Abstract
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 Bs-type with K1:1 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 Bs-type while those of dovitinib/HPγCD/counter ion and dovitinib/SBEγCD/counter ion were of AN-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.
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This research was granted by Icelandic center of Research (RANNÍS).
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Pitsiree Praphanwittaya: investigation, formal analysis, data curation, writing—original draft. Phatsawee Jansook: Methodology. Thorsteinn Loftsson: Funding acquisition, Supervision, Writing—original draft.
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The authors declare that there is no conflict of interest. The work was performed by Pitsiree Praphanwittaya and will be part of her PhD dissertation.
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Praphanwittaya, P., Jansook, P. & Loftsson, T. Aqueous solubility of kinase inhibitors: III the effect of acidic counter ion on the dovitinib/γ-cyclodextrin complexation. J Incl Phenom Macrocycl Chem 98, 57–67 (2020). https://doi.org/10.1007/s10847-020-01009-7
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DOI: https://doi.org/10.1007/s10847-020-01009-7