Silibinin solubilization: combined effect of co-solvency and inclusion complex formation

Abstract

Objective

Belonging to the class II drugs according to the biopharmaceutics classification system, silibinin (SLB) benefits from high permeability but suffers poor solubility that negatively affects the development of any delivery system. This research aimed to improve SLB solubility by combined use of co-solvency and complexation phenomena.

Methods

Solubility studies were performed using the phase solubility analysis according to the shake-flask method in the presence of ethanol and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) as a co-solvent and inclusion complexing agent, respectively. SLB release studies from chitosan nanoparticles were carried out in double-wall, diffusion cells using the optimized drug release medium.

Results

SLB solubility was mathematically optimized constraining to using the lowest concentrations of ethanol and HP-β-CD. SLB solubility increased linearly with the increase of HP-β-CD concentration. The solubility in PBS-ethanol mixtures followed a log-linear model. SLB solubility in the presence of the ethanol co-solvent and HP-β-CD complexing agent was optimized by adopting a genetic algorithm suggesting the phosphate buffer saline solution supplemented by 6%v/v ethanol and 8 mM HP-β-CD as an optimized medium. The optimized solution was examined to study SLB release from chitosan nanoparticles (4.5 ± 0.2% drug loading) at 37 °C under static conditions. The sigmoidal release profile of SLB from the particles indicated a combination of erosion and diffusion mechanisms governing drug release from the nanoparticles.

Conclusion

SLB solubility in a buffered solution supplemented by ethanol co-solvent and HP-β-CD complexing agent is a function of free drug present in the semi-aqueous media, the drug-ligand binary complex, and the drug/ligand/co-solvent ternary complex.

Graphical Abstract

Keywords:

• Silibinin
• solubilization
• complexation
• co-solvency
• genetic algorithm

Acknowledgment

The authors express their sincere gratitude to Iran National Science Foundation (IPPI) for supporting this research (INSF Grant No. 97023355).

Authors contributions

Azam Dehghan: Investigation; Formal analysis; Resources; Writing - Original Draft; Visualization; Funding acquisition.

Saeed Ghanbarzadeh: Resources; Writing - Review & Editing.

Majid Ghias: Formal analysis.

Mohammad Imani: Conceptualization; Methodology; Validation; Formal analysis; Resources; Data Curation; Writing - Review & Editing; Supervision; Funding acquisition; Project administration.

Disclosure statement

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The research was solely funded by Iran National Science Foundation (INSF) as a research grant and supported in terms of providing facilities by our affiliated institute i.e. Iran Polymer and Petrochemical Institute with the same no financial or non-financial interest in the subject matter or materials discussed in this manuscript.

Data availability statement

The research data used for the preparation of this manuscript is accessible by the authors upon request.

Additional information

Funding

The authors express their sincere gratitude to Iran National Science Foundation (INSF) for supporting this research (INSF Grant No. 97023355).