The pharmaceutical industry has had to resort to rather inefficient, environmentally harmful chemical synthesis routes for the production of the active ingredient levetiracetam, a drug which is used to treat epilepsy. A consortium led by acib has now developed a chemoenzymatic manufacturing route that promises twice the yield of current production methods while being environmentally friendly. The production method could be ready for industrial use in a year’s time. Epilepsies are the most common neurological disorder and are considered as one of the most common chronic diseases of childhood worldwide. About one percent of the population has active epilepsy and one in ten people will experience an epileptic seizure by the age of 80. For the medical treatment of epilepsy, today a drug that it is marketed under the name Keppra with a global market share of €770 billion (as of 2018) is frequently used. The active pharmaceutical ingredient in Keppra is levetiracetam, a compound that is mainly produced via chemical synthesis routes.

Current manufacturing processes are unfortunately characterized by low atom efficiency. This means, that only a fraction of the materials used end up in the desired final product, while the majority of the material ultimately serves only as an auxiliary material and is thus produced as an unwanted by-product. Numerous purification steps are therefore necessary to separate these substances and ultimately obtain the desired product in high quality and purity. These separation processes additionally pollute the environment, consume a lot of energy and lead to high production costs of Keppra. Until now, the market has been dependent on these synthesis routes due to the lack of smart alternatives. Thanks to a new, revolutionary manufacturing method, these drugs could soon be produced in a more environmentally friendly and much more efficient way.

New synthesis route twice as effective as previous routes

Established methods, such as the classical Strecker synthesis, have the disadvantage of forming a racemate. This is a mixture of two substances that, metaphorically speaking, are like an image and its mirror image. However, only the image provokes the desired effect. The inactive mirror image has no effect or it could cause side effects in patients and must therefore be separated from the desired active substance as unwanted waste. This is complex and wasteful. These factors have so far limited the yield of industrial production to less than 50 percent.

The new synthesis utilizes an enzyme. A nitrile hydratase enzyme can select between blueprints of image and mirror image. The biocatalytic process produces only the image. By automatic recycling of the mirror image blueprint, the yield of the image theoretically increases to 100%, making the new route twice as effective as conventional production routes. As a final step, an oxygen atom is introduced with the help of periodate – finally producing the desired, finished active ingredient in pure form. The spent periodate is regenerated by electrical current and can be used again and again in a cost-saving and sustainable manner.

The new route offers the industry the added benefit of being more environmentally friendly in production as well, since the process can be carried out under mild conditions in an aqueous solution at room temperature and ambient pressure. Currently, the researchers are working to scale up the process to industrial size. The new route could be used by industry in a year’s time. The idea to merge biocatalysis with electrochemistry could also inspire the production of other pharmaceuticals to make them more efficient and much greener.

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This article is based on the scientific publication “The sustainable synthesis of levetiracetam by an enzymatic dynamic kinetic resolution and an ex-cell anodic oxidation” in Green Chemistry, Issue 1, 2021

Picture credits:  Gerd Altmann on Pixabay