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Ketoconazole salt and co-crystals with enhanced aqueous solubility

机译：酮康唑盐和水溶性增强的共晶体

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摘要

Crystal structures of ketoconazole oxalate salt (1) and three co-crystals with fumaric (2), succinic (3), and adipic (4) acids in 1:1 stoichiometry were determined by single-crystal X-ray diffraction in which 1 forms oxalate dimers involved in ionic interaction with the imidazole ring of ketoconazole molecules, while 2-4 display 4-member circuit networks between hydrogen-bonded ketoconazole and coformer molecules. The salt and co-crystal nature of 1-4 was confirmed by combining single-crystal X-ray diffraction, ss-NMR, and lattice energy calculations. Ketoconazole molecules show highly similar conformations and crystal packing in co-crystals 2 and 3, while different conformers are present in the 1, 2, and 4 structures. For all salt and co-crystals, powder dissolution measurements revealed a significant solubility improvement compared to ketoconazole, and the solubility of 1-4 is contrary to the solubility values of the corresponding acids. A 100-fold solubility increase in water was obtained by ketoconazole co-crystallization with fumaric and adipic acids. Additionally, 1-4 are stable in suspensions for at least 1 week and on storage at 40 C/75% RH for at least 4 months. The melting points of 1, 3, and 4 are in line to their solubility, while the solubility difference between the highly similar co-crystals 2 and 3 is reflected in their different lattice energy. Our study emphasizes the benefit of crystal engineering in the landscape of the formulation techniques used to enhance the dissolution rate of poorly water-soluble drugs such as ketoconazole.
机译：通过单晶X射线衍射确定了酮康唑草酸盐（1）以及与富马酸（2），琥珀酸（3）和己二酸（4）形成的三种共晶体的化学结构，它们的化学计量比为1：1。草酸盐二聚体参与与酮康唑分子的咪唑环的离子相互作用，而2-4显示氢键合酮康唑与共成型分子之间的4元电路网络。通过结合单晶X射线衍射，ss-NMR和晶格能计算，确认了1-4的盐和共晶性质。酮康唑分子在共晶体2和3中显示出非常相似的构象和晶体堆积，而在1，2，和4结构中存在不同的构象剂。对于所有盐和共晶体，粉末溶解度测量结果表明，与酮康唑相比，溶解度显着提高，并且1-4的溶解度与相应酸的溶解度值相反。通过将酮康唑与富马酸和己二酸共结晶，可以使水中溶解度提高100倍。另外，1-4在悬浮液中稳定至少1周，并在40 C / 75％RH下储存至少4个月。 1、3和4的熔点与其溶解度一致，而高度相似的共晶2和3之间的溶解度差异则反映在它们不同的晶格能量上。我们的研究强调了用于提高水溶性差的药物（例如酮康唑）的溶解速率的配制剂技术中晶体工程的益处。

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