Formation of the ternary inclusion complex of limaprost with α- and β-cyclodextrins in aqueous solution

The inclusion mode of Limaprost in the presence of α- and β-cyclodextrins (CDs) was investigated to gain insight into the stabilization mechanism of Limaprost-alfadex upon the addition of β-CD in the solid state. The inclusion sites of α- and β-CDs were studied by NMR spectroscopic and kinetic methods. With the addition of α- and β-CDs, displacements in (13)C chemical shifts of prostaglandin F2α (PGF2α) were observed in the ω-chain and the five-membered ring, respectively, of the drug. Similar shift changes were observed with the addition of both α- and β-CDs. In two-dimensional (2D) (1)H-NMR spectra, intermolecular correlation peaks were observed between protons of PGF2α and protons of both α- and β-CDs, suggesting that PGF2α interacts with α- and β-CDs to form a ternary complex by including the ω-chain with the former CD and the five-membered ring with the latter. In kinetic studies in aqueous solution, Limaprost was degraded to 17S,20-dimethyl-trans-Δ(2)-PGA1 (11-deoxy-Δ(10)) and 17S,20-dimethyl-trans-Δ(2)-8-iso-PGE1 (8-iso). The addition of α-CD promoted the dehydration to 11-deoxy-Δ(10), while β-CD promoted the isomerization to 8-iso, under these conditions. In the presence of both α- and β-CDs, dehydration and isomerization were also accelerated, supporting the formation of the ternary Limaprost/α-CD/β-CD complex.