Optimization and Standardization of Liquid Chromatography‐Mass Spectrometry Systems for the Analysis of Drug Discovery Compounds

Abstract

An approach for improving the speed and effectiveness of orthogonal, low and high pH, LC/MS‐based methods for routine applications is presented. Considering HPLC column performance as an integral part of an LC/MS system, advantages and disadvantages of three modern column technologies are thoroughly discussed as alternatives to conventional silica‐based packing materials. Instrument performance assessment strategies, using a standard mix composed of four drug‐like compounds, are discussed where parameters such as peak capacity and retention are used as key performance indicators. These procedures have been standardized and evaluated across two different sites within Lilly Research Laboratories. The value of alternating orthogonal low and high pH methods, in a high throughput mode, on a single system is demonstrated. The development of software for simulating the LC/MS open access sample queues is also presented.

Keywords:

• Liquid chromatography‐mass spectrometry
• Drug discovery compounds
• Orthogonality
• Low pH and high pH methods
• Peak capacity
• Standard mix
• System suitability test
• Simulation software

Acknowledgments

The authors thank Bernard Olsen (Lilly, USA) for careful evaluation of the manuscript and some helpful discussions. The authors also thank Almudena García (Lilly, Spain) for technical assistance.