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

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Physical Chemistry

Background:

• Poorly water-soluble drugs often exhibit low oral bioavailability.
• Supersaturated drug solutions can enhance absorption but require stabilization.
• Hydrophobically modified polymers and cyclodextrins are explored for drug stabilization.

Purpose of the Study:

• To evaluate the stability of indomethacin (IM) supersaturated solutions.
• To investigate the stabilizing effects of hydrophobically modified hydroxypropylmethylcellulose (HM-HPMC) with and without cyclodextrins (CDs).
• To explore the mechanism of stabilization for poorly soluble drugs.

Main Methods:

• Preparation and evaluation of indomethacin supersaturated solutions in HM-HPMC.
• Addition of alpha-cyclodextrin (α-CD) and beta-cyclodextrin (β-CD) to assess stabilization.
• Fluorescence spectroscopy using Nile Red probe to detect hydrophobic environments.
• Cryogenic transmission electron microscopy (Cryo TEM) to visualize aggregates.

Main Results:

• HM-HPMC solutions maintained a supersaturated state of IM.
• Addition of α-CD and β-CD further stabilized IM supersaturation, with HM-HPMC/α-CD showing highest stability up to 120 hours.
• Phase separation and formation of colloidal amorphous aggregates were observed, confirmed by Nile Red fluorescence and Cryo TEM.
• α-CD facilitated HM-HPMC dissociation, increasing hydrophobic interactions with IM aggregates.

Conclusions:

• The combination of HM-HPMC and α-CD effectively stabilizes colloidal amorphous aggregates in IM supersaturated solutions.
• This stabilization mechanism enhances the concentration and longevity of the supersaturated state.
• This approach holds promise for improving the oral bioavailability of poorly water-soluble drugs like indomethacin.