Organic synthesis in pharmaBy Dr Fritjof Weidner, Market Manager Advanced Intermediates at Biesterfeld Spezialchemie - 9th September 2019
We speak to Dr Fritjof Weidner, Market Manager Advanced Intermediates at Biesterfeld Spezialchemie, about the transformation effect of organic synthesis on drug discovery, and how the science is driving demand for organic intermediates and products for pharmaceuticals.
Organic chemistry – the study of carbon-containing compounds – was originally limited to compounds produced by living organisms. However, since Robert Burns Woodward received the 1965 Nobel Prize for Chemistry for organic synthesis – the intentional construction of organic compounds – it has developed into one of the most important branches of organic chemistry. Organic synthesis is now used in an enormous range of industry sectors, with recent advances such as late-stage functionalization, new bond-forming techniques, and the intersection of biomolecules with synthetic chemistry, continuing to push the field forward.
We spoke to Dr Fritjof Weidner, Market Manager Advanced Intermediates at Biesterfeld, about the growing demand for intermediates and products for organic synthesis, and the trends and opportunities behind those demands.
Drug discovery and development
“Within the chemical industry, the pharmaceutical industry is considered to be the most important customer base for advanced intermediates,” says Dr Weidner. “These are being used to produce Active Pharmaceutical Ingredients (API), which are then formulated with inactive components (excipients), to generate the finished dosage form, sold as a drug product.“Of course, advanced intermediates – made by organic synthesis – are not only used to produce active ingredients for human but also for veterinary pharmaceuticals, as well as for agrochemicals and for many other speciality chemical industries.”
However, within the pharmaceutical industry, it is generally agreed that organic synthesis is poised to transform drug discovery. To consider the impact of the science on current drug discovery and development, Dr Weidner provided a quick analysis of newly-approved drugs.
“In 2018 the US Food and Drug Administration (FDA) approved a total of 59 novel drugs and biologics of which 38 drugs were small molecules, made by traditional chemical synthesis, starting from intermediates,” he explains. “The 2018 number 1 top selling drug was the antibody Humira, made by gene synthesis, followed by Lyrica and Eliquis, both being made by chemical synthesis. Therefore, on the basis of only these examples it can be assumed that chemical or organic synthesis still dominates drug synthesis.”
“Drug discovery involves screening for biological activity, definition of lead compounds and design. Chemical synthesis is already involved during the screening process, to synthesize large numbers of different chemicals, to finally select target or lead compounds having sufficient potency and drug properties”, elucidates Dr Weidner. “Once a lead compound has been identified, the drug development process commences with preclinical and clinical trials. In this way, the chemical synthesis or process is optimized for scaling-up from milligrams to kilograms or even tons.”
“So,” he concludes,"organic or chemical synthesis is of crucial importance during the entire drug discovery and development process.”
Process and technology
“For fine chemicals and advanced intermediates, chemical synthesis and biotechnology are the most frequently used technologies”, the chemist reveals. However, if just one technology should be highlighted as particularly well-suited for pharmaceuticals, Dr Weidner thinks it would be stereospecific synthesis with chiral catalysts to generate single-enantiomer products.
Organic synthesis typically consists of multiple steps in its process, with intermediates formed at each step of the reaction.
“Organic compounds, or intermediates, are produced either from petrochemical starting materials or from extracts or by means of biotechnology processes,” says Dr Weidner. “The number of chemical steps leading on from the basic, commodity-type starting materials, via fine chemicals or advanced intermediates through to the final product, e.g. pharmaceuticals or any other specialty product, can vary from two to many steps, sometimes even more than twenty.”
“A multitude of chemical reactions, such as nitration, hydrogenation, halogenation, cyclization, palladium-catalysed coupling, and more, can be used for each step,” he continues. “Basic starting material (commodities) are usually produced in large-scale and dedicated plants, whereas fine chemicals or advanced intermediates are produced in multi-purpose plants, by means of multi-step synthesis and in limited quantities, rarely exceeding more than several hundred tons per year.”
Could artificial intelligence (AI) have a potential role in organic synthesis, we wondered.
“Machine-assisted synthesis of biomacromolecules or the use of AI for synthesis planning is a quite specialized field,” replied Dr Weidner. “We are aware of this potential and believe will gain importance in the near future.”
We asked Dr Weidner whether achieving stability of the intermediates was an important factor in reaching the end product.
“I wouldn’t put it quite like that,” he mused. “The stability of any chemical is directly linked to its reactivity and chemical properties, respectively, and appropriate packing and storage. Specific chemicals can be stabilized by adding a stabiliser. Otherwise it would be replaced by utilizing different or more stable compounds, leading to same end product.”
Clearly, replacing compounds in this way reflects a confident expertise in organic synthesis reaction pathways. This begged the question – how do you choose the optimal route for synthesis of a compound/intermediate?
“The diversity of chemical reactions allows the synthesis of a specific molecule using various routes of synthesis, which is crucial to optimizing a process in view of patent infringements, economic viability and environmental safety, among other factors,” says Dr Weidner. ”Making the most of our close working relationship with innovative partners and our market expertise and knowledge, we at Biesterfeld can meet current market demands with our flexible product portfolio, which we are able to customise whenever required. We have an in-depth and extensive knowledge of our customers' requirements, and can, therefore, supply the raw materials needed while ensuring the quality, packaging and delivery time demands are met by the application involved.”
Biesterfeld offers a wide portfolio of organic and inorganic base chemicals, solvents and intermediates for organic synthesis. Specifically within organic synthesis portfolio, the company provides fine chemicals and advanced intermediates, such as pyridines and piperidines, phase-transfer catalysts and fluorine compounds, for a wide range of applications and market segments.
“These include industries such as pharmaceuticals, flavours and fragrances, agriculture, polymers and personal care,” says Dr Weidner. “We also develop customer-specific products. Working with our suppliers, we are able to develop a tailored intermediate for each of our customers, to meet their exact needs, and in compliance with requirements such as REACh”.
It is not necessary for all of these products to be REACh registered, he explained, as – for example – there is no obligation to register substances that are produced in amounts below one metric ton per year. However, to comply with the REACh regulations, Biesterfeld has already completed registration for more than 155 materials, of which eight are registered as ‘Full’, and the rest are registered as ‘Intermediates’ in accordance with Article 18. Biesterfeld is currently working on submission dossiers for another 30 materials for registration, to be completed by the end of 2019 or early 2020.
“Our REACh expertise gives our customers real added value and an additional service in the sense of providing reliability for our available products,” adds Dr Weidner.
“However, at present, the market for advanced intermediates used in organic synthesis is being impacted by shortages of raw materials, and simultaneous high demand,” Dr Weidner spotlights.
This, he explains, is because many manufacturers are struggling to comply with new regulatory requirements, such as REACh, and environmental protection regulations – especially in China.
“This is resulting in ever more frequent production stops or even shutdowns,” he explains. “However, we are still able to provide our customers with excellent service, thanks to our close relationships with leading international suppliers, primarily in Asia, fostered by our long-standing collaboration.”
It is Dr Weidner’s view that organic synthesis was, and will continue to be, the main driver not only in the drug discovery process, but also for many products made and used in the life science industry, as it has proven to be a valuable and successful technique. Consequently, at Biesterfeld this segment Advanced Intermediates, as part of the HealthCare department, already plays, and will continue to play, an important role.
“We at Biesterfeld believe in innovation and change”, explains Dr Weidner. “As our Managing Director Peter Wilkes always says ‘it’s a marathon, not a race!’ Therefore, we are constantly working to enhance our business processes and the service we offer in order to increase the added value for our customers and suppliers. For example, this not only includes an extensive and innovative product portfolio but also continuing and expanding our consultancy services such as laboratory support, product formulation and beyond. 2020 will be a particularly exciting year for Biesterfeld in this regard.”
Dr Fritjof Weidner, Market Manager, Advanced Intermediates, Biesterfeld Spezialchemie, Ferdinandstraße 41, 20095 Hamburg, Germany
T: +49 40 32008 349