Role of the\nPower Function Value in Linearity and\nUniversality for Charged Aerosol Detectors: Theoretical Elucidations\nfrom a Validated Model

High-throughput drug discovery on the microgram scale\nis now common,\nmaking analyte quantitation without molecule-specific calibration\nimperative. The charged aerosol detector (CAD) was invented to be\na next-generation universal liquid chromatography (LC) detector with\nexcellent response universality for nonvolatile analytes as well as\nsensitivity for nonchromophoric compounds. Although the CAD is a mass\nflow-sensitive detector, its response to mass is inherently nonlinear,\nwhich challenges traditional quantitation. In CAD software, there\nis a “power function value” (<i>p</i>) setting\nthat can be used to linearize the signal through digital signal processing.\nThe exact workings of this power function value algorithm remain unknown;\nhowever, its optimization is a crucial aspect of analytical method\ndevelopment for LC-CAD. Herein, we developed a theoretical relationship\nthat can be used to predict the chromatogram (plus peak area, width,\nand height) at any <i>p</i> if the data are collected at <i>p</i> = 1. This model was validated using a diverse dataset\ncomprising 1440 measurements including peak heights, areas, and widths.\nPredicted areas had an average error of less than 2% showing excellent\nagreement between calculated and experimental results. An open-access\nautomated code is tested and provided, which predicts the power function\nvalue that produces the most linear response. It is vital to note\nthat optimizing the power function value affects peaks of different\nheights disproportionately. Low-level impurities were shown to be\nminimized and eventually eliminated by increasing the power function\nvalue. This model provides an easy-to-implement tool (MATLAB or Excel)\nthat assists in choosing the optimal <i>p</i> for each LC-CAD\nmethod, increasing the speed of method development and improving the\naccuracy of quantitative workflows.