Thermodynamic enthalpy–entropy compensation effects observed in the complexation of basic drug substrates with β-cyclodextrin

Abstract

Measurement of the variation of inherent drug solubility (So) and 1:1 drug/cyclodextrin complex formation constants (K11) with temperature were used to estimate the thermodynamic parameters (ΔHo, ΔSo and ΔGo). A plot of TΔSo against ΔHo indicates the extent of enthalpy–entropy compensation; that is, how much of the enthalpic gain is cancelled by entropy loss or vice versa (the slope indicates the fraction of conformational change contribution to enthalpy gain that is cancelled by an accompanying entropy loss). The remaining fraction of enthalpy gain contributes to complex formation. The intercept is the inherent contribution to complex stability, which is due to desovation. Extensive phase solubility studies combined with rigorous analysis were conducted in the temperature range 20–45°C for the following basic drugs complexing with β-cyclodextrin (β-CD): astemizole (Astm), cisapride (Cisp), dipyridamole (Dipy), ketotifen (Keto), pizotifen (Pizo), terfenadine (Terf), fexofenadine (Fexo), sildenafil (Sild), and celecoxib (Celox). The results indicate that inherent drug solubility is accompanied by unfavorable conformational changes to the extent of 86%, which are counterbalanced by opposite favorable entropy changes. Only 14% of the favorable enthalpy change contributes to drug solubility. The extent of solvation (hydration) accompanying solubility amounts to −30 kJ/mol, which retards solubility as an unfavorable entropy change. In contrast, 1:1 drug/β-CD complex formation is accompanied by favorable conformational changes to the extent of 94%, which are counterbalanced by unfavorable entropy changes. Only about 6% of enthalpy changes contribute to complex stability. However, the extent of favorable entropy change (desolvation) accompanying complex formation amounts to 26 kJ/mol.