INSTRUMENT SYSTEM FOR RAPID HPLC/MS ANALYSIS OF DRUGS

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The aim of the proposed work is to develop an instrument system based on time-of-flight mass spectrometry (TOF-MS) and high performance liquid chromatography (HPLC) specifically for the rapid and sensitive analysis of drugs and their metabolites in blood and urine. This instrument will enable the future development of an automated drug-screening system that will conduct wide-spectrum drug analyses in five minutes or less, enabling the results to be used in emergency diagnostic procedures. Analytes eluting from the HPLC will be ionized by a spray ionization technique. The continuously formed ions are transferred to, and stored in, a unique three-dimensional ion trap from which they are periodically extracted for time-of-flight mass analysis. Extracted ions arrive at the detector, in order of their mass, over an interval of less than 500 mus during which time, a transient signal containing full mass spectral information with unit mass resolution to m/z 2000 or greater is produced. An integrating transient recorder acquires, sums, and processes the 2000 transient signals per second from the detector to produce and record 10 to 100 mass spectra per second. This combination of processes will achieve extremely high sensitivity (detection limits of less than 10-9 mole) due to the very efficient use of sample in each stage of analysis and the compacting of analyte response that occurs in the HPLC and the ion-trap/TOF/MS. The high sensitivity and spectral generation rates enable the effective application of data deconvolution for the identification and quantitation of chromatographically unresolved components. Reduced reliance on chromatographic separation allows 10- fold or more reduction in chromatographic run time with no sacrifice in sensitivity or analytical information. The assembled LC/MS system will be used to identify the stationary phase, the moving phase, the instrumental configuration, and the experimental protocol that will minimize the analysis time for the identification and quantitation of single or mixed drugs and/or their metabolites in blood and urine while still maintaining full analytical integrity. An LC/MS analysis time of 90-180 seconds is sought, enabling a broad spectrum analysis of drugs to be accomplished in a fraction of the time presently required. A final objective will be to delineate the components and processes that will combine with the LC/MS technique to perform fully automated drug analyses in a time frame suitable for diagnostic effectiveness.