Microionization constants: novel approach for the determination of the zwitterionic equilibrium of hydroxyphenylalkylamines by photometric titration

The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

“…We assume that ionization of each site is independent of the other one and is described by mass action law, so that equilibrium dissociation constants are not the same. 16 Such a consideration requires very detailed information about ionization properties of the molecule, which is not readily available, and the calculation of f i would also be significantly more complicated.…”

Substituent effects on the ionization and partitioning of p-(aminoethyl)phenols and structurally related compounds: Electrostatic effects dependent on conformation

“…Several publications have reported microscopic ionization constants for such compounds,12–18 however, the various reported values do not agree. Even quite recent publications such as the work by Nagy and Takacs‐Novak,14 and Peinhardt and Wiese13 report widely disparate values for the microscopic ionization constants for tyramine when compared with each other, and both conflict with earlier work such as that by Riegelman et al12 or those predicted by a fragment based approach 2. These discrepancies, up to 1 p K a unit, are larger than the typical variation in reported p K a values generated for the same compound in multiple labs, and may be due to various reasons including incorrect assignment of the microscopic constants, experimental error, or other factors.…”

Best of Both Worlds: Combining Pharma Data and State of the Art Modeling Technology To Improve in Silico pKa Prediction

“…Changes in dominant protonation states can alter pharmacological interactions drastically and thereby influence potency. A drug candidate’s predominant charge state at a given pH can be a major determinant of pharmacological activity, aqueous solubility, permeability, plasma protein binding, cardiotoxicity, and metabolism, and the level of general interest in such ionization phenomena is evident from the large number of recent publications on the topic. − …”