Introduction
Platinum group metal (PGM) catalysts, referring to platinum, palladium, ruthenium, rhodium and iridium complexes, have become a staple of active pharmaceutical ingredient (API) synthesis. Favoured for their high activity and selectivity, they have found routine application as homogeneous catalysts. With stringent regulatory guidelines in place to limit residual metal levels within APIs, process chemists are often presented with challenges of identifying and implementing techniques to remove contaminant metals from synthetic products during process development.
In addition to this, the high value of PGMs and a greater focus on sustainability have led to a heightened interest in the extraction and refining of waste streams that contain these metals for reuse in catalysis. This has been further driven by a growing demand for homogeneous catalysts across the pharma, agrochemical, and fine chemicals industries. By taking a circular approach, chemists can significantly reduce carbon emissions and capital expenditure associated with PGM catalysis in industrial processes.
Effective metal extraction and refinement from waste streams is often technically challenging and there is no one-size-fits-all approach. Identifying the ideal metal scavenging technique involves careful consideration of reaction conditions and reagents, screening specific reagents or scavengers, and the assessment of their net costs versus savings. Examining the methods available and deciding on refining techniques in the early stages of process development is key to building effective metal management into one’s processes. This saves both time and money when transitioning to late stage or commercial scales.
Removing metals from homogeneous catalysis applications – benefits and challenges
The treatment route taken to extract and refine homogeneous waste streams is highly dependent on the reaction pathway used. Solvent selection, functional group presence, and reaction conditions can all alter the efficacy of a given technique.
During process development, it is sometimes possible to remove residual PGM waste in API synthesis through more conventional methods, such as crystallisation. However, due to the complexity in crystallising modern, structurally elaborate APIs, this can pose a challenge. Alternatively, either metal scavengers or complex chemical treatments can be highly effective in removing metals from complex process streams.
Heterogeneous metal scavengers are highly attractive alternatives for removing PGMs as they are functionalised specifically to efficiently target and remove them from solution with very high recoveries. Generally effective at low temperatures, they are appropriate in both organic and aqueous solutions. After treating a process or waste stream with the metal scavenger via a packed bed or in-line filter, the complexed scavenger can be separated, thermally processed and refined. Both silica- and polymer-based varieties of scavengers are available, which allows for specific tailoring towards different reaction conditions. Scavengers are particularly appropriate for highly aqueous waste streams since they circumvent the need for energy intensive and costly distillations, and heat-sensitive solutions, where products can decompose. The scavengers then work very well to generate a small, solid, mass of loaded scavenger which can be thermally refined. Conversely, in the case of waste processing organic solvents, distillation is generally sufficient, resulting in high metal recovery and low energy consumption.
While highly effective, scavengers can also be expensive to implement at scale and are not chemically inert due to the presence of reactive functional groups. This can cause them to generate new impurities, triggering potential regulatory issues.
As an alternative to scavengers, a complexing agent or chemical treatment can be introduced to remove PGMs from APIs. Cysteine derivatives and dithiocarbamates, such as N-Acetyl cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC), can complex residual metals in solution, allowing for separation through aqueous extractions. However, this method, like the use of metal scavengers, can trigger impurity generation in certain reaction pathways. The process also needs to be done under basic conditions, which can cause chemical incompatibility with the API or intermediates. In addition, depending on the number of extractions required, this method can result in a highly diluted aqueous waste stream, which will increase the cost and time required for metal refinement.
Building your waste stream for refining
With such a wide range of in-process metal extraction methods available, implementing the right waste stream early in process development is more important than ever and ensures recoverability is built into the product. While the potential savings from metal recovery may initially seem insignificant, it can quickly grow during scale-up and commercial-scale manufacturing. Efficient metal reclamation may even allow for more applications of iridium and rhodium-based catalyst systems, which are widely used in other industries, but historically avoided in the pharmaceutical industry. By integrating a plan for metal refining into processes before scale-up, industrial chemists can create more sustainable, cost-effective synthetic routes.
Considering techniques for waste stream refining from the beginning of the research process allows refiners to lend their expertise and support the creation of optimal, cost-saving waste streams. By sampling and testing a typical waste stream, they can help identify the most cost-effective in-process and post-process refining solution based on a customer’s unique needs. If needed, they can also identify where metal loss occurs during a synthetic process by working collaboratively with customers during scale-up to determine the optimal extraction and refinement route.
Since regulatory requirements dictate the detection of residual metals, commonly used characterization tools to assess metal impurities in API intermediates can be used in the development of waste streams. By applying techniques such as X-ray fluorescence (XRF) and inductively coupled plasma optical emission spectroscopy / mass spectrometry (ICP-OES/ICP-MS), pharmaceutical companies can successfully quantify the metal content of waste streams.
Waste streams can also incorporate other forms of circularity, beyond metal recovery. For instance, following chemical treatments where the resultant solution may contain large quantities of solvent, refiners can distil and recycle the solvent. Depending on the purity of the solvent, refiners can then find alternative routes for it across other industries, helping to promote circularity beyond the pharmaceutical value chain.
Fundamentally, creating an effective waste stream for metal refining must be done on a case-by-case basis. The economics are different for any given process, and with additional reclamations being possible, many factors need to be considered when building and scaling up a synthetic pathway.
Closing the loop
With a growing demand for homogeneous catalysts and an increasing focus on environmental regulations, the need for efficient metal recycling has never been greater.
Additionally, across the world, governments are deploying critical mineral strategies, aimed at improving their supply resilience and sustainability in the face of growing demand and geopolitical uncertainty. Therefore, incorporation of reclamation strategies across synthetic pathways is a fundamental need of the pharmaceutical industry.
While there are challenges associated with refining complex catalyst residues, there are also many potential benefits. Beyond alignment with sustainability strategies, cost savings upon scale-up—especially when using higher value PGMs such as iridium and rhodium—can be significant when a product reaches commercial scale.
By working with a knowledgeable technology partner, industrial chemists and process engineers can collaboratively design optimal waste streams from an early stage that deliver the desirable cost savings and sustainability metrics. Through careful process design, greater resilience and cost-savings can be built into API syntheses and bring a more sustainable approach to the pharmaceutical industry.
