Solubilization of vorinostat by cyclodextrins

P>Background: Vorinostat (suberoylanilide hydroxamic acid) is the first histone deacetylase inhibitor approved by US FDA for use in oncology. However, as a hydrophobic acid, its limited aqueous solubility poses a problem for parenteral delivery. Such limited solubility may also affect its oral bioavailability. Objective: The aim of this study was to evaluate whether cyclodextrins (CDs), common excipients used in pharmaceutical industry, could increase the aqueous solubility of vorinostat. Methods: The actual aqueous solubility of vorinostat was investigated by phase-solubility method. Molecular simulation was employed to predict the interaction energy and preferred orientation of vorinostat in CD cavities. Results: Phase-solubility studies indicated that the solubility of vorinostat (7 center dot 24 x 10-1 mm) was substantially increased when complexed with various CDs, in the following order: randomly methylated-beta-cyclodextrin (RM-beta-CD) > hydroxypropyl-beta-cyclodextrin (HP-beta-CD) > alpha-cyclodextrin > hydroxypropyl-alpha-cyclodextrin > Hydroxypropyl-gamma-cyclodextrin > gamma-cyclodextrin. RM-beta-CD 300 mm increased vorinostat solubility to 70 center dot 8 mm, almost two orders of magnitude higher than the baseline solubility. Such findings were in good agreement with the results obtained from molecular simulation. Conclusion: CDs, particularly RM-beta-CD and HP-beta-CD, increased vorinostat's solubility. Future studies could be focused on the application of HP-beta-CD in parenteral delivery of vorinostat or using RM-beta-CD as an oral absorption enhancer. Molecular simulation appeared to be a useful tool for the selection of appropriate CD as excipient for drug delivery.