Customers and process scientists have concerns about the scalability of metal scavengers for drug synthesis – a topic we’ve touched on before in other posts but haven’t yet fully explored.

We’ve previously discussed the use of metal scavengers in drug manufacturing and how scavengers address the growing need to remove synthesis catalysts. We’ve also published videos showing how easy it is to calculate the quantity of scavenger you need.

So, how common a problem is metal contamination during drug synthesis?

It’s a growing and increasingly important area – most notably in small molecule pharma manufacturing where the use of catalysts to synthezise molecules has become prevalent. While using catalysts has its benefits, the downside of the technique is the introduction of metals, most of which are toxic and must be removed. Not surprisingly, this has led to a significant increase in the need for scavenging processes.

As an alternative to crystallization (which has thermal risks), solvent extraction (requires large solvent volumes) and chromatography (very costly and often not commercially scalable), functionalized silica is well-known for its scavenging properties:

  • No leaching
  • High purity
  • High selectivity
  • Wide range of metal affinities
  • Fast kinetics
  • Cost-efficient
  • Broad solvent & pH compatibility
  • Compatible with microwave synthesizers and flow chemistry
  • Excellent thermal and mechanical stability
  • Easy to use
  • Flexible formats
  • Available in bulk
  • Scalable
Heavy Metals in Drug Manufacturing?

Check out the following metal removal case studies to see how common a challenge this has become:

What Makes Seasoned Scientists Sweat?

It’s that last bullet in the list – scalability – that is often on the minds of process chemists. How scalable is metal scavenging with silica? More importantly, how straightforward is the scaling process?

These are important questions, to be sure. For the drug industry, scalability is never simple – and it can cause nightmares. Whether it’s due to process efficiency and cost, or broader Environment, Health & Safety (EHS) concerns, scalability can make even the most seasoned scientist sweat.

Unfortunately, scale-up is tricky. It would be lovely if it were as simple as doubling the number of tomatoes to make a larger batch of spaghetti sauce. But drug process development is often anything but straightforward or perfectly linear…and unanticipated challenges always seem to arise.

The good news is linear scale-up does exist! Whether by an in-house or external R&D team, the process can be optimized. Once the drugmaker is satisfied with the scavenging results, direct scale-up with silica-based metal scavengers is feasible.

Let’s explore how it works. (Heads up: there will be a quiz at the end!)

3 Steps to Scale Up Silica-Based Metal Scavengers

There are three key steps involved in scaling up: scavenger selection, scavenger optimization and process transfer across scales.

  1. Choose the Right Scavenger.

    As you might expect, selecting the right scavenger chemistry is accomplished using feasibility studies to find the most effective scavenger for your sample. The selection is typically narrowed down either by drugmakers opting to develop processes in-house or by a scavenger manufacturer’s R&D team based on the nature of the catalyst.

        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 TAACONa
    SiliaMetS Thiourea
    SiliaBond Tosic Acid
    SiliaMetS Triamine

    For effective metal removal, the amount of scavenger used is critically important. [Here are two methods SiliCycle uses to calculate equivalents and determine the amount of metal scavenger needed for an application: 1) based on residual metal concentration in ppm, or 2) from the amount of metal catalyst used.] In a typical screening test, up to 48 solutions can be screened to identify the most efficient scavenger.

    Popular & Versatile SiliCycle Metal Scavengers
    SiliaMetS Thiol - Metal Scavenger

    SiliaMetS Thiol (Si-Thiol)

    Our most versatile and robust metal scavenger for a variety of metals under a wide range of conditions.
    Best scavenger for: Ag, Hg, Os, Pd & Ru.
    Good scavenger for: Cu, Ir, Pb, Rh, Se & Sn.

    SiliaMetS Thiol - Metal Scavenger

    SiliaMetS DMT

    The silica-bound equivalent of 2,4,6 - trimercaptotriazine (trithiocyanuric acid, TMT), SiliaMetS DMT is a versatile metal scavenger for a variety of metals and the preferred metal scavenger for ruthenium catalysts and hindered Pd complexes.
    Best scavenger for: As, Ir, Ni, Os, Pd, Pt, Rh, Ru & Se.
    Good scavenger for: Cd, Co, Cu, Fe, Sc & Zn.

  2. Optimize Scavenging Parameters.

    There are multiple parameters which must be optimized prior to scale-up. These include temperature, reaction time, solvent, pH, additional filtration steps, mixing rate, the nature and the volume of scavenger equivalents.

    Optimization also includes selection of a scavenger mode. Scavenging efficiency can often be improved by changing the mode. SiliCycle’s SiliaMetS offers excellent compatibility with various methods and technologies including batch, fixed bed (SPE or Flash cartridges), flow chemistry or microwave.

    Ideally, this preliminary work is completed at the lab scale, with adaptations later to conditions discovered at the pilot or commercial scales. Lab scale optimization is the basis for all subsequent larger scales, and it is important to reproduce the conditions as closely as possible.

    In this study using SiliaMetS Metal Scavengers on various metal catalysts commonly used in organic synthesis, the key parameters which influence the robustness of a scavenger are discussed (solvent, number of equivalents, temperature, reaction time and nature of the catalyst).

  3. Process Transfer.

    The process is now ready to move to pilot or commercial scale – and this is where functionalized silica scavengers shine. Sizes and capacities are selected based on reactor style – batch mode (SiliaMetS) or fixed bed/flow (E-PAK). Scale-up projections based on linear extrapolation of adsorbent mass have proven to be quite accurate when test conditions are held constant.

    Here’s a scale-up study with SiliaMetS Thiol demonstrating the ease of scaling 125X – while maintaining comparable scavenging results.

    Pd(OAC)2 : Residual Palladium, Concentration and % of captation

    Test Sample Volume Screening test ... scale up Residual Concentration % of captation
    Screening 8 mL - < 1 ppm 99.99%
    Medium Scale 150 mL 20 times < 1 ppm 99.99%
    Large Scale 1 000 mL 125 times < 1 ppm 99.99%

    Experimental conditions: 4 eq. of SiliaMetS Thiol, 4h, 80°C. Initial concentration: 200 ppmn in DMF.

    In recent years, drug manufacturers, CMOs and CDMOs have increasingly turned to the latest flow cartridge scavenger technology. SiliCycle’s E-PAK flow cartridges, for example, deliver linear scale-up from bench to pilot to commercial production - helping further shortcut the scale-up process. (Learn more about SiliCycle E-PAK flow cartridges).

Are you wondering how silica-based scavengers perform in real-world scale-up situations?

Here’s an example:

An article published in Organic Process Research & Development discusses the chemistry behind the first fully-synthetic broad spectrum 7-fluorotetracycline in clinical development. The key reaction was a Dieckmann condensation between a suitable substituted aromatic moiety and a cyclohexanone derivative.

Scale-Up of Hydrogenation and Pd Scavenging Results

Entry1 Hydrogenation Time Time for Slurry in EtOH / H2O Yield / Amount Pd Content after treatment
112 h2 h82.5% / 25.7 g0.4 ppm
24 h17 h79.3% / 36.2 g0.2 ppm
37 h2 h77.0% / 155.5 g0.39 ppm
410 h2.5 h79.6% / 186.6 g1.11 ppm
511 h4 h85.8% / 349.2 g< 0.2 ppm

1 6.2 to 10 wt % Pd/C was used

Subsequent hydrogenolysis was extensively studied, using a Pd/C catalyst. Without any treatment, residual palladium levels as high as 2,000 ppm were detected. SiliaMetS DMT, was found to reduce the residual Pd content to more than acceptable levels (less than 0.2 ppm) with a scale-up factor of ≈14.

Linear Scale-Up with Radial-Flow Cartridges

Scaling up silica-based metal scavengers is a straightforward process when following the steps described above, but radial flow cartridges can further simplify the transfer across scales.

In radial-flow cartridges functionalized silica exhibits perfect scale-up linearity. Scale-up projections based on a linear extrapolation of adsorbent mass have proven to be quite accurate when test conditions including contact time, temperature, solvent type, contaminant and compound levels are held constant. Here it is demonstrated in palladium removal following a typical Suzuki-Miyaura reaction:

When it comes to metal removal in drug development, process chemists can rest easy: scale-up with silica is generally much more straightforward than with other metal recovery options. Silica-based metal scavengers are a powerful, selective and cost-effective tool. providing incredible versatility with different solvents and pH. In addition, they are compatible with batch flow operations and microwave use.

Think you’re a metal scavenger hot shot?

You were warned! Challenge yourself & your friends with this quiz!



Having a Scavenger Scale-Up Challenge?

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