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Strategies for Acetonitrile Supply Issues Shortages could drive change toward lower-solvent, more efficient and overall greener technologies. by Steven Aspey, Thermo Fisher Scientific
Reduce, Replace, Recycle for acetonitrile supply. | Factors contributing to the shortage of acetonitrile are primarily related to the global recession. Unlike other solvents, such as methanol, there are no facilities dedicated to the manufacture of acetonitrile. Instead, raw acetonitrile is a by-product in the production of acrylonitrile—a plastic used in automotive and consumer products. The collapse in the automotive industry and reduced demand for acrylonitrile has significantly reduced the supply of acetonitrile.
This shortage has increased the price of acetonitrile by as much as 8x. Even as supply increases through late-2009, it is anticipated that the price could remain high. This is partly because global consumption of acetonitrile is forecast to grow by 5% per year over the next five years, due to its increasing use in the production of engineered drugs, generic pharmaceuticals and pesticides in Asia.
Reduce
If the chromatographer has a ready supply of acetonitrile but wants to use less, there are approaches to take. Reducing consumption per injection can be achieved by using columns with smaller length and internal diameter. In addition, packing materials with a smaller particle diameter, generally sub-2 µm, will also reduce consumption.
Simply reducing column length from 150 to 100 mm can result in solvent savings of up to 30%, and reducing the internal diameter from 4.6 to 2.1 mm can deliver 79% saving. Reduced column dimensions, resulting in decreased interstitial volumes, mean samples can be eluted in a fraction of the usual solvent. In addition, the use of sub-2-µm particles is becoming increasingly popular for applications in high-throughput screening assays or in UHPLC. Sub-2-µm particle packed columns also offer advantages by improving resolving power, sensitivity and peak capacity. Thus, shorter columns can be used for equivalent separations with reduced solvent use.
A combination of these—smaller columns packed with small particles—can reduce 95% of solvent, compared to a conventional HPLC method, while maintaining chromatographic integrity. These savings have been demonstrated in a case study where Simvastatin tablets were analyzed using high-speed LC, with the added benefit of increasing throughput 10-fold. This method also exceeds U.S. Pharmacopeia method requirements.
To maintain equivalent chromatography when adjusting methodologies, care must be taken to ensure operating flow rate, gradient profiles and injection volumes are all scaled accordingly. Consequently, many chromatography vendors have developed online solvent tools to guide chromatographers through method transfers and to help them establish the cost savings of using new columns and smaller particles.
Figure 1. Comparison of several water-miscible solvents to replace acetonitrile.
Click to enlarge.
| Replace
For those concerned about an extended acetonitrile shortage, replacing acetonitrile with other solvents can be considered for both HPLC and UHPLC applications. For alternative solvents, such as methanol, a structured approach to a new method development must be adopted to ensure that differing eluent properties are taken into account.
For any change in mobile phases, it is important to consider how this change will affect retention factors, selectivity, peak shapes and resolution. In general, elutropic and polarity index values are a good first reference for consideration.
If considering these parameters as a starting point, methods that employ acetonitrile (P'=5.8) could be evaluated with methanol (P'=5.1) as a replacement solvent. For example, a mobile phase comprising 50% water : 50% acetonitrile would give the same elutropic strength as a mobile phase comprising 44% water : 56% methanol.
It is important to keep in mind that any solvent change affects the maximum pressure achieved by a method (due to changes in mobile phase viscosity). In addition, the actual results cannot be predicted based solely on solvent polarity index and strength parameters; rather, these parameters should be used as a starting point in the new method development.
Hints and tips for method development
When replacing the mobile phase, an alternate stationary phase may also be considered to ensure good selectivity with the new solvent. It is necessary to use a quality new-generation column that encompasses a range of chemistries bonded onto the latest ultra-high purity base-deactivated silica to deliver a good peak shape. Obtaining narrow, symmetrical peaks helps to facilitate method development by offering improved resolution. In evaluating an alternative stationary phase, differing column chemistries will provide differing selectivities with the solvent.
Also, because the mobile phase plays a key role in analyte retention and selectivity, optimizing the mobile phase pH and buffer will ensure that the necessary separation is obtained.
Finally, the correct UV wavelength must be selected when working with UV detection. The UV cut-off is 205 nm for methanol and 190 nm for acetonitrile.
 
Figure 2. (a) Separation of purines and pyrimidines with acetonitrile (click to enlarge) and (b) separation of purines and pyrimidines with high temperature water (click to enlarge). | High-temperature water
Another option is to replace the organic in the mobile phase with high-temperature water. This can be done with Hypercarb columns, which are packed with 100% porous graphite carbon with no bonded chemistry. The inertness of PGC makes Hypercarb columns chemically stable and robust, enabling them to be used at up to 200 C under isothermal or gradient conditions without losses.
At room temperature, water is too weak as a solvent to elute all but the most polar analytes. As temperatures increase above its boiling point, its dielectric constant decreases. Therefore, water can be used as a reversed-phase eluent. High-temperature LC can also improve elution speeds and peak symmetries.
Recycle
As a final approach, chromatographers should consider recycling the eluent, particularly for isocratic solvents. While this has economic and environmental benefits, it hasn’t been extensively practiced. This is because traditional recycling systems tend to be cumbersome (requiring frequent manual resets to allow for baseline drift), take up valuable bench space, and can only be used to recycle a single solvent or set mixture. However, modern recycling systems are now microprocessor controlled and can overcome some of these issues, reducing consumption by up to 90%.
Such systems redirect untainted mobile phase to the solvent reservoir during isocratic HPLC operation. Through continuous monitoring of the detector, the mobile phase is only recycled to a reservoir when the baseline is below a threshold. If this value is exceeded as a peak is eluted, the tainted eluent flow is redirected to waste. When the signal returns below the threshold, the mobile phase is switched back to the reservoir.
While this article discusses strategies to minimize the impact of acetonitrile shortage, do not forget that changing methods may require full revalidation.
For more information, E-mail analyze@thermofisher.com or visit www.thermo.com/gcfoodsafety
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