Drug–Polymer Interactions and Molecular Miscibility in Amorphous Solid Dispersions: The Duality of Hydrogen Bond-Donor Groups

Hydrogen bonds (H-bonds) can have a critical impact on the stability and drug release characteristics of amorphous solid dispersions (ASDs). Based on the structure of the ASD components, it remains however difficult to predict the strength and influence of these H-bond interactions on the phase behavior of the ASDs. Therefore, this study assessed the miscibility and H-bond interactions of diflunisal (DIF) and four structural analogues in ASDs with Eudragit S100 (ES100) as a model polymer that contains H-bond-donor as well as H-bond-acceptor groups. The highest possible drug loading in the ASDs was smaller for native DIF and the DIF methyl ester derivative (25 wt %) as compared to the methoxy DIF and dimethyl DIF derivatives (35 wt %). Solid-state NMR relaxometry was employed to evaluate the molecular miscibility of the ASD components. In addition, ¹³C-CPMAS ssNMR spectroscopy was performed on spray-dried ASDs to evaluate the H-bond interactions between the API and polymer. It was observed that the ES100 carboxyl group interacted as an H-bond donor with the C═O carbonyl group of the DIF derivatives, leading to homogeneous mixing for all ASDs. However, it was also shown that competition between intermolecular H-bonds and intramolecular H-bonds, present as stable six-membered rings, is possible. The competition limited the availability of the API acceptor C═O group and explains the lower maximum drug loadings for native DIF and the DIF methyl ester. A comparison was also made between these ES100-based ASDs and PVPVA-based ASDs studied in a previous study. It became clear that for ASDs with a polymer that only carries H-bond-acceptor groups (like PVPVA), the availability of API H-bond-donor groups is crucial for the formation of H-bonds between the drug and the polymer. Contrastingly, for ASDs formed with a polymer that carries both H-bond-donor and -acceptor groups (like ES100), it seems to be the availability of API H-bond-acceptor groups that is crucial for intermolecular H-bond formation and drug-polymer miscibility.