Echezarreta-López María Magdalena, Otero-Mazoy Iria, Ramírez Héctor Luís, Villalonga Reynaldo, Torres-Labandeira Juan José
Departamento de Farmacia e Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Sur, Santiago de Compostela, Spain.
Curr Drug Discov Technol. 2008 Jun;5(2):140-5. doi: 10.2174/157016308784746328.
The aim of this work is to analyze the effect of cyclodextrin (CD) complexation on the solubilization and stabilization of sodium dicloxacillin in acid aqueous solutions. The effect of four cyclodextrins alpha-, beta-, gamma- and hydroxypropyl-beta-CD was studied. Phase solubility diagrams obtained are AL or BS type, depending on the cyclodextrin used and on the pH of the solution. The highest stability constants of the inclusion complexes are obtained with gamma-CD at pH 1 and 2 and HPbeta-CD at pH 3. The structure of the inclusion complex in solution is characterized by nuclear magnetic resonance (1H-NMR). This study suggests that the 7-oxo-4-thia-1-azabicyclo group is located in the CD cavity. Nevertheless, molecular modelling calculations predict two different orientations of dicloxacillin in the gamma-CD cavity in vacuum and in aqueous solution. In vacuum, the results predict the inclusion of the dichlorophenyl ring of dicloxacillin instead of 7-oxo-4-thia-1-azabicyclo group into the gamma-CD cavity. However, the results are different in aqueous solution and this conformation is confirmed by the NMR study. The effect of gamma-CD and HPbeta-CD in the stability of the drug in solution was studied. The degradation of sodium dicloxacillin in solution follows a pseudo-first-order kinetics and the cyclodextrin do not change this fact. Both cyclodextrins increase the stability of the drug but the efficacy is higher with gamma-CD.
这项工作的目的是分析环糊精（CD）络合对双氯西林钠在酸性水溶液中的增溶和稳定作用。研究了四种环糊精，即α-、β-、γ-和羟丙基-β-环糊精的作用。根据所使用的环糊精和溶液的pH值，得到的相溶解度图为AL型或BS型。在pH 1和2时，γ-环糊精形成的包合物稳定性常数最高；在pH 3时，羟丙基-β-环糊精形成的包合物稳定性常数最高。通过核磁共振（1H-NMR）对溶液中包合物的结构进行了表征。该研究表明7-氧代-4-硫杂-1-氮杂双环基团位于环糊精腔内。然而，分子模拟计算预测在真空和水溶液中，双氯西林在γ-环糊精腔内有两种不同的取向。在真空中，结果预测双氯西林的二氯苯环而非7-氧代-4-硫杂-1-氮杂双环基团会被包入γ-环糊精腔内。然而，在水溶液中的结果不同，且这种构象通过核磁共振研究得到了证实。研究了γ-环糊精和羟丙基-β-环糊精对溶液中药物稳定性的影响。双氯西林钠在溶液中的降解遵循准一级动力学，环糊精并未改变这一事实。两种环糊精都提高了药物的稳定性，但γ-环糊精的效果更佳。
