Ong J K, Sunderland V B, McDonald C
School of Pharmacy, Curtin University of Technology, Bentley, Australia.
J Pharm Pharmacol. 1997 Jun;49(6):617-21. doi: 10.1111/j.2042-7158.1997.tb06855.x.
Hydroxypropyl beta-cyclodextrin (HP beta CyD) has been shown to stabilize a wide variety of chemically distinct pharmaceutical entities through inclusion-complex formation between drug and cyclodextrin. The effect of HP beta CyD on the acid-catalysed hydrolysis of benzylpenicillin (penicillin G) was evaluated in chloroacetate buffer at pH 2.20. At penicillin G: cyclodextrin molar concentration ratios from 1:1 to 1:10, HP beta CyD effected stabilization of penicillin G by 1.56- to 5.21-fold. At all temperatures, the observed first-order rate constant (kobs) values assumed a non-linear, Michaelis-Menten type decrease as a function of increasing HP beta CyD concentration. Degradation of penicillin G complexed with HP beta CyD (penicillin G-HP beta CyD), was approximately ninefold slower than uncomplexed penicillin G. The proportion of penicillin G degrading in either of these forms was, in turn, determined by the equilibrium constant for the complexation. The apparent thermodynamic and activation parameters for the complexation between penicillin G and HP beta CyD have also been evaluated. The negative standard enthalpy change (delta H degrees) for the complexation implied that the penicillin G-HP beta CyD complex would be predisposed towards enhanced stability, and thus the kobs value for the hydrolysis of penicillin G decreased with reduction of temperature in these systems. The lack of difference between the enthalpies of activation (delta H ++) for the hydrolysis of uncomplexed and complexed penicillin G seemed to be compensated by the significant difference between the entropies of activation (delta S ++) for these hydrolytic reactions. The results indicate that HP beta CyD represents a viable means of stabilization of penicillin G solutions at the pH employed in this study.
羟丙基-β-环糊精（HPβCyD）已被证明可通过药物与环糊精之间形成包合物来稳定多种化学性质不同的药物实体。在pH 2.20的氯乙酸盐缓冲液中评估了HPβCyD对苄青霉素（青霉素G）酸催化水解的影响。在青霉素G与环糊精的摩尔浓度比为1:1至1:10时，HPβCyD使青霉素G的稳定性提高了1.56至5.21倍。在所有温度下，观察到的一级速率常数（kobs）值随着HPβCyD浓度的增加呈非线性的米氏类型下降。与HPβCyD络合的青霉素G（青霉素G-HPβCyD）的降解速度比未络合的青霉素G慢约九倍。这两种形式中降解的青霉素G的比例又由络合平衡常数决定。还评估了青霉素G与HPβCyD络合的表观热力学和活化参数。络合的负标准焓变（ΔH°）表明青霉素G-HPβCyD络合物倾向于具有更高的稳定性，因此在这些系统中，青霉素G水解的kobs值随温度降低而降低。未络合和络合的青霉素G水解的活化焓（ΔH‡）之间缺乏差异，似乎由这些水解反应的活化熵（ΔS‡）之间的显著差异所补偿。结果表明，在本研究采用的pH值下，HPβCyD是稳定青霉素G溶液的一种可行方法。
