Loftsson T
Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
Pharmazie. 2010 Jun;65(6):404-7.
To the naked eye there is no sharp boundary between true solutions, where solute molecules are fully dispersed in the solvent, and colloidal solutions, where the solute molecules form very small (diameter < 50 nm) water-soluble aggregates, and smaller aggregates (diameter < 5 nm) are not easily detected by light scattering. In some cases small aggregates can have higher affinity than the individual test molecules for some specific receptors, but most activity studies are based on interactions of individual test molecules with some specific receptor and, thus, it is more likely that aggregate formation will result in decreased apparent activity during high throughput screening (HTS) and false negative results. Furthermore, aggregate formation will influence the physicochemical properties of drugs, such as their aqueous solubility, chemical stability and partitioning. Formation of drug/cyclodextrin inclusion complexes can be used to mimic nonspecific drug-receptor interactions. Studies in aqueous cyclodextrin solutions have shown that practically insoluble drugs (solubility < 0.05 mg/ml) form small molecular aggregates and formation of such aggregates increases with decreasing drug solubility. Novel methods for solubility determinations, which can distinguish between individual solute molecules and small molecular aggregates, can possible improve the efficacy of HTS for new drug candidates.
对于肉眼而言，在真溶液（溶质分子完全分散于溶剂中）与胶体溶液（溶质分子形成非常小的（直径<50nm）水溶性聚集体，且较小的聚集体（直径<5nm）不易通过光散射检测到）之间没有明显的界限。在某些情况下，小聚集体对某些特定受体可能具有比单个测试分子更高的亲和力，但大多数活性研究基于单个测试分子与某些特定受体的相互作用，因此，在高通量筛选（HTS）过程中聚集体形成更有可能导致表观活性降低和假阴性结果。此外，聚集体形成会影响药物的物理化学性质，例如它们的水溶性、化学稳定性和分配。药物/环糊精包合物的形成可用于模拟非特异性药物-受体相互作用。在环糊精水溶液中的研究表明，实际上不溶性药物（溶解度<0.05mg/ml）会形成小分子聚集体，并且这种聚集体的形成随着药物溶解度的降低而增加。能够区分单个溶质分子和小分子聚集体的新型溶解度测定方法可能会提高针对新药候选物的高通量筛选的功效。
