Codexis received the 2006 Presidential Green Chemistry Challenge Award from the US Environmental Protection Agency (EPA) for its technology to manufacture hydroxynitrile (HN).
HN, chemically named ethyl (R)-4-cyano-3-hydroxybutyrate, is the key chiral building block in the synthesis of atorvastatin, the active pharmaceutical ingredient (API) in the cholesterol drug Lipitor, and so has an annual demand of around 440,000 pounds.
Codexis designed a green HN process, called "Directed Evolution of Three Biocatalysts," around the exquisite selectivity of enzymes and their ability to catalyse reactions under mild, neutral conditions to yield high-quality products.
Traditional commercial processes for HN require a resolution step with 50 per cent maximum yield or syntheses from chiral pool precursors. They also need hydrogen bromide to generate a bromohydrin for cyanation.
What is more, these processes ultimately substitute cyanide for halide under heated alkaline conditions, forming extensive byproducts, and they require a challenging high-vacuum fractional distillation to purify the final product, lowering the yield even further.
To address these issues of activity, selectivity, and stability necessary for a practical and economic process, Codexis developed three enzymes using recombinant-based, directed evolution technologies.
The evolved enzymes are so active and stable that Codexis can recover high-quality product by extracting the reaction mixture.
In the first step, two evolved enzymes catalyse the enantioselective reduction of a prochiral chloroketone (ethyl 4-chloroacetoacetate) by glucose to form an enantiopure chlorohydrin.
In the second step, a third evolved enzyme catalyzes the novel biocatalytic cyanation of the chlorohydrin to the cyanohydrin under neutral conditions.
On a biocatalyst basis, the evolved enzymes have improved the volumetric productivity of the reduction reaction by approximately 100-fold and that of the cyanation reaction by approximately 4,000-fold.
The process involves fewer unit operations than earlier processes, most notably obviating the fractional distillation of the product.
Thus, Codexis' process provides environmental and human health benefits by increasing yield, reducing the formation of byproducts, reducing the generation of waste, avoiding hydrogen gas, reducing the need for solvents, reducing the use of purification equipment, and increasing worker safety.
"We are greatly honoured to receive this recognition for the advances we have made in developing novel biocatalysts to enable green manufacture of pharmaceutical chemicals," said John Grate, Codexis' chief technology officer.
"We believe our work represents the next wave in environmentally sound pharmaceutical production that can also contribute to lowering the cost of manufacturing life-saving drugs."
Codexis estimates that its protein and strain engineering technology platform can reduce the cost of goods by 40 to 70 per cent and capital expenditures by over 35 per cent.
The Californian company has more than 15 partnerships with proprietary and generic pharmaceutical manufacturers worldwide.