Another excellent question we received following seminars and presentations relates to the function and activity of metal scavengers. IUPAC nomenclature rules combined with various naming systems and also a chemists appetite for simple readily identifiable reagents, has led to a rather unfortunate conclusion, that to the uninitiated, metal scavengers can seem all the same. Unfortunately, there are other (and inferior) metal scavengers on the market – I don’t want this to be one of those competition bashing blogs, so I have edited out those details and will only focus on the science here.
Metal scavengers are functionalized polymers designed to specifically attract a metal of interest from an organic product or mixture. They are generally white / off white cream powders, based on a polystyrene or silica polymeric backbone, and some of them claim to have similar functionalities so it’s no surprise that newcomers to the science could get that impression that they are all the same.
I thought I would share some information which shines some more light on this and could help to avoid falling into the trap of selecting a ‘fake’ or a lesser alternative, for your precious metal mitigation processes.
At Biotage, when we design metal scavengers, our goals are simple, to provide a solution to the growing regulatory need to output purer and purer compounds, such as API in pharma. Part of this relates to extractables and the chapter in ICH, namely Q3D relating to elemental limits is particularly relevant.
In one of our first studies into metal scavenging, we compared two resin-based TMT scavengers. (One of these was the original Biotage® MP-TMT and the other, I am not going to name it here was a similarly named alternative. That alternative did not end up being able to stand the test of time and is no longer commercially available – so my point has already been proven already by market forces).
Science is timeless, and great science will never age, so even a bit old, I still enthusiastically refer to this study using Biotage® MP-TMT (Figure 1) as an example something to be cautious of when faced with a barrage of alternative metal scavengers.
In our analysis, we created a 852ppm Pd solution of dichlorobis(DPP)ferrocene Palladium in THF/DMF (1/1), which we then portioned. An increasing quantity of Biotage MP-TMT metal scavenger or the ‘other’-TMT, was then applied, and the resulting metal scavenging performances measured and compared.
In another blog article we have written on the dangers of using loading capacity as the main guide to expectations of a metal scavengers’ performance. But in this case, it was a bit different. The ‘other’-TMT we used in this study, on paper was similar to Biotage MP-TMT in terms of loading capacity, so it’s a bit harder for chemist and especially the non-chemist or purchasing group, to choose between them.
We simply exposed increasing quantities of two metal scavengers to a standard stock solution of our palladium catalyst, for a std period of time, and analyzed to see how much palladium had been removed over time from each (Figure 2)
Figure 2 – Comparison of 2 similar named TMT metal scavengers. The dark blue line shows Biotage MP-TMT removed all of the palladium from solution, with nearly 4 times less metal scavenge needed compared to the ‘other’ TMT metal scavenger.
The darker purple trace represents Biotage-TMT and the lighter (magenta curve) was the ‘other-TMT’ in our experiment. Starting from the same point (852ppm) the level of Pd indeed comes down with increasing resin, in both cases, but the blue line, MP-TMT shows almost complete removal at 50mg (4 equivalents) of scavenger. The other scavenger needed almost 4 times as much to get the same result.
So, ultimately, the ‘other’ scavenger may have checked the technical feasibility box or looked good on paper as a POC (proof of principle) but it would have let its users down from a process economics and scale up perspective. The years of polymer and chemistry expertise that went into in designing effective Biotage metal scavengers such as Biotage MP-TMT was clearly not evident in this other ‘copy’.
What we are finding is that when ‘other’ /poorer copies of Biotage metal scavengers find their way into the hands of genuine scientists it wastes everyone’s time and adds unnecessary cost, resource and time to already stretched drug development and process development targets. The other scavenger we tested (the fake, so to speak) claimed to be as strong as a MP-TMT, but clearly it could not even come close when tested under scientific conditions. It was about 4 times worse from a process economics perspective (Figure 3).
Figure 3 – An alternative view of Figure 2, showing that the dark blue line (Biotage® MP-TMT) removed all of the palladium when added to the system in only 25% of the mass of the ‘competitor’ scavenger.
Our findings have over the years helped to shed a lot of light and help a number of clients who’s preconceptions of metal scavengers, had been initially tainted by these lesser alternatives. Since making pure product is usually the goal of the chemist, purification and metal mitigation steps are just incidental steps, that ideally, we would not need to do, but when needed, they need to be relied upon to work efficiently and get the job done. Gold standards in metal scavenging such as Biotage MP-TMT are powerful tools in the battle to reduce metal content.
Read our other blog posts to learn more about metal scavenging, just follow the link below!