Safer, cheaper fluorination – a boon for pharmaceutical manufacturing
The development of chemical agent Selectfluor by Manchester professor Eric Banks has transformed the production of fluorinated pharmaceuticals.
Selectfluor bypasses hazardous fluorine processing steps and makes the production of drugs containing fluorine much cheaper and safer. Every year around 25 tonnes (worth $7.5 million) of Selectfluor are used in industry, making this agent the most commonly used electrophilic fluorinating agent in pharmaceutical manufacturing.
Fluorine is well known to have a transformative effect on many drugs, helping to make them more potent, selective and metabolically stable. Indeed, more than one fifth of pharmaceutical products contain fluorine, including around a third of the top 30 ‘best sellers’.
But the process of adding fluorine to other molecules – fluorination – is extremely dangerous. Originally it involved the use of the highly reactive and toxic perchloryl fluoride, but following the death of two production workers, the pharmaceutical industry refused to take the risk of fluorinating its products.
Different methods of adding fluorine were investigated but each of the electrophilic fluorinating agents came up short. The fluorination agents were either insufficiently reactive, too hazardous or too expensive.
In the mid-1990s Professor Eric Banks and colleagues here in Manchester developed and characterised the novel fluorination agent Selectfluor.
Around 80% of fluorinated steroids are made using Selectfluor.
Described as "a game-changing innovation", Selectfluor rapidly became the world’s most widely used electrophilic fluorinating agent. It is now produced on a multi-tonne scale in America, China and other countries. Every year 25 tonnes of the reagent sell for $7.5 million.
The discovery of Selectfluor revitalised the use of fluorination by the pharmaceutical industry, enabling them to manufacture more potent and efficacious drugs. Today 134 patents have been published which cite Selectfluor and around 80% of all fluorinated steroids are produced using the agent. These products include one of the most prescribed billion-dollar fluorosteroid products in the modern pharmaceutical industry, a compound that was developed by Pfizer.
Many of the world’s largest pharmaceutical companies have benefited either in the discovery phase or in production from the discovery of Selectfluor. The agent has been used in the production of pest control products, antibacterials and drugs for a wide range of conditions and diseases including hypertension, congestive heart failure, chronic kidney disease, Alzheimer’s disease, schizophrenia, bipolar disorders, diabetes, inflammatory diseases and cancers.
The asthma and chronic obstructive pulmonary disease therapeutic fluticasone propionate, marketed under a variety of brand names worldwide, is a fluorinated product. It was initially manufactured using hazardous fluorination processes, but now Selectfluor makes the manufacturing process safer and cheaper. Between 2009 and 2012 global sales of fluticasone propionate therapeutics totalled approximately $17 billion.
Each year around 25 tonnes of Selectfluor are used in industry.
The research of Professor Eric Banks and his team in Manchester was funded by Air Products Inc. Following the discovery of F-TEDA-BF4, the researchers carried out extensive laboratory experiments throughout the mid-1990s to assess the effectiveness, range of applications and utility of the agent as an electrophilic fluorinating agent, an oxidising agent and as a fluorine-transfer reagent.
In particular the researchers demonstrated that Selectfluor was as effective as DesMarteau’s reagent for fluorination, but it was safer and cheaper. The team also established that the agent could be used under a fluorine-transfer protocol to prepare other classes of fluorinating agents. This research led to the later development of asymmetric fluorinating agents and specialist contrast agents for PET scanning.
Throughout this work, the researchers were conscious of the commercial interest in the product and performed extensive studies to understand the limitations of the reagent (eg fluorodemethylation side-reactions) and how to protect against them.