Characterization of the interaction of 2-hydroxypropyl-β-cyclodextrin with itraconazole at pH 2, 4, and 7

✍ Scribed by Jef Peeters; Peter Neeskens; Jan P. Tollenaere; Pieter Van Remoortere; Marcus E. Brewster

• Publisher: John Wiley and Sons
• Year: 2002
• Tongue: English
• Weight: 140 KB
• Volume: 91
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.10126

✦ Synopsis

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.