Don’t Discount Another Particle Technology Revolution

When you look back over the past 10 years, has HPLC innovation lived up to expectations? Which types of hyphenation have emerged as winners?

I would say the past 10 years were evolutionary rather than revolutionary, but that doesn't take away from the fact that steady improvements were made nonetheless. For example, the uniformity of commercially available particles has improved significantly, and new microfluidic techniques are being developed to improve this further still.

In terms of hyphenation, I spontaneously think of the clever ways devised by some instrument manufacturers to facilitate and improve the connection between the column and the MS. Thermo’s Easy-Spray for use with nano-LC columns, or Water’s vacuum-jacketed column-MS interface that eliminates nearly all post-column band broadening, are interesting examples of this evolution.

So, has HPLC peaked?

It is undeniable that research on HPLC columns and instruments is declining, especially in academia, and that most of the significant strides forward have already been made. However, nobody saw the core-shell revolution coming (and I really mean nobody, because their advantage turned out to be much bigger than can be explained based on their presumed advantage: the reduced intra-particle diffusion distances). So who’s to say we won’t get surprised again? Indeed, there is still room for improvement: about 50 to 60 percent of the band broadening in our columns is today still wasted to omissible eddy-dispersion.

A few years ago we were close to a new breakthrough when Agilent researchers worked on core-shell particles with radially-only oriented mesopores, showing a 33 percent decrease in plate height compared to the “normal” core-shell particles. Unfortunately, the material never made it to the production and commercialization phase. However, if someone can solve the impediments, we may just be in for another unexpected revolution in particle technology.

What are some of the hottest trends in HPLC today?

The evolution towards the analysis of ever larger molecules, originating from the surge in biopharmaceutical drug development, is for sure the hottest trend. The analysis of oligonucleotides and the characterization of adeno-associated viruses (AAVs) are clear examples of this. At the other end of the spectrum, I also find the quest for sensitive single-cell proteomics and robust clinical proteomics very interesting and promising.

Is AI having an impact on the HPLC field today?

Not yet – at least as much as it could have or should have. Because, with the number of HPLC practitioners without a strong separation science foundation growing bigger and bigger, it seems natural to compensate by making the instruments more intelligent. However, so far most AI and machine learning efforts are still limited to the academic groups, often focused on developing better retention time prediction models. This work has yet to led to new products for the users community.

Could machine learning be used to take control of instruments and propose new, better gradients by reviewing the results of the past gradient runs? That would certainly be interesting. Some work in that direction has been done at the University of Amsterdam, in Belgium in Brussels and Leuven too, as well as in some vendor companies, which is good news. (I happen to know some of them will report on this at the upcoming HPLC conference...)

In the decade to come, what might the next “HPLC gamechanger” look like?

In the area of column technology, I still expect a lot from new particle morphologies. I already mentioned the possibility of core-shell particle with radial-only oriented pores to produce columns with a reduced minimal plate height of 1; but other particle formats – such as spiky particles, for example, which would generate a drastically lower hydrodynamic resistance than conventional spherical particles – could one day emerge and surprise us all.

I also expect some important breakthroughs from the pillar-array column technology. Whereas particle packed columns have clearly reached their limit in terms of size reduction, the development of pillar array columns still only in its infancy and is far from reaching its fundamental operation limits. Nor has it already fully exhausted its potential to increase flow rate ranges.

Then there’s the design of our instruments – which still have the same “hi-fi tower” design as 40 years ago and therefore generate too much extra-column band broadening compared to that created by today’s state-of-the-art columns, especially when trying to meet industry’s desire to work with smaller i.d. columns. Our current instruments are also not user-friendly and foolproof enough to provide a proper response to the declining degree of chromatography training of today’s chemical analysts. Therefore, in the not too distant future I expect to see the emergence of radically novel instrument lay-outs, allowing columns to be installed as a simple cartridge – like we do in our printers or coffee machines – and that have enough intelligence on-board to operate fully autonomously.

Overall, are you optimistic about the future of HPLC?

Sure, as long as the ion-suppression problem of MS detection does not get fundamentally solved, chromatography will remain the key technology to analyze and quantify complex samples. And given that the fundamental performance limits of the technology in terms of speed and efficiency have not been reached yet – by far – I am quite confident we will continue to witness new breakthroughs in the future.

Gert Desmet is Full Professor and Department Head, Vrije Universiteit Brussel, Belgium

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