Enthalpy–entropy relations in the acid–base equilibrium of warfarin and 10-hydroxywarfarin; joint experimental and theoretical studies

Abstract

In this work we delineate basic thermodynamic factors that govern the acid-base equilibrium of the phenolic drug warfarin, pK a ¼ 4.99, and its metabolite 10-hydroxywarfarin, pK a ¼ 5.95. By applying experimental and theoretical approaches we have determined the enthalpic and entropic contributions to the dissociation free energy for both molecules. We have found that formation of specific intramolecular hydrogen bonds: OH/O by warfarin and OH/OH/O by 10-hydroxywarfarin, respectively, may be of a great importance for the changes in enthalpy and entropy during dissociation.The Car-Parrinello molecular dynamics have shown that these bonds are present at both temperatures T ¼ 298 K and T ¼ 378 K. We infer that an uncommon double bridge of 10-hydroxywarfarin, OH/OH/ O, imposes lower flexibility on the molecule and thereby a stronger rise of heat capacity and enthalpy upon dissociation than the single OH/O bond noted for warfarin. It has been proposed, in addition, that the entropic contributions derive from the two opposite effects related to: solvation of ionsit leads to a loss of entropy, and breaking of intramolecular bondsit causes a gain of entropy. For 10hydroxywarfarin these effects seem to be equal in magnitude, and thereby, its dissociation entropy is close to zero. Furthermore, we show that addition of a surfactant and aprotic cosolvent changes the enthalpy-entropy relations and induces the upward pK a shifts of both molecules, up to 1.5 pH unit. The changes in thermodynamics which are caused by these two additives are, however, totally different. † Electronic supplementary information (ESI) available: The calculated dissociation (deprotonation) enthalpies and entropies. The Hirshfeld atomic charges and the electrostatic potentials of WAR and W10. See

Modulation of pKa by cyclodextrins; subtle structural changes induce spectacularly different behaviors

“…The reference plots corresponding to CD-free medium have been taken from our different work. 26 Table 1 The values of thermodynamic parameters describing dissociation in the free and CD-bounded state, together with the selected pK a shifts obtained in the particular systems…”

Enhancing effectiveness of capillary electrophoresis as an analytical tool in the supramolecular acidity modification

“…As it was mentioned before, the differences in the behavior of 4-HC and CT upon temperature increase follow most likely from the interactions specific for the deprotonation process. In general, the positive sign of Δ H ° observed for the deprotonation (acid dissociation) equilibrium may be ascribed to breaking the chemical bonding with proton entailing the rise of the system heat capacity; in this case, the O–H interaction [ 5 , 10 ]. Thus, the significant gain of Δ H ° observed for 4-HC upon the addition of DM-β-CD and TM-β-CD (from around 7 to 20 and 17 kJ mol −1 , respectively) may result from a specific host-guest interaction involving the protonated form of guest, broken upon deprotonation analogously as the O–H interaction.…”

“…However, our current knowledge on these effects is still scarce and limited, and our ability to predict the magnitude of p K a shifts is weak. Hence, one of the most promising directions of research in this field is the analysis of novel p K a modification systems and thermodynamic investigations focusing on the basic molecular forces governing p K a shifts, expressed quantitatively by the enthalpic and entropic factors [ 8 – 10 ].…”

Seven Approaches to Elimination of the Inherent Systematic Errors in Determination of Electrophoretic Mobility by Capillary Electrophoresis

“…Because of its intrinsic independence from EOF, it is often a better criterion of peak identification than migration time and relative migration time. , Electrophoretic mobility also is not dependent on capillary dimensions and separation potential, enabling a transfer of methods between different experimental setups. Moreover, the transformation of an electropherogram from a traditional time scale into an alternative electrophoretic mobility scale may improve the reliability of the quantitative analysis. − An accurate determination of electrophoretic mobility is also crucial in physicochemical analysis, in determination of the acid–base dissociation constant, − the affinity/binding constant, − and their thermal dependencies. , …”

“…1−6 An accurate determination of electrophoretic mobility is also crucial in physicochemical analysis, in determination of the acid−base dissociation constant, 7−11 the affinity/binding constant, 12−14 and their thermal dependencies. 15,16 Despite the fact that eq 1 is broadly used in the literature, it yields a parameter value that is inherently affected by several different systematic errors. The first effect, which has been widely studied in the past, is a rise in the actual temperature inside the capillary (see Figure 1A).…”