The Future of Chromatography

[Robert Classon]

Liquid chromatography took off in the 1970s mostly because of 'bonded phase' or what we now call reverse phase columns and pumps that could operate up to 6000 psi. The applications that drove product development were generally related to pharmaceuticals and small molecules. Things have changed quite a bit over the past 40 years and will likely keep changing.

I'm doing a survey to assess what the future of chromatography will be like in the near future (over the next 5-10 years) for a discussion on the subject I plan for next year. I would like to ask for your inputs for the following questions:

1. What are the future problems in the next 5-10 years that HPLC needs to solve. Is there an application area or technical limitation that needs to be developed better or changed dramatically that will propel HPLC development forward for the future. For example, column development for proteins is still not very far along in terms of handling large proteins.
2. Are there any new products or chromatographic techniques that you would like to see in the near future that will change how we do HPLC? What will be the most important ones?
3. What chromatographic techniques, column chemistries or other aspects will likely either disappear or become less significant in the future? For example, will we still be doing ion exchange? Will alumina disappear from the HPLC arena? Etc?
4. Where will the future technical breakthroughs come from? From within the existing HPLC world or from outside (such as from trickle down from clinical analyzers or from some new detection technology for example)? Will HPLC 'instruments' be etched on a chip and turned into disposables? Will columns be replaced by chips? Will both be replaced by something else?
5. What will the applications be like 5-10 years from now? Is it realistic to expect analysis times to get much shorter than we have now? Will we be doing less of a separation and more detection and deconvolution? At what point will we have enough selectivity that we won't need expensive detectors? Etc?

Thanks for sharing your ideas.
Bob Classon

[paul_b]

I suspect there will be a move towards 'black box' solutions. Miniturisation of columns means that solvent consumption is reduced to the point where extended operation without topping is possible, LIMS systems often allow full reporting with little human input. Analytical groups have been cut to the point where it may be economic to outsource the whole maintenance / development to an external company.

An instrument provider would team up with a column supplier and supply a QC 'solution' (complete with pre-prepared standards and solvents) with an on-call technician to maintain the system with a 'hot swap system for servicing / breakdowns. A 'staff-free' operation could be an attractive proposition for smaller companies.

This tend can already be seen in both IR and NMR.

[Robert Classon]

Thanks Paul.

There are already a number of 'black box' systems used in the clinical analysis market. Most of these are keyed to a specific analysis or a limited number of analytes, but the concept could be expanded to cover a large variety of analytes with just a little creativity.

I believe that the biggest limitation to HPLC at this point in time is still the injector. They are big, costly, complicated, and a source of a lot of problems.

Do you think that we will continue to use syringe type injectors also with liquid samples as we have for so many years, or will we find a way to deal with solid samples directly? There are currently more than a dozen types of atmospheric sampling devices for LCMS that deal with solid samples. Seems these could be extended to separations with other types of detectors also.

[Vlad Orlovsky]

We are working on the future of chromatography where analysis can be run by anybody, even a monkey. (no offence to people or monkeys)

It will be revealed in 6 months

[Gerhard Kratz]

That question about the future of HPLC is on the table since HPLC was established. Miniaturization, even injection Systems, for example a glass Body with lasered channels, injection done with Nitrogen pressure or with vacuum, HPLC System of the size of a fountinpen, all this was discussed 30 years ago. Lab on a chip - still the HPLC System is the same size, sample prep is the same. Clinical or diagnostic Systems MUST be a black box - mainly medical doctors are running These Systems. Still, a Standard 4,6 x 250 column is the most sold and most used column Dimension. Capillary columns were "in" a few years ago, now number of sold columns is decreasing.
Looking on Pharmaceutical Analysis, both in stability testing and QC, I would be highly concerned if a monkey would operate the System.
New developed stationary phases will come, more standardized instruments, better Service Systems.
In 10 years I can retire, if I want, and I'm sure in this Forum we will still have beginners, more experianced users, experts and we will be here and answer all the old and new questions. And we are waiting for the next MARKETING Revolution in HPLC. First was FPLC, second was UHPLC. But the princip of Operation is still the same. HPLC will remain as what it is, a phantastic technique, simple, challanging, difficult, sometimes a miracle, gives fun.
Vlad, please let me know about the new System in 6 months

[krickos]

Hi

Well my view from a pharmaceutical point of view, is that our branch is slowing things down. With more flexible regulations you would have seen a larger spike in UHPLC for instance.
While new Products may enbrace new techniques, still important organizations such as USP/Ph Eur/JP/PMDA/EMEA/FDA etc have not published a common approach to make it possible to switch over to UHPLC without significant costs(variation fees etc)/time frames.

Wont help much if for instance USP would go first as it is "only" one market, especially for global companies. Such slowness to embrace new techniques adds to the difficulties to cut non manufacturing costs. Especially on the generic market both for generic companies and those who inveted it in the first place.

At some point we did simultanious validations on UHPLC and traditional HPLC as some countries/rugulatory bodies did not accept UHPLC (do not have technique and does import testing).

18-24months approval time in some major markets do not help either (applies for manufacturing improvements as well unless uyou have more recent/modern approved design space you can operate within).

So I think it safe to say that different areas will progress in different paces, sometimes big leaps, sometimes small steps.

[MestizoJoe]

Very funny Vlad. I was literally lol.

I think the near future will have smaller particle sizes for stationary phase which would increase resolution by dramatically increasing efficiency. The problem there is pressure, void volumes, sample detection, and mass load limitations. I think the first few problems may be solved already, but loading small amounts of sample without massive dilution may be tricky.

I think UPLC injectors already suffter from issues of clogging. So they will have to figure out a way to introduce a small amount of sample perhaps without a syringe. They used a split for solving this problem in GC. I wonder if we can do the same with HPLC.

I also wonder at what pressure some of our common mobile phases will become super critical. Of course there is already super critical chromatography which i've never used but i hear it's awesome. We need to bring that to industry.

[Vlad Orlovsky]

Five monkeys with access to great selectivity of mixed-mode (and mixed-mode core-shell we have already) and our concept will leave 1 PhD, 2 MS and 7 BS chemist with 10 UPLC systems in the dust. And my monkeys will only need bananas, a pat on the back and a regular pressure "system". So if you are not a monkey you are in trouble.

This is a no-laughing matter

[lmh]

There are fundamentally different markets, and, if anything, they're diverging. Universities and research labs will always need control and flexibility, so they will diverge from process-monitoring and straightforward clinical applications.

High-pressure UPLC will fade slightly as people find solid core is quite robust and offers many of the same advantages, provided it's run on a UPLC-optimised system.

Cost recovery is becoming a big issue even in universities, so I expect short runtimes will be in demand. But lab-on-a-chip solutions can be expensive, so there will be a tension between consumable costs and costs of human time.

Coupling polar analyses to mass specs will grow: hilic and mass-spec-compatible ion-exchange mechanisms may be important.

Capillary electrophoresis might emerge from the wardrobe and assert itself.

Detectors won't get less sophisticated: on the contrary, someone might realise that conventional chromatography with DAD is a bit like driving a car with the windows blacked out: go forwards 300 yards, turn right, and assume it's your driveway. The thing that eluted at 5.73minutes is defintely my analyte.

Boxes will get taller and narrower still, until all chromatographers have to be over 6' tall or have a surgically-implated kick-stool.

Someone will start to make chromatography systems in pink or orange. Blue and grey will go the way of cream, and become passé.

Phenomenex adverts will finally become so weird that no one knows what they're advertising. But they will be released in a bound volume for geeks.

Triple quad manufacturers will claim sub-yocto-molar sensitivity, thereby requiring an injection volume of a cubic meter to guarantee that the injection contains the single available molecule. Sooner or later someone will realise that increased sensitivity is of limited use, and there will be a Big Change: instead of instruments always costing the same, but getting steadily better, the instruments may stay the same, but get cheaper.

People will worry more about power-consumption of big instruments.

Helium will go up. In every sense.

Software will become steadily more important; hardware isn't enough if you can't view the data in loads of interesting ways. Bugs (sorry, "features") will rise, plateau, and eventually fall. In the non-regulated world, free software will gradually become more compatible with commercial offerings, and the manufacturers will realise that many of their special packages are actually being undermined by freebie stuff. This won't matter, because by then the freeby stuff will actually work. Instrument manufacturers will then realise that the hardware is their unique strength, and they'll welcome compatibility with freebie things, while maintaining their own, ever-more-diverse software for regulated environments.