Precious metal catalysts are key to bulk waste reduction in a growing number of pharma processes. However, with metal supplies diminishing and prices soaring, this area now faces some challenges. Jon R Clipsham, director of commercial operations, and Angela D Morris, chief operations officer of Reaxa, explore the issues
Since the ratification of the Kyoto Protocol in 1997, the term "Carbon Footprint" has become part of our daily language. Increasing global attention is focused on the rate at which the planet's natural carbon-based resources are being converted to carbon dioxide (CO2) and the consequences this is having on the world's environment. With so much political and societal attention directed towards preserving the carbon economy, the spiralling demand and price increase for natural resources, such as precious metals, is passing comparatively unnoticed by the popular media and decision-makers.
Overarching raw materials supply and demand is the Sustainable Development agenda, which takes a holistic approach to the life cycle of raw materials - from extraction, to manufacturing, to end of life disposal and, ideally, recycling included in the waste management process.
With the increased emphasis on sustainability, the chemical industry knows it is a target for increasing attention when it comes to waste management, and the pharmaceutical and fine chemicals sector is currently identified as having significant waste management concerns -- it is estimated that for each kilo of API produced, some 25 to 100 kg of waste is also produced.1
Along with ageing populations, pressured healthcare budgets, depleted r&d pipelines, erosion of profit and market share by generic and "copycat" drugs and increased regulatory requirements, not to mention increasing corporate and shareholder expectations, waste management is now also an issue to be considered by pharma companies.
One strategy for pharma companies is to out-source the complex and costly "in-house" manufacture of intermediates and APIs and while this cost-saving exit brings significant job losses within pharma companies, it has in turn, led to a rapid growth of Contract Manufacturing Organisations (CMOs) and shifted the burden of waste management.
One of the ways in which bulk waste can often be reduced is to incorporate catalytic steps into a process. Currently, it is estimated that 80% of all chemical processes use a catalyst, and integrated into most API manufacturing processes is at least one catalytic step. Using catalysts in chemical production is one of the 12 principals of Green Chemistry2, and their use is generally considered an environmental gain when compared to the alternative reactions that use stoichiometric or near-stoichiometric quantities of reagents. Catalysis, it would appear, is good news for all chemicals producers.
Within the pharma and CMO sectors, precious metal catalysed reactions - notably using palladium, platinum, rhodium, ruthenium and iridium - are increasingly being used as more and more pipeline routes using catalytic steps are being developed.
The pressures conspiring against those wishing to embrace the benefits that precious metal catalysis and optimise waste management can essentially, be divided into metal pricing, metal losses and supply chain.
Over the past 10 years, demand for palladium, platinum and rhodium supplies has steadily grown - principally due to mounting use of these metals in catalytic converters within the automotive industry.
In the case of palladium, supply has been able to keep pace with demand and this is reflected in palladium's pricing; however, for platinum and rhodium (and, to some extent iridium and ruthenium), supplies are under strain, and with continued growth in demand from many sectors, it is little surprise that prices for these relatively scarce metals have been escalating, with platinum and rhodium now trading at record levels.
Looking specifically at ruthenium, historically one of the less expensive precious metals, this metal is now being used in an increasingly diverse range of chemistries (e.g. chiral hydrogenation, oxidation, and metathesis), plus potential application in fuel cell manufacture. Its usefulness versus availability has pushed purchase prices to a point whereby the whole economics surrounding use of this, once thought of as a "disposable", metal are now having to be re-assessed. As well as developing applications, customers are now also looking for ruthenium recovery technologies.
A recent study by the OKO Institute4 established the scale of losses within the catalyst cycle in Germany, where it is estimated that as much as 20% of all precious metals used in industrial catalysis (excluding environmental catalysts) are "lost". Homogeneous catalysis in particular can have a metal loss of up to 50%, which given the current pricing situation can represent a significant cost burden when precious metals are used at scale.
Precious metal losses often occur at three stages in the catalyst life cycle: catalyst manufacture; catalyst use (e.g. leaching and plating out); and in catalyst recovery and metal refining of spent catalysts.
Within the pharma industry, aside from the cost, metal losses during catalyst use may also have other important consequences. Increasingly, stringent FDA and EMEA regulations on permissible limits of platinoid (and other metal) elements within APIs is ensuring that pharma companies additionally address issues of metal leaching from heterogeneous catalysts and metal contamination carried through from homogeneous catalysts.
To meet the permissible limits5 (<5 ppm of Pt, Pd, Ir, Rh, Ru and Os for oral drug delivery; and 0.5 ppm for parenteral delivery) a clean-up or polishing step to remove contaminating heavy metals complexing with intermediates or final APIs, can often be indispensable. In these cases, metal scavengers are finding increased use, and over recent years an array of carbon, polymeric, and silica-based metal scavenger systems have all been used in batch processes to successfully reduce contamination.
One of the latest developments by Reaxa has been the introduction of iridium scavengers. These scavengers target the developing segment of asymmetric hydrogenation. As iridium metal is very scarce, a major increase in demand that is not offset by a suitable recovery process, will invariably lead to price escalation, which may in turn hinder uptake of the catalytic technology. The iridium scavengers, therefore, are a first step to at least isolating the iridium that should facilitate the refining process.
Work on the applications of metal scavengers in cartridge formats6, led by Professor Steven V Ley and Dr Ian R Baxendale, at the Innovation Technology Centre, University of Cambridge, is also highlighting the flexibility of metal scavenger systems in flow methodologies. In the industry, Reaxa, in partnership with Clear Edge, is progressing process scale cartridge formats.
A separate problem also associated with metal catalysis is the deposition of the metal on reactor walls, stirrers, and other parts of process plant. The issue of "plating out" presents a costly problem to pharma and CMOs, as they have to deal with complex washing protocols to clean up equipment for which downtime for cleaning carries a premium. Pioneering work by Professor Steven Ley in the mid to late 1990s provided a solution in the form of polyurea encapsulation of catalysts aimed at reducing metal loss and making them more user-friendly.
Encapsulating palladium3 led to the 2003 Avecia launch of the EnCat catalyst range, which in 2005 came under the Reaxa brand. The range has been further extended to other metals and complementary QuadraPure and QuadraSil metal scavengers have been developed as part of a "reduce and recover" strategy.
From the perspective of precious metal refiners, metal recovery from the pharma sector can present numerous challenges due to:
- the often diverse compositions of residues from pharma processes - variable concentrations, solvents, oxidation states and volume of precious metals contained in the mixture plus the possible presence of ligands
- the availability of flexible, economically viable processes for metal recovery - the example of ruthenium being particularly pertinent as to date there are only a few existing, but limited, processes for recovery of this metal
- knock-on issues associated with organic intermediates and API contained within the input residue to be refined; this comes under the umbrella of Waste Management
Legislation, which can restrict transportation of the waste (especially across national boundaries), and necessitates official permits to properly handle and process waste from pharma companies.
In conclusion, technically, precious metal catalysis is proven as a useful and developing tool in many areas within the chemical industry and is on the increase in the pharmaceutical and fine chemicals sector. The precious metals market is seeing increasing demands from several industrial sectors and, in general, metal prices are escalating.
In order to realise continued long term use of these strategic resources, technologies to further minimise metal losses in catalytic cycles and maximise metal recovery and refining need to be implemented to try to near-fully recuperate both metal resource and chemical value. It could be argued, that recovery of precious metals by the users should become a prerequisite.