Growing pressure from the authorities and ever more stringent regulations has led to greater emphasis on making chemical processes for pharma ingredients cleaner and greener. But pressure from regulators is only part of the story. It often turns out that by engineering--or re-engineering--processes to be cleaner, the chemistry is more efficient. And more efficient chemistry is more economical, so substantial cost savings can be made.
At the heart of many cleaner chemistry processes is catalysis, where old fashioned stoichiometric reactions are replaced by chemistry that uses cheaper reagents alongside modem catalysts. All three forms of catalysis--homogeneous, heterogeneous and enzymatic--are growing in importance as the pressures to save money and reduce waste increases.
Professor Roger Sheldon of the Technical University of Delft in the Netherlands believes that, ultimately, almost all reactions will be replaced with catalytic processes. "Catalysts may in themselves be expensive, but the actual cost of the catalyst is not really relevant," he says.
Reagents that are consumed in a reaction and are not incorporated into the product molecules end up as waste. The best reactions are those like the Diels Alder reaction, Sheldon says, where all the reagents end up in the product, and a catalyst may nor even be needed.
A further advantage, as well as eliminating waste, is that cleaner chemistry saves money. "Waste usually has a price rag, and you're saving that," says Sheldon. "And, in addition, you're also replacing what can be a very expensive oxidant with oxygen or hydrogen peroxide, which are much cheaper. Or, in the case of a reduction, costly metal hydrides are replaced by hydrogen and a catalyst." Most novel processes these days are being developed with these issues in mind.
The use of toxic reagents also has to be considered. "Toxicity is relative," says Sheldon, "You can replace cyanide in carbonylarions with carbon monoxide, which may seem illogical as carbon monoxide is also toxic, but it is much easier to handle than sodium cyanide. The authorities are clamping down on the use, transport and storage of toxic reagents, making it nigh on impossible to use a number of chemicals that, in the past, were commonly used. A typical example is phosgene. It's not forbidden, but it is very difficult to store or transport it, so it has to be made and used in situ. Or a less toxic alternative reagent must be used instead."
Another important way in which chemistry can be made cleaner is by encapsulating reagents. An excellent example of this is the Encat reagents developed by Steve Ley's group at Cambridge, which are being commercialized by Avecia. The principle is simple--a metal catalyst such as palladium acetate is surrounded by a polyurea shell which acts as a chemical barrier to entrap the metal inside so it can't leach out, but it is sufficiently porous to allow substrates to penetrate and for products to escape.
Metals can be difficult to recover, and are often toxic, providing a potential environmental problem. The encapsulated reagents are simple to remove, just requiring filtration. And they can be reused after filtration, which is important with expensive metal catalysts. "They are robust, and can be recycled many times," says Ley. "They can be used in many important industrial reactions, including Suzuki and Heck cross couplings, and both hydrogenarions and transfer hydrogenarions."
The concept of encapsulating reagents into polyurea beads is nor limited to metal catalysts. In principle, it could be applied to many other reagents, such as Lewis acids and bases, or even enzymes. These 'mini reactor wells' have potential in multi-step continuous processes, as they can be designed so they will only react with the correct substrate, and nor themselves. "The idea of compressing chemical processes into one pot will allow operations to be faster, as well as cleaner, because intermediates would not need to be isolated between every step," says Ley. His group recently proved this principle in the lab with a multi-step synthesis of the potent anticancer agent epothiolone C, which made extensive use of immobilized reagents and scavengers and, remarkably, used no chromatography, crystallization or distillation to purify reaction mixtures-just filtration.
Solvents are another key issue that must be addressed in pharmaceutical processes. Around 80% of the non-aqueous mass in the processing of pharmaceuticals is the solvent. The percentage recoveries of these solvents are not good, so the solvents end up in air emissions or ground water, or have to be incinerated. Reducing the volumes of solvents used at a stroke makes chemical processes cleaner.
As well as choosing solvents with lower environmental impact and running processes in a more concentrated fashion, alternatives are being developed.
The use of biocatalytic processes also has an impact on solvent use. It is often possible to reduce the number of steps in a multistage process using biocatalytic reactions. Additionally, biocatalytic reactions are frequently carried out in water, a big advantage from the point of view of solvent reduction.
Process efficiency is now a fundamental part of the design of synthetic routes to pharmaceutical ingredients. "We take a sustainable, forward-looking approach to our chemical development so we aim to develop good science for our processes," explains Joanna Negri, assistant director in the department of chemical R&D at Pfizer's Groton, CT facility.
Negri explains that the company's aim is always to build in as much efficiency into a process as possible at the outset. It managed just this with the process to manufacture sildenafil, the active ingredient for Viagra, which was developed at Pfizer in Sandwich, UK. But, Negri adds, it is also essential to look at the processes used to make existing products and improve them, too. This is exactly the approach that led to the redesign of the process used to make the anti-depressant sertraline for the drug Zoloft that recently won the company the 2002 Alternative Synthetic Pathways award from the US EPA.
The new process improves yields, reduces solvents and eliminates waste products. A process that took three steps in the original synthesis was reduced to one, with imine formation of monemerhylamine with a tetralone being followed by reduction and mandelic acid diastereomer resolution to give chirally-pure sertraline in a much higher yield, and at greater levels of selectivity than the original route. The reduction step was carried out with a more selective palladium catalyst, reducing the formation of impurities and the need for reprocessing. Raw material use was cut dramatically; by 60% for monomethylamine; 45% for terralone; and 20% for mandelic acid.
A further improvement was to the solvent. The whole process was carried out in ethanol, compared to the original process, which used methylene chloride, tetrahydrofuran, toluene and hexane, removing several purification steps. Other improvements included the use of solubility differences to drive the equilibrium toward the imine in the first reaction, which eliminates about 140-m.t./year of titanium tetrachloride, and 100-m.t./year of 50% sodium hydroxide. The amount of 35% HCI waste was also reduced by 150-m.t./year, and solid titanium dioxide wastes by 440-m.t./year.
Past winners of the Alternative Synthetic Pathways awards have included new routes to pharma ingredients, too. Roche Colorado won in 2000 for the manufacture of the antiviral agent Cytovene, used to treat cyromegalovirus retinitis infections in immunocompromised patients. The guanine triester process was redesigned, and the second generation process reduced the number of chemical reagents and intermediates needed from 22 to 11, while eliminating the two hazardous waste streams from the process, and four of the five ingredients that were not incorporated into the final product were efficiently reused or recycled.
The new process increased overall yield by over 25%, and production throughput was raised by 100%. Over 1 million kg of liquid waste and 25,000 kg of solid waste a year were eliminated, along with numerous toxic wastes and by-products.
- Chemical Week