The interaction of nifedipine with selected cyclodextrins and the subsequent solubility-permeability trade-off

The purpose of this study was to investigate the interaction of 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) and 2,6-dimethyl-beta-cyclodextrin (DM beta CD) with the lipophilic drug nifedipine and to investigate the subsequent solubility-permeability interplay. Solubility curves of nifedipine with HP beta CD and DM beta CD in MES buffer were evaluated using phase solubility methods. Then, the apparent permeability of nifedipine was investigated as a function of increasing HP beta CD/DM beta CD concentration in the hexadecane-based PAMPA model. The interaction with nifedipine was CD dependent; significantly higher stability constant was obtained for DM beta CD in comparison with HP beta CD. Moreover, nifedipine displays different type of interaction with these CDs; a 1:1 stoichiometric inclusion complex was apparent with HP beta CD, while 1:2 stoichiometry was apparent for DM beta CD. In all cases, decreased apparent intestinal permeability of nifedipine as a function of increasing CD level and nifedipine apparent solubility was obtained. A quasi-equilibrium mass transport analysis was developed to explain this solubility-permeability interplay; the model enabled excellent quantitative prediction of nifedipine's permeability as a function of CD concentrations. This work demonstrates that when using CDs in solubility-enabling formulations, a trade-off exists between solubility increase and permeability decrease that must not be overlooked. This trade-off was found to be independent of the type of CD-drug interaction. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption. (C) 2013 Elsevier B.V. All rights reserved.