Characterization of the interaction of 2-hydroxypropyl-beta-cyclodextrin with itraconazole at pH 2, 4, and 7.
Phase-solubility techniques were used to assess the effect of pH on itraconazole complexation with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). In addition, molecular modeling using beta-cyclodextrin as a surrogate for HPbetaCD was completed. Data suggested A(p)-type solubility relationships, indicating higher order complexation at higher HPbetaCD concentrations. Stability constants were derived from the solubility isotherms using a simplex optimization procedure. At pH 2 (2 units below the pK(a4)), a 1:2 complex formation was observed, whereas at pH 4 (i.e., the pK(a4) for itraconazole) and at pH 7, 1:3 complexation occurred. The lower order of complexation observed at lower pH may be related to substructure protonation which reduced HPbetaCD interaction. Molecular mechanics also suggest 1:3 complex formation for the neutral species, indicating that possible interaction sites may include (in order of binding) triazole > 1,4-diaminophenyl > 2-butyl approximate, equals piperazine.
Peeters
Jef
J
Department of Drug Delivery Research, Johnson & Johnson Pharmaceutical Research and Development, Beerse 2340, Belgium.
Neeskens
Peter
P
Tollenaere
Jan P
JP
Van Remoortere
Pieter
P
Brewster
Marcus E
ME
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism*; D003505:Cyclodextrins / Q000737:chemistry / Q000378:metabolism*; D004347:Drug Interactions; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D017964:Itraconazole / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D012995:Solubility; D047392:beta-Cyclodextrins
D000935:Antifungal Agents; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017964:Itraconazole