Filippa Mauricio, Sancho Matías I, Gasull Estela
Area de Química Física, Departamento de Química, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, 5700 San Luis, Argentina.
J Pharm Biomed Anal. 2008 Nov 4;48(3):969-73. doi: 10.1016/j.jpba.2008.06.005. Epub 2008 Jun 14.
The complexation of methyl salicylate (MS) and ethyl salicylate (ES), non-steroidal analgesic, anti-inflammatory and antirrheumatic drugs with beta-cyclodextrin (betaCD) has been studied from thermodynamic and structural points of view. The complexation with betaCD has been investigated using reversed-phase liquid chromatography. Retention behavior has been analyzed on a reverse-phase column Luna 18(2) 5 microm. The mobile-phase was methanol:water in different ratios (55:45 to 70:30) in which betaCD (1-9 mM) was incorporated as a mobile-phase additive. The decrease in retention times with increasing concentrations of betaCD enables the determination of the apparent stability constant of the complexes. Values at 30 degrees C with 55% methanol were K(MS:betaCD): 15.84 M(-1) and K(ES:betaCD): 12.73 M(-1) for MS and ES, respectively. The apparent stability constants decrease as the polarity of the solvent decreases. The low solubility of MS and ES in aqueous solution has been improved by complexation with betaCD (1-9 mM). The stability constants of the complexes obtained from the phase-solubility diagrams using a UV-vis spectrophotometric method were K(MS:betaCD): 229 M(-1) and K(ES:betaCD): 166 M(-1). In addition, semi-empirical quantum mechanics calculations using AM1 and PM3 methods in vacuum were performed. The energetically favorable inclusion structures were identified and the most favorable orientation for the inclusion process was found to be the head-down orientation for both complexes. Enthalpy for encapsulation processes was found to be favorable (DeltaH degrees <0), while entropy (DeltaS degrees <0) and Gibbs free energy were unfavorable (DeltaG degrees >0). By means of HPLC and UV-vis measurements and quantum mechanics calculations, it was found that MS and ES form a 1:1 inclusion complex with betaCD. The theoretical results are in agreement with the experimental parameters associated with the encapsulation process.
从热力学和结构角度研究了非甾体类镇痛、抗炎和抗风湿药物水杨酸甲酯（MS）和水杨酸乙酯（ES）与β-环糊精（βCD）的络合作用。采用反相液相色谱法研究了与βCD的络合作用。在反相柱Luna 18(2) 5微米上分析了保留行为。流动相为甲醇和水的不同比例（55:45至70:30），其中加入了βCD（1-9 mM）作为流动相添加剂。随着βCD浓度的增加，保留时间缩短，从而能够测定络合物的表观稳定性常数。在30℃和55%甲醇条件下，MS和ES的K(MS:βCD)分别为15.84 M(-1)和K(ES:βCD)为12.73 M(-1)。表观稳定性常数随着溶剂极性的降低而降低。MS和ES在水溶液中的低溶解度通过与βCD（1-9 mM）络合得到改善。使用紫外可见分光光度法从相溶解度图获得的络合物稳定性常数为K(MS:βCD)：229 M(-1)和K(ES:βCD)：166 M(-1)。此外，在真空中使用AM1和PM3方法进行了半经验量子力学计算。确定了能量上有利的包合结构，发现两种络合物包合过程最有利的取向都是头向下取向。发现包封过程的焓是有利的（ΔH°<0），而熵（ΔS°<0）和吉布斯自由能是不利的（ΔG°>0）。通过高效液相色谱和紫外可见测量以及量子力学计算，发现MS和ES与βCD形成1:1的包合络合物。理论结果与包封过程相关的实验参数一致。
