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Miniaturization of Columns in Chromatography

Dr. Milton Lee, Professor of Chemistry in the Depart­ment of Chemistry and Biochemistry at Brigham Young University, talks to AZoM about the miniaturization of columns in chromatography and what the future may hold for this technology in separation science.

Please can you give us a brief overview of the miniaturization of columns in chromatography?

The miniaturization of columns in chromatography originated with the theoretical work of Marcel Golay on open tubular columns in gas chromatography in the late 1950s. Until that time, columns packed with various types of particles were used exclusively. While even today packed columns still provide higher efficiencies per unit length compared to open tubular columns, they cannot be utilized in lengths much longer than a meter because of the significant pressure drop along the length of the column. In contrast, open tubular columns are “open” and, even though they have small diameters (i.e., 100 – 500 micrometers), they can be used in lengths anywhere from several meters to approximately 100 meters before back pressure becomes a problem. Since performance (i.e., theoretical plates) improves with the length of the column, open tubular columns have become the column type of choice. Packed capillary columns for liquid chromatography were first reported in the mid to late 1970s. The first micro-fabricated column for gas chromatography was reported in 1979; however technological problems and limited performance have so far hindered its widespread commercialization and use. On the other hand, packed microfabricated liquid chromatography columns have been much more successful.  

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What have been the main key drivers behind the miniaturization of columns and why?

The key drivers are (1) improved column efficiency and (2) easier coupling to mass spectrometry. In the case of gas chromatography, columns can be made long for improving efficiency as described above. In the case of liquid chromatography, very small particles (< 3 micrometers diameter) and high pressures (> 10,000 psi) can be used for improving efficiency (small columns dissipate frictional heat readily). Small columns in both gas chromatography and liquid chromatography reduce the load on the mass spectrometer vacuum system.

How has the development of simpler coupling of chromatography to mass spectrometry improved the research in separation sciences?

This has had tremendous impact in separation science. Mass spectrometry is the most desirable detector for chromatography. Miniaturized columns reduce vacuum pump requirements, improve separation efficiency, accommodate very small samples (especially important in biomedical applications) and improve detection limits.

What specific breakthroughs in gas chromatography influenced the miniaturization of columns?

The most significant breakthrough was the invention of flexible fused silica columns in 1979. Additional advances in column surface deactivation, immobilization of the stationary phase on the capillary wall, and improving the thermal stability of stationary phases have all been important.

What have been the most critical developments in liquid chromatography?

A wider variety of improvements have contributed to the success of liquid chromatography compared to gas chromatography. These include smaller particles, more uniform particles, more stable stationary phases, improved bed structure (i.e., more uniform packing across the column diameter and along the column length), higher pump pressure (up to 20,000 psi), very uniform (reproducible) low flow rates (nanoliters to microliters per minute), and improved coupling to mass spectrometry.

How has the development of supercritical fluid chromatography (SFC) contributed to improved column technology?

Supercritical fluid chromatography forced the development of more robust column technology. Specifically, immobilization of the stationary phase in the column directly improved column technology for all chromatographic techniques. Columns had to be stable under high temperatures, elevated pressures, and with solvating mobile phases.

Why have efforts to incorporate chromatographic separation channels in microfluidic platforms been relatively slow to progress?

There are a number of issues that have contributed to the slow growth of microchip gas chromatography: (1) non-cylindrical channels, (2) shorter channels, (3) column temperature control, and (4) coupling of the chip to injector and detector. A non-cylindrical channel is difficult to coat evenly with stationary phase because of pooling of the stationary phase in areas of greater curvature. Since separation efficiency is related to column length, lower efficiencies are inherent with microchip columns (< 10 meters). Resistive heating is the logical choice for microchip gas chromatography; however, approaches are not easily available and upper temperatures are limited. Integrated injectors and detectors are needed for microchip gas chromatography to be successful; however, this has been difficult to date. Except for some limited applications with thermal trapping/desorption and thermal conductivity detection, integrated systems are generally rare.

What are your first hand experiences in developing column technology for chromatography?

One of the main areas of focus of my research group for over 39 years has been column technology for capillary separation techniques. We started with capillary gas chromatography, and moved into supercritical fluid chromatography, capillary electrophoresis, and liquid chromatography. We have worked on column deactivation, stationary phase immobilization, monolith development, and synthesis of new stationary phases.

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Where do you think the future opportunities are for improved chromatographic performance?

I believe that gas chromatography, as it exists today, needs considerable renovation. The air convection oven is old technology that should be replaced with some form of resistive heating technology. Gas chromatography can be considerably reduced in size without sacrifice in performance and, perhaps, with improved performance. Column technologies that don’t require such high pressures as needed for the 1.7 micrometer particle packed columns would be a major advance (core-shell particles, monolithic stationary phases, pillar-array columns, and slip-flow columns are movements in this direction). I am also a proponent of hand-portable instrumentation that can be taken to the sampling location for immediate analysis (as opposed to bringing the sample to the laboratory), which would lead to less tracking documentation, better preservation of sample integrity, better quality results and more timely response time.

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Where can our readers learn more?

The abstract for my 2016 Pittcon talk is as follows: Miniaturization of columns in chromatography began with gas chromatography (GC) and continued steadily over the past half century. The main driving forces have been prospects for increasingly higher chromatographic resolution and simpler coupling of chromatography to mass spectrometry (MS). Major breakthroughs in GC include flexible fused silica columns, robust column deactivation methods, high viscosity stationary phases, understanding of Raleigh instability, rapid static coating, free-radical crosslinking, and thermally stable stationary phases. In liquid chromatography (LC), developments in small particle morphology and uniformity have been most critical, with optimized packing methods following close behind. Development of supercritical fluid chromatography (SFC) introduced its own unique requirements that contributed to improvements in column technology for the other chromatographic techniques as well. Although continually exciting to consider, efforts to incorporate chromatographic separation channels in microfluidic platforms have been relatively slow. This presentation will describe the author’s first-hand experience in developing capillary column technology for chromatography over the past 40 years, followed by speculation of emerging opportunities that may provide even better chromatographic performance in the future.

About Dr. Milton Lee

Dr. Milton Lee

Milton L. Lee received a B.A. Degree in Chemistry from the University of Utah in 1971 and a Ph.D. in Analytical Chemistry from Indiana University in 1975. Dr. Lee spent one year (1975‑76) at the Massachusetts Institute of Technology as a Post­doctoral Research Associate before accepting a faculty position in the Depart­ment of Chemistry and Biochemistry at Brigham Young University, where he is the H. Tracy Hall Professor of Chemistry.

Dr. Lee is best known for his research in capillary separation techniques and mass spectrometry detection. He is an author or co‑author of over 570 scientific publications, and has given over 500 technical present­a­tions on various aspects of his research. He has received a number of national and international awards including the American Chemical Society Award in Chromatography (1988), Martin Gold Medal (1996), American Chemical Society Award in Chemical Instrumentation (1998), Eastern Analytical Symposium Award for Outstanding Achievements in Fields of Analytical Chemistry (2008), Pittsburgh Analytical Chemistry Award, (2008), the American Chemical Society Award in Separations Science and Technology (2012), and the LCGC Europe Lifetime Achievement Award (2014). Dr. Lee has mentored over 70 M.S. and Ph.D. students.

Professor Lee is also an entrepreneur and has been involved in transferring technology from his university research laboratory to the private sector. He co‑founded three analytical instrument companies, the most recent of which is Torion Technologies, which markets hand-portable gas chromatography-mass spectrometry detection systems for first responders. He is listed as a co-inventor on 20 issued patents.

About Pittcon

Pittcon® is a registered trademark of The Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, a Pennsylvania non-profit organization. Co-sponsored by the Spectroscopy Society of Pittsburgh and the Society for Analytical Chemists of Pittsburgh, Pittcon is the premier annual conference and exposition on laboratory science.

Proceeds from Pittcon fund science education and outreach at all levels, kindergarten through adult. Pittcon donates more than a million dollars a year to provide financial and administrative support for various science outreach activities including science equipment grants, research grants, scholarships and internships for students, awards to teachers and professors, and grants to public science centers, libraries and museums.

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