Pharmaceutical Applications of Calorimetry. Thermodynamic Aspects of Multiple Inclusion Complexation between Barbiturates and 2-Hydroxypropyl-.BETA.-cyclodextrin in Aqueous Solution.

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Other Title
  • 医薬品開発と熱測定　　バルビツール酸誘導体と２‐ヒドロキシプロピル‐β‐シクロデキストリンの水溶液中多種包接複合体形成についての熱力学的考察
  • バルビツールサン ユウドウタイ ト 2-ヒドロキシプロピルーベーターシクロデキ

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Isothermal titration calorimetry has been employed to evaluate inclusion mechanism associated with complexation between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and barbiturates (BAs). The association constants, stoichiometry, and enthalpic changes were calculated from calorimetric titration curves using a non-linear least squares method. The inclusion modes (structures) were explored by relating the thermodynamic parameters to the chemical structures of BAs molecule and the cavity size of HPβCD. Two different types of BAs-HPβCD inclusion complexes at 1:1 stoichiometry were realized by un-ionized BAs, whereas only one type of inclusion was by barbital. The first type of BAs-HPβCD with higher association constant was largely entropically driven with the constant values of ΔG1, ΔH1 and ΔS1 at various pH, thus the hydrophobic interaction dominated the stabilization of the complexes. The second type was characterized by large negative values of ΔH2 and small ΔS2 at pH < pKa values of BAs, reflecting van der Waals' interaction and/or hydrogen bonding formation, and all the thermodynamic parameters markedly decreased at pH > pKa. It is indicated that the R2 substituent at 5C in barbituric acid ring of BAs was included within HPβCD cavity in the first type of com-plexes and that the barbituric acid ring penetrated into the cavity in th second type. In both types, the ethyl-side chain of R1 substituent remained out-side of the cavity. The results were agreed with those from 13C-NMR spectrometry. The inclusion geometry of the complexes were estimated by molecular dynamics calculations.

Journal

  • Netsu Sokutei

    Netsu Sokutei 25 (4), 117-125, 1998

    The Japan Society of Calorimetry and Thermal Analysis

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