Automated Sampling for Chemical Reactions

Automated sampling is an approach used to overcome challenges associated with common laboratory sampling tools (such as pipettes and syringes), including accuracy, reproducibility and availability of personnel.

EasySampler is an automated and unattended sampling technology – delivering high-quality samples, day and night. This unique, patented probe-based technology has a micro-pocket, which:

• Takes samples at scheduled intervals
• Quenches the sample in-situ and at reaction conditions
• Dilutes the sample in preparation for offline analysis

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

Representative, reproducible results are achieved by:

• Sampling the same position in the reactor, at reaction conditions
• Samples are time stamped and can be integrated with results from offline analytical methods
• Increased data quality through automatic and seamless data collection
• Increased sampling accuracy and precision provides higher quality analytical results versus manual sampling

EasySampler's intuitive touchscreen allows scientists to preprogram sampling and dilution sequences to track reaction progression over time, without manual intervention. This allows chemists to understand key reaction mechanisms including pathway, kinetics, intermediates and impurity profiles.

Samples can also be taken as function of reaction parameters or attributes, including temperature, stirring, dosing, pH or other PAT related information. 

Seamlessly integrate with chemical reactors, including EasyMax, OptiMax, RX-10 or RC1 to identify the impact of process conditions on reaction events.

Traditionally, experiments were performed during regular work hours and therefore workflows were designed around the presence and availability of scientists,  leading to data blind spots and gaps in information and understanding.

EasySampler allows fit-for-purpose experimentation and improves the way scientists work, allowing collection of samples for offline analysis 24/7. This enables you to get accurate, reproducible and HPLC ready samples, which are already diluted to desired concentrations.

EasySampler automated sampling technology is convenient and easy to use, allowing for effortless planning and high quality samples.

Laboratories typically operate with intensity during the day, but slow down or shut down at night. Experiments are inefficiently scheduled as scientists must be present to take samples or change process variables.

A scientist's workflow can be optimized from end-to-end using platform technologies that eliminate non-value added tasks and manage the data that is collected. Experiments can be scheduled around the clock and samples taken automatically at any time. Data is collected for every single experiment and can be automatically stored and shared according to the needs of the organization. 

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

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

Sampling multiphase and slurry chemical reactions is tedious as these are highly viscous, heterogeneous mixtures. With EasySampler, these reactions can be sampled, even under challenging and changing reaction conditions. 

Highly reactive chemistry, viscous and slurry reaction mixtures, toxic and hazardous substances are quite difficult to handle when it comes to sampling. EasySampler's unique micro-pocket is designed to take samples from a wide range of reactions, in an automated and unattended manner.

Sample chemical reactions in an easy and safe way. EasySampler is exposed to chemistry, not you. 

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. EasySampler eliminates manual handling and exposure to hazardous chemicals, reducing risks and improving user safety.

Bring your R&D studies to the next level of understanding and catalyze your research with automated and unattended chemistry sampling solutions. 

Reactions with atmospheres from inert gas for air and water-sensitive chemistries to pressurized reactions, such as hydrogenation reactions, are very difficult to sample. Studying these types of reactions is tedious and time-consuming, unless you employ automated and unattended EasySampler technology. The micro-pocket technology is immersed in the liquid phase and effortlessly takes samples under various reaction conditions. 

Building an understanding of how a reaction works helps identify the best synthetic route and supports the development of the best process in the shortest amount of time.

Chemical synthesis reactors integrate seamlessly with in-situ probes, including EasySampler, ReactIR and ReactRaman. The consolidated data stream of reaction parameters together with the information on kinetics, reaction mechanisms and impurity profiles provides critical answers when developing processes from lab-to-plant. The integrated solution enables scientists to deliver life-changing products faster and more cost-efficiently.

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.

• Kukor, A. J., Guy, M. A., Hawkins, J. M., & Hein, J. E. (2021). A robust new tool for online solution-phase sampling of crystallizations. Reaction Chemistry & Engineering. Published. https://doi.org/10.1039/d1re00284h
• 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
• 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
• Chemical Reaction Kinetics
• DoE Studies
• Synthesis Reactions
• Flow Chemistry
• High Pressure Reactions
• Hydrogenation Reactions
• Quality by Design