It is important to understand the adsorption mechanism of chemicals and active pharmaceutical ingredients (API) on sewage sludge since wastewater treatment plants are the last barrier before the release of these compounds to the environment. Adsorption models were developed considering mostly hydrophobic API–sludge interaction. They have poor predictive ability, especially with ionisable compounds. This work proposes a solid-phase extraction (SPE) approach to estimate rapidly the API–sludge interaction. Sludge-filled SPE cartridges could not be percolated with API spiked mobile phases so different powders were tested as SPE sludge supports. Polytetrafluoroethylene (PTFE) was selected and tested at different PTFE/sludge ratios under eight different adsorption conditions with three API ionisable compounds. The PTFE/sludge mixtures with 50% or less sludge could be used in SPE mode for API sorption studies with methanol/water liquid phases. The results gave insights into API–sludge interactions. It was found that π–π, hydrogen-bonding and charge–charge interactions were as important as hydrophobicity in the adsorption mechanism of charged APIs on sludge.