Environment & Regulations

Nothing left Toulouse?

MEPI is trialling alternative chemistries for fine and speciality chemicals in Toulouse. Andrew Warmington found out more

One of the most devastating accidents to hit the European chemicals industry took place on 21 September 2001, when a blast rocked AZF's fertiliser plant at Total's Grande Paroisse subsidiary Toulouse in south-west France. As well as the immediate victims killed in the disaster, it cast a very big shadow over the chemicals industry in the region.

Isochem, for one, saw its large-scale phosgenation activities at the site permanently shut down, even though they demonstrably had nothing to do with the explosion, and was never quite the same firm again afterwards. Overall, the number of people working in chemicals in the area fell from about 1,000 to under 100. Now, however, a new association is seeking to do something with all the wasted talent in the area.

MEPI - the name stands for La Maison Européenne des Procédés Innovants, or European House for Innovative Processes - was created in late 2007. It was in part, says business director Laurent Pichon, the results of a regional brainstorming event by a group of industrial companies, academic bodies and local authorities led by the local Chamber of Commerce and called Chimie autrement - 'Chemistry another way'.

MEPI demonstrates and pilots industrial processes on the premises of the Safran SME production site in Toulouse. The basic offer is based on technology studies - turning a batch process into continuous and advising on how to run intensified processes best suited to specific syntheses - production of small volumes of chemical entities via intensified processes, re-engineering chemistry to intensified processes and setting up plants, all backed up by training.

"We are trying to promote technology change from batch to continuous and process intensification in the chemicals and related industries," says Pichon. More precisely, he adds, MEPI aims to answer simple questions which have so far proved to be difficult to answer:

• Manufacturing eco-friendly products, using renewable raw materials where possible
• Designing safer and cleaner processes with the equipment available
• Saving energy and costs
• Monitoring the quality of chemical reactions with online analytical tools

The founder members, assisted by national and EU funding, included Sanofi-Aventis, Pierre Fabre, Safran SME, and Libragen, a local biocatalysis firm. Two of the major local educational establishments, the gigantic University of Toulouse, which has some 150,000 students, and INPT (Institut National Polytechnique de Toulouse), are also involved.

After a marketing study confirmed the viability of the project, MEPI was set up as a not-for-profit organisation in 2007. Next year, MEPI was accredited by the local technology clusters Cancer Bio Santé in healthare and Agrimip in bio-resources, the first studies were carried out and a workshop was built. A second, covering 150 m², followed in 2009.

The founders, Pichon says, carried out the first studies but MEPI has since grown to a national and now into an international body, with customers from Germany, the Netherlands, the UK, Italy and Switzerland. At present it has ten to 15 clients and about 50 prospects. There are six employees, with another expected to be added this year.

MEPI has also expanded its coverage from an original focus on pharmaceuticals to fine chemicals and now speciality chemicals. Most clients within this potentially huge market come from the paint additives, polymers and aerospace chemicals sectors but, says Pichon, they could potentially come from any area. "It's just another way of doing chemistry."

Most importantly for now, perhaps, MEPI has invested heavily in systems and equipment. Having started out with a heat exchange reactor from Corning, it acquired €4 million worth of intensification equipment via INPT. It now has heat exchange reactors in glass, stainless steel, hastelloy, titanium, polymers and silicon carbide, including what Pichon calls "a little beauty" developed by a local company called Boostec in partnership with the University of Toulouse.

The MEPI laboratory (left) houses a reactor from local firm Boostec (right)

MEPI has also acquired a continuous oscillatory baffled reactor from NiTech of the UK that has been used for continuous crystallisation and enzyme-catalysed reactions, among others. Other important pieces of kit include a continuous isolator, a thin film evaporator a hastelloy reactor for reactive extraction and mixing for viscous reagents and others for supercritical fluid and online analysis.

Equipment providers and industrial clients, says Pichon, are part of a 'golden triangle' of long-term partnership. The third side is technology providers, including local laboratories such as LGC, LCA, and INSA, which specialises in biocatalysis, INPT itself and Solvionic, a supplier of specialised ionic liquids that is based next to MEPI.

MEPI has both micro- and supermeso-reactors, but most of its equipment is at the meso-scale, with flows of 0.5-10 litres/hour, or 1-100 tonnes/year, putting it at typical pharmaceuticals industry volumes. It also has a large range of analytical tools, both online and batch, at its disposal, either its own or via its academic partners.

The reactions MEPI has run to date include organometallic synthesis and reactions, nitrations with various catalysts, amine deprotection, hydrazine synthesis, electrophilic and nucleophilic additions and substitutions, peroxydation, phosgenation, fluorination and biocatalysed reactions. Polymerisation, by cutting out competing reactions in batch, has been another recent addition to the armoury.

The media used can be single, two- or three-phase and have included liquid, liquid, liquid/liquid, liquid/gas, liquid/liquid/gas, anhydrous and viscous. Reactions have been run at temperatures from -70 to +150°C. Studies have varied in length from two to 12 weeks, costing on average €40,000.

"It has included some quite nasty stuff, such as fluorination with fluorine gas, and we are currently investigating sodium azide," Pichon says. "This makes sense. You should really do all dangerous chemistry continuously. Enzymatic chemistry, where the residence times can be days, is another interesting area."

Effluent treatment is another area of interest, particularly for the pharmaceuticals industry, which generates vast amounts for relatively low volumes of product. A client has challenged MEPI to recover high added value material from pipe effluent where it is found at ppm levels.

To date, intensified processes have found a number of advantages, Pichon adds. They can improve yields and selectivity and can control strong exothermic reactions or ones where unstable intermediates and/or hazardous chemicals are involved. Cryogenic reactions that need -70°C in batch can work better at -20°C when done continuously, while high temperature ones can be speeded up by smaller residence times.

Among the projects completed to date was a single-phase organometallic synthesis that was done to investigate the feasibility and safety of a continuous process. In place of a 100 litre fed batch processs that took 210 minutes at -70°C, the intensified process yielded a volume reduction to 150 ml, a residence time of three minutes and took place at -40 to -20°C.

 

(L-R) An Alfa Lavel ART 37, a Corning Gen2 and a NiTech COBR are some of the reactors available for trials at MEPI

Similarly, a two-phase, 4 m³, liquid/liquid carbonate synthesis that took place in a four-hour fed-batch process was reduced to 100 ml and two minutes. In addition, the previously low selectivity was improved and both solvent and reagent consumption were reduced.

Regulatory requirements are another issue. MEPI has worked with the FDA and the University of Washington, supported by online analytics, and found that its system are "easily compliant" with any requests the FDA typically makes regarding API synthesis. Reduced reagent excesses and avoiding solvent use are other environmental bonuses.

That there is interest in shifting from batch to continuous in the fine and speciality chemicals sectors is not news, but batch is the incumbent and a lot of money has been spent on kit. So, does MEPI encounter resistance based on sheer intertia? Pichon points to the four axes of technology change - safety, quality, environment and cost. Most chemistry, he says, is carried for issues related to the first three. Cost is often a factor of these, though not always and it is certainly not insignificant.

"If someone is thinking only of cost and the challenges in switching from used, empty, amortised batch reactors, there has to be an average saving of 30% for this to make sense," he says. "This is actually the average saving in fine chemicals, according to most of our clients but if there is a strategic interest or something that you can't do well in batch, managers may see the need to investigate."

Pichon also makes the comparison with the way photography went from chemical to digital. This will not be as quick, he admits, because the cost of vessels is greater, but the trend is "unavoidable. We have been talking about this for ten years and now we feel it bubbling up." The massive interest at Chemspec Europe 2011, where the RSC's parallel conference focused on the subject, is clear evidence of it.

Concluding by pointing to MEPI's 'road map', Pichon says that they started where the triangle is. "People came to us and tried to carry out reactions to achieve targets. At the end, they know what sort of equipment they want - and we can help them set it up."

 

 

From Online Issue: February 2012