Removal of Soluble Palladium Complexes from Reaction Mixtures by Fixed-Bed Adsorption

Efficient removal of soluble palladium complexes in reaction mixtures is critical to meet drug substance palladium specifications (< 2 ppm). The objective of this project is to develop a well-grounded methodology to remove these complexes by fixed-bed adsorption (see diagram below), which offers key advantages over adding adsorbents as fine particles to vessels: (a) avoiding vessel fouling and time-consuming cleaning, (b) eliminating a slow slurry filtration, and (c) the possibility of regenerating adsorbents, thus reducing waste. A Heck coupling reaction was used to generate a reaction mixture containing palladium complexes. A technique was developed to quantify the partitioning of palladium complexes in the reaction mixtures between the solid and liquid phase, and thus allow for rapid screening of adsorbents and determination of the optimal adsorption temperature. A laboratory-scale adsorption column was designed and constructed. Under optimal conditions, palladium removal by fixed-bed adsorption exceeded 99.9%. Comparison of actual column performance with that from a mathematical model implicated axial dispersion as a cause of unfavorable column behavior.