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Process Optimisation and Scale-up – Case Study

Endeavour is specialised in the handling and use of a range of hazardous and often highly odorous compounds and since our acquisition by Robinson Brothers in 2008 and the successful implementation of new technology transfer processes, we are now able to offer our customers quantities ranging from a few grammes through to thousands of Kilograms.

The following case study provides an excellent example of how the technology transfer process works in practice and also highlights Endeavour-Robinson Brothers ability to rapidly scale a product from laboratory to plant.

Introduction

As part of Endeavour’s commitment to new product development, the intermediates division undertook synthesis of a variety of thioamides. These molecules are of interest as they can be used in the synthesis of hydrogen-sulphide releasing drugs (e.g. ATB-346 – a Naproxen analogue, Scheme 1).

Scheme 1

Scheme 1: Retrosynthesis of ATB-346

They can also be used to make thiazoles via reaction with -haloketones - the Hantzsch reaction (e.g. in the synthesis of Febuxostat – an oral non-purine selective xanthine oxidase inhibitor, Scheme 2).

Scale Up

Scheme 2: An example of the Hantzsch reaction – the synthesis of Febuxostat

Thioamides are normally synthesised using hydrogen sulphide – a highly odorous and toxic gas. This product group was an ideal fit for Endeavour, not only because of its commercial interest, but also because Endeavour is already equipped with an efficient containment facility that removes 99.9% of all harmful and/or malodorous compounds.

The project

In mid-2008, Endeavour was approached by a blue-chip global pharmaceutical company to supply 2,2-Dimethylthiopropionamide (Figure 1) - a compound which was already part of their existing product range.

Figure 1

Figure 1: 2,2-Dimethylthiopropionamide structure

The initial enquiry was for 5 kg with a strict lead time. Previously, Endeavour had only furnished this compound on research (gram) scale; however, using in-house process development expertise, the required compound was delivered on time and in full, meeting all customer criteria.

Further process improvements enabled Endeavour to offer a further 8 kg in half the original lead time, which was furnished in early 2009. In late 2009/early 2010, two further orders of 45 kg and 80 kg were required but the scale of these enquiries, coupled with the stringent customer lead time, meant Endeavour could not fulfil the orders directly.

Technology transfer

Endeavour’s parent company, Robinson Brothers Limited, acquired Endeavour in April 2008. Robinson Brothers has significant expertise in scale-up from 10 kg to multi-tonnes and crucially has its own containment facility for highly odorous and toxic compounds. This allowed the project to be transferred to Robinson Brothers to fulfil the 45 kg and 80 kg orders in the desired time-frame.

The chemistry was seamlessly scaled to pilot-scale and both quality and yield were improved through further optimisation of the process. As the customer’s product trials progressed and the finished drug continued to show great promise, it became clear that the chances of commercial launch were increasing and this lead to calls for an even tighter specification than the original (>98%) purity

In early 2011, the customer requested specification revisions to both the assay (product now had to be >99.5% assay) and the sulphur content (level had to be below 0.2%). These specification revisions were then to be incorporated into a further 120 kg order for delivery in mid-2011. Thanks to the skill of Robinson Brothers’ process development team, the necessary changes were made to the reaction scheme and the finished product was delivered on-time and in full.

Future

Currently, the drug, which 2,2-dimethylthiopropionamide is used for, is in late-stage clinical trials with a view to full-scale manufacturing in the near future.

Conclusions

Few companies in Europe are capable of handling Hydrogen Sulphide on both a laboratory and commercial scale. With Endeavour-Robinson Brothers high-efficacy containment systems, a range of hazardous chemical processes are possible from gram to multi-Kilo scale.

Endeavour-Robinson Brothers can offer customers access to both an extremely diverse set of technologies and chemistries and extensive experience of process development and optimisation. With our high standards of customer service and over 140 years of successful project completion, Contact us today to find out how we can make your next project our latest success.

 


© Endeavour Speciality Chemicals Ltd
2009-2017
Endeavour Speciality Chemicals Ltd
Unit 12, Low March Industrial Estate
Daventry, Northants NN11 4SD UK

P: +44 (0)1327 310 079
F: +44 (0)1327 310 701
enquiries@endeavourchem.co.uk
Endeavour Speciality Chemicals Ltd is part of the Robinson Brothers Group

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