Solubility Behavior and Solution Chemistry of Indomethacin Cocrystals in Organic Solvents
Solubility Behavior and Solution Chemistry of Indomethacin Cocrystals in Organic Solvents
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DOI：
10.1021/cg200517r
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发表时间：
2011-09-01
影响因子：
3.8
通讯作者：
Velaga, Sitaram P.
中科院分区：
文献类型：
--
作者：
Alhalaweh, Amjad;Sokolowski, Anders;Velaga, Sitaram P.
本文主要研究吲哚美辛-糖精（IND-SAC）共晶在有机介质中的溶解行为和溶液化学。我们还评估了以前提出的共晶在有机溶剂中的溶解度模型。此外，IND-SAC共晶的溶解度行为进行了比较，吲哚美辛-烟酰胺（IND-NIC）共晶使用的共晶常数的方法。IND-SAC共晶在各种溶剂中的相溶解度图的生成和过渡浓度，在该浓度下，药物和共晶与溶剂处于平衡，进行了测定。用溶度积和溶液络合作用解释了IND-SAC共晶的溶解性。所建立的模型与实验数据吻合较好，能较好地解释共晶的溶解行为。IND和SAC的溶液络合在乙酸乙酯中可忽略不计，在甲醇和乙醇中低。在所有研究的溶剂中，IND-NIC共晶比IND-SAC共晶更可溶。共晶常数预测了共晶的溶解度和稳定性。了解共晶的溶解度行为和溶液化学对于这种固体形式的筛选、放大和制剂开发具有重要意义。此外，共晶常数的测定是获得共晶稳定性和溶液行为的关键信息的简单且节省资源的手段。
The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacin-saccharin (IND-SAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of IND-SAC cocrystals was compared with that of indomethacin-nicotinamide (IND-NIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of IND-SAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of IND-SAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The IND-NIC cocrystals were more soluble than the IND-SAC cocrystals in all the solvents studied. The eutectic constants predicted both the solubility and the stability of the cocrystals. Understanding the solubility behavior and solution chemistry of cocrystals has important implications for the screening, scale-up, and formulation development of this solid form. Further, the determination of eutectic constants is a simple and resource sparing means of obtaining key information on cocrystal stability and solution behavior.