Molecular interactions in remdesivir-cyclodextrin systems

Remdesivir (REM) is the first antiviral drug (Veklury™) approved by the Food and Drug Administration for the therapy of COVID-19. Due to its poor water solubility, the preparation of Veklury™ requires a suitable solubilizing excipient at pH 2 conditions. For this purpose, the final formulation contains the randomly substituted sulfobutylether-β-cyclodextrin (SBEβCD) as a complexing agent. Herein, extensive NMR spectroscopic study with various cyclodextrin (CD) derivatives were conducted to understand the interactions in SBEβCD - REM systems at the molecular level. The pKa value of REM has been determined experimentally for the first time, as the protonation state of the aminopyrrolo-triazine moiety can play a key role in CD-REM inclusion complex formation as SBEβCD has permanent negative charges. The UV-pH titration experiments yielded a pKa of 3.56, thus the majority of REM bears a positive charge at pH 2.0.