Organic extractables (substances extracted from materials used in pharmaceutical packaging) are discovered, identified, and quantified via screening of extracts with analytical methods including liquid chromatography with mass spectrometric detection (LC-MS). Because extractables include a large number of diverse compounds that are typically present in plastic extracts at low levels, the LC-MS methods must be broad scope and sensitive. To accomplish these objectives, screening studies typically couple gradient reversed-phase separations with electrospray MS detection (both positive and negative ion modes). While such methods are generally applicable for a number of extractables, they are not optimal for some commonly encountered extractables due to either poor chromatographic performance (e.g., peak tailing) or poor MS response. Modifications to mobile phase composition (e.g., pH adjustment) were examined to improve the performance of an LC-MS screening method. The use of 0.1% acetic acid with 1 mM ammonium acetate (pH 3.6) as the aqueous portion of the mobile phase provided favorable sensitivities for a number of extractables both in positive and negative ion modes. In positive ion mode, the acidic mobile phase improved responses for moderately weak basic compounds by increasing their degree of protonation. For very weak basic compounds such as amides, ammonium ions in the mobile phase promoted proton adduct responses. In negative ion mode, an acidic mobile phase containing acetate anion improved ESI responses for acidic compounds, primarily due to gas phase effects.