Stephenson Brian C, Rangel-Yagui Carlota O, Pessoa Junior Adalberto, Tavares Leoberto Costa, Beers Kenneth, Blankschtein Daniel
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Langmuir. 2006 Feb 14;22(4):1514-25. doi: 10.1021/la052530k.
Surfactants can be used to increase the solubility of poorly soluble drugs in water and to increase drug bioavailability. In this article, the aqueous solubilization of the nonsteroidal, antiinflammatory drug ibuprofen is studied experimentally and theoretically in micellar solutions of anionic (sodium dodecyl sulfate, SDS), cationic (dodecyltrimethylammonium bromide, DTAB), and nonionic (dodecyl octa(ethylene oxide), C12E8) surfactants possessing the same hydrocarbon "tail" length but differing in their hydrophilic headgroups. We find that, for these three surfactants, the aqueous solubility of ibuprofen increases linearly with increasing surfactant concentration. In particular, we observed a 16-fold increase in the solubility of ibuprofen relative to that in the aqueous buffer upon the addition of 80 mM DTAB and 80 mM C12E8 but only a 5.5-fold solubility increase upon the addition of 80 mM SDS. The highest value of the molar solubilization capacity (chi) was obtained for DTAB (chi = 0.97), followed by C12E8 (chi = 0.72) and finally by SDS (chi = 0.23). A recently developed computer simulation/molecular-thermodynamic modeling approach was extended to predict theoretically the solubilization behavior of the three ibuprofen/surfactant mixtures considered. In this modeling approach, molecular-dynamics (MD) simulations were used to identify which portions of ibuprofen are exposed to water (hydrated) in a micellar environment by simulating a single ibuprofen molecule at an oil/water interface (modeling the micelle core/water interface). On the basis of this input, molecular-thermodynamic modeling was then implemented to predict (i) the micellar composition as a function of surfactant concentration, (ii) the aqueous solubility of ibuprofen as a function of surfactant concentration, and (iii) the molar solubilization capacity (chi). Our theoretical results on the solubility of ibuprofen in aqueous SDS and C12E8 surfactant solutions are in good agreement with the experimental data. The ibuprofen solubility in aqueous DTAB solutions was somewhat overpredicted because of challenges associated with accurately modeling the strong electrostatic interactions between the anionic ibuprofen and the cationic DTAB. Our results indicate that computer simulations of ibuprofen at a flat oil/water interface can be used to obtain accurate information about the hydrated and the unhydrated portions of ibuprofen in a micellar environment. This information can then be used as input to a molecular-thermodynamic model of self-assembly to successfully predict the aqueous solubilization behavior of ibuprofen in the three surfactant systems studied.
表面活性剂可用于提高难溶性药物在水中的溶解度，并提高药物的生物利用度。在本文中，我们对非甾体抗炎药布洛芬在具有相同烃“尾”长度但亲水头部基团不同的阴离子（十二烷基硫酸钠，SDS）、阳离子（十二烷基三甲基溴化铵，DTAB）和非离子（十二烷基八聚环氧乙烷，C12E8）表面活性剂的胶束溶液中的水相增溶作用进行了实验和理论研究。我们发现，对于这三种表面活性剂，布洛芬在水中的溶解度随表面活性剂浓度的增加呈线性增加。特别是，我们观察到在加入80 mM DTAB和80 mM C12E8后，布洛芬的溶解度相对于在水性缓冲液中增加了16倍，但在加入80 mM SDS后溶解度仅增加了5.5倍。DTAB的摩尔增溶能力（χ）最高（χ = 0.97），其次是C12E8（χ = 0.72），最后是SDS（χ = 0.23）。最近开发的计算机模拟/分子热力学建模方法被扩展，以从理论上预测所考虑的三种布洛芬/表面活性剂混合物的增溶行为。在这种建模方法中，通过在油/水界面（模拟胶束核心/水界面）模拟单个布洛芬分子，使用分子动力学（MD）模拟来确定在胶束环境中布洛芬的哪些部分暴露于水（水合）。基于此输入，然后实施分子热力学建模以预测（i）作为表面活性剂浓度函数的胶束组成，（ii）作为表面活性剂浓度函数的布洛芬在水中的溶解度，以及（iii）摩尔增溶能力（χ）。我们关于布洛芬在水性SDS和C12E8表面活性剂溶液中溶解度的理论结果与实验数据吻合良好。由于在准确模拟阴离子布洛芬和阳离子DTAB之间的强静电相互作用方面存在挑战，布洛芬在水性DTAB溶液中的溶解度被略微高估。我们的结果表明，在平坦油/水界面上对布洛芬进行计算机模拟可用于获得关于胶束环境中布洛芬水合和非水合部分的准确信息。然后，这些信息可作为自组装分子热力学模型的输入，以成功预测布洛芬在所研究的三种表面活性剂体系中的水相增溶行为。
