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Improving the Chemical Synthesis and Production of Duloxetine through Biocatalysis
- Rose A Lance, Senior Marketing Manager, Novozymes Biopharma

This article will discuss the benefits of utilising an enzymatic route rather than chemical synthesis route in the context of the manufacture of Duloxetine to outline the disadvantages of chemical synthesis and the benefits of using enzymes in the product manufacture in terms of cost savings, reduction in steps, improved quality of the final API, the technical advantage over chemical route and the sustainable process.

With new product innovation decreasing and several blockbuster drugs going or about to go off patent, the generic pharmaceutical market is becoming more and more prevalent. Pharmaceutical manufacturers that previously developed patent-protected therapies, known as innovators, increasingly have to compete with generics manufacturers. It is expected that generics will be adopted in almost all major markets around the world within the next three to five years, fuelled by the desire of many countries to reduce healthcare costs. Thanks to their ability to undertake cost effective API and pharmaceutical intermediate manufacturing, India and China are seen to be especially important in the generic and intermediates markets. Due to this increased level of competition over products whose patents have just or are just about to expire, cost reduction is at the forefront of manufacturer’s minds.

Cutting Costs Earlier
Changes in manufacturing procedures are a major contributor in improving operating margins. By pursuing a new manufacturing process, the original innovator of a pharmaceutical can compete with generic manufacturers using a different, more effective manufacturing process. Traditionally, production cost reductions have taken place in the later stages of clinical development, as innovators have been reluctant to make process changes after a product has been launched.

However, pressures to reduce costs have increased alongside regulatory demands and generic competition. As a result, innovators have increasingly been pursuing cost reductions earlier in product development.

By investing in new technologies, productivity and efficiency of manufacturing processes for intermediates and active pharmaceutical ingredients (APIs) can be improved. Biocatalysis is one recognised technique that can be employed to reduce costs, providing a sustainable process and improving the quality of the API. By pursuing this type of manufacture earlier, the pharmaceutical innovator can protect themselves much better against future generic manufacturers and remain aligned to the latest regulatory demands.

Implementation of Biocatalysis
Biocatalysis involves the implementation of natural catalysts, such as enzymes, in place of chemical catalysts in synthetic processes. This change can enable new, more sustainable routes for the production of intermediates and APIs. One of the biggest advantages of enzymes in organic synthesis is their remarkable selective properties, which gives a number of commercial benefits including better production of single stereoisomers, fewer side reactions, less reprocessing or purification steps, easier product separation and less pollution. The combination of all of these means lower costs. Biocatalysis has become an increasingly important tool for medicinal chemists, process chemists and polymer chemists, allowing the development of efficient and highly attractive organic synthetic processes on an industrial scale.

The Changing Face of Duloxetine
Duloxetine (sold under the brand names including Cymbalta, Ariclaim and Dulane) is a serotonin-norepinephrine re-uptake inhibitor. It is used in the treatment of a wide range of conditions, including major depressive disorder, general anxiety disorder, painful peripheral neuropathy, and chronic musculoskeletal pain associated with osteoarthritis and chronic lower back pain. The main brand name Duloxetine is sold under, Cymbalta, will go off patent this month. This has made its manufacture an ideal candidate for cost reductions through biocatalysis.

Using this example, this article will outline the specific disadvantages of chemical catalyst synthesis and the benefits of using biocatalysis enzymes during the manufacture of APIs and intermediates. It will go on to demonstrate how both cost savings and improved end products can be achieved through improved API quality, streamlined synthesis routes, process sustainability and technical advantages.

Chemical Synthesis of Duloxetine
As demonstrated in Figure 1, Duloxetine is manufactured by chemical synthesis in eight or nine steps. Initially, racemic 3-(N,N-Dimethylamino)-1-(2-thienyl) propan-1-ol is formed, involving two steps. The racemic mixture then undergoes resolution to form (S)-N,NDimethyl-N-[3-hydroxy-3-(2-thienyl) propyl]ammonium (S)-Mandelate. Finally, this is converted in five steps to (S)- Duloxetine Hydrochloride.

This is the traditional method for creating the product and comes with several disadvantages. For instance, numerous chemical steps are included within the process, increasing the overall cost of manufacture. Extra steps are also included for the recycling of the resolving agent and required isomer-recycling, which takes place by heating of the (R) isomer with hydrochloric acid. As well as adding stages to the process, this results in the formation of impurities which carry forward in to the API and impacts the quality of the end product.

As a further challenge, the final yield from this process is restricted to around 10-12 per cent of the acetyl thiophene starting material. A key area that results in such a high loss of yield is the chemical resolution of 3-(N,N-Dimethylamino)-1- (2-thienyl)propan-1-ol and the removal of one or two methyl groups of the dimethyl amino side chain. This removal of an extra methyl group requires extra treatment of (S)-3-(N,N-Dimethylamino)-1-(2-thienyl) propan-1-ol with corrosive reagents, such as phenyl or ethyl chlorformate, and basic hydrolysis before condensation with1-Fluoronapthalene.

Importantly, the vital resolution step creates a low enantiomeric excess, meaning the final product is not as pure as often required. The chemical resolution of key intermediate formation also requires the use of costly (S)- Mandelic acid in half molar quantities. In order to create a more cost-efficient and sustainable manufacturing process, different techniques and methods need to be considered, including the use of biocatalysis enzymes.

Synthesis of Duloxetine through Biocatalysis
In contrast, the enzymatic routes for the synthesis of Duloxetine are shown in Table 1, where notable improvements on the chemical synthesis route are demonstrated.

Reducing Cost of Manufacture
Costs of manufacture are reduced through various channels using this enzymatic method. Biocatalysis provides an opportunity for formulators and manufacturers to use enzymes to efficiently resolve an existing racemic mixture, creating new chiral centres or delivering a chirally pure compound through asymmetric reactions. This improves the production of single stereoisomers, creates fewer side reactions, allows easier separation of products and reduces waste. Due to the efficiency of the technique, the total cost of implementing biocatalysis in drug manufacture is relatively low.

The synthesis of Duloxetine through biocatalysis is vastly more cost-efficient due to the reduction in raw material input and raw material consumption. Raw materials no longer required include isopropyl alcohol, L-mandelic Acid, acetyl thiophene, formaldehyde, phenyl chloroformate/ethylchloroformate , diisopropylethylamine and 2-Methoxy- 2-methylpropane (MTBE). Therefore, the amount of components needed to be purchased and included into the formulation is reduced by as much as 10–15 per cent. There is also a notable reduction in overhead costs due to less process steps being involved - equipment costs, labour costs and energy savings can be reduced by up to 15%. The streamlined process, which has been dropped from nine steps to five or six, results in higher throughput and financial savings, with more batches being produced in the same timeframe. Combined, these factors have a positive effect on the cost of manufacture.

A Sustainable Process
As previously mentioned, with high selectivity enzymes used in biocatalysis, the number of stages used during product synthesis can be reduced. This in turn decreases the production of process waste and toxic chemical waste. The biocatalysis enzymes themselves can be created from renewable sources and mostly operate in water, eliminating the need for organic solvents and thus replacing hazardous chemicals. Overall, the entire manufacturing process becomes more sustainable and environmentally friendly.

Technological Advances for a Purer Product
Alongside the financial impact, there are additional technological advantages to this new method. The enzymatic process for Duloxetine synthesis uses an immobilised enzyme providing enhanced stability under both storage and operational conditions (for example towards denaturation by heat, organic solvents or by autolysis) and allows for convenient handling of the enzyme. Importantly, these have the added ability to be recycled and reused multiple times, decreasing the overall cost of use and improving efficiency. If required, the enzymatic synthesis route can also be converted into a continuous packed column/membrane based process.

These advances in technology go on to have an impact on the final product. It has been noted that biocatalysis creates more linear synthesis routes with fewer intermediates. In addition to improving productivity, this allows opportunity for a better quality of API or intermediate to be produced.

Using the biocatalysis method creates fewer opportunities for intermediates to be passed over to the final API, creating a purer product. In addition, the chiral resolution itself is very clean, so the risk of carry over from of chiral impurities will also be less. Finally, by reducing the use of solvents in the process, there is reduced chance of contamination from this source.

Conclusion
Within API and intermediates manufacture, there is an increasing demand for opportunities to improve operating margins while still producing a high quality final product, and manufacturers are eager to incorporate these cost reduction measures earlier and earlier in the product lifecycle. As shown by the successful implementation of biocatalysis in the synthesis of Duloxtine, biocatalysis enzymes are efficient catalysts which can greatly benefit both final drug products and the manufacturing processes.

It has been shown that by providing an alternative manufacturing procedure, the entire process becomes more cost efficient and streamlined. These enzymes are capable of creating a unique route for manufacturers seeking to enhance sustainability, improve performance and reduce costs. By achieving these goals, companies are better placed to contend with generic or other generic manufacturers in this increasingly competitive marketplace.