Driving forces for the inclusion of the drug tolmetin by β-cyclodextrin in aqueous medium.: Conductometric and molecular modeling studies
Driving forces for the inclusion of the drug tolmetin by β-cyclodextrin in aqueous medium.: Conductometric and molecular modeling studies
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DOI：
10.1021/la9817011
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发表时间：
1999-06-22
期刊：
影响因子：
3.9
通讯作者：
Aicart, E
中科院分区：
文献类型：
--
作者：
Junquera, E;Mendicuti, F;Aicart, E
采用电导和分子力学的方法，从热力学和结构的角度分析了β -环糊精（P-CD）对非甾体抗炎和抗风湿药物托美汀的包封。在15 ~ 40℃的不同温度下，对甲苯咪酸盐（TOL-）水溶液的电导率进行了测量，得到了络合物的化学计量（1:1）、缔合常数（近似于2000 M-1）以及游离(lambda(DRUG)(0)和络合(lambda（CD:DRUG)(0)）无限稀释时的离子摩尔电导率。由K值随温度的变化关系可知，焓的变化为负，熵的变化为正，说明焓和熵都有利于包合过程。分子力学（MM）计算也用于研究真空和有水的络合作用，结果表明，药物倾向于通过较宽的入口进入β - cd腔，甲苯基端首先进入。从MM计算和实验结果来看，可能由分子间氢键引起的疏水效应和静电相互作用似乎在水介质中β - cd:TOL-络合物的形成中起着相关作用。
The encapsulation of tolmetin, a nonsteroidal antiinflammatory and antirrheumatic drug, by beta-cyclodextrin (P-CD) has been analyzed from thermodynamic and structural points of view, by means of conductometric and molecular mechanics studies. Conductivity measurements of aqueous solutions of tolmetinate (TOL-) were performed as a function of beta-CD concentration, at different temperatures ranging from 15 to 40 degrees C. The stoichiometry of the complex ( 1: 1), its association constant (similar to 2000 M-1),and the ionic molar conductivities at infinite dilution of the free (lambda(DRUG)(0)) and complexed (lambda(CD:DRUG)(0)) drug were obtained from these conductivity data. A slightly negative change in enthalpy and a positive change in entropy, obtained from the dependence of K values with the temperature, reveal that both the enthalpy and the entropy favor the inclusion process. Molecular mechanics (MM) calculations, also employed to study the complexation in vacuo and in the presence of water, show that the drug prefers to penetrate into the beta-CD cavity by the wider entrance, with toluol group end first. From both MM calculations and experimental results, the hydrophobic effect and electrostatic interactions, possibly arising from the presence of intermolecular hydrogen bonds, seem to have a relevant role in the formation of the beta-CD:TOL- complex in aqueous media.