Preparation of a Stable Indomethacin Supersaturated Solution Using Hydrophobically Modified...

In the present study, the stability of a supersaturated solution of indomethacin (IM) was evaluated in hydrophobically modified hydroxypropylmethylcellulose (HM-HPMC) solutions, with and without parent cyclodextrins (CDs). A highly supersaturated state of IM was maintained in the HM-HPMC solution and was further stabilized by the addition of α-CD and β-CD. Notably, the highest level of supersaturation was achieved in HM-HPMC/α-CD solution, which maintained a high concentration of IM for up to 120 h. IM concentrations in these solutions exceeded the amorphous solubility, indicating that phase separation had occurred. To explore this phase separation, Nile Red, a fluorescent probe sensitive to hydrophobic environments, was added to the supersaturated solutions. A higher fluorescence intensity was observed in the HM-HPMC/α-CD solution compared with the HM-HPMC solution, indicating a significant formation of colloidal amorphous aggregates in the supersaturated solution. Cryogenic transmission electron microscopy (Cryo TEM) analysis confirmed the presence of these aggregates, which appeared irregularly shaped. These findings suggest that the combination of HM-HPMC and α-CD effectively stabilized the colloidal amorphous aggregates in the IM supersaturated solution. The addition of α-CD facilitated the dissociation of HM-HPMC into smaller particles, increasing the number of hydrophobic stearyl moieties available for interactions with amorphous IM aggregates, thereby enhancing the stability of the supersaturated state. The combination of HM-HPMC and α-CD offers a promising approach to improving the oral bioavailability of drugs with poor water solubility.