The present study shows how specific and selective particle-beam liquid chromatography mass spectrometry (PB-LC/MS) can be for certain biopharmaceutical applications and by which strategy maximum sensitivity can be achieved. The utility of PB-LC/MS in the analysis of different pharmaceutical drugs and endogenic substances with different molecular structures has been investigated. Using the PB interface in combination with a triple quadrupole mass spectrometer, the effects of mobile phase composition and flow rate, interface parameters-such as desolvation temperature and pressure of the nebulization gas-and the temperature of the ion source, on detection limits and sensitivity, are demonstrated, A particular substance specificity of this interface type for creatinine, naloxone and methadone could be observed after optimizing the transmission of the interface, The best sensitivity is achieved only in a narrow working range, indicating the necessity of an individual optimization of interface conditions for each substance. Linearity, sensitivity and precision of transfer rate using the EI and selected-ion monitoring modes were demonstrated. Investigation of the so-called "carrier effect" on the transfer of the selected compounds indicated that the addition of ammonium acetate as "carrier" changed the detection sensitivity in a completely different order. (C) 1998 John Wiley & Sons, Ltd.