Cirri M, Maestrelli F, Corti G, Furlanetto S, Mura P
Dipart. di Scienze Farmaceutiche, Università di Firenze, Polo Scientifico di Sesto Fiorentino, Via U. Schiff 50019 Sesto Fiorentino, Firenze, Italy.
J Pharm Biomed Anal. 2006 Sep 11;42(1):126-31. doi: 10.1016/j.jpba.2005.11.029. Epub 2006 Jan 6.
The effect of pH variation on complexation and solubilization of naproxen (pK(a) 4.2) with natural betaCyclodextrin (betaCyD) and various neutral, cationic and anionic betaCyD-derivatives has been investigated. The combined effect of pH variation and hydrophilic polymer addition on CyD solubilizing and complexing efficiency has also been determined. Phase-solubility analysis in buffered aqueous solutions (pH from 1.1 to 6.5) was used to study the interaction of the drug with each CyD, in the presence or not of the water-soluble polymer. A clear influence of the substituent type was observed, the methylderivative being the most efficient agent; on the contrary, unexpectedly, no influence of the CyD charge in the interaction with the ionizable drug was detected. As expected, total drug solubility increased with increasing pH; however, the solubility increment with respect to drug alone obtained by CyD complexation progressively decreased, with a parallel reduction of the complex stability, attributed to the reduced affinity of charged drug for the hydrophobic CyD cavity. The addition of the polymer in part counterbalanced the destabilizing effect obtained with increasing pH, by improving the CyD complexation power towards naproxen. In particular, the presence of PVP allowed an increase of the complex stability constant with hydroxypropyl betaCyD up to 60% with respect to the corresponding drug-CyD binary system. Therefore, the combined strategy of pH control and polymer addition to the CyD complexing medium can be successfully exploited to improve naproxen solubilization and reduce the amount of CyD needed. The construction of theoretical drug solubility curves as a function of pH for any given CyD and polymer concentration enables selection of the best experimental conditions for obtaining the desired drug solubility value.
研究了pH值变化对萘普生（pK(a) 4.2）与天然β-环糊精（βCyD）以及各种中性、阳离子和阴离子β-环糊精衍生物的络合和增溶作用。还确定了pH值变化和亲水性聚合物添加对环糊精增溶和络合效率的综合影响。在缓冲水溶液（pH值为1.1至6.5）中进行相溶解度分析，以研究在有无水溶性聚合物存在的情况下药物与每种环糊精的相互作用。观察到取代基类型有明显影响，甲基衍生物是最有效的试剂；相反，出乎意料的是，未检测到环糊精电荷在与可电离药物相互作用中的影响。正如预期的那样，药物的总溶解度随pH值升高而增加；然而，通过环糊精络合获得的相对于单独药物的溶解度增量逐渐降低，同时络合物稳定性也相应降低，这归因于带电药物对疏水性环糊精空腔的亲和力降低。聚合物的添加部分抵消了随着pH值升高而产生的去稳定作用，通过提高环糊精对萘普生的络合能力。特别是，聚乙烯吡咯烷酮（PVP）的存在使羟丙基β-环糊精的络合物稳定性常数相对于相应的药物-环糊精二元体系提高了60%。因此，pH值控制和向环糊精络合介质中添加聚合物的联合策略可以成功用于提高萘普生的溶解度并减少所需环糊精的量。构建作为任何给定环糊精和聚合物浓度函数的理论药物溶解度曲线，能够选择获得所需药物溶解度值的最佳实验条件。
