Physically stable cyclodextrin metal–organic frameworks formed via a drug-assisted amorphous to crystal phase transition

Abstract

Formation of cyclodextrin metal–organic frameworks (CD-MOFs) for drug-loading applications is challenging due to the long preparation time and low loading capacity. In this study, the amorphous–crystal phase transition in CD-MOFs during spray drying was exploited to efficiently synthesize drug-loaded CD-MOFs by incorporating hydrophobic etodolac (ETD) and hydrophilic theophylline (THP) molecules. Spray drying of a precursor mixture consisting of ETD and/or THP, along with CD-MOF components (γ-CD and KOH) in 40% ethanol, was completed within 30 min. Rapid solvent evaporation during the spray drying process enabled the incorporation of ETD and THP molecules into the slightly crystalline CD-MOF particles, resulting in high drug loading (>90% w/w). The mechanistic understanding of CD-MOF formation in the presence of drugs was elucidated based on the solution-phase interactions and solid-state configurations using NMR and Raman spectroscopies, respectively. More importantly, ETD molecules within CD-MOF cavities act as linkers between γ-CD units, thereby contributing to the structural formation and enhancing the physical stability of the CD-MOFs. Our study demonstrates the potential of spray-drying for large-scale production of CD-MOFs for pharmaceutical applications.