Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies

Int J Mol Sci. 2023 May 16;24(10):8822. doi: 10.3390/ijms24108822.

Abstract

Thyroid diseases affect a considerable portion of the population, with hypothyroidism being one of the most commonly reported thyroid diseases. Levothyroxine (T4) is clinically used to treat hypothyroidism and suppress thyroid stimulating hormone secretion in other thyroid diseases. In this work, an attempt to improve T4 solubility is made through the synthesis of ionic liquids (ILs) based on this drug. In this context, [Na][T4] was combined with choline [Ch]+ and 1-(2-hydroxyethyl)-3-methylimidazolium [C2OHMiM] + cations in order to prepare the desired T4-ILs. All compounds were characterized by NMR, ATR-FTIR, elemental analysis, and DSC, aiming to check their chemical structure, purities, and thermal properties. The serum, water, and PBS solubilities of the T4-ILs were compared to [Na][T4], as well as the permeability assays. It is important to note an improved adsorption capacity, in which no significant cytotoxicity was observed against L929 cells. [C2OHMiM][T4] seems to be a good alternative to the commercial levothyroxine sodium salt with promising bioavailability.

Keywords: T4 based ionic liquids (T4-ILs); cytotoxicity; ionic formulations; levothyroxine (T4); permeability; solubility.

MeSH terms

  • Animals
  • Biological Availability
  • Ionic Liquids* / chemical synthesis
  • Ionic Liquids* / pharmacokinetics
  • Ionic Liquids* / toxicity
  • L Cells
  • Mice
  • Permeability
  • Solubility
  • Thyroxine* / chemical synthesis
  • Thyroxine* / pharmacokinetics
  • Thyroxine* / toxicity

Substances

  • Thyroxine
  • Ionic Liquids

Grants and funding

This work was supported by Portuguese funds from FCT/MCTES through the Associate Laboratory for Green Chemistry—LAQV (UIDB/50006/2020 and UIDP/50006/2020) and the project numbers PTDC/QUI-QOR/32406/2017 and PTDC/EAM-AMB/2023/2021. Ana R. Jesus and Ana Rita C. Duarte acknowledge the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme, under grant agreement No ERC-2016-CoG 725034.