Preformulation studies of dovitinib free base: Solubility, lipophilicity and stability

Suppakan Sripetch, Alexey Ryzhakov, Thorsteinn Loftsson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Dovitinib has been investigated as an anti-tumor drug due to its ability to inhibit multiple receptor tyrosine kinases. Dovitinib free base has a poor water solubility leading to poor absorption. Salts and lipid-based formulations have been used to improve drug availability. Here, we investigated the physiochemical properties of the dovitinib free base in the presence of some pharmaceutical excipients. We sought to study the effect of acidic counterions on the aqueous solubility and lipophilicity of dovitinib and how pH, buffer species, and cyclodextrin (CD) influenced dovitinib stability. pH-solubility studies were performed by titration against five different acids. Aqueous solubility of dovitinib salt depended on the counterion. Lactic acid greatly increased the aqueous solubility of dovitinib. The counterion effect on the solubility was also investigated in the aqueous complexing media. Unexpected synergistic solubilization was found with γ-CD/phosphoric acid and γ-CD/maleic acid. The counterion did not affect the lipophilicity of dovitinib at physiological pH. Accelerated degradation of dovitinib was carried out at high temperature. Stability was studied across a range of pH values, buffer species and in the presence of two CDs. Dovitinib was most stable at pH 4 in the phosphate buffer species. γ-CD stabilized the drug at relatively low pH.

Original languageEnglish
Article number121721
Pages (from-to)121721
JournalInternational Journal of Pharmaceutics
Volume619
DOIs
Publication statusPublished - 1 May 2022

Bibliographical note

Funding Information:
This work was supported by Oculis ehf, Reykjavik, Iceland.

Publisher Copyright:
© 2022 Elsevier B.V.

Copyright © 2022 Elsevier B.V. All rights reserved.

Other keywords

  • Counterion
  • Dovitinib
  • γ-Cyclodextrin
  • Cyclodextrins/chemistry
  • Benzimidazoles
  • Excipients/chemistry
  • Drug Stability
  • Solubility
  • Water/chemistry
  • Hydrogen-Ion Concentration
  • Quinolones

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