Analytical Research, CMC Japan, Pharmaceutical Science & Technology Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
Int J Pharm. 2011 Oct 31;419(1-2):170-4. doi: 10.1016/j.ijpharm.2011.07.045. Epub 2011 Aug 4.
96-well plate based anti-precipitant screening using bio-relevant medium FaSSIF (fasted-state simulated small intestinal fluid) is a useful technique for discovering anti-precipitants that maintain supersaturation of poorly soluble drugs. In a previous report, two disadvantages of the solvent evaporation method (solvent casting method) were mentioned: precipitation during the evaporation process and the use of volatile solvents to dissolve compounds. In this report, we propose a solvent shift method using DMSO (dimethyl sulfoxide). Initially, the drug substance was dissolved in DMSO at a high concentration and diluted with FaSSIF that contained anti-precipitants. To evaluate the validity of the method, itraconazole (ITZ) was used as the poorly soluble model drug. The solvent shift method resolved the disadvantages of the evaporation method, and AQOAT (HPMC-AS) was found as the most appropriate anti-precipitant for ITZ in a facile and expeditious manner when compared with the solvent evaporation method. In the large scale JP paddle method, AQOAT-based solid dispersion maintained a higher concentration than Tc-5Ew (HPMC)-based formulation; this result corresponded well with the small scale of the solvent shift method.
基于 96 孔板的抗沉淀剂筛选，使用生物相关介质 FaSSIF（禁食状态模拟小肠液），是发现能够维持低溶解度药物过饱和度的抗沉淀剂的有用技术。在之前的报告中，提到了溶剂蒸发法（溶剂浇铸法）的两个缺点：蒸发过程中的沉淀和使用挥发性溶剂来溶解化合物。在本报告中，我们提出了一种使用 DMSO（二甲基亚砜）的溶剂转移方法。最初，药物在 DMSO 中以高浓度溶解，并与含有抗沉淀剂的 FaSSIF 稀释。为了评估该方法的有效性，使用伊曲康唑（ITZ）作为低溶解度模型药物。溶剂转移方法解决了蒸发方法的缺点，与蒸发方法相比，AQOAT（HPMC-AS）以简单快捷的方式被发现是 ITZ 的最合适的抗沉淀剂。在大规模 JP 桨法中，基于 AQOAT 的固体分散体保持的浓度高于基于 Tc-5Ew（HPMC）的制剂；这一结果与小规模的溶剂转移方法非常吻合。
