Solubilization of vorinostat by cyclodextrins

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.

The aim of this study was to evaluate whether cyclodextrins (CDs), common excipients used in pharmaceutical industry, could increase the aqueous solubility of vorinostat.

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.

Phase-solubility studies indicated that the solubility of vorinostat (7·24×10(-1) mm) was substantially increased when complexed with various CDs, in the following order: randomly methylated-β-cyclodextrin (RM-β-CD)>hydroxypropyl-β-cyclodextrin (HP-β-CD)>α-cyclodextrin>hydroxypropyl-α-cyclodextrin>Hydroxypropyl-γ-cyclodextrin>γ-cyclodextrin. RM-β-CD 300 mm increased vorinostat solubility to 70·8 mm, almost two orders of magnitude higher than the baseline solubility. Such findings were in good agreement with the results obtained from molecular simulation.

CDs, particularly RM-β-CD and HP-β-CD, increased vorinostat's solubility. Future studies could be focused on the application of HP-β-CD in parenteral delivery of vorinostat or using RM-β-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.