A microtube screening approach affords simple and convenient assessment of the selective adsorption of metal impurities by a variety of different process adsorbents. This approach is helpful in identifying rapid solutions to metal impurity problems in pharmaceutical process research. Several examples illustrating the utility of the approach are presented.

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The feasibility of the determination of sub ppm to percentage levels of halogen elements (fluorine, chlorine, bromine, and iodine) in solid organic compounds and drug substances by double focusing sector field highresolution inductively coupled plasma mass spectrometry (HR-ICP-MS) was investigated. Samples were dissolved in appropriate solvents and then diluted in either deionized water or 5% (v/v) ammonium hydroxide. By applying medium or high resolution, the background counts can be lowered by up to five orders of magnitude compared to conventional quadrupole ICP-MS systems. The signal sensitivities and memory effects of all four elements in different solvents were compared and assessed. The methods were applied to the determination of sub ppm to percentage levels of F, Cl, Br and I in a series of organic compounds and Merck drug substances. The results were found to be in excellent-to-reasonable agreement with the known or theoretical values of these compounds or drug substances. The limit of detection in solution for F was estimated to be 5 mg ml 21 (medium resolution), and for Cl, Br and I was 3 (high resolution), 0.08 (high resolution) and 0.03 (high resolution) ng ml 21 , respectively.

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Information on chemical speciation is much needed in mechanistic and kinetic studies on catalyst formation processes in pharmaceutical research. Speciation analysis was applied to the identification and quantification of various rhodium species involved in a ligand exchange process leading to formation of catalyst dirhodium(II) tetrakis[methyl 2-oxopyrrolidin-5(S)-carboxylate]. Inductively coupled plasma mass spectrometry (ICPMS) was used as an element-specific detector following species separation by reversed-phase high-performance liquid chromatography (RP-HPLC), and electrospray ionization mass spectrometry (ESI-MS) was used for species identification and confirmation. A novel interface between the HPLC and ICPMS, which consisted of an eluent splitter, a desolvation unit, and the ICPMS built-in peristaltic pump, enabled the use of RP-HPLC with gradient elution and up to 100% organic components in the LC eluent without organic loading in the plasma. A variety of reaction intermediates were identified and quantified along the pathway to formation of the desired product, including isomeric di-, tri-, and tetrasubstituted species previously believed to be absent. This has provided new insights into the mechanism and kinetics of the reaction. The combination of HPLC-ICPMS and HPLC-ESI-MS has proven to be a valuable tool for the investigation of species evolution in catalyst formation process.