Molecular interactions in remdesivir-cyclodextrin systems

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In a recently published study intermolecular interactions of remdesivir and various cyclodextrin derivatives were characterized by extensive NMR spectroscopy. The aim of the study was to understand in detail the molecular-level interactions between remdesivir and its excipient in Veklury™ (sulfobutylether-β-cyclodextrin – SBEβCD) and with other β- and CD derivatives.
Complex stabilities and stoichiometries were determined based on 1H NMR titrations while potential complex structures were elucidated based on 2D ROESY NMR experiments.NMR spectroscopic studies revealed that βCD complexes are one order of magnitude more stable than their γCD counterparts. It has been also demonstrated that the introduction of the anionic sulfobutylether-sidechains on the CD hosts contributes to a significant stability enhancement, furthermore the primary side sulfobutylation of the host plays the most critical role in the stability of the inclusion complex.
In addition, pKa value of remdesivir was determined experimentally by UV-pH titration method for the first time in the present study. The pKa value of the heterocyclic aminopyrrolo-triazin moiety yielded a value of 3.56. These results have been demonstrated that the charge state of the host and the guest may remarkably contribute to the inclusion complex formation of remdesivir.
This is the first comprehensive study of remdesivir-CD complexation, allowing the design of new CD derivatives with tailored stabilities, thereby aiding the formulation or production and even the analytical characterization of remdesivir.

Bianka Várnai, Milo Malanga, Tamás Sohajda, Szabolcs Béni, Molecular interactions in remdesivir-cyclodextrin systems, Journal of Pharmaceutical and Biomedical Analysis, 209, 2022, 114482,
https://doi.org/10.1016/j.jpba.2021.114482.

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