Introduction
Parasitic infections pose significant challenges to both human and animal health, particularly in regions where hygiene and sanitation infrastructure remains limited. Among the arsenal of antiparasitic agents, albendazole (ABZ) stands out as a broad-spectrum anthelmintic drug recommended by the World Health Organization (WHO) for treating cystic echinococcosis and other helminthic diseases. However, its clinical utility is hampered by poor water solubility (a mere 0.2 μg/mL), leading to suboptimal absorption in the gastrointestinal tract and necessitating higher doses that often trigger adverse effects like nausea, dizziness, and diarrhea. Moreover, ABZ’s low solubility limits its effectiveness against non-intestinal parasites, with cure rates stagnating at around 30%. To address these limitations, researchers have explored various strategies, including lipid-based formulations, polymeric carriers, and nanotechnology. Among these, cyclodextrin (CD)-based inclusion complexes have emerged as a promising solution due to their ability to form stable host-guest complexes with hydrophobic drugs, enhancing solubility and bioavailability without compromising therapeutic efficacy.
Research Objectives
This study aimed to:
- Develop an optimized formulation of albendazole-methyl-β-cyclodextrin (ABZ-Me-β-CD) inclusion complexes to improve ABZ’s aqueous solubility and dissolution rate.
- Identify the most effective preparation method and critical process parameters (e.g., temperature, time, and host–guest ratio) using systematic experimental designs.
- Characterize the physicochemical properties of the resulting complexes using advanced analytical techniques, including X-ray diffraction (XRD) and scanning electron microscopy (SEM).
Methodology
Materials
- Key reagents: High-purity ABZ (>98%), methyl-β-cyclodextrin (Me-β-CD), and other cyclodextrin derivatives (β-CD, HP-β-CD) were sourced from reputable suppliers.
- Equipment: Analytical tools included a high-performance liquid chromatography (HPLC) system (Agilent 1260 Infinity), XRD (Empyrean), SEM (ZEISS Sigma 300), and a Fourier-transform infrared spectrometer (FTIR).
Experimental Design
Phase Solubility Studies
To evaluate the solubilizing capacity of different cyclodextrins, ABZ was mixed with varying concentrations of Me-β-CD, β-CD, and HP-β-CD in aqueous solutions. The resulting equilibrium solubility data were analyzed to determine stability constants (Kc) using the Benesi-Hildebrand equation.
Key finding: Me-β-CD exhibited the highest Kc value (2330 M⁻¹), confirming its superiority as a solubilizing agent for ABZ.
Preparation of Inclusion Complexes
Four methods were compared:
- Ultrasonication: Mixing ABZ-acetic acid solution with Me-β-CD aqueous solution under sonication at controlled power (360–720 W) and time (30–60 min).
- Magnetic stirring: Conventional stirring at ambient temperature.
- Microwave irradiation: Rapid heating via microwave energy.
- Supercritical CO₂-assisted synthesis: Utilizing high-pressure CO₂ for molecular encapsulation.
Among these, ultrasonication at 60% power (360 W) for 60 minutes yielded the highest solubility enhancement.
Optimization Using Orthogonal Experiments
A L₉(3⁴) orthogonal array was designed to fine-tune three critical parameters:
- Molar ratio (ABZ:Me-β-CD): 1:2, 1:3, or 1:4.
- Ultrasonic power: 50%, 60%, or 70% (300–720 W).
- Sonication time: 30, 45, or 60 minutes.
The optimal conditions were identified as 1:3 molar ratio, 60% power, and 60-minute sonication, achieving a drug loading efficiency of 16.5% and recovery yield of 95%.
Results and Discussion
Solubility Enhancement
The aqueous solubility of the ABZ-Me-β-CD complex reached 22.3 ± 0.66 mg/mL, a staggering 110,000-fold improvement over pristine ABZ (0.2 μg/mL). This enhancement was attributed to Me-β-CD’s ability to form stable inclusion complexes via hydrophobic interactions, effectively shielding ABZ’s lipophilic core while exposing its polar groups to water.
Dissolution Rate
In vitro dissolution tests revealed that the complex achieved 80% drug release within 10 minutes, surpassing the dissolution rate of raw ABZ by 8-fold. This accelerated release profile aligns with the AL-type phase solubility curve, confirming the formation of a 1:1 ABZ-Me-β-CD complex.
Structural Characterization
X-ray Diffraction (XRD)
The XRD pattern of the physical mixture showed overlapping peaks of ABZ and Me-β-CD, indicating minimal interaction. In contrast, the ABZ-Me-β-CD complex exhibited broad, diffuse peaks characteristic of amorphous materials, confirming the loss of crystallinity upon encapsulation (Fig. 5).
Scanning Electron Microscopy (SEM)
SEM imaging revealed that ABZ existed as irregular fragments in the physical mixture, while Me-β-CD formed spherical aggregates. The complex, however, displayed a homogeneous, non-crystalline morphology, further corroborating the XRD results (Fig. 6).
Implications and Applications
The development of ABZ-Me-β-CD complexes holds transformative potential for veterinary medicine:
- Improved Dosage Regimens: Enhanced solubility enables lower, more palatable doses, reducing stress on livestock and minimizing environmental contamination.
- Cost-Effective Production: Ultrasonication is a scalable, energy-efficient technique suitable for industrial-scale synthesis.
- Broader Therapeutic Applications: The stabilized amorphous form may extend ABZ’s efficacy against non-intestinal parasites, addressing the current 70% treatment gap.
Conclusion
This study demonstrates that molecular encapsulation via Me-β-CD is a robust strategy to overcome ABZ’s solubility limitations. The optimized protocol—ultrasonication at 60% power for 60 minutes with a 1:3 molar ratio—yields a stable, highly soluble complex with superior dissolution kinetics. Coupled with its simplicity and scalability, this approach paves the way for next-generation anthelmintic formulations that could revolutionize parasite control in both human and veterinary medicine. Future work will focus on in vivo pharmacokinetic studies to validate these promising in vitro results.
