Formulation and Evaluation of Dexlansoprazole-Loaded Solid Lipid Nanoparticles for Solubility Enhancement

Poor aqueous solubility remains one of the most critical challenges in modern drug development, particularly for drugs belonging to the Biopharmaceutical Classification System (BCS) Class II, where solubility becomes the rate-limiting step for oral absorption. Approximately 40–60% of newly synthesized drug molecules exhibit poor water solubility, which directly impacts their oral bioavailability, therapeutic efficacy, and clinical translation. Dexlansoprazole, an acid-labile proton pump inhibitor (PPI) used for the treatment of gastroesophageal reflux disease (GERD), erosive esophagitis, and related acid-peptic disorders, is one such drug whose low solubility and poor stability in acidic medium limit its systemic exposure and overall therapeutic performance. Conventional approaches such as enteric-coated granules or delayed-release capsules have made significant strides in improving the pharmacokinetic behavior of Dexlansoprazole; however, they often suffer from issues such as inconsistent absorption, variable bioavailability, and limited dissolution in the intestinal environment. Therefore, advanced formulation strategies that can enhance the solubility, protect the drug from acidic degradation, and improve absorption are of paramount importance. Nanotechnology has emerged as a revolutionary tool in pharmaceutical sciences, particularly for formulating poorly water-soluble drugs. Among various nanocarrier systems, Solid Lipid Nanoparticles (SLNs) have attracted immense attention owing to their excellent biocompatibility, ability to encapsulate both hydrophilic and lipophilic molecules, controlled and sustained release behavior, and stability in physiological environments. SLNs are submicron colloidal carriers composed of physiological lipids that remain solid at both room and body temperatures. They are stabilized by surfactants such as Tween 80, Poloxamers, or phospholipids, enabling the formation of a stable dispersion. The high drug-loading capacity, protection of sensitive drug molecules from environmental degradation, improved solubility, and relatively simple manufacturing processes make SLNs an attractive alternative to conventional drug delivery systems such as emulsions, liposomes, and polymeric nanoparticles [4–7]. Dexlansoprazole is the R-enantiomer of lansoprazole and exhibits greater systemic exposure, longer residence time, and superior pharmacodynamic profile compared to its racemic counterpart. Despite these advantages, the drug suffers from extremely low aqueous solubility (~0.1 mg/mL at neutral pH), acid-labile nature, pH-dependent dissolution, and incomplete intestinal absorption. To address these limitations, Dexlansoprazole is commercially formulated using a dual delayed-release capsule technology wherein two types of enteric-coated granules dissolve at different intestinal pH values. This provides a biphasic drug release and prolonged plasma exposure [31–33]. While this system offers improved acid protection and extended action, challenges such as dose-related variability, delayed onset of therapeutic effect, and dissolution-limited absorption persist. Solid Lipid Nanoparticles provide an innovative drug delivery approach for Dexlansoprazole, offering crucial advantages beyond those of enteric-coated or conventional delayed-release formulations. By entrapping Dexlansoprazole within a solid lipid matrix such as Glyceryl Monostearate (GMS), the drug can be shielded from acidic degradation, improving its stability in gastric pH. The nanoscale size of SLNs significantly enhances surface area, facilitating improved dissolution and absorption across the gastrointestinal epithelium. Additionally, the lipid core slows down drug release, providing a sustained effect and potentially reducing dosing frequency. Surfactants such as Tween 80 not only stabilize the SLNs but also enhance solubility and modify membrane permeability, contributing to improved oral bioavailability [8–12]. The preparation of SLNs traditionally involves techniques such as high-pressure homogenization, solvent emulsification-diffusion, microemulsion techniques, ultrasonication, and spray drying. Among these, ultrasonication-assisted solvent evaporation stands out due to its simplicity, reproducibility, cost-effectiveness, and ability to produce nanocarriers with narrow particle size distribution without the need for high temperatures or harsh organic solvents [25–28]. In the present study, Dexlansoprazole-loaded SLNs were prepared using a modified single emulsification–solvent evaporation method assisted by probe sonication. GMS was used as the lipid matrix, Tween 80 as the surfactant, and dimethylformamide (DMF) as the organic solvent. During formulation, the lipid was melted, the drug was dissolved in DMF, and the aqueous phase containing Tween 80 was added dropwise to form a coarse emulsion. Ultrasonication was then applied to reduce particle size, and solvent traces were removed via rotary evaporation. This method allowed efficient entrapment of the drug in the lipid matrix while ensuring stability of the nanoparticulate dispersion. One of the critical aspects of SLN formulation is the evaluation of compatibility between the drug and excipients. Fourier Transform Infrared Spectroscopy (FTIR) serves as an essential tool for confirming the presence of characteristic functional groups and identifying potential interactions. FTIR studies conducted in the present research revealed the absence of significant drug–excipient interactions, as the characteristic peaks of Dexlansoprazole were retained in the SLN formulation. This confirms that the drug was physically entrapped without undergoing chemical modification. Moreover, particle size, polydispersity index (PDI), and zeta potential were assessed using Dynamic Light Scattering (DLS). The optimized formulation achieved a particle size of 156 nm with a low PDI, indicating a uniform and stable dispersion. Zeta potential measurements further confirmed the stability of the nanoparticles, as adequate charge repulsion minimizes aggregation. Entrapment efficiency and drug loading capacity are crucial parameters for evaluating the performance of SLNs. In the current work, formulations with optimized lipid-to-drug ratios demonstrated significantly higher entrapment efficiency compared to initial experimental batches, confirming the role of lipid and surfactant concentrations in determining the encapsulation potential of SLNs. In vitro release studies revealed a sustained drug-release pattern, which can greatly contribute to prolonged therapeutic efficacy of acid-labile drugs like Dexlansoprazole. Stability studies conducted at 4 °C further confirmed that the optimized formulation maintained its physicochemical integrity over the study period, demonstrating the suitability of SLNs for long-term storage and therapeutic use. The rising prevalence of GERD and other acid-related disorders further underscores the need for improved therapeutic formulations. Epidemiological studies across Asian populations indicate that the prevalence of GERD has nearly doubled in recent years, attributed largely to lifestyle modifications, dietary changes, and increased diagnostic awareness [29,30]. PPIs remain the cornerstone of GERD management, but therapeutic failures are not uncommon due to factors such as rapid metabolism, inconsistent absorption, and poor solubility of specific PPIs including Dexlansoprazole. Therefore, innovative formulation strategies such as SLNs provide a promising alternative to conventional oral drug delivery systems. SLNs offer multiple advantages in the context of Dexlansoprazole delivery. The lipid matrix not only enhances solubility and dissolution but also protects the drug from enzymatic and pH-induced degradation. The small particle size facilitates improved surface area, resulting in enhanced solubilization and absorption. Furthermore, the ability of SLNs to modulate drug release helps in maintaining therapeutic plasma levels for prolonged durations, reducing the dosing frequency and improving patient compliance. The use of physiological lipids such as GMS ensures biocompatibility, while surfactants like Tween 80 improve dispersion stability and prevent particle aggregation. Additionally, lipid-based nanocarriers are known to enhance lymphatic uptake, which may further improve the bioavailability of poorly soluble drugs [19]. Literature evidence strongly supports the use of SLNs for improving solubility and bioavailability of several water-insoluble drugs. Studies on PPIs such as omeprazole and lansoprazole have shown significant improvements in dissolution rate, stability, and pharmacokinetic behavior when formulated using SLNs. While extensive research exists for PPIs in nanoformulations, Dexlansoprazole-loaded SLNs remain largely unexplored, presenting a significant opportunity to investigate their potential for enhancing solubility and therapeutic efficacy. The present research addresses this gap by developing and evaluating Dexlansoprazole-loaded SLNs with optimized particle size, entrapment efficiency, stability, and dissolution characteristics [20]. An additional strength of the present study lies in the use of a factorial design approach for optimization. Statistical experimental design methods such as factorial design help in evaluating the effect of multiple formulation variables simultaneously while minimizing the number of experimental trials required. Factors such as lipid concentration, surfactant concentration, and sonication time were systematically varied to assess their impact on the particle size of SLNs. This approach allowed identification of the optimal formulation conditions that produced SLNs with desirable physicochemical properties. Mathematical modeling and response surface analysis generated during this process serve to improve understanding of interaction effects among variables, facilitating reproducible and efficient formulation development [21]. Evaluation of the formulated Dexlansoprazole SLNs included comprehensive physicochemical characterization involving FTIR, particle size analysis, zeta potential determination, scanning electron microscopy (SEM), entrapment efficiency assessment, and in vitro dissolution studies. The SEM micrographs revealed spherical particles with smooth surfaces, further validating uniformity of the formulation. Sustained drug release observed from the optimized SLN batch indicates potential for prolonged therapeutic effect and reduction in dosing frequency. The stability of the SLNs under refrigerated conditions further confirms robustness of the formulation approach [22].

2. MATERIALS AND METHODS

2.1 MATERIALS

2.1.1 Drug (Dexlansoprazole)

Dexlansoprazole, the active pharmaceutical ingredient used in this study, was received as a gift sample from a certified laboratory source. It is a well-known proton pump inhibitor (PPI) classified under the Biopharmaceutical Classification System (BCS) as a Class II drug, indicating low aqueous solubility but high permeability. Due to its poor solubility and susceptibility to degradation in acidic environments, enhancing its dissolution and stability is essential for improving its therapeutic performance. The drug sample obtained was of pharmaceutical grade quality and was used directly in the formulation process without any further purification.

2.1.2 Lipid (Glyceryl Monostearate, GMS)

Glyceryl monostearate (GMS) was selected as the lipid matrix for the preparation of solid lipid nanoparticles. GMS is a commonly used, biocompatible, and biodegradable lipid widely employed in nanoparticle formulations due to its excellent safety profile and ability to encapsulate lipophilic drugs. The lipid used in this study was of analytical grade and obtained from laboratory stock. Its physicochemical properties such as a suitable melting point, stability, and compatibility with Dexlansoprazole make it an ideal candidate for forming the solid lipid core required for SLN preparation.

2.1.3 Surfactant (Tween 80)

Tween 80 (Polysorbate 80) was employed as the surfactant in the formulation process. Being a nonionic surfactant with high solubilizing and stabilizing capabilities, Tween 80 plays a critical role in reducing interfacial tension during emulsification and ensuring the formation of uniform, stable nanoparticles. Its steric stabilization effect helps prevent aggregation of lipid particles, thereby enhancing the long-term physical stability of the SLN dispersion. Only analytical-grade Tween 80 was used in the study.

2.1.4 Solvent and Other Chemicals

Dimethylformamide (DMF) was used as the organic solvent to dissolve Dexlansoprazole during the formulation process. DMF’s strong solvent properties facilitate the complete dissolution of the lipophilic drug, enabling its efficient incorporation into the molten lipid phase. Distilled water of HPLC grade was used as the aqueous phase throughout the preparation steps to ensure purity and consistency. All chemicals and reagents used in the study were of analytical grade and were utilized as supplied, without the need for any additional purification steps.

2.2 Equipment

Table No.1: instruments were employed throughout the study

2.3 Preparation of Dexlansoprazole-Loaded Solid Lipid Nanoparticles (SLNs)

Dexlansoprazole-loaded solid lipid nanoparticles were formulated using a modified single-emulsion solvent evaporation technique, aided by probe sonication to achieve nanoscale particle size and uniform distribution. The method was optimized to ensure maximum drug entrapment, minimal particle size, and high formulation stability. The composition of the optimized batch consisted of 40 mg Dexlansoprazole, 400 mg Glyceryl Monostearate (GMS), 100 mg Tween 80 (0.5% w/v), 3 mL DMF, and 20 mL distilled water as the aqueous phase.

2.3.1 Preparation of the Lipid Phase

The lipid phase was prepared by accurately weighing 400 mg of GMS and melting it at 60 °C using a thermostatically controlled water bath. In a separate step, 40 mg of Dexlansoprazole was dissolved in 3 mL of dimethylformamide (DMF) to obtain a clear, homogeneous drug solution. This drug–solvent solution was then slowly introduced into the molten lipid under continuous stirring to ensure complete mixing and uniform dispersion of the drug within the lipid matrix. Throughout this process, the temperature was strictly maintained at 60 °C to prevent premature solidification of the lipid.

2.3.2 Preparation of the Aqueous Phase

The aqueous phase was prepared by dissolving 100 mg of Tween 80 in 20 mL of distilled water, yielding a 0.5% w/v surfactant solution. The surfactant plays a crucial role in stabilizing the emulsion and preventing particle aggregation. The aqueous phase was pre-heated to 60 °C to match the temperature of the lipid phase, ensuring seamless mixing during emulsification.

2.3.3 Formation of Coarse Emulsion

The hot aqueous phase was added gradually in a dropwise manner to the lipid phase while continuously stirring at 1000 rpm for approximately 5–10 minutes. This controlled addition facilitated the formation of a milky oil-in-water (o/w) coarse emulsion, which served as the precursor for nanoemulsion formation.

2.3.4 Probe Sonication (Nanoemulsion Formation)

To reduce the droplet size and produce a fine nanoemulsion, the coarse emulsion was subjected to probe ultrasonication using a Rivotek sonicator. Sonication was carried out at 40% amplitude, operated in pulsed cycles of 30 seconds ON and 15 seconds OFF to avoid overheating. The total sonication time ranged between 120–150 seconds, and an ice bath was used throughout the process to maintain temperature stability. This step effectively reduced the emulsion droplet size, leading to the formation of nanoscale particles.

2.3.5 Solvent Removal and Solidification

Following sonication, the nanoemulsion was transferred to a rotary evaporator to remove DMF under reduced pressure at 40–45 °C. This step allowed the evaporation of organic solvent and facilitated the solidification of lipid droplets into solid lipid nanoparticles. The resulting dispersion was then cooled to room temperature and subsequently stored at 4 °C for 1 hour to ensure complete particle solidification.

2.3.6 Purification of SLNs

The SLN dispersion was purified by centrifugation at 15,000 rpm for 30 minutes at 4 °C using a Remi cooling centrifuge. The supernatant was collected to analyze the amount of unentrapped (free) drug, while the pellet containing the SLNs was washed with distilled water to remove residual surfactant or impurities. The purified nanoparticles were then re-suspended to obtain the final SLN formulation.

2.4 Optimization of Formulation Parameters

A factorial design approach using Design Expert® Version 12 was adopted to systematically optimize the formulation. Three critical independent variables were evaluated:

Lipid concentration: 80–400 mg

Surfactant concentration: 10–100 mg

Sonication time: 5–25 minutes

The dependent variable selected for optimization was particle size (nm). A total of eight experimental formulations were generated as per the factorial matrix. From these, the optimized batch was selected based on achieving the smallest particle size, lowest polydispersity index (PDI), and highest entrapment efficiency. This statistical approach enabled the identification of significant factors and their interactions affecting nanoparticle characteristics.

2.5 Evaluation of Dexlansoprazole-Loaded SLNs

2.5.1 Particle Size, Polydispersity Index (PDI), and Zeta Potential

The mean particle size, PDI, and zeta potential of the SLNs were measured using Dynamic Light Scattering (DLS) on a Malvern Zetasizer. Particle size and PDI provided insights into the uniformity and distribution of nanoparticles, whereas zeta potential indicated the electrostatic stability of the dispersion. All measurements were performed at room temperature, and samples were appropriately diluted to avoid multiple scattering effects.

2.5.2 Entrapment Efficiency (EE%)

Entrapment efficiency was determined by quantifying the amount of free drug present in the supernatant after centrifugation. The concentration of unentrapped drug was analyzed spectrophotometrically at 284 nm using a UV–Visible spectrophotometer. EE% was calculated using the following formula:

EE%=Total drugFree drugTotal drug×100

This parameter reflects the drug-loading capacity of the formulation and the affinity between the drug and lipid matrix.

2.5.3 FTIR Analysis

Fourier Transform Infrared (FTIR) spectroscopy was performed using a Shimadzu FTIR instrument to evaluate possible chemical interactions between Dexlansoprazole and formulation excipients. FTIR spectra of pure drug, blank SLNs, and drug-loaded SLNs were recorded within the range of 4000–400 cm?¹. Characteristic absorption peaks were assessed to confirm drug compatibility and retention of functional groups.

2.5.4 In-Vitro Drug Release Study

In-vitro drug release was studied using a dialysis membrane method in phosphate buffer (pH 6.8) to mimic intestinal conditions. The SLN dispersion was placed inside the dialysis bag and immersed in the dissolution medium maintained at 37 ± 0.5 °C. Samples were withdrawn at predetermined time intervals, filtered, and analyzed at 284 nm. The release profile of the SLN formulation was compared against that of pure Dexlansoprazole to evaluate enhancement in dissolution characteristics.

2.5.5 Stability Studies

Stability of the optimized SLN formulation was assessed by storing the sample at 4 °C for 30 days. Particle size, PDI, and entrapment efficiency were periodically evaluated to determine any physical changes over time. These observations provided insight into the long-term stability and shelf-life of the nanoparticles.

2.5.6 Surface Morphology (SEM Analysis)

Scanning Electron Microscopy (SEM) was used to visualize the shape and surface characteristics of the SLNs. A small quantity of lyophilized nanoparticles was mounted on an aluminum stub, sputter-coated with gold, and examined under SEM at appropriate accelerating voltages. This analysis confirmed the spherical shape, surface smoothness, and morphological uniformity of the nanoparticles.

RESULTS & DISCUSSION:

Physicochemical Characterization of Dexlansoprazole

1. Chemical Identity

Dexlansoprazole is chemically identified as (R)-2-([3-methyl-4-(2,2,2-trifluoroethoxy) pyridin-2-yl] methyl sulfinyl)-1H-benzimidazole. It has a molecular formula of C??H??F?N?O?S with a molecular weight of 369.36 g/mol. The drug belongs to the class of substituted benzimidazole derivatives and represents the (R)-enantiomer of lansoprazole, which is known to exhibit improved pharmacokinetic performance and prolonged acid suppression compared to the racemic form.

2. Appearance

Dexlansoprazole was observed as a white to off-white crystalline powder, indicating its well-defined solid-state structure. This crystalline nature plays a critical role in its dissolution behavior and formulation stability.

3. Solubility

Dexlansoprazole exhibits very low aqueous solubility, approximately 0.1 mg/mL at pH 7, which significantly limits its oral bioavailability. The drug shows marked pH-dependent solubility, being freely soluble in acidic conditions (pH < 4) while remaining practically insoluble in neutral to alkaline environments (pH 6–8). However, it is readily soluble in organic solvents such as methanol, ethanol, dichloromethane, and dimethylformamide, confirming its lipophilic character. Based on these solubility and permeability properties, Dexlansoprazole is classified as a BCS Class II drug.

4. Partition Coefficient (log P)

The partition coefficient (log P) of Dexlansoprazole ranges between 2.0 and 2.3, indicating moderate lipophilicity. This property facilitates passive diffusion across biological membranes, enhancing permeability, but simultaneously contributes to poor dissolution in aqueous gastrointestinal fluids.

5. pKa Values

Dexlansoprazole exhibits two characteristic pKa values, with a primary pKa of approximately 4.0 attributed to the pyridine nitrogen and a secondary pKa of about 1.1 associated with the benzimidazole moiety. These ionization constants significantly influence the drug’s pH-dependent solubility, chemical stability, and absorption behavior.

6. Melting Point

The reported melting point of Dexlansoprazole lies between 138–140 °C, with slight variations depending on the purity and crystalline form of the drug. This thermal property is important for assessing processing conditions during formulation development.

7. Stability

Dexlansoprazole is acid-labile and undergoes rapid degradation in gastric acidic conditions, which poses a major challenge for oral delivery. In contrast, it remains relatively stable in neutral and alkaline media. Additionally, the drug is sensitive to light, heat, and moisture, necessitating appropriate protection during formulation, packaging, and storage.

8. Crystallinity

Dexlansoprazole exists predominantly in a crystalline form. However, it is susceptible to polymorphic transformations under stress conditions, which can affect its dissolution rate, stability, and overall performance in pharmaceutical formulations.

9. UV Absorption

The drug exhibits a characteristic UV absorption maximum (λmax) at approximately 284 nm in methanol–water systems. This property is commonly utilized for UV spectrophotometric estimation of Dexlansoprazole in analytical and formulation studies.

10. Pharmacokinetic Relevance of Physicochemical Properties

The physicochemical properties of Dexlansoprazole have a direct impact on its pharmacokinetic behavior. Despite its high membrane permeability, poor aqueous solubility limits its oral absorption. Furthermore, its acid-labile nature necessitates protective delivery approaches such as enteric coating or advanced nanocarrier systems, including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). The development of dual delayed-release capsule technology specifically addresses these limitations by enhancing stability, prolonging drug release, and improving therapeutic efficacy.

UV–Visible Spectrophotometer Analysis of Dexlansoprazole

Principle

The UV–Visible spectrophotometric analysis is based on the Beer–Lambert law, which establishes a direct relationship between the absorbance of light and the concentration of the absorbing species in a solution. According to this law, the absorbance of a compound is directly proportional to its concentration and the path length of the cell, provided the system follows linearity within a specific concentration range. Dexlansoprazole exhibits strong absorption in the ultraviolet region due to the presence of conjugated aromatic and heterocyclic structures in its chemical composition. When scanned in a suitable solvent system, Dexlansoprazole shows a sharp and well-defined absorption maximum (λmax) at 282 nm. This characteristic absorption peak enables the accurate and reliable quantitative estimation of Dexlansoprazole using UV–Visible spectrophotometry.