Simultaneous Determination of Residual Palladium and Thiol Homogeneous Scavenger N-Acetylcysteine in Active Pharmaceutical Ingredients Using Inductive Coupled Plasma-Mass Spectrometry

Abstract

To ensure compliance with regulations regarding levels of residual metals in pharmaceutical products, process research and development (PR&D) in the pharmaceutical industry makes wide use of metal scavengers characterized by high selectivity and effective removal ability. Thiol homogeneous scavengers are notably effective in terms of eliminating palladium from intermediates and active pharmaceutical ingredients (APIs) during production. The strategies for detecting residual thiol homogeneous scavengers such as N-acetylcysteine are presently problematic within pharmaceutical analysis. Herein a simple and effective method using inductively coupled plasma-mass spectrometry (ICP-MS) for the simultaneous detection of N-acetylcysteine (based on sulfur determination) and palladium is described. The method was successfully validated with regard to linearity, accuracy, repeatability, the limit of quantification (LOQ), and the limit of detection (LOD).

A Streamlined, Safe and Sustainable Process for Gemlapodect

“…Hence, the base and solvent in the palladium‐catalyzed coupling step to 7 were changed from Cs 2 CO 3 to NaO t Bu and from dioxane to Me‐THF, respectively, and a treatment with acetyl cysteine (0.8 equiv.) as Pd scavenger [10] was implemented after the coupling step. After filtration, the crude solution of 7 was telescoped to the deprotection step performed in Me‐THF, allowing the yield to increase to 77 % over the two steps.…”

“…MS and 1 H-NMR spectra were in accordance with literature data. [26] 1-Methyl-5-[(2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamoyl]-1H-pyrazole-4-carboxylic Acid (10). A 2 L glass vessel, equipped with mechanical stirrer, reflux condenser, dropping funnel, internal thermometer and nitrogen gas supply, was charged with ethyl 1-methyl-5-[(2-phenyl [1,2,4]triazolo[1,5-a]pyridin-7yl)carbamoyl]-1H-pyrazole-4-carboxylate (16; 82.60 g, 212 mmol) and tetrahydrofuran (1 L).…”