Comparison of Orthogonal Determination Methods of Acid/Base Constants with Meta-Analysis

The accurate determination of acid/base constants (proton dissociation constants-pK_a, or equivalently protonation constants-logK) is essential for the physicochemical characterization of new molecules, especially in drug design and development, as these parameters thoroughly influence the pharmacokinetics and pharmacodynamics of drug action. While pH/potentiometric titration remains the gold standard method for determining acid/base constants, spectroscopic techniques-particularly nuclear magnetic resonance spectroscopy (as NMR/pH titrations)-have emerged as powerful alternatives for specific challenges in analytical chemistry, providing also information on the structure and site of protonation. In this study, we performed a comprehensive meta-analysis of protonation constants reported in the literature, measured using both potentiometry and NMR titrations. Our analysis compiled the available literature data and assessed the agreement between the two methods, taking into consideration various experimental conditions, such as temperature and ionic strength. The results provide insights into the reliability and applicability of NMR titrations compared with potentiometry, offering guidance for selecting appropriate methodologies in drug design.