Mechanisms and surface chemical prediction of imipramine ‐induced hemolysis suppressed by modified cyclodextrins

Abstract The suppression of imipramine hydrochloride (IMP)‐ induced hemolysis by native cyclodextrins (α‐, β‐, and γ‐CDs) and β‐CD derivatives is measured as a function of CD concentration and is quantitatively correlated with the surface tension of the solution determined at 37.0 °C. The modified β‐CDs are more or less adsorbed onto the air–water interface and occupy larger areas than the wider rim of β‐CD. The surface tension data at low CD concentrations in the presence of 3 mM IMP allow us to estimate the 1:1 binding constants of IMP with CDs. Both the capabilities of hemolysis suppression and surface tension elevation for 3 mM IMP are strong in the order carboxymethyl‐β‐CD (CM) > β‐CD ≈ 6‐ O ‐glucosyl‐β‐CD (G 1 ) > γ‐CD > 2‐hydroxypropyl‐β‐CD (HP) > α‐CD ≥ 2,6‐di‐ O ‐methyl‐β‐CD (DM). The suppression of IMP‐induced hemolysis is ascribed to the decrease in the concentration of free IMP molecules. This concentration can be quantitatively estimated from the surface tension data determined at 37 °C. Therefore, the suppression of IMP‐induced hemolysis by most of the CDs can be quantitatively predicted from these surface tension data, regardless of the kind and concentration of CD. However, α‐CD, HP, and DM are outliers of this prediction. This failure for α‐CD and HP is ascribed to their weaker competitive binding to IMP than to membrane phospholipid. Because DM has a strong hemolytic activity, it does not almost suppress the IMP‐induced hemolysis. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1056–165, 2001