Ternary inclusion complex formation and stabilization of limaprost, a prostaglandin E1 derivative, in the presence of α- and β-cyclodextrins in the solid state

Limaprost/alpha-cyclodextrin (CD)/beta-CD ternary inclusion complex was prepared by freeze-drying a solution containing all three components. Under humid conditions, limaprost was more stable in the ternary alpha-/beta-CD inclusion complex than in the binary alpha- or beta-CD complex. Specifically, during storage at 30 degrees C/75% relative humidity (R.H.) for 4 weeks, about 19% of limaprost degraded into 17S,20-dimethyl-trans-Delta(2)-prostaglandin A(1) (referred as 11-deoxy-Delta(10)) in the beta-CD complex, 8.1% degraded in the alpha-CD complex, and only 2.2% degraded in the alpha-/beta-CD complex. The mechanism of limaprost stabilization in the presence of both CDs was investigated by Raman and solid-state NMR spectroscopy and powder X-ray diffractometry. The fast degradation of limaprost to 11-deoxy-Delta(10) in the beta-CD complex was due to the rapid crystallization of beta-CD from the complex, liberating the free amorphous drug, which is susceptible to degradation. The dissociation and crystallization of beta-CD from the inclusion complex were suppressed by freeze-drying limaprost in the presence of both alpha- and beta-CDs. In addition, the interaction between limaprost and the two CDs was reinforced by inclusion of different moieties of limaprost: alpha-CD predominantly included the alkyl omega-chain, whereas beta-CD included the five-membered ring. Thus, a stable ternary inclusion complex was formed that included limaprost, maintaining the amorphous state of the complex and dramatically stabilizing the drug under humid conditions. (C) 2016 Elsevier B.V. All rights reserved.