General Observations Residual Metal Contamination

A soluble metal-catalysed reaction should ideally be placed as early as possible in the synthetic sequence.

In order to maximise process economics and minimise issues with residual metals, the amount of metal added should be optimised. A trade–off is often required between metal/catalyst loading and process robustness. It may not always be feasible to use a homeopathic metal loading.

It should not be assumed that a supported or heterogeneous catalyst will not leach metal. This is very dependant on the nature of the heterogeneous catalyst, solvents, additives/ligands added and the ability of reactants/product to ligate metals.

If the catalyst support is a synthetic material – resin, polymer etc. then a risk assessment needs to be carried out on the potential to leach small organic monomers/cross linkers/ oligomers that could be classed as PGI’s–specially if used in parts of the synthesis under c-GMP / close to the final API product.  This also applies to any synthetic scavenger solids used.

If a product compound /API ligates metals, the formation of a cationic or anionic salt can often reduce metal levels.

A heterogeneous hydrogenation step post the metal-catalysed reaction can often drastically reduce contaminating metal levels.

The robustness and scalability of a metal scavenging methodology depends on the speciation of the metal(s) present – nanoparticulate/particulate/ discrete zero valent complexes, M+, M2+ etc.

In order to successfully remove a range of metal species, some scavenging methods use two reagents – one to remove charged metal species and another to remove particulates and/or zero oxidation state complexes.

A lack of reproducibility in metal removal on scale-up has often been traced to differing levels of O₂ entering the reaction vessel during the work-up and changing the speciation of the metal bi products.  This could be oxidation of the metal or any ligands present (especially phosphines). A strategy sometimes adopted is to add an oxidant after the reaction to ensure that the metal is always present in a consistent high oxidation state.

If this technique is used, the usual safety issues around solvents and oxidizing agents need to be considered.