Dovitinib, a hydrophobic kinase inhibitor (KI), is lipophilic anticancer agent that forms water-soluble complexes with cyclodextrins (CDs). However, dovitinib’s very low intrinsic solubility hampers the complex formation and, consequently, the CD solubilization. The aim of the study was to enhance the CD solubilization through formation of more water soluble dovitinib salts. When dovitinib is unionized (i.e. at pH above its pKa value) the phase-solubility profile of the binary dovitinib/γCD complex is of B s -type with K 1:1 of 684 M −1 . Then the complex has limited solubility in water. Upon protonization, (i.e. at pH below the pKa value) the solubility of dovitinib was increased but the increase was dependent on the negatively charged counter ion. Citrate, acetate, EDTA and chloride resulted in the greatest solubility enhancement and, thus, were selected to further studies. The ternary phase-solubility profiles of dovitinib/γCD/counter ion were also of B s -type while those of dovitinib/HPγCD/counter ion and dovitinib/SBEγCD/counter ion were of A N -type. The counter ions had greater solubilizing effect in SBEγCD solutions than in γCD and HPγCD solutions. This is due to the influence of charge-charge interaction between the positively charged dovitinib and negatively charged SBEγCD. Citrate was the most effective counter ion particularly in aqueous SBEγCD solutions. The complexation was verified by NMR. The highest dovitinib flux through semi-permeable membrane was observed from medium containing dovitinib/CDs/citrate complexes. In conclusion, citrate provided the highest dovitinib solubilization and complexation.

中文翻译：

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激酶抑制剂的水溶性：III 酸性反离子对多维替尼/γ-环糊精络合的影响

多维替尼是一种疏水性激酶抑制剂 (KI)，是一种亲脂性抗癌剂，可与环糊精 (CD) 形成水溶性复合物。然而，多维替尼非常低的内在溶解度阻碍了复合物的形成，从而阻碍了 CD 的溶解。该研究的目的是通过形成更水溶性的多维替尼盐来增强 CD 溶解。当多维替尼被电离时（即在高于其 pKa 值的 pH 值下），二元多维替尼/γCD 复合物的相溶解度曲线是 B s 型，K 1:1 为 684 M -1 。然后复合物在水中的溶解度有限。在质子化后（即在低于 pKa 值的 pH 值下），多维替尼的溶解度增加，但增加取决于带负电荷的反离子。柠檬酸盐、醋酸盐、EDTA 和氯化物导致最大的溶解度增强，因此，被选中进行进一步研究。多维替尼/γCD/抗衡离子的三元相溶解度曲线也为B s 型，而多维替尼/HPγCD/抗衡离子和多维替尼/SBEγCD/抗衡离子的三元相溶解度曲线为AN型。抗衡离子在 SBEγCD 溶液中比在 γCD 和 HPγCD 溶液中具有更大的增溶作用。这是由于带正电的多维替尼和带负电的 SBEγCD 之间的电荷-电荷相互作用的影响。柠檬酸盐是最有效的抗衡离子，尤其是在 SBEγCD 水溶液中。通过NMR验证络合。从含有多维替尼/CDs/柠檬酸盐复合物的培养基中观察到通过半透膜的最高多维替尼通量。总之，柠檬酸盐提供了最高的多维替尼溶解和复合。多维替尼/γCD/抗衡离子的三元相溶解度曲线也为B s 型，而多维替尼/HPγCD/抗衡离子和多维替尼/SBEγCD/抗衡离子的三元相溶解度曲线为AN型。抗衡离子在 SBEγCD 溶液中比在 γCD 和 HPγCD 溶液中具有更大的增溶作用。这是由于带正电的多维替尼和带负电的 SBEγCD 之间的电荷-电荷相互作用的影响。柠檬酸盐是最有效的抗衡离子，尤其是在 SBEγCD 水溶液中。通过NMR验证络合。从含有多维替尼/CDs/柠檬酸盐复合物的培养基中观察到通过半透膜的最高多维替尼通量。总之，柠檬酸盐提供了最高的多维替尼溶解和复合。多维替尼/γCD/抗衡离子的三元相溶解度曲线也为B s 型，而多维替尼/HPγCD/抗衡离子和多维替尼/SBEγCD/抗衡离子的三元相溶解度曲线为AN型。抗衡离子在 SBEγCD 溶液中比在 γCD 和 HPγCD 溶液中具有更大的增溶作用。这是由于带正电的多维替尼和带负电的 SBEγCD 之间的电荷-电荷相互作用的影响。柠檬酸盐是最有效的抗衡离子，尤其是在 SBEγCD 水溶液中。通过NMR验证络合。从含有多维替尼/CDs/柠檬酸盐复合物的培养基中观察到通过半透膜的最高多维替尼通量。总之，柠檬酸盐提供了最高的多维替尼溶解和复合。