Interaction of fentanyl with various cyclodextrins in aqueous solutions

Water-soluble fentanyl citrate salt has been used in sublingual or buccal formulations for the breakthrough pain treatment. However, fentanyl absorption through the lipid mucosal membrane may be improved by enhancing the non-ionic lipophilic fentanyl base solubility. Therefore, the interaction between cyclodextrins (CDs) and fentanyl base has been evaluated to obtain basic information for its application.

Parent CDs (α-, β- and γ-CD) as well as α- and β-CD derivatives were used for solubility studies with fentanyl base. Nuclear magnetic resonance (NMR) studies were applied in a system including β-CD or glucosyl-β-CD (G1-β-CD) with fentanyl base or fentanyl citrate. (1) H- and (13) C-NMR studies and a two-dimensional rotating frame Overhauser effect spectroscopy (ROESY) study were conducted to confirm inclusion complexes formation.

Parent CDs displayed BS type phase solubility diagrams; β-CD exhibited a strong interaction with fentanyl base. Hydrophilic β-CD derivatives, such as G1-β-CD, displayed AL type phase diagrams and higher solubilizing effects compared with parent CDs. ROESY study suggested that fentanyl phenyl groups were included in β-CD cavity.

This study revealed that hydrophilic β-CD derivatives, such as G1-β-CD, could be useful pharmaceutical additives for oral mucosal formulations because of the improved fentanyl base solubility via inclusion complexation.