The Continuing Acetonitrile Shortage: How to Combat it or Live with It -

The Continuing Acetonitrile Shortage: How to Combat it or Live with It

Jun 1, 2009
By: Ronald E. Majors
LCGC North America

Ronald E. Majors

The worldwide shortage of the popular solvent acetonitrile started in the early fall of 2008. Many laboratories were caught unaware of this pending shortage and did not address the problem quickly enough while others who sensed the problem stocked up on the available supply at the time. Unlike methanol and other solvents that are manufactured for industrial use, acetonitrile is available only as a byproduct of another chemical production. Surprisingly, even the solvent companies, who supply high-grade acetonitrile, experienced a shortage of feedstock for their purification and, hence, could not obtain sufficient acetonitrile to address their customer needs, and the scramble was on. Prices have skyrocketed. Since last October, internet blogs and on-line chromatography forums have been discussing and debating the issue, even referring to the shortage as a "conspiracy of solvent companies." Depending upon the laboratory and the country reporting, there was more than a sufficient amount or none at all. Many ideas to handle the "short-term" shortage were floated around, some of which were practical, some of which were off-the-wall. Many of the ideas were generated by commercial entities, some of whom slanted the possible solution to suit their business needs. In this article, I will present an unbiased look at some of the more practical aspects of coping with the acetonitrile shortage. Currently, as of this writing, there is no prediction when normal supplies will resume.

Why is Acetonitrile So Popular?

Acetonitrile is a solvent that has favorable properties for many chemical applications. It shows minimal chemical reactivity, low acidity, and is reasonably low boiling. Important for reversed-phase high performance liquid chromatography (HPLC) and hydrophilic interaction liquid chromatography (HILIC) applications is its miscibility with water, wide range of achievable polarities with water mixtures, low viscosity (resulting in low pressure drop, even with water binary systems), and low ultraviolet cutoff (down to 192 nm). For HILIC, large volume percentages of acetonitrile in water are favored and thus, its use can be more affected by the acetonitrile shortage than reversed-phase chromatography. Particularly hard hit are those who do preparative- and process-scale LC purification using acetonitrile eluents. Acetonitrile is also a very popular solvent for sample preparation techniques such as dilution, protein precipitation of biological fluids, and as a good eluent for solid-phase extraction (SPE). Acetonitrile also finds use in solid-phase oligonucleotide–DNA synthesis, for peptide synthesis, and in the manufacturing of drug substances and drug products, sometimes in copious amounts. So there are many reasons why there is concern over limited supplies.

What Are The Reasons for The Shortage?

When first reported, there were a couple of reasons why the acetonitrile shortage arose so quickly. One of the first reports was that during the 2008 Summer Olympics, Chinese factories where acetonitrile was produced as a synthetic by-product were shut down to minimize air pollution. One of the plants was reportedly the largest producer of acetonitrile in China. Some of the factories have not returned to production. Secondly, the September 2008 Hurricane Ike in the Texas Gulf Coast temporarily shutdown one of the major producers in Texas. This facility also had planned a shutdown in production for a factory update and expansion in January 2009. To add to the problem, this company is reported to be in financial difficulty. But the general consensus is that the worldwide demand for acrylonitrile has decreased severely due to the economic downturn.

It turns out that acetonitrile is a minor by-product of the manufacturing of acrylonitrile using the Sohio process. About 2–4% of the Sohio process results in the formation of acetonitrile that is then removed and purified for further use. Most manufacturers of acrylonitrile incinerate this by-product as fuel rather than trying to reclaim it. So, there are a limited number of acrylonitrile producers who reclaim the acetonitrile.

Acrylonitrile has been used widely in plastic products such as polyacrylonitrile and acrylonitrile-butadiene-styrene (ABS) resins. These products are used in automobile manufacturing (bumpers and other parts), carpeting, acrylic and carbon fibers, luggage, small appliances, telephones, computer housings, and other industries. Obviously, the reduced purchase of cars, the housing slump, and purchase of other consumer products has decreased the demand for acrylonitrile-based plastics and production has been curtailed. There also have been reports of a decrease in demand due to acrylic fibers losing market share to polyester fibers. With a large amount of pharmaceutical manufacturing moving to China and India, some of the acetonitrile production will stay in Asia, and that could be another factor in influencing the worldwide availability of acetonitrile down the road.

Thus, because the amount of acetonitrile is proportional to the reduction in acrylonitrile production, there is currently a shortage of this widely used solvent, relative to a year ago. There are other synthetic routes to produce acetonitrile but many of them are not as economical as that obtained from the acrylonitrile process. However, there have been some reports that opportunistic entrepreneurs in China are considering starting production of acetonitrile by alternative methods.

What Are The Consequences of The Acetonitrile Shortage?

Referred to as "The Great Acetonitrile Shortage" or "The Great Acetonitrile Drought" thereby creating "Acetonitrile Anxiety," obviously, when a commodity product falls in supply and the demand still exists, there are going to be cost consequences. The current prices for high-quality and HPLC-grade acetonitrile have gone through the roof with quotes of over $1000 for a 4 X 4-L case fairly commonplace. Price gouging seems to be in fashion. Prices have risen by factors of 6–8 since the summer of 2008. Distributors and suppliers are allocating their available supplies to favored customers based upon their past purchases. In some cases, laboratory chemical suppliers have not been selling this solvent at all, especially to new customers. In some parts of the world, supplies are not even available and deliveries as long as six months have been quoted. In other places, supplies seem to be recovering and prices moderately reduced. The general feeling is that acetonitrile prices will never return to 2008 levels.

Besides price gouging, another consequence of the shortage is that a number of speculators are showing up on internet blogs offering large quantities of bulk acetonitrile of questionable or unknown purity. Most avoid such transactions that also could raise suspicions when importing large amounts of solvent from abroad.

Some feel that the acetonitrile crisis is a "wake-up" call and that laboratories should now develop short-term and long-term strategies to come up with alternative solvent systems. The movement to "greener" solvent systems or miniaturized liquid-phase chromatographic systems could be a positive outcome.

Those most concerned about the acetonitrile shortage are those who work in regulated laboratories, particularly in the pharmaceutical industry. The United States Food and Drug Administration has received many inquiries related to the shortage of acetonitrile, most of which revolve around substituting an alternative solvent to use to validated methods. Their comment on this issue can be found in reference (1). Basically, they have maintained their position that "regardless of the changes a firm makes to address the (acetonitrile) shortage, appropriate method validation and compliance with relevant good manufacturing practices (CGMPs) are necessary" (1).

The most obvious consequence is that many laboratories are looking for a continued supply to maintain their current methods. In the absence of meeting their acetonitrile demands, they are looking for alternatives that can solve their analytical or synthetic problems with a minimum disruption. We will now explore approaches that can be used to eliminate or minimize the use of acetonitrile in their laboratory. We will not address those who use large amounts of acetonitrile in their manufacturing or synthesis processes.

Methods to Reduce HPLC Use of Acetonitrile Based Upon Changing Column Dimensions or Particle Size

Shorter columns with the same internal diameter: Depending upon the resolution of your important analytes of your current method, you might be able to reduce the length of your column without sacrificing the method resolution requirements. Because column length (L) is proportional to analysis time (t), when you reduce the column length and keep the flow rate constant, the amount of solvent required is proportionally reduced. Thus, for an isocratic separation, cutting the column in half, separation time and solvent required is halved. However, there is a proportional loss in theoretical plates (N), but because resolution is proportional to N^½, one does not sacrifice as much resolution as you might think and the separation might be sufficient.

However, for gradient elution, if one cuts the column in half, the gradient time must be reduced proportionally also. Otherwise, your method can be compromised. When changes are made in column length, column internal diameter, flow rate, the change from the initial composition to the final composition, and gradient time, conditions must be adjusted to satisfy equation 1. According to equation 1, which refers to the apparent k value for gradient elution (or k*), a change in length must be accompanied by a proportional change in gradient time (t_g).

Where
k* = apparent k value in gradient elution
t_g = gradient time (min)
F = flow rate (mL/min)
S = constant
ΔB = change in %B over gradient time
V_m = elution volume (min)

So, if the column length is decreased by a factor of two, then t_g must be reduced to ½ to obey equation 1. If, in addition, one would choose to speed up the separation by an increase in flow rate by a factor of two, then t_g would be further decreased by a factor of two. Such a twofold change in conditions can have a detrimental effect on resolution but it could be tested easily.

Figure 1

Shorter column with smaller particles: The use of smaller particles packed into shorter columns is the current trend in higher throughput LC. In this case, a reduction in length is accompanied by a proportional reduction in particle size to maintain separation efficiency and perhaps resolution as well. Because L ~ N, there is a loss of plates in going to shorter columns but N ~ 1/d_p (where d_p is the average particle diameter) and therefore, plates are increased to maintain the overall resolution. Figure 1 provides the separation of some xanthines as an example of increasing speed by simultaneously reducing the column length from 25 cm to 5 cm and particle diameter from 5 μm to 1.8 μm while keeping the flow rate and the column diameter the same. The separation time (t) and the solvent consumption are reduced proportionally with each reduction in L. For this example, the solvent consumption in Figure 1a was 12 mL, in Figure 1b, 4.5 mL, and in Figure 1c, a total of 2.3 mL. Here, the resolution remained more or less the same so there was no sacrifice in method performance but a fivefold solvent savings.

Table I: Commercial two and sub-2 μm totally porous HPLC columns*

There is one caveat: as one decreases the particle size, there is a slight shift in the minimum of the van Deemter curve so that flow rate might have to be increased slightly to take full advantage of the particle size reduction. Thus, the separation time could be further decreased. The new submicrometer sized particles are particularly attractive here because separation times and reduction in solvent can be up to an order of magnitude compared to longer columns packed with larger particles. I have updated my listing of suppliers of 2-μm and sub-2-μm columns for high-throughput LC (Table I). With a visit to the websites of these companies, one can get method translation equations, calculators, and software to perform the necessary calculations for changing experimental parameters.

The new superficially porous packings can provide some of the same advantages with the added benefit of lower pressure drops because column lengths are generally 5 cm and the particles are in the range of 2.7 μm, but the efficiencies noted are in the neighborhood of the sub-2-μm columns.

Reduction of the column internal diameter: An easy approach to reducing solvent consumption is changing the internal diameter of the column with or without decreasing the column length. According to equation 1, if one reduces the diameter and desires to keep the same separation time, the flow rate must be reduced proportionally to the inverse of the radius ratios squared. Thus, if a column internal diameter is reduced from 4.6-mm to 3.0-mm i.d. at constant length, then the flow rate would be reduced by (3.0/4.6)² to a factor of 0.43. Thus, if one originally had a method using 1.0 mL/min and switched to the 3.0-mm i.d. column, the flow rate would be reduced to 0.43 mL/min and there would be resultant solvent savings of 57%. With 3.0-mm columns, almost any modern HPLC instrument could be employed because instrumental extracolumn volumes and gradient delay volumes are sufficiently small enough not to cause method variances. Decreasing column diameter with a concurrent decrease in flow rate (to maintain constant linear velocity) allows the separation time to remain constant, and users should see a very similar chromatogram as the original.

Figure 2

One can continue to reduce the column internal diameter and achieve further reductions in solvent usage. For example, changing from a 4.6-mm i.d. column to a 2.0-mm i.d. column (referred to as microbore or semimicro columns) will result in approximately 80% solvent savings without affecting the separation characteristics. Such a change can be seen in Figure 2, which shows a separation performed on a 4.6-mm column and a 2.1-mm column, both with a 150-mm length. The flow rate was reduced from 1.0 mL/min to 0.2 mL/min. Note that the sample size was reduced from 5 μL to 1 μL because the cross sectional area of the 2.0-mm column is 1/5. In the case of internal diameter reduction, the response increases fivefold if the sample size is injected. To keep the same response, the sample mass injected was decreased proportionally because a concentration-sensitive detector was used. If the same sample volume (at the same concentration) is injected onto the smaller internal diameter column, an increase in sensitivity should result (if no band spreading results from the larger injection volume), which makes microbore columns ideal for sample mass-limited situations.

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