAr Aminolysis in Acetonitrile under Synthetically Relevant Conditions. The Journal of Organic Chemistry. https://doi.org/10.1021/acs.joc.1c01768
• Pollack, S. R., & Dion, A. (2021). Metal-Free Stereoselective Synthesis of (E)- and (Z)-N-Monosubstituted β-Aminoacrylates via Condensation Reactions of Carbamates. The Journal of Organic Chemistry, 86(17), 11748–11762. https://doi.org/10.1021/acs.joc.1c01212
• Zhao, X., Webb, N. J., Muehlfeld, M. P., Stottlemyer, A. L., & Russell, M. W. (2021). Application of a Semiautomated Crystallizer to Study Oiling-Out and Agglomeration Events—A Case Study in Industrial Crystallization Optimization. Organic Process Research & Development, 25(3), 564–575. https://doi.org/10.1021/acs.oprd.0c00494
• Jurica, J. A., & McMullen, J. P. (2021). Automation Technologies to Enable Data-Rich Experimentation: Beyond Design of Experiments for Process Modeling in Late-Stage Process Development. Organic Process Research & Development, 25(2), 282–291. https://doi.org/10.1021/acs.oprd.0c00496
• Malig, T. C., Yunker, L. P. E., Steiner, S., & Hein, J. E. (2020). Online High-Performance Liquid Chromatography Analysis of Buchwald–Hartwig Aminations from within an Inert Environment. ACS Catalysis, 10(22), 13236–13244. https://doi.org/10.1021/acscatal.0c03530
• Malig, T. C., Tan, Y., Wisniewski, S. R., Higman, C. S., Carrasquillo-Flores, R., Ortiz, A., Purdum, G. E., Kolotuchin, S., & Hein, J. E. (2020). Development of a telescoped synthesis of 4-(1H)-cyanoimidazole core accelerated by orthogonal reaction monitoring. Reaction Chemistry & Engineering, 5(8), 1421–1428. https://doi.org/10.1039/d0re00234h
• Wang, K., Han, L., Mustakis, J., Li, B., Magano, J., Damon, D. B., Dion, A., Maloney, M. T., Post, R., & Li, R. (2019). Kinetic and Data-Driven Reaction Analysis for Pharmaceutical Process Development. Industrial & Engineering Chemistry Research, 59(6), 2409–2421. https://doi.org/10.1021/acs.iecr.9b03578
• Beutner, G. L., Coombs, J. R., Green, R. A., Inankur, B., Lin, D., Qiu, J., Roberts, F., Simmons, E. M., & Wisniewski, S. R. (2019). Palladium-Catalyzed Amidation and Amination of (Hetero)aryl Chlorides under Homogeneous Conditions Enabled by a Soluble DBU/NaTFA Dual-Base System. Organic Process Research & Development, 23(8), 1529–1537. https://doi.org/10.1021/acs.oprd.9b00196
• Huffman, M. A., Fryszkowska, A., Alvizo, O., Borra-Garske, M., Campos, K. R., Canada, K. A., Devine, P. N., Duan, D., Forstater, J. H., Grosser, S. T., Halsey, H. M., Hughes, G. J., Jo, J., Joyce, L. A., Kolev, J. N., Liang, J., Maloney, K. M., Mann, B. F., Marshall, N. M., & McLaughlin, M. (2019). Design of an in vitro biocatalytic cascade for the manufacture of islatravir. Science, 366(6470), 1255–1259. https://doi.org/10.1126/science.aay8484
• Mennen, S. M., Alhambra, C., Allen, C. L., Barberis, M., Berritt, S., Brandt, T. A., Campbell, A. D., Castañón, J., Cherney, A. H., Christensen, M., Damon, D. B., Eugenio de Diego, J., García-Cerrada, S., García-Losada, P., Haro, R., Janey, J., Leitch, D. C., Li, L., Liu, F., Lobben, P. C., MacMillan, D. W. C., Magano, J., McInturff, E., Monfette, S., Post, R. J., Schultz, D., Sitter, B., Stevens, J. M., Strambeanu, I. I., Twilton, J., Wang, K., & Zajac, M. A. (2019). The Evolution of High-Throughput Experimentation in Pharmaceutical Development and Perspectives on the Future. Organic Process Research & Development, 23(6), 1213–1242. https://doi.org/10.1021/acs.oprd.9b00140
• Carter, H. L., Connor, A. W., Hart, R., McCabe, J., McIntyre, A. C., McMillan, A. E., Monks, N. R., Mullen, A. K., Ronson, T. O., Steven, A., Tomasi, S., & Yates, S. D. (2019). Rapid route design of AZD7594. Reaction Chemistry & Engineering, 4(9), 1658–1673. https://doi.org/10.1039/c9re00118b
• Zawatzky, K., Grosser, S., & Welch, C. J. (2017). Facile kinetic profiling of chemical reactions using MISER chromatographic analysis. Tetrahedron, 73(33), 5048–5053. https://doi.org/10.1016/j.tet.2017.05.048
• Gurung, S. R., Mitchell, C., Huang, J., Jonas, M., Strawser, J. D., Daia, E., Hardy, A., O’Brien, E., Hicks, F., & Papageorgiou, C. D. (2016). Development and Scale-up of an Efficient Miyaura Borylation Process Using Tetrahydroxydiboron. Organic Process Research & Development, 21(1), 65–74. https://doi.org/10.1021/acs.oprd.6b00345
• Rougeot, C., Situ, H., Cao, B. H., Vlachos, V., & Hein, J. E. (2017). Automated reaction progress monitoring of heterogeneous reactions: crystallization-induced stereoselectivity in amine-catalyzed aldol reactions. Reaction Chemistry & Engineering, 2(2), 226–231. https://doi.org/10.1039/c6re00211k
• Duan, S., Place, D., Perfect, H. H., Ide, N. D., Maloney, M., Sutherland, K., Price Wiglesworth, K. E., Wang, K., Olivier, M., Kong, F., Leeman, K., Blunt, J., Draper, J., McAuliffe, M., O’Sullivan, M., & Lynch, D. (2016). Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling. Organic Process Research & Development, 20(7), 1191–1202. https://doi.org/10.1021/acs.oprd.6b00070
• Malig, T. C., Koenig, J. D. B., Situ, H., Chehal, N. K., Hultin, P. G., & Hein, J. E. (2017). Real-time HPLC-MS reaction progress monitoring using an automated analytical platform. Reaction Chemistry & Engineering, 2(3), 309–314. https://doi.org/10.1039/c7re00026j
• Nykaza, T. V., Ramirez, A., Harrison, T. S., Luzung, M. R., & Radosevich, A. T. (2018). Biphilic Organophosphorus-Catalyzed Intramolecular Csp2–H Amination: Evidence for a Nitrenoid in Catalytic Cadogan Cyclizations. Journal of the American Chemical Society, 140(8), 3103–3113. https://doi.org/10.1021/jacs.7b13803

• Impurity Profiling
• Parallel Synthesis
• Organometallic Synthesis and Chemistry
• C-H Activation Reactions
• Chemical Reaction Kinetics
• DoE Studies
• Synthesis Reactions
• Flow Chemistry
• High Pressure Reactions
• Hydrogenation Reactions
• Quality by Design