Generic Ion Chromatography–Conductivity Detection Method for Analysis of Palladium Scavengers in New Drug Substances

Abstract

The revolution of palladium-catalyzed reactions in the synthesis of new molecules has created an unprecedented need for highly efficient palladium (Pd) removal processes. Metal scavengers with very selective and efficient removal properties are being extensively applied across process research and development (PR&D) to meet very tight specifications for residual Pd levels. Analytical procedures for the determination of residual Pd are well-established; however, developing methodologies to detect a variety of Pd scavengers in multicomponent reaction mixtures is currently considered an emerging challenge in pharmaceutical analysis. Herein a simple and efficient generic ion chromatography−conductivity detection (IC−CD) method on a Dionex IonPac AS19 column in conjunction with a fully aqueous eluent profile (potassium-hydroxide-based) capable of chromatographically resolving over 10 Pd scavenger species commonly used in PR&D workflows is described. Computerassisted separation modeling using an ACD Labs/LC simulator served to generate 3D resolution maps with excellent separation conditions that matched the outcome of subsequent experimental data. Method validation experiments showed excellent analytical performance in linearity, recovery, repeatability, and LOQ/LOD. In addition, these same chromatographic conditions can separate multiple anionic species and active pharmaceutical (API) counterions along with Pd scavengers in the same experimental run. We also provide strategic examples where API counterion interferences (e.g., sulfate) can be minimized by treating the API sulfate form with barium acetate to enhance the recovery of the Pd scavenger analyte.

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

“…Furthermore, this analysis is usually employed during the manufacture of the drug substance to ensure batch quality; therefore, a quick and sensitive method is needed for this purpose. Recently, a generic ion chromatography-conductivity detection (IC-CD) procedure, for simultaneous analysis of palladium scavengers in new drug substances was introduced . To the best of the author’s knowledge, there is no methodology available to determine both residual N -acetyl cysteine and catalyst, simultaneously.…”

Generic Enhanced Sub/Supercritical Fluid Chromatography: Blueprint for Highly Productive and Sustainable Separation of Primary Hindered Amines

“…This is a cost-effective and time-efficient approach that translates into a rapid turnaround of results which is vital to accelerating process development and manufacturing of new drug substances. Some examples include the analysis of solvents and volatile amines by gas chromatography (GC), ,,,, a generic method for nucleotides and palladium scavengers by ion exchange chromatography (IEC), dehalogenation impurities and mixtures of halogen isomers, ,− drug metabolites and analogues, − direct analysis of chiral active pharmaceutical ingredients (APIs) and their counterions by UHPLC, enantiopurity analysis across an entire synthetic route using a single chiral core–shell column in LC mode, generic chiral method development in SFC, and synthetic intermediates containing multiple stereocenters by two-dimensional LC, among others …”

Mapping the Separation Landscape of Pharmaceuticals: Rapid and Efficient Scale-Up of Preparative Purifications Enabled by Computer-Assisted Chromatographic Method Development

“…Environmental stewardship through sustainable practices is quickly becoming a primary target of process development and manufacturing in the pharmaceutical industry and, with it, greening analytical and preparative chromatography toward more generic and efficient approaches. ,,− Promoting sustainability in chromatography by reducing the cumulative use of mobile phase solvents and the waste generated from chromatographic instrumentation has been extensively targeted as an important element in the pursuit of a greener laboratory, though efforts to date have predominantly focused on the analytical scale. − There remains a clear opportunity to refine workflows for large-scale purification laboratories, in which method development and optimization are substantially more costly and generate significantly more hazardous waste than their analytical counterparts. Turnaround time, cost savings, and method “greenness” are of paramount importance in any scale-up separation process for delivering highly pure drug substances quickly and efficiently.…”