Acyclic Cucurbit[<i>n</i>]uril-type Molecular Containers: Influence of Aromatic Walls on their Function as Solubilizing Excipients for Insoluble Drugs

Abstract

We studied the influence of the aromatic sidewalls on the ability of acyclic CB­[<i>n</i>]-type molecular containers (<b>1a</b>–<b>1e</b>) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit good water solubility and weak self-association (<i>K</i>_s ≤ 624 M^–1). We constructed phase solubility diagrams to extract <i>K</i>_rel and <i>K</i>_a values for the container·drug complexes. The acyclic CB­[<i>n</i>]-type containers generally display significantly higher <i>K</i>_a values than HP-β-CD toward drugs. Containers <b>1a</b>–<b>1e</b> bind the steroidal ring system and aromatic moieties of insoluble drugs. Compound <b>1b</b> displays highest affinity toward most of the drugs studied. Containers <b>1a</b> and <b>1b</b> are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and <b>1a</b>–<b>1e</b>, lower concentrations of <b>1a</b>–<b>1e</b> are required to achieve identical [drug]