The importance of removing residual metallic impurities from pharmaceutical products before commercialization is no surprise to anyone in the industry. These elemental impurities are known to cause health concerns and as such, are controlled by guidelines for their trace residue in pharmaceutical products.

Well before the clinical trials and commercialization of Active Pharmaceutical Ingredients (API), metal residues can impact your research as they can interfere with biological assays, causing false positives.

In drug discovery campaigns for the identification of potentially active small molecules, one of the strategies is High-Throughput Screening (HTS). When false positives are caused by residual impurities, a useless project could be pursued unfortunately wasting valuable time and resources that should be used on more promising ventures.

The Problem with Metal Residue

While the purity of the compounds is always evaluated before submitting to biochemical assays, it is usually verified using either NMR or mass spectra. These analyses are great to check for organic impurities but will not reveal any underlying metallic residues.

Experiments from Roche demonstrated just that.1 A compound exhibiting promising IC50 and KD values in an enzyme-linked immunosorbent (ELISA) enzyme assay, gave hope of a series of potentially active molecules.

After spending time and resources resynthesizing the series of molecules and their analogs, the structures were run through a Structure-Activity Relationship (SAR) with inconclusive data and large variations in biological activities from batch-to-batch.

As it turned out, the resynthesized molecules and analogs did not all go through the same synthetic route. A correlation was shown between the batches with high residual zinc (leftover catalyst) concentrations and the activity. The compounds that were previously thought promising were in fact not active. But the zinc ions were.

Undertaking a project on a lead compound that was in fact a false positive can be avoided by simply checking for metal impurities before starting a lead optimization campaign and using proper metal removal purification techniques.

And not only for zinc ions. Going back to Roche, the team there ended up checking the activity of different metals against Pad4 and found potency in most of those tested. 1

IC50 of Different Metals against Pad4
Metal IC50 (µM)
Zinc (Zn2+)1
Iron (Fe3+)192
Palladium (Pd2+)231
Nickel (Ni2+)242
Copper (Cu2+)279
Barium (Ba2+)1,000
Calcium (Ca2+)1,000
Magnesium (Mg2+)1,000

These metals all have a somewhat high risk of being present in small molecules tested for potency due to their common use as catalysts in organic synthesis. This is where SiliCycle can help.

The Solution to Metal Residue

SiliaMetS Metal Scavengers are selective towards metal impurities. They selectively bind to the undesired residues and, when filtered out, leave the product of interest free of impurities.

There is a scavenger for most metals commonly used in organic synthesis. A quick screening can help determine which ones to pursue, and then the usual parameters can be optimized as suggested in the Application Note Appn_SM001-1 Experimental Procedure Optimization for SiliaMetS Metal Scavengers.

    Best Scavenger     Good Scavenger

Scavenger Ag Al Ca Cd Ce Co Cr Cs Cu Fe Gd Hg Ir La Li Mg Ni Os Pb Pd Pt Rh Ru Sc Se Sn Ti V W Zn
SiliaMetS Thiol
SiliaMetS DMT
SiliaBond Amine
SiliaMetS AMPA
SiliaMetS Cysteine
SiliaMetS DEAM
SiliaMetS Diamine
SiliaMetS DOTA
SiliaMetS Imidazole
SiliaMetS TAAcOH
SiliaMetS Thiourea
SiliaBond Tosic Acid
SiliaMetS Triamine

Why Is Scavenging the Best Solution?

What is even better about scavenging impurities with SiliaMetS before running the products of interest through activity screenings, is that once the product of interest is confirmed active (and resynthesized and eventually scaled-up for clinical trials), these scavengers have what it takes to follow-up and scale-up the purification linearly.

Not only is time saved by avoiding the pursuit of the wrong candidates after a false positive, but time is also saved when it comes to scaling-up and the purification parameters are already working. And metal limits for pharmaceutical compounds are already respected. Three birds, one scavenger.

Calculating how much scavenger is needed is way easier than a quantum chemistry class. Even your 10 ten years old nephew can do it if he follows this video.

In the case that you do not want to screen yourself all scavengers or to quantify residual metals, SiliCycle can help there too: our R&D team can do it for you. Whatever you prefer, there is no need for any special equipment to use SiliaMetS scavengers and they are available in different formats to meet you where your needs are.

Using preparative HPLC for your purifications? You can add a SiliaMetS guard column to your system. Already own an E-PAK housing? Check out SiliaMetS E-PAK cartridges. They are also available in flash cartridges, SPE cartridges, or simply in bulk that you can throw in your round-bottom flask or in your reactor when scaling-up. Even in an Erlenmeyer after your work-up: removing metals is as easy as removing water with magnesium sulfate. There is no reason to lose time with false positives. Only solutions.


1 Hermann, J. C. et al. ACS Med. Chem. Lett. 2013, 4, 197-200

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