Improvements to the Sample Manipulation Design of a LEAP CTC HTS PAL Autosampler Used for High-Throughput Qualitative and Quantitative Liquid Chromatography - Mass Spectrometry Assays

摘要

To produce high-quality drug candidates and to support drug discovery decision making, compounds are subjected to predictive in vitro and in vivo absorption, distribution, metabolism, excretion, toxicology, drug metabolism, and pharmacokinetics assays, in which samples are typically analyzed using automated liquid chromatography-mass spectrometry (LC-MS). Depending on sample preparation and clean-up efforts, matrix components such as salts, nonprecipitated small molecules, and particulate matter can remain in the sample, thus having a detrimental effect on the performance of the autosampler, especially if the sample manipulation mechanism is syringe-based. This issue is amplified in high-throughput qualitative and quantitative LC-MS-based assays due to the large sample load and associated mechanical "wear-and-tear" of the syringe, resulting in poor data quality, increased costs, and lost time as a result of sample re-analysis. Described here are improvements made to the sample manipulation design and mechanism of a LEAP CTC HTS PAL autosampler. This setup completely eliminates the contact of samples and potentially abrasive and corrosive matrix components with both the syringe plunger and barrel through the use of a Teflon tubing loop, thus significantly extending the life of the injection device. In our high-throughput in vitro assay to assess the metabolic stability of compounds, we observed a 20-fold increase in the syringe lifetime using the improved sample manipulation design versus the standard setup with similar analytical performance such as reproducibility, accuracy, and precision. (JALA 2007;12:152-6)