The diverse range of opportunities offered by ISEs has been broadly used in a number of pharmaceutical applications, with topics presented ranging from bioanalysis of drugs and metabolites, to green chemical analysis, impurity profiling, and drugs' dissolution in biorelevant media. Attractively, solid-contact ISEs (SC-ISEs) have been implemented in many approaches due to their ability to offer stable and miniaturizable sensors. In this contribution, gold SC-ISEs were used in bare and thiol-doped forms for the analysis of the two co-formulated drugs namely, naproxen sodium and diphenhydramine hydrochloride in tablets. The unique ability of thiol to form a hydrophobic self-assembled monolayer on gold surface, resulted in more sensitive, stable, and drift-free potentiometric signals. The special advantages offered by the gold-thiol electrodes empowered us to utilize them as real-time analyzers to investigate the protein-binding behavior of the studied drugs by continuous in-situ monitoring of the drug in presence of serum albumin. The proposed sensors could offer a prediction of the pharmacokinetics of each component drug, giving the healthcare professionals the opportunity to provide a personalized medicine for the patients according to their different protein-binding characteristics. (c) 2017 The Electrochemical Society. All rights reserved.