Characterization of the 13-cis-retinoic acid/cyclodextrin inclusion complexes by phase solubility, photostability, physicochemical and computational analysis.

13-cis-Retinoic acid (13-cis-RA) is a synthetic retinoid commonly used in the treatment of severe acne. It has also been found to possess potential chemopreventive activity. It has extremely low aqueous solubility and high photo-sensitivity. This study investigated the effects of the complexation of 13-cis-RA with alpha-cyclodextrin (alpha-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on its phase solubility. HP-beta-CD was found to be more effective in increasing the aqueous solubility of 13-cis-RA compared to alpha-CD. Phase solubility studies indicated that the solubility of 13-cis-RA was increased dramatically by the formation of inclusion complex with HP-beta-CD. The solubility was further enhanced by pH adjustment. The photostability of the selected inclusion complex of 13-cis-RA:HP-beta-CD was then evaluated. Complexation with HP-beta-CD was found to delay the photo-degradation of 13-cis-RA in aqueous solution. The physicochemical properties of the solid inclusion complex were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). Molecular modeling with MMFF94s force field (SYBYL V6.6) was utilized to predict the preferred orientation of 13-cis-RA in the CD cavity and the main structural features responsible for the enhancement of its solubility and photostability. The energy scores estimated from the computational analysis were found capable of reflecting the stability constants of the cyclodextrin complexes obtained in the phase solubility studies. The results showed that HP-beta-CD was a proper excipient for increasing solubility and stability of 13-cis-RA.