Barbosa Leandro R S, Itri Rosangela, Caetano Wilker, Neto Diógenes de Sousa, Tabak Marcel
Instituto de Física da Universidade de São Paulo, Cx. Postal 66318, CEP 05315-970 - São Paulo, SP, Brazil.
J Phys Chem B. 2008 Apr 10;112(14):4261-9. doi: 10.1021/jp710332t. Epub 2008 Mar 18.
Small-angle X-ray scattering (SAXS) and electron paramagnetic resonance (EPR) have been carried out to investigate the structure of the self-aggregates of two phenothiazine drugs, chlorpromazine (CPZ) and trifluoperazine (TFP), in aqueous solution. In the SAXS studies, drug solutions of 20 and 60 mM, at pH 4.0 and 7.0, were investigated and the best data fittings were achieved assuming several different particle form factors with a homogeneous electron density distribution in respect to the water environment. Because of the limitation of scattering intensity in the q range above 0.15 A(-1), precise determination of the aggregate shape was not possible and all of the tested models for ellipsoids, cylinders, or parallelepipeds fitted the experimental data equally well. The SAXS data allows inferring, however, that CPZ molecules might self-assemble in a basis set of an orthorhombic cell, remaining as nanocrystallites in solution. Such nanocrystals are composed of a small number of unit cells (up to 10, in c-direction), with CPZ aggregation numbers of 60-80. EPR spectra of 5- and 16-doxyl stearic acids bound to the aggregates were analyzed through simulation, and the dynamic and magnetic parameters were obtained. The phenothiazine concentration in EPR experiments was in the range of 5-60 mM. Critical aggregation concentration of TFP is lower than that for CPZ, consistent with a higher hydrophobicity of TFP. At acidic pH 4.0 a significant residual motion of the nitroxide relative to the aggregate is observed, and the EPR spectra and corresponding parameters are similar to those reported for aqueous surfactant micelles. However, at pH 6.5 a significant motional restriction is observed, and the nitroxide rotational correlation times correlate very well with those estimated for the whole aggregated particle from SAXS data. This implies that the aggregate is densely packed at this pH and that the nitroxide is tightly bound to it producing a strongly immobilized EPR spectrum. Besides that, at pH 6.5 the differences in motional restriction observed between 5- and 16-DSA are small, which is different from that observed for aqueous surfactant micelles.
已开展小角X射线散射（SAXS）和电子顺磁共振（EPR）研究，以探究两种吩噻嗪药物，即氯丙嗪（CPZ）和三氟拉嗪（TFP）在水溶液中的自聚集体结构。在SAXS研究中，对pH值为4.0和7.0时浓度分别为20 mM和60 mM的药物溶液进行了研究，并在假设几种不同粒子形状因子且相对于水环境具有均匀电子密度分布的情况下，实现了最佳数据拟合。由于在q范围高于0.15 Å⁻¹时散射强度的限制，无法精确确定聚集体形状，所有测试的椭球体、圆柱体或平行六面体模型对实验数据的拟合效果均相同。然而，SAXS数据表明，CPZ分子可能在正交晶胞的基组中自组装，在溶液中以纳米微晶形式存在。这种纳米晶体由少量晶胞组成（沿c方向最多10个），CPZ聚集数为60 - 80。通过模拟分析了与聚集体结合的5 - 和16 - 二氧硬脂酸的EPR谱，并获得了动力学和磁学参数。EPR实验中吩噻嗪的浓度范围为5 - 60 mM。TFP的临界聚集浓度低于CPZ，这与TFP较高的疏水性一致。在酸性pH 4.0时观察到氮氧化物相对于聚集体有明显的残余运动，EPR谱及相应参数与报道的水性表面活性剂胶束的相似。然而，在pH 6.5时观察到明显的运动限制，氮氧化物的旋转相关时间与根据SAXS数据估算的整个聚集粒子的旋转相关时间非常吻合。这意味着在该pH值下聚集体紧密堆积，氮氧化物与之紧密结合，产生强烈固定的EPR谱。除此之外，在pH 6.5时，5 - 和16 - DSA之间观察到的运动限制差异较小，这与水性表面活性剂胶束的情况不同。
