PhD Scientific Days 2022

Pharmaceutical Sciences II. (Poster discussion will take place in the Aula during the Coffee Break)

Molecular interactions in remdesivir-cyclodextrin systems probed by NMR and CE

Text of the abstract

Introduction
Remdesivir (REM), the first antiviral drug (Veklury™) approved by the FDA for the therapy of COVID-19 possesses low aqueous solubility, thus the final formulation necessitates a solubilizing excipient. For this purpose, the randomly substituted sulfobutylether-β-cyclodextrin (SBEβCD) is used.
Aims
In this study we aimed at determining the intermolecular interactions between REM and various β- and γ-cyclodextrin (CD) derivatives by NMR spectroscopy to understand their interactions at the atomic level. Moreover, as the synthesis of REM provides a diastereomeric mixture of RP- and SP-REM bearing different pharmacological properties, we also aimed to explore the selectivity of various CDs towards REM diastereomers by capillary electrophoresis (CE).
Results
1H NMR titrations were performed to determine the stability constants of various CDs and REM at pH 2.0. Job’s method was used to determine the stoichiometries and it resulted in a 1:1 complex in each case. The NMR data revealed that the anionic sulfobutylether-sidechains of the hosts contribute to a significant stability enhancement (γCD < SBEγCD < βCD < SBEβCD < per-6-SBEβCD), and the primary side sulfobutylation of the host plays a critical role in this process. The complex structures were proposed based on the 2D ROESY NMR data. The applicability of CD derivatives to separate RP- and SP-REM in CE (using a pH 9.0 background electrolyte containing up to 20 mM selector) was also investigated. It was found that sugammadex (SGM) provides the highest resolution (Rs = 5.9 at 20 mM SGM) of REM diastereomers and their separation is driven by stability differences. The separation mechanism in CE has also been supported by NMR results investigating the individual REM isomers with SGM.
Funding
Supported by the New National Excellence Program of the Ministry of Innovation and Technology (ÚNKP-21-3-I-SE-52).