Nanocrystalline Albendazole: Fabrication, Stability, and Anthelmintic Efficacy Enhancement through Spray Drying and Nanotechnology

Albendazole is extensively used in the treatment of various helminthic infections including neurocysticercosis, hydatid disease, and soil-transmitted helminths. Nanocrystal technology has emerged as a novel formulation strategy to enhance the solubility, stability, and bioavailability of poorly water-soluble drugs like Albendazole [1]. Albendazole (ABZ), a benzimidazole-class anthelmintic drug, has been extensively used in clinical practice since its approval in 1982 for the treatment of a broad spectrum of parasitic infections, including echinococcosis. Recognized by the World Health Organization (WHO) as an essential drug, ABZ is the preferred choice for systemic parasitic diseases due to its high efficacy, limited toxicity, and emerging potential in anticancer therapies, particularly against pancreatic, gastric, and colorectal cancer cells. Despite its therapeutic promise, ABZ's clinical application is significantly hindered by its poor aqueous solubility (0.0228 mg/mL in water at 25?°C) and low oral bioavailability (less than 5%), classifying it as a Biopharmaceutics Classification System (BCS) Class II drug [2].

To address these limitations, various formulation strategies have been explored to enhance ABZ’s solubility and bioavailability. These include solid dispersions, nanocrystals, liposomes, cyclodextrin complexes, inclusion complexes, and self-emulsifying drug delivery systems. However, these methods often face challenges such as low drug loading efficiency, use of high surfactant concentrations, complex processing, and stability concerns, limiting their scalability and industrial application [3]. Among newer strategies, salt formation has gained prominence as a straightforward, scalable, and cost-effective approach to improve solubility. Approximately 50% of FDA-approved drugs are formulated as salts. ABZ salts, including hydrochloride, methane sulfonate, and fumarate, have shown promising improvements in solubility and dissolution behavior. Salt formation depends on the ΔpKa rule, wherein acids such as fumaric acid, tartaric acid, and hydrochloric acid are selected based on their ability to form stable salts with ABZ (pKa 9.51). These salts are synthesized using solvent evaporation techniques and characterized using FT-IR, NMR, PXRD, DSC, SEM, and other analytical tools to confirm structure and assess physicochemical stability [4].

In parallel, nanotechnology-based approaches, particularly nanocrystal formulation, have emerged as effective means to enhance the dissolution rate of poorly soluble drugs. Nanocrystals, composed of pure drug particles in the nanometer range, exhibit increased surface area and saturation solubility, leading to improved oral bioavailability. Two primary methods are used for nanocrystal production: the top-down approach (e.g., media milling, high-pressure homogenization) and the bottom-up approach (e.g., antisolvent precipitation). Although top-down techniques are effective, they are energy-intensive and equipment-dependent. Bottom-up techniques are more economical but susceptible to particle agglomeration and growth, necessitating the use of stabilizers [5]. Spray drying has gained traction as a viable drying and stabilization technique for nanocrystals due to its scalability, cost-effectiveness, and continuous processing capabilities. Compared to freeze drying, spray drying offers a simpler route for transforming nanocrystal suspensions into stable dry powders. Recent research demonstrates that spray-dried albendazole nanocrystals significantly improve dissolution rates and pharmacokinetic performance. Furthermore, the use of factorial design in formulation optimization allows for a systematic understanding of how process variables influence drug release and bioavailability [6].

2. NANOCRYSTAL TECHNOLOGY: A BRIEF OVERVIEW

Nanocrystal technology is an innovative strategy to enhance the solubility and bioavailability of poorly water-soluble drugs like albendazole [7]. Drug nanocrystals are pure drug particles reduced to submicron size (typically <500?nm) and stabilized by surfactants or polymers to prevent agglomeration. This approach increases the surface area and saturation solubility, leading to improved dissolution rates and faster drug absorption [8]. Nanocrystals can be produced by top-down techniques such as wet media milling and high-pressure homogenization, where larger drug crystals are broken down mechanically. Alternatively, bottom-up techniques like precipitation and solvent–antisolvent crystallization involve controlled nucleation from drug solutions. Combination methods, which integrate both approaches, offer better control over particle size and stability [9]. The nanosuspension formed can be post-processed into a solid form using carriers (e.g., microcrystalline cellulose) through drying techniques, such as tray drying, to enhance shelf life and convert it into a solid dosage form [10]. Upon reconstitution, the nanocrystals retain their original size, preserving enhanced dissolution characteristics. Solid-state characterization techniques like SEM, AFM, and XRD help confirm size, morphology, and physical state changes. Overall, nanocrystal technology is a versatile platform for overcoming solubility-limited drug delivery challenges [11].

Fig. 1: Nanocrystals can be produced by top-down techniques and bottom-up techniques

3. FABRICATION OF NANOCRYSTALLINE ALBENDAZOLE

Nanocrystal technology has emerged as a transformative strategy to enhance the solubility and therapeutic efficacy of poorly water-soluble benzimidazoles like Albendazole (ABZ). Several formulation techniques have been optimized for ABZ, including wet milling, high-pressure homogenization, antisolvent precipitation, and spray drying. Wet milling, a top-down approach using media mills, is among the most widely used methods for reducing ABZ particle size. Stabilizers such as Poloxamer 188 and Tween 80 are essential to prevent agglomeration and Ostwald ripening. High-pressure homogenization involves shearing ABZ suspensions through narrow valves under high pressure, producing uniform nanocrystals [12]. Antisolvent precipitation, a bottom-up method, rapidly precipitates ABZ from organic solvents into aqueous stabilizer solutions, yielding fine crystals through supersaturation. Spray drying is frequently employed post-nanocrystallization to obtain stable, free-flowing powders suitable for solid dosage forms [13]. A notable advancement includes the development of self-dispersible nanocrystals (SDNCs) of fenbendazole (FBZ) and its derivative Valero-fenbendazole (VAL-FBZ) using media milling and spray drying. These formulations, particularly with a 1:1 FBZ: Poloxamer 188 ratio, exhibited significantly enhanced dissolution (80% in 15 min vs. 14% in controls), suggesting the applicability of this strategy to Albendazole. Such nanocrystalline systems represent a promising direction to combat anthelmintic resistance and improve oral bioavailability [14].

4. STABILITY OF NANOCRYSTALLINE ALBENDAZOLE

Stability remains a critical factor in nanocrystal formulations. Key considerations include:

• Physical Stability: Prevention of crystal growth and aggregation using stabilizers.
• Chemical Stability: Albendazole’s susceptibility to oxidation and degradation can be reduced via encapsulation and antioxidant inclusion.
• Storage Stability: Spray drying and lyophilization enhance the shelf-life of nanocrystalline formulations.

Initial screening of stabilizers for albendazole nanosuspension involved PVPk30, PVA, Tween 80, and HEL-40 at 5% concentration with saturated malic acid as cosolvent. PVPk30 led to stratification, while HEL-40 caused agglomeration and poor mobility. In contrast, PVA and Tween 80 produced a uniform, milky suspension with minimal sedimentation. PVA exhibited excellent stability, maintaining homogeneity even after one week. Consequently, PVA was selected as the optimal stabilizer. Ensuring nanocrystal stability is vital, encompassing physical stability (preventing aggregation), chemical stability (minimizing degradation), and storage stability [15]. Techniques like spray drying and lyophilization significantly improve the long-term preservation and efficacy of albendazole nanocrystals. Stability is a critical parameter in drug formulation, reflecting a compound's capacity to maintain its identity, strength, quality, and purity over time. The stability of pharmaceutical compounds, particularly benzimidazole derivatives like albendazole, is influenced by various factors, including temperature, humidity, light, and pH. These compounds are susceptible to degradation, which can lead to reduced efficacy and potential toxicity. Studies indicate that albendazole and its analogs are more stable under acidic conditions and degrade rapidly under alkaline or oxidative environments. Stability assessments, such as accelerated and long-term testing, help predict shelf-life and optimal storage conditions. Incorporation of stabilizing agents and formulation strategies-like spray drying, solid dispersions, and nanoformulations-has shown promise in enhancing stability. For instance, spray drying can convert albendazole into amorphous forms, improving its stability and solubility. Moreover, proper packaging, such as using moisture-impermeable materials, plays a vital role in preserving drug stability. Regulatory guidelines emphasize the importance of comprehensive stability data for approval of new drug products. Overall, maintaining the stability of albendazole through innovative formulation and stringent storage controls is essential to ensure its therapeutic effectiveness throughout its shelf life [16]. Nanocrystalline albendazole exhibits improved solubility and bioavailability; however, its stability is influenced by factors such as particle size, surface energy, and crystallinity. Due to high surface area, nanocrystals are prone to agglomeration and recrystallization, potentially affecting dissolution and therapeutic efficacy. Stabilizers like Poloxamer 188, PEG6000, and PVP K30 are crucial in maintaining dispersion stability by preventing aggregation and preserving the amorphous state. Storage conditions, particularly humidity and temperature, significantly impact stability. Proper formulation and packaging are essential to ensure prolonged shelf life and consistent performance. Overall, nanocrystalline albendazole remains stable with optimized carrier and environmental control [17].

5. ANTHELMINTIC EFFICACY OF NANOCRYSTALLINE ALBENDAZOLE

Nanocrystalline Albendazole has demonstrated significantly improved pharmacodynamic profiles compared to conventional formulations:

The enhancement of bioavailability and dissolution rate is a pivotal focus in modern pharmaceutical formulation, particularly for poorly water-soluble drugs like Albendazole. Albendazole, a broad-spectrum anthelmintic, suffers from low aqueous solubility, leading to suboptimal absorption and therapeutic efficacy. Recent advancements in formulation strategies have addressed these limitations through innovative techniques such as spray drying, solid dispersion, and nanotechnology. Spray drying has emerged as a promising approach to enhance drug solubility by producing amorphous solid dispersions that improve wettability and surface area. This method transforms Albendazole into a fine, uniform powder with improved physicochemical properties, facilitating rapid dissolution and gastrointestinal absorption. The incorporation of hydrophilic carriers and polymers further promotes drug dispersion and stabilization in the gastrointestinal tract. Numerous in vitro and in vivo studies demonstrate that optimized spray-dried formulations significantly increase the dissolution rate and systemic bioavailability of Albendazole, translating to improved therapeutic outcomes. Such advancements contribute not only to enhanced efficacy but also to reduced dosage requirements and improved patient compliance [18].

Albendazole, a broad-spectrum anthelmintic, suffers from poor aqueous solubility and low oral bioavailability, which limits its therapeutic effectiveness. Recent advancements in nanotechnology, particularly the development of nanocrystalline formulations, have shown promise in overcoming these challenges. Nanocrystals, composed of pure drug particles stabilized by surfactants or polymers, significantly enhance the dissolution rate and absorption of poorly water-soluble drugs like Albendazole. The reviewed studies demonstrate that reducing particle size to the nanometer range improves Albendazole’s surface area, saturation solubility, and permeability. Various techniques such as wet milling, high-pressure homogenization, and antisolvent precipitation have been successfully employed to produce stable Albendazole nanocrystals. These formulations show marked improvements in bioavailability, leading to higher plasma drug concentrations and enhanced therapeutic efficacy against parasitic infections. Furthermore, nanocrystalline Albendazole exhibits improved stability, reduced dosing frequency, and potentially fewer side effects due to better targeting and controlled release. This approach represents a cost-effective and scalable strategy for optimizing Albendazole delivery, especially in regions burdened by parasitic diseases. Overall, nanocrystal technology emerges as a promising platform for enhancing the pharmacokinetic and pharmacodynamic profiles of Albendazole [19]. Albendazole, a poorly water-soluble benzimidazole, exhibits limited oral bioavailability, restricting its therapeutic efficacy. Nanocrystallization enhances solubility and dissolution rate by increasing surface area and saturation solubility, leading to improved absorption and systemic availability. Various studies on nanocrystalline albendazole formulations, including nanoprecipitation, high-pressure homogenization, and media milling, have demonstrated enhanced pharmacokinetic profiles. These nanoformulations show superior anthelmintic activity, reduced dose frequency, and minimized side effects. Overall, nanocrystalline technology represents a promising strategy to overcome biopharmaceutical limitations of albendazole, offering a significant improvement in oral bioavailability and therapeutic outcomes [20].

Nanocrystalline Albendazole, prepared via antisolvent precipitation using varying concentrations of PVP K-30 as a stabilizer, demonstrated significantly enhanced anthelmintic efficacy due to improved dissolution properties. The reduction in particle size and partial amorphization, confirmed by XRD analysis, contributed to increased drug release rates. As PVP K-30 concentration increased, both dissolution and particle stability improved, enhancing Albendazole's bioavailability. These nanocrystals offer a promising formulation strategy to overcome the solubility-limited therapeutic performance of conventional Albendazole. However, further studies are required to assess their physical stability under accelerated storage and confirm sustained anthelmintic activity in vivo [21]. Albendazole, a widely used broad-spectrum anthelmintic, exhibits limited therapeutic efficacy due to its poor aqueous solubility. Recent advancements in nanotechnology, particularly the development of albendazole nanocrystals using tea saponins as natural stabilizers, have demonstrated significant improvements in its pharmacokinetic and pharmacodynamic profiles. The nanosuspension, prepared via wet grinding, yielded particles averaging 180?nm in size and exhibited markedly enhanced solubility (up to 2602-fold) and dissolution in both acidic and neutral pH conditions. The improved permeability across intestinal segments, as shown by increased apparent permeability (Papp) in everted gut sac studies, supports enhanced absorption. Notably, the oral bioavailability of albendazole was substantially increased, with a 4.65-fold rise in plasma AUC of its active metabolite, albendazole sulfoxide. These findings highlight the superior anthelmintic potential of albendazole nanocrystals and underscore the role of tea saponins as effective natural stabilizers for enhancing the oral delivery of poorly soluble antiparasitic agents [22]. Albendazole, a poorly water-soluble anthelmintic, exhibits limited oral bioavailability. To address this, albendazole nanosuspensions (ABZNS) were formulated using surfactants (Polysorbate 80, Poloxamer 188) and Hydroxypropyl Methylcellulose via pre-homogenization followed by high-pressure homogenization. Characterization revealed particle sizes of 385.7±4.3 to 576.2±4.8 nm and zeta potentials of –23.5±1.8 to –40.5±0.8 mV. Pharmacokinetic studies in Wistar rats showed a 2.14–2.96-fold increase in oral bioavailability compared to conventional suspensions. These findings highlight the effectiveness of nanosuspension technology in enhancing the solubility and bioavailability of lipophilic drugs like albendazole, suggesting its promise for improved anthelmintic therapy [23].

Table 1: Overview of Nanocrystalline Albendazole: Fabrication, Stability, and Anthelmintic Efficacy Enhancement

6. CHALLENGES AND FUTURE PERSPECTIVES

Despite the promise, several challenges need addressing:

Toxocariasis remains a significant zoonotic parasitic disease, particularly challenging due to the tissue-dwelling nature of Toxocara larvae and the limited efficacy of existing anthelmintics. Despite the availability of the Toxocara canis draft genome, the scarcity of validated molecular targets and a restricted chemical space explored for drug discovery represent major hurdles [24]. Current therapies rely heavily on decades-old benzimidazole derivatives, such as albendazole, which show limited bioavailability and suboptimal tissue penetration. This necessitates the development of more effective, targeted anthelmintic agents [25]. Recent advances have focused on albendazole analogues, reactive quinone derivatives, natural products, and novel drug delivery systems including nanoparticles. While these innovations offer promising in vitro and in vivo results, several translational challenges must be addressed. Key among them is scalability-many novel formulations are developed at the laboratory scale, and transitioning them to commercial production remains complex and cost-intensive. Regulatory approval also presents a significant barrier, particularly for nanomedicine-based therapies, which require extensive toxicological and pharmacokinetic evaluations to meet stringent global health and safety standards [26].

Table no.2: Summary of Key Findings on Nanocrystalline Albendazole: Fabrication, Stability, and Anthelmintic Efficacy