PURPOSE: The aim was to develop a miniaturized method for solubility and residual solid screening of drug compounds in aqueous and non-aqueous vehicles in early drug development. METHODS: Different crystal modifications of caffeine, carbamazepine, and piroxicam were added into 96-well filter plates and solubility was determined in 100 microl of 17 pharmaceutical vehicles. After filtration, drug concentration was determined by Ultra Performance Liquid Chromatography (UPLC). Residual solid drug in the filter plates was analyzed by high-throughput (HT) transmission X-ray Powder Diffraction (XRPD). RESULTS: HT XRPD analysis revealed solid form conversions of all compounds during solubility determination, e.g., formation of hydrates in aqueous vehicles (caffeine, carbamazepine, piroxicam) or conversion of a metastable crystal form to the stable form (caffeine). Drug solubility was strongly dependent on the crystal modifications formed during the solubility assay. CONCLUSIONS: The new assay allows the simultaneous, small scale screening of drug solubility in various pharmaceutical vehicles and identification of changes in solid form. It is useful for the identification of formulations and formulation options in non-clinical and clinical development.

中文翻译：

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早期药物开发中溶解度和残留固体筛选 (SORESOS) 的小型化测定。

目的：目的是开发一种小型化方法，用于在早期药物开发中对水性和非水性载体中药物化合物的溶解度和残留固体进行筛选。方法：将不同晶型的咖啡因、卡马西平和吡罗昔康加入96孔滤板中，测定100微升17种药物载体的溶解度。过滤后，通过超高效液相色谱（UPLC）测定药物浓度。通过高通量 (HT) 透射 X 射线粉末衍射 (XRPD) 分析滤板中的残留固体药物。结果：HT XRPD 分析揭示了在溶解度测定过程中所有化合物的固体形式转化，例如在水性载体中形成水合物（咖啡因、卡马西平、吡罗昔康）或将亚稳态晶体形式转化为稳定形式（咖啡因）。药物溶解度强烈依赖于溶解度测定过程中形成的晶体修饰。结论：新的检测方法可以同时进行小规模药物在各种药物载体中的溶解度筛查和固体形式变化的鉴定。它可用于在非临床和临床开发中确定配方和配方选择。