Green Solvents and UHPLC: Balancing Chromatographic Performance with Environmental Sustainability

Assessing the fifth principle of green chemistry in liquid chromatography requires both quantitative metrics (waste volume, energy use, AMGS) and qualitative evaluations of solvent benignity (toxicity, biodegradability, recyclability). Ultrahigh-pressure liquid chromatography (UHPLC) with superficially porous particles (SPPs) improves efficiency by lowering van Deemter terms, enabling shorter columns, faster runs, and reduced solvent consumption, though at higher cost and maintenance demands. Carbonate esters such as dimethyl, diethyl, and propylene carbonate offer greener alternatives to acetonitrile, with distinct effects on miscibility, elution strength, viscosity, and ultraviolet (UV) cut-off. Tools such as ternary phase diagrams and additives like tetrabutylammonium perchlorate expand selectivity control while ensuring stable, single-phase mobile phases. Overall, the work highlights how greener solvent systems and advanced LC technologies can reduce waste and energy use while maintaining chromatographic performance, if miscibility, sensitivity, and operational limits are carefully managed.

A recent joint study by the University of Lyon (Villeurbanne, France) and the University of Texas at Arlington studied the chromatographic variations induced by replacing classical solvents with carbonate esters using simple reverse phase liquid chromatography (RPLC), hydrophilic interaction chromatography (HILIC), and normal phase liquid chromatography (NPLC) separations of model compounds. LCGC International spoke to Sakil Islam, one of the authors of the resulting paper (1).

How can the fifth principle of green chemistry be quantitatively assessed in LC method development, and what metrics would you use to compare solvent benignity?

The fifth, sixth, and seventh principles of green chemistry all impact solvent choice, amounts, and energy demands. Having metrics that have been predetermined for these aspects allows for use in comparing different conditions and approaches. One can track waste volume, instrument energy use (power × time), etc. If a single numerical measure is desired, the Analytical Method Greenness Score (AMGS) can be calculated.

For solvent benignity, consider toxicity to people and aquatic life, flash point, and biodegradability. Also, the manufacturing cost (including energy) and recyclability must be considered. However, it must be noted that if a benign system does not produce adequate results, such as chromatographic figures of merit, it is useless.

Explain how the van Deemter equation is affected by ultrahigh-pressure liquid chromatography (UHPLC) operating pressures and superficially porous particle (SPP) design, and how that influences both resolution and solvent consumption.

With UHPLC, one uses very small particles in the column. Well-packed small particles make flow paths more uniform, lowering the “A” term (eddy diffusion), and shorten diffusion distances, reducing the “C” term (mass transfer). As a result, the van Deemter curve’s minimum drops, and the rise at higher flow rate is less. So, one can obtain high-efficiency separations with shorter columns and run times, generating less waste solvent.

SPP (core-shell) particles push this further. Their solid core and thin, porous shell keep diffusion paths short and particle packing uniform, which again lowers “C” and “A.” Bonus: for the same efficiency, SPP backpressure is lower than that of fully porous sub-2 µm particles, so the van Deemter curve is flat at higher flow rates.

Resolution depends on selectivity, efficiency (number of plates), and separation time. UHPLC and SPPs both raise efficiency and shorten the run times. Shorter runs and smaller columns reduce power consumption and solvent usage significantly.

What are the environmental gains of UHPLC, and how do they compare to its cost, maintenance complexity, and instrument lifetime?

UHPLC cuts solvent use and shortens run times, leading to higher throughput with less waste and lower energy consumption per unit of analysis. However, there are trade-offs: systems are more costly, run at higher pressures, solvent filtration/degassing matters more, and columns can be expensive. It is important to use fully miscible mobile phases and avoid very viscous blends which result in pressures that can be too high.

When methods use shorter columns, narrower internal diameters, and appropriate flow rate, the solvent savings and faster runs can outweigh the added cost and maintenance of UHPLC. Obviously, with guards/inline filters and clean samples, both column and instrument lifetimes can be improved.

For carbonate esters, discuss how polarity index, dipole moment, and hydrogen-bonding ability influence their miscibility and elution strength in RPLC and HILIC.

The polarity of carbonate esters controls how they were used in both modes. Their polarity differs; propylene carbonate (PC) is much more polar than DMC/DEC (PC dipole moment≈ 4.9 Debye), which helps water miscibility and increases elution power. All three carbonate esters are only partly water-miscible, so a co-solvent such as methanol or acetonitrile (ACN) is still used to keep single-phase blends. In RPLC, these differences show up as different elution strength; propylene carbonate often gives stronger elution, which can shorten runs. In HILIC, replacing ACN with carbonate esters raises viscosity; PC is about 2.5 centipoise (cP) vs 0.37 cP for ACN, so backpressure climbs, and selectivity changes can be observed. These solvents are not only greener; they also give useful control of retention and resolution.

How does high ultraviolet (UV) cut-off of some green solvents influence method sensitivity, and what detection strategies could overcome this limitation?

Carbonate esters have a higher UV cut-off than acetonitrile. At high organic content, this raises the baseline and limits low-wavelength detection for analytes with weak chromophores. This was addressed by choosing a slightly longer detection wavelength when possible. Each solvent’s transparency was checked before finalizing a method, and instrument settings, such as reference wavelength, being used to reduce noise. Detection was matched to the solvent, so sensitivity remained acceptable while still reducing environmental impact.

Interpret how ternary phase diagrams guide mobile-phase optimization when replacing conventional LC solvents with partially water-miscible carbonate esters.

Ternary diagrams were central to the method work, thanks to Alain Berthod at the University of Lyon, from whom I learned it. Carbonate esters are partly water-miscible, so the phase diagrams were used to find single-phase regions with a co-solvent. Those fixed compositions were then prepared and tested. This avoided clouding, pressure jumps, and baseline drift. Salt can move the phase boundaries, so the diagrams were checked again for hydrophilic interaction liquid chromatography. Using the phase diagrams kept runs in the clear single-phase region and made method development more reliable.

Discuss how the addition of tetrabutylammonium perchlorate can alter the stationary-phase solvation layer and retention mechanism in HILIC separations.

Tetrabutylammonium perchlorate modifies the stationary-phase solvation layer and superimposes ion-specific interactions on partitioning, providing a powerful, orthogonal “knob” for tuning HILIC retention and selectivity. The salt also affects the phase boundary in some carbonate esters systems, so solvent ratios were adjusted to keep the mobile phase in single-phase region. Overall, it gave another way to tune selectivity with carbonate esters that behave quite differently than acetonitrile.

In RPLC, why must an alcohol or acetonitrile be present when using carbonate esters, and how does this impact method design and selectivity?

Carbonate esters do not fully mix with water in all proportions; therefore, a small amount of a co-solvent, either an alcohol or acetonitrile, is required to keep the mobile phase single-phase throughout the run. Ternary phase diagrams were used to select suitable compositions, and distinct blends were tested rather than time-programmed gradients. The co-solvent sets a minimum for miscibility, while the carbonate esters level is the key factor for elution strength and run time under isocratic conditions. The identity of the co-solvent matters: short-chain alcohols often give a wider workable region with water and carbonate esters than acetonitrile, and it shifts interactions differently. The phase diagrams also make method transfer and routine operation easier so that the composition never crosses a phase boundary while the carbonate esters level is adjusted to meet retention and resolution needs.

Compare the thermodynamic and kinetic factors that set different substitution limits for carbonate esters in RPLC, HILIC, and NPLC mobile phases.

Carbonate esters behave differently in each chromatographic mode. In RPLC, the limits come from miscibility and viscosity; using too much risks phase separation or high backpressure (for traditional HPLC, the limit is 400 bar). Dimethyl carbonate and propylene carbonate worked well with a small amount of alcohol or acetonitrile to keep single-phase blends. In HILIC, carbonate esters act as weak eluents, so higher levels can be used, but salts can shift miscibility limits, so that was kept in mind. In NPLC, carbonate esters are much more polar than the usual nonpolar solvents, so they act as strong modifiers. Here, the limit is the selectivity you want and any loss of efficiency from higher viscosity. Overall, the usable percentage is set by phase behavior, viscosity, and pressure. Each mode has its own best range.

References

1. Berthod, A.; Islam, S.; Armstrong, D. W. Carbonate Esters as Green Alternatives in Chromatographic Separations. Anal. Chim. Acta 2025, 1373, 344471. DOI: 10.1016/j.aca.2025.344471
   
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