Marching Ever Onward

In a recent survey looking back to 2002, my research group set out to compare optimal performances of LC. The starting date was well before the arrival of sub-2- µm columns. In those days, we found that the time needed to obtain 20,000 plates took about seven minutes, which with today’s technology and techniques only takes 50 seconds (to measure a compound eluting with a retention factor of 10). And, in 2002 it took an impractically long 100 minutes to do an N=100,000 plates separation, whereas today we can do it in just over 20 minutes. It’s impressive progress that contradicts those who say that chromatography is fully matured and so doesn’t deserve further R&D.

LC has been – and continues to be – a platform for innovation. The first major breakthrough, for example, was the introduction of UHPLC inspired by the seminal work of James Jorgenson and promoted by the late Uwe Neue. The second big breakthrough was the reintroduction of core-shell particles around 2007. The latter breakthrough was somewhat serendipitous because the increase in efficiency compared to fully porous particles was much larger than could theoretically be expected, based on the reduction of the differential paths inside the particles alone. Nothing stands still in LC. I think demands for faster and more efficient separations will continue hand in hand with the development of more efficient columns that reduce the time needed for method development – a very costly process in industry. We do need more efficient columns to support the current search for biomarkers; and, we need them for more general research, such as analyzing how the cells in our bodies are functioning and how we could cure them when something goes wrong. 2D-LC will certainly be needed to produce the required peak capacities for this type of research, but even then, the efficiency of the individual dimensions will first need to go up as well. And as biologists dig ever deeper into our bodies, aiming at single cell or even sub-cell level analysis, miniaturization of LC systems could become an important issue again.

Design is the limiting factor of today’s instruments. They still have the same “hi-fi tower” design as those produced in the 1970s and 1980s. This form factor leads to such high levels of extra-column band broadening that we can say that our columns have become too good for our instruments, and we (or better, the instrument manufacturers) should do something about it to bring their designs into the 21st century! Pressure is not an issue, as it seems theoretically and practically possible to run a column up to 3000 bar or so. As a matter of fact, Ken Broeckhoven and I are running a project on 2600 bar separation using normal bore columns and up until now things are going very well – we’ve had no explosions so far! So, in terms of mechanical strength there might be no fundamental impediment. What is trickier are the compressibility effects that make it more difficult to generate a precise flow rate, but perhaps there are ways to circumvent that as well. No one can second-guess the future, but I do believe that we should be able to operate columns up to 2000 bar without any difficulty. I also think it should be possible to automatically couple up to three 10-cm columns packed with 1.5 µm core-shell particles within an integrated system that clamps the columns directly between the injector and detector to eliminate all connecting tubing. Finally, because of the gradual decline in chromatography training for analytical scientists, we must improve the ability of instrument software to assist the analyst with decision-making. This – and more powerful instruments – will undoubtedly take our field even further forward.

Expanding LC Boundaries

Have We Really Peaked?

Marking Progress

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