Using MD simulations, the possible role of SBE-β-CDs aggregates in the solubilization of remdesivir was studied. Both the effect of the number and location of the different SBE substitutions in the CDs present in the excipient and the protonation state of the drug were addressed. It has been illustrated how both the neutral and the protonated remdesivir molecules spontaneously aggregate in aqueous solution. The aggregates of the protonated structure are smaller than those for the neutral form of the drug, due to the electrostatic repulsion that takes place for the charged molecule. The addition of SBE-β-CD to the solution clearly prevents the self-aggregation of remdesivir in both protonation states, even at very high drug concentrations. The solubilization mechanism seems to be the encapsulation of the remdesivir molecule in small clusters formed by a few (2-4) CDs. All our simulations exhibit a dynamic equilibrium between clusters, with molecules exchanging from one to another in a time scale of several hundred ns. The spontaneous formation of inclusion complexes was not observed in any of the simulations but the interaction between CDs and remdesivir was through the peripheral groups of the cyclic molecule. The number of substitutions and the protonation state of the drug significantly affect the interactions between molecules and thus their aggregation. The protonated form of the drug seems to favor the cross-aggregation in the presence of SBE-β-CD, as can be seen from the number of total clusters for the charged molecule, typically lower than that for the neutral structure. This results from the electrostatic interaction between the charged form of the drug and SBE-β-CD. The interaction between protonated remdesivir and CD is significantly stronger than that with the neutral structure, showing approximately double amount of CD-drug H-bonds in the former case. Regarding the structure of the aggregates, the pattern observed in the simulations consists of one or two molecules of the drug and approximately three CD molecules. Increasing the number of substitutions in the CD leads to a lower aggregation of the excipient, while the self-aggregation of the drug slightly increases. This behavior is clearer for the protonated form of the drug than for the neutral structure.
A. Piñeiro, J. Pipkin, V. Antle, R. Garcia-Fandino, Aggregation versus inclusion complexes to solubilize drugs with Cyclodextrins. A case study using sulphobutylether-β-cyclodextrins and remdesivir, Journal of Molecular Liquids (2021), doi: https://doi.org/10.1016/j.molliq.2021.117588