Accelerating the development of new pharmaceuticals: Erik Regalado, the 2021 winner of the Emerging Leader in Chromatography Award

Published on: 
LCGC North America, April 2021, Volume 39, Issue 4
Pages: 194–196

Erik Regalado is a Principal Scientist in the Analytical Research and Development (AR&D) department at Merck Research Laboratories where he leads the Method Screening and Purifications group. His industrial research focuses on analytical and preparative enabling technologies for the development of new pharmaceuticals. He is studying automated methods, ultrafast and computer-assisted analysis, multidimensional chromatography, and many other methods. He is the 2021 winner of the LCGC Emerging Leader in Chromatography Award, which recognizes the achievements and aspirations of a talented young separation scientist who has made strides early in his or her career toward the advancement of chromatographic techniques and applications. He recently spoke to us about his current research and career.

In one of your publications in Science (1), Merck reported a miniaturized automation platform for nanomole-scale synthesis of pharmaceuticals combining the use of robotics with emerging liquid chromatography (LC) and mass spectrometry (MS)–based high-throughput analysis (HTA) techniques. This publication has drawn the attention of many laboratories across both academic and industrial sectors. Why was this research important to Merck and the pharmaceutical industry? What were the major analytical challenges you encountered in enabling this platform?

At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available, and timelines are tight. With this platform, more than 1500 chemistry experiments can be carried out in less than a day, using as little as 0.02 milligrams of material per reaction. At that point, analytical chemistry quickly became the bottleneck in this endeavor. Our team came up with an HTA methodology based on mixed-(multiple injections in a single experimental run) MISER LC–MS that enabled analysis of 1536 reactions in about 2.4 h. It was a very collaborative project among a multidisciplinary team of organic and analytical chemists, a phenomenal experience.

In other work you have carried out fundamental studies in ultrafast chiral separations, and reported new applications for high-throughput analysis (2) and 2D-LC (3), overcoming limitations of traditional approaches. Would you explain the significance and meaning of this work for the readers of LCGC?

Ultrafast chiral chromatography offers tremendous potential for high-throughput enantiopurity assays, with analysis time that is competitive with sensor-based analytical approaches, while providing great selectivity. At the time of this publication (2), investigations of high-speed chiral separations in the academia were quickly growing. However, most of those reports were fundamental in nature involving simple mixtures to prove a concept. We joined forces with academia to develop ultrafast chromatographic enantioseparations for a variety of complex pharmaceutically related drugs and intermediates, showing that sub-minute resolutions were possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed-phase LC (RPLC). Half of these chiral mixtures were separated in an impressive time window ranging from 5 to 20 s using readily available instrumentation without any modification. New applications were also introduced, illustrating how such methods can be routinely developed and used for ultrafast high-throughput analysis to enable enantioselective synthesis investigations and enzymatic processes.

In addition, our work laid the foundation for the use of ultrafast chiral chromatography as a second dimension of 2D-LC analysis (3). This paper introduced a variety of multiple achiral x chiral and chiral x chiral 2D-LC examples (single and multiple heart-cutting, high-resolution sampling, and comprehensive) using highly efficient chiral selectors (sub-2-μm fully porous and 2.7 μm fused-core particles) in the second dimension. This concept enabled the separation and analysis of complex mixtures of closely related pharmaceuticals and synthetic intermediates, including chiral and achiral drugs and metabolites, constitutional isomers, stereoisomers, and organohalogenated species.

You have also published a recent work that introduces multifactorial peak crossover (MPC) via computer-assisted chromatographic modeling to address challenging coelutions of critical pairs and poor chromatographic productivity of purification methods (4). How is this work important for industrial pharmaceutical laboratories? How do you envision MPC assisting a broader pharmaceutical analytical community?

MPC is a software-based technique that focuses on mapping the separation landscape of pharmaceutical mixtures to quickly identify spaces of peak coelution crossover, which enables one to conveniently switch the elution order of target analytes (4). We can gain massive productivity increases (shorter cycle time and higher sample loading) by simply moving a target peak from the tail to the front of an undesired component. MPC chromatography dramatically reduces the time spent developing productive analytical- and preparative-scale separations. This concept can also be used to improve signal-to-noise ratio substantially, enabling straightforward ppb detection of low-level target components with direct impact in the quantitation of metabolites and potential genotoxic impurities (PGIs).


What issues and problems would you define as previously ignored or neglected specifically in the field of new and important pharmaceutical analysis methods? What major developments do you see as important in automating screening methods, and in multidimensional chromatography? What is your vision for improvements that could be made in separation instrumentation, columns, data processing algorithms, or high-speed computing power?

Every day brings something new and different to these labs. Because Merck’s pipeline is very rich and diverse, it is important to upgrade our analytical toolkit constantly. Analytical chemistry is quickly becoming the bottleneck in the development of more complex targets. Certainly, pushing the boundaries of analytical innovation today will help us overcoming many of the pharmaceutical challenges of tomorrow. One of my current research projects focuses on the integration of modern automated screenings with computer-assisted modeling approaches to accelerate method development. Despite recent advances in this area, current multidimensional chromatography technology requires a series of arduous method development activities poorly suited for a fast-paced industrial environment. I believe that moving away from “guru dependency” is very important to our future success. Recent contributions are laying the foundation for systematic ways to facilitate method development through automated multicolumn 2D-LC screening (5) and computer-assisted optimization of 2D-LC separations (6), which are key in securing the viability of 2D-LC as a mainstay for industrial applications.

What were some of the key challenges you encountered during your work recently? What would you consider to be the most useful contributions of your work?

The development of novel and increasingly challenging process chemistries requires a commensurate level of analytical innovation to develop meaningful and reliable assays of reaction outcomes, with rapid data turnaround, to enable decision making toward the next round of experiments. The time constraints of developing robust quantitative methods prior to each processing step can easily lead to sample analysis becoming a bottleneck in synthetic route development. I found this extremely challenging, and in my view, it pushes you out of your comfort zone. Simply put, process chemistry and target molecules dictate the kind of analytical tool you will end up using, no matter your background or preferences. In this regard, our recent research on introducing new “generic or more universal” chromatographic workflows helped us tremendously to minimize the time spent developing new analytical assays, while also facilitating method transfer to manufacturing facilities and application in regulatory settings. Our recent review paper in Accounts of Chemical Research covers some of these breakthroughs (7).

What are some key aspects that motivate you? Would you share some of your work and organizational habits that have helped you be productive and successful professionally?

Everything gets easier when you find a meaningful purpose in life. I’ve accepted the fact that any innovation or invention comes with a risk of failure. Although I always try to make the right choices, sometimes I don’t succeed, but every day I get back up and move forward. Over the years, I became more disciplined and incorporated very good habits in my routine that help me to stay focused and eliminate distractions.

What can you share with our readers regarding your next area of interest for your research?

Pioneering measurement science to accelerate the development of new medicines and vaccines is my focus at MRL. I’m very interested in incorporating more automation and predictive algorithms to my routine, as well as feedback-controlled instrumentation. Artificial intelligence, machine learning, and deep learning advances are also capturing my attention.


(1) A. Buitrago Santanilla, E. L. Regalado, T. Pereira, K. Bateman, L-C. Campeau, S. Berritt, Y. Liu, M. Shevlin, Z-C. Shi, J. Voigt, J. Schneeweis, C. J. Welch, R. Helmy, P. Vachal, I. Davies, T. Cernak, and S. Dreher, Nanomole-scale high-throughput chemistry for the synthesis of complex molecules, Science 347(6217), 4953 (2015).

(2) C.L. Barhate, L.A. Joyce, A.A. Makarov, K. Zawatzky, F. Bernardoni, W.A. Schafer, D.W. Armstrong, C.J. Welch,and E.L. Regalado, Ultrafast chiral separations for high throughput enantiopurity analysis, Chem. Comm. 53, 509–512 (2017).

(3) C.L. Barhate, E.L. Regalado, N.D. Contrella, J. Lee, J. Jo, A.A. Makarov, D.W. Armstrong, and C.J. Welch, Ultrafast chiral chromatography as the second dimension in two-dimensional liquid chromatography experiments, Anal. Chem. 89(6), 3545–3553 (2017).

(4) I.A. Haidar Ahmad, V. Shchurik, T. Nowak, B.F. Mann, and E.L. Regalado, Introducing multifactorial peak crossover in analytical and preparative chromatography via computer-assisted modeling, Anal. Chem. 92(19), 13443–13451 (2020).

(5) H. Wang, H.R. Lhotka, R. Bennett, M. Potapenko, C.J. Pickens, B.F. Mann, I.A. Haidar Ahmad, and E.L. Regalado, Introducing Online Multicolumn Two-dimensional Liquid Chromatography Screening for Facile Selection of Stationary and Mobile Phase Conditions in both Dimensions, J. Chromatogr. A 1622, 460895 (2020).

(6) D.M. Makey, V. Schurik, H. Wang, H.R. Lhotka, D.R. Stoll, I. Mangion, E.L. Regalado, and I. Haidar Ahmad, Mapping the separation landscape in two-dimensional liquid chromatography: blueprints for efficient analysis and purification of pharmaceuticals enabled by computer-assisted modeling, Anal. Chem. (2021).

(7) E.L. Regalado, I.A. Hadar Ahmad, R. Bennett, V. D’Atri, A.A. Makarov, G.R. Humphrey, I. Mangion, and D. Guillarme, The emergence of universal chromatographic methods in the research and development of new drug substances, Acc. Chem. Res. 52(7), 1990–2002 (2019).

Erik Regalado, the 2021 winner of the Emerging Leader in Chromatography Award, is a Principal Scientist in the AR&D department at Merck Research Laboratories (MRL) where he leads the Method Screening and Purifications group. His industrial research focuses on analytical and preparative enabling technologies that accelerate the development of new pharmaceuticals, including automated method screenings, multidimensional chromatography, HTA, ultrafast and computer-assisted separations. Regalado completed a Postdoctoral Fellowship at MRL (2013-2015), received a PhD in Chemistry from the University of Havana (UH), Cuba in collaboration with the University of Nice Sophia Antipolis, Nice, France (2011), a Master of Science in Organic Chemistry (2007), and a Bachelor of Science in Chemistry (2003) from UH.

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