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Enhancing the Pharmaceutical Profile of Alpha Lipoic Acid: Cyclodextrin Inclusion Complexation for Improved Stability
Karolina Miljak1, Kristina Radić1, Emerik Galić1
1University of Zagreb Faculty of Pharmacy and Biochemistry, Department of Nutrition and Dietetics, A. Kovačića 1, 10000 Zagreb, Croatia.
Pharmaceutics
|July 28, 2026
Summary
Formulating alpha-lipoic acid (ALA) with hydroxypropyl-β-cyclodextrin (HPβCD) significantly enhances its dissolution and stability. This cyclodextrin complex improves ALA
Area of Science:
- Pharmaceutical Sciences
- Drug Delivery Systems
- Biopharmaceutics
Background:
- Alpha-lipoic acid (ALA) exhibits therapeutic promise but suffers from poor aqueous solubility (BCS Class II), gastric instability, and low oral bioavailability.
- These limitations hinder its effective application in nutraceuticals and pharmaceuticals.
Purpose of the Study:
- To formulate cyclodextrin (CD) inclusion complexes of ALA to enhance its solubility, stability, and oral bioavailability.
- To investigate the complexation efficiency and characterize the resulting ALA-CD formulations.
Main Methods:
- Phase solubility studies were conducted in simulated gastric and intestinal fluids to identify the optimal cyclodextrin host.
- Molecular dynamics simulations and MM-PBSA calculations were employed to predict binding affinities.
- Inclusion complexes were prepared using grinding, spray-drying, and lyophilization techniques.
- Solid-state characterization, pH-shift dissolution studies, permeability assays (PermeaPad®, Caco-2), and stability testing (ICH guidelines) were performed.
Main Results:
- Hydroxypropyl-β-cyclodextrin (HPβCD) was identified as the optimal host for ALA complexation.
- Spray-dried and lyophilized HPβCD-ALA complexes (HPβALA-sd, HPβALA-lyo) demonstrated complete amorphization of ALA.
- These complexes achieved near-complete dissolution within 5 minutes under biorelevant conditions, significantly outperforming free ALA.
- Enhanced storage stability was observed, with 88-90% ALA retention after 6 months compared to 36% for free ALA.
- Moderate permeability (Papp 8-9 × 10⁻⁶ cm/s) was maintained, while UV stability was not improved.
Conclusions:
- HPβCD inclusion complexation significantly improves the dissolution rate of alpha-lipoic acid.
- The enhanced dissolution profile suggests a better expected oral bioavailability for ALA-CD complexes compared to free ALA.
- While permeability remains moderate, the improved solubility and stability are key advantages for nutraceutical applications.
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