Enthalpy–entropy compensation for some drugs dissociation in aqueous solutions

The observed enthalpy–entropy compensation seems to be strongly indicative of a common mechanism of drugs dissociation. The regression triplet (data, model, method) is used for the estimation of dependencies between thermodynamic parameters ΔH0, ΔS0, ΔG0 derived from dissociation constant measurements at two different temperatures and Van’t Hoff equation. The orthogonal regression analysis involves 87 experimental pKa values performed on 44 drugs to give unbiased parameter estimates for a linear dependence ΔH0 = 40.43 + 0.966 TΔS0 with the Pearson's correlation coefficient r = 0.8953. The standard free energy change ΔG0 for the dissociation reaction may be decomposed on ΔH0vs. pKa dependence and TΔS0vs. pKa dependence. The ΔH0 is sensitive to changes in pKa because of electrostatic effects. Increasing the Brönsted basicity of the drug causes an increase of the ΔH0 term and decreases the TΔS0 term. When ΔH0 is negative, then the value TΔS0 is the dominant factor, which determines that ΔG0 is positive. The ionization of a neutral acid involves formation of two ions so that the entropy decreases. On the second ionization of the same acid, there are now three ions and the anion has a charge, so the entropy again only decreases.

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► Enthalpy–entropy compensation is indicative of a mechanism of drugs dissociation.
► Regression triplet estimates dependencies between ΔH, ΔS, ΔG derived from pKa's.
► Orthogonal LS involves 87 pKa to give ΔH0 = 40.43 + 0.966 T ΔS0 with r = 0.8953.
► Increasing basicity of drug causes increase of ΔH0 term and decreases TΔS0 term.