- The aim of this research was to study the interaction of sulfobutyl ether 7 β-cyclodextrin (captisol) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) with the poorly soluble antiarrhythmic drug amiodarone, and to investigate the consequent solubility–permeability interplay. Phase-solubility studies of amiodarone with the two cyclodextrins, followed by PAMPA and rat intestinal permeability experiments, were carried out, and the solubility–permeability interplay was then illustrated as a function of increasing cyclodextrin content. Equimolar levels of captisol allowed ∼10-fold higher amiodarone solubility than HPβCD, as well as binding constant. With both captisol and HPβCD, decreased in vitro and in vivo amiodarone apparent permeability was evident with increasing CD levels and increased apparent solubility. A theoretical model assuming direct proportionality between the apparent solubility increase allowed by the CD and permeability decrease was able to accurately predict the solubility–permeability tradeoff as a function of CD levels. In conclusion, the addition of ionic interactions (e.g. amiodarone–captisol) to hydrophobic interactions of the inclusion complex formation may result in synergic effect on solubilization; however, it is not merely the solubility that should be examined when formulating an oral poorly soluble compound, but the solubility–permeability balance, in order to maximize the overall drug exposure.