Image-Based Investigation: Biorelevant Solubility of α and γ Indomethacin
Image-Based Investigation: Biorelevant Solubility of α and γ Indomethacin
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DOI：
10.1021/acs.analchem.8b05290
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发表时间：
2019-03-19
影响因子：
7.4
通讯作者：
Yliruusi, Jouko
中科院分区：
文献类型：
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作者：
Stukelj, Jernej;Svanback, Sami;Yliruusi, Jouko
溶解度是一种物理化学性质，高度依赖于化合物的固态形式。因此，可以改变化合物的固态形式以增强难溶性药物化合物的溶解度。在生物制药分类系统（BCS）中，药物是根据其水溶性和渗透性进行分类的。然而，水溶性并不总是与体内溶解度和因此的生物利用度最佳相关。因此，使用生物相关介质是模拟体内条件的更合适的方法。在这里，通过一种新的基于图像的单颗粒分析（SPA）方法进行评估，我们报告了吲哚美辛在生物相关介质中的α和γ固态之间的溶解度增加的恒定比例为3.3 +/- 0.5。该比率与pH、离子强度和表面活性剂浓度无关，这些都随着药物通过胃肠道而变化。根据溶解度比，估计两种多晶态的自由能差为2.9 kJ/mol。最后，使用SPA方法来评估溶解度已被证明是简单、快速的，并且既节省溶剂又节省样品，使其成为药物开发的有吸引力的工具。
Solubility is a physicochemical property highly dependent on the solid-state form of a compound. Thus, alteration of a compound's solid-state form can be undertaken to enhance the solubility of poorly soluble drug compounds. In the Biopharmaceutics Classification System (BCS), drugs are classified on the basis of their aqueous solubility and permeability. However, aqueous solubility does not always correlate best with in vivo solubility and consequently bioavailability. Therefore, the use of biorelevant media is a more suitable approach for mimicking in vivo conditions. Here, assessed with a novel image-based single-particle analysis (SPA) method, we report a constant ratio of solubility increase of 3.3 +/- 0.5 between the alpha and gamma solidstate forms of indomethacin in biorelevant media. The ratio was independent of pH, ionic strength, and surfactant concentration, which all change as the drug passes through the gastrointestinal tract. On the basis of the solubility ratio, a free energy difference between the two polymorphic forms of 2.9 kJ/mol was estimated. Lastly, the use of the SPA approach to assess solubility has proven to be simple, fast, and both solvent- and sample-sparing, making it an attractive tool for drug development.