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Colorimetric solid-phase extraction (C-SPE) is an integrated technique in which a selected analyte is concentrated onto a disk by SPE and then measured quantitatively by diffuse reflectance spectroscopy (DRS). Although several C-SPE methods have been tested successfully in microgravity simulations, incorporation of air bubbles often makes it difficult to accurately measure the volume of aqueous sample used for the analysis. This paper investigates the application of negligible depletion (ND) to C-SPE. ND is based on reaching an equilibrium in which the concentration of analyte in the original sample and in the outflow from the disk are equal after a minimum volume of sample has passed through the disk. As a result, the amount of extracted analyte is proportional to the sample concentration but independent of sample volume. With this approach, called C-SPE-ND, the precise measurement of sample volume is no longer necessary.