Beating 'acetonitrile crunch'

Talk of the credit crunch has filled the headlines in the past few months - but there is another ‘crunch’ that is lurking in the sidelines - Here, Lee Petts explains the background to the ‘acetonitrile crunch’ and how businesses might be able to beat it by taking advantage of green options

SINCE SEPTEMBER 2008, worldwide supplies of acetonitrile have been shrinking rapidly. Used extensively in high performance liquid chromatography, particularly by the pharmaceutical sector to establish both the purity and potency of drugs, supply shortages of this solvent could soon affect the availability of much-needed medicines.

Acetonitrile (ACN) is a solvent used widely by the pharmaceutical sector to test both the potency and impurity levels of drugs. It is chosen as an indifferent medium that has low acidity and minimal chemical reactivity, in high performance liquid chromatography (HPLC).

Commercially, ACN is derived from the production of acrylonitrile, another organic compound that is used to make acrylic fibres and plastics. As a consequence, the availability of ACN is directly linked to demand for Acrylonitrile-based products. 

The automotive sector is perhaps one of the biggest users of acrylonitrile-based plastics, and is one of the industries that has been hit hardest by the global economic downturn. As car sales have plummeted around the world, demand for acrylonitrile has fallen steeply too, leading to a shortage in the starting material required to manufacture ACN. With no end to the recession in sight, it is unlikely that ACN production levels will bounce back any time soon, and certainly not in 2009. The problem has been compounded by a reduction in ACN output at a Texan chemical plant damaged by Hurricane Ike in September 2008.

Makers of drugs rely heavily on ACN for their HPLC needs. Such companies are going to find it hard to secure supplies of this solvent. A quick look at the websites of major distributors Fisher Scientific and VMR confirms that ACN is now available only as an allocation to existing users, with new customers unlikely to source any at all.

These businesses face the very real prospect of being unable to release their finished pharmaceutical products for sale, which in turn, could restrict the availability of medicines where they are needed most. Perrigo UK Limited, a pharmaceutical company based in Devon, certainly recognises how critical ACN supplies are to their business. 

“Our ability to release product to the market is directly affected by the availability of acetonitrile within the quality control laboratory,” says Roger Steward, stability chemist.  “We have implemented a strategy for conserving our existing stocks, which includes more efficient campaigning of analysis and the licensing of alternative test methods where possible.”

It may be possible for businesses to reduce their exposure to this crisis by taking similar steps to Perrigo UK and making their supplies of ACN go further. One way of doing this is to switch from HPLC to UPLC (ultra performance liquid chromatography) which uses less solvent and, correspondingly, may conserve existing stocks. This is certainly a resource-efficient strategy, and one that Remsol would recommend. However, it is likely to involve substantial change control and validation efforts and may therefore not help to ease the situation much in the short-term.

An alternative being explored by Remsol includes the toll-recovery and resupply of ACN extracted from HPLC solvent wastes, and is already being seen by many as an exciting prospect. It is technically very challenging: ACN forms an azeotropic mixture with the Methanol that is often also present in HPLC solvent wastes, making straightforward distillation unlikely to achieve the purity levels required (99.95%).

Instead, additional separation techniques will be needed, possibly including ‘washing’ the wastestream with another solvent in order to extract the ACN before further processing this by fractional distillation. Making this commercially viable will rely on capturing a sizeable quantity of HPLC solvent waste. Unfortunately, very few pharmaceutical manufacturers, or those businesses involved in the testing of medicines for release, generate sufficiently large volumes of this waste to warrant recovery themselves.

Since the start of the year, Remsol has been busy putting together a unique scheme aimed at encouraging users of ACN to effectively ‘pool’ their HPLC solvent waste arisings in order to overcome the issue of scale and improve the chances of toll-recovery and resupply becoming successful.

So far, a number of major pharmaceutical manufacturers including CMOs (contract manufacturing organisations) and ‘generics’ manufacturers have pledged to commit their HPLC solvent wastes to the scheme. However, much more is still needed.

For ease of administration, the scheme has been designed in a way that means organisations that commit their HPLC solvent waste for recovery will be resupplied with an equivalent percentage of recovered ACN based on their starting contributions. So, a business that contributes 15% of the input quantity for toll-recovery will be resupplied with 15% of the recovered ACN yield. Remsol will facilitate the collection of HPLC solvent wastes from around the UK, as well as the distribution of the laundered product.

Inadequate starting volume is by far the biggest barrier to making toll-recovery and resupply a viable proposition. Without the necessary input quantity, the additional separation chemistry required simply isn’t cost effective. To proceed would make such a project cost-prohibitive. So, Remsol is urging users of ACN that rely on it for HPLC testing of pharmaceuticals to quickly pledge their HPLC waste solvent to the scheme in order to make it both technically and economically feasible.

Another significant barrier to success is the purity required for use of the recovered ACN in HPLC.  Wherever possible, businesses wishing to participate in the pooling scheme are being encouraged to supply HPLC solvent waste with no Methanol present and, where this is not possible, to try and limit the concentrations of Methanol in the wastestream.  With the additional separation techniques employed, it is expected that it will be possible to achieve the necessary product specification but this will be easier and less expensive if Methanol can be excluded from, or limited in, the starting material presented for recovery.

Historically, HPLC solvent waste has been collected from the organisations that produce it and then submitted either to high temperature incineration (HTI) or for recycling into secondary liquid fuel (SLF) used as an alternative to Heavy Fuel Oil to power cement kilns.

In the first of these options, no further value is gained from the waste. In the latter, the latent energy value of the waste is utilised in an effort to reduce demand for non-renewable fossil fuels where SLF can be used, but it could be argued that this is still a wasteful practice overall because the ACN is still ultimately destroyed. Although designed initially in reaction to the current crisis facing the pharmaceutical sector, the pooling and toll-recovery scheme being developed by Remsol could actually provide the industry with a long-term solution instead that will limit future exposure to supply-side volatility.

By extending supplies of ACN through recovery and reuse, businesses that rely on it as a critical raw material could help to insulate themselves from subsequent shortages. It should also be possible to stabilise the price of ACN, both virgin and recovered too.

“Whilst having a beneficial effect, our efforts to conserve existing stocks of Acetonitrile do not provide a long-term solution for the lack of reliable supplies,” concludes Steward of Perrigo UK. “Recovering acetonitrile from our bulk solvent wastes is the logical next step, and in the absence of in-house facilities, the Remsol scheme may provide just such an opportunity. If the recycled solvent meets the relevant specifications, we would be very interested in participating.”

Owing to unfortunate timing, coupled with a coincidental series of natural and man-made events, world supplies of Acetonitrile are diminishing. With the pharmaceutical industry largely dependent on this solvent for testing the purity and potency of the products they make, there is a real danger that the availability of much-needed medicines could be affected in coming months unless a solution can be found.

Reducing consumption of ACN is something that all businesses should now be considering, and can be achieved either by substituting another solvent or by switching analytical method from HPLC to UPLC. However, these may both require significant change control and validation efforts to achieve.

Toll-recovery of ACN from HPLC solvent wastes is another alternative that could contribute to extending the life of this valuable compound whilst also boosting green credentials and reducing future exposure to repeat difficulties. This is unlikely to be feasible for individual organisations to achieve in isolation, but much more likely to work if a collaborative approach is adopted.

Thinking further ahead, the impact of a repeat supply shortage in the future could be limited by incorporating toll-recovery into the overall waste management strategies pursued by users of ACN for HPLC purposes, rather than simply using it as a means of overcoming the current crisis.