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An Amgen Case Study

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In 2009, Amgen published a chapter in “ Catalysis of Organic Reactions ” related to the use of scavengers for the removal of palladium in small to multi-kilogram production scale. In their study, they evaluated various parameters such as the scavenging efficiency, the influence of the scavenger loading and the loss of product to adsorption (recovery). The study was made on a palladium catalyzed sulfonamide coupling and scavenger screening was performed at both room temperature and 65°C using 31 different scavengers.

case-study-amgen

 

Amgen Scavenger Screening Results

Conditions: 20 mg of each scavenger (20% wt) in 2 mL HPLC vial that contains 1 mL of crude reaction mixture containing 100 mg of product. Each vial was sealed and agitated overnight. Initial palladium concentration was 423 ppm.

The best scavenger identified during their study was the SiliaMetS Thiourea providing the lowest Pd content (residual palladium concentration: 3 % or < 14 ppm) without product sequestration. They mentioned that SiliaMetS Thiourea was used extensively in early process development work.

case-study-thiourea

 

Cost Comparison for Most Efficient Scavengers (≥ 80%)

In pilot-plant scale, the best compromise between the cost per ppm removed and the scavenging efficiency is crucial. The histogram at right shows a cost comparison on best scavengers identified.
Results highlighted by the graph reduced the number of options to only 4 candidates for further evaluation: in pole position the SiliaMetS Thiourea , and then the TMT, TMT-Na3, and the Smopex 234.

most-efficient-metal-scavengers

 

Top 4 scavengers overview

A screening validation was conducted on 1 g scale purification (10 mL of solution) with 20% w/w of each top 4 scavengers at 65°C overnight. After filtration, residual metal concentration was analyzed by ICP-MS as well as product recovery by HPLC (see table below). SiliaMetS Thiourea was chosen for the large scale purification. See Amgen’s paper for further details.

Screening Validation Results on Top 4 Scavengers
Scavengers Residual Metal Concentration (ppm) Product Recovery Comments
Screening Exp. in Solution Validation Exp. in Solution Validation Exp. in Solid Product1
SiliaMetS Thiourea 14 11 158 102 % Best performance but also most expensive.
TMT 33 15 264 104 % Fine in suspension, filterability concerns on scale.
Smopex 234 36 38 496 84 % Favorable cost but product recovery not satisfied.
TMT-Na3 85 81 1 555 78 % Very basic compounds (not good with base sensitive groups). Low recovery.
Purification Scale: 100 mg 1 g 1 g 1 g  
Initial Concentration: 423 ppm 381 ppm 3 577 ppm    
Note: 1 Solid product refers to dividing the metal concentration in ppm by the amount of product in the test (1g).

 

Amgen’s Conclusion

“Scavengers offer a practical and expedient option for removing Pd from process streams to ensure quality of organic products... The screening protocol involves treatment of a candidate process stream with 20 % w/w scavenger on product at both room temperature and 65°C followed by analysis of Pd and product adsorption. High-temperature treatment increased the efficiency of Pd removal... Evaluation of process costs is key to identifying Pd removal solutions. While scavengers add cost to a process, their use is often justified by the speed to production in early phase development.

 

Catalysis of Organic Reactions, Chapter 5. Application of Scavengers for the Removal of Palladium in Small Lot Manufacturing
Allgeier et al., Amgen Inc., Thousand Oaks (California)

 

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  1. SiliaMetS Thiol (SH) (R51030B)

    SiliaMetS Thiol (SH) Metal Scavenger (R51030B)

    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.
  2. SiliaMetS Thiourea (THU) (R69530B)

    SiliaMetS Thiourea (THU) (R69530B)

    SiliaMetS Thiourea (Si-THU) is a versatile metal scavenger for all forms of palladium, and is widely used in the pharmaceutical industry. Once complexed with a transition metal, it has also been reported as being an effective catalyst. Best scavenger for: Pd & Ru. Good scavenger for: Ag, Cu, Fe, Os, Rh, Sc & Sn.

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