1. INTRODUCTION:

Diclofenac, a widely prescribed nonsteroidal anti-inflammatory drug (NSAID), is primarily used to alleviate inflammation and pain by selectively inhibiting cyclooxygenase enzymes, particularly COX-2¹, thereby suppressing prostaglandin synthesis. It is commonly indicated for conditions such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and acute migraine attacks¹. Beyond its established anti-inflammatory and analgesic effects , Emerging preclinical studies have suggested diclofenac’s potential anticancer properties, including the induction of cancer cell apoptosis via mechanisms such as microtubule destabilization, increased reactive oxygen species (ROS) production^1,2, and disruption of autophagic flux, which enhance tumor cell sensitivity to chemotherapeutic agents like 5-fluorouracil³.

Despite its therapeutic benefits, the clinical use of diclofenac is constrained by significant adverse effects, notably gastrointestinal irritation, ulceration⁴, renal insufficiency, mucosal damage, and increased risks of cardiovascular events such as myocardial infarction and stroke, especially with long-term or high-dose therapy ^1,5. These safety concerns limit its prolonged administration and underscore the need for improved delivery strategies to mitigate systemic toxicity.

To address these limitations, diclofenac-loaded nanoparticles have been developed as controlled drug delivery systems⁶. These nanoparticles, typically fabricated from biodegradable polymers such as poly(lactide-co-glycolide) (PLGA), enable sustained drug release, enhance stability, and allow targeted delivery^5,7–11. This approach reduces systemic exposure and toxicity while preserving non-tumoral cell viability and augmenting anti-inflammatory and antitumoral efficacy^12,13. Diclofenac acid, characterized by its relatively low solubility compared to its salts, is particularly suitable for incorporation into nanoparticles to achieve prolonged release profiles¹⁴, minimizing initial burst release and extending therapeutic action.

Polycaprolactone (PCL), an FDA-approved biodegradable polymer, is gaining prominence for long-term drug delivery applications due to its slow hydrolytic degradation spanning months to years. Its biocompatibility and prolonged degradation profile make it an ideal candidate for implantable drug delivery systems designed for sustained therapeutic effects, as demonstrated in devices releasing monoclonal antibodies over extended periods without significant changes in release kinetics^15–17.

Conventional nanoparticle fabrication methods, like emulsification solvent evaporation and spontaneous emulsification solvent diffusion methods, often rely on toxic organic solvents such as dichloromethane and chloroform^18,19, which pose risks of residual contamination and compromise formulation safety and biocompatibility. To overcome these challenges, alternative green solvents^20,21 and solvent-free or reduced-solvent techniques have been explored. Bio-based solvents like Cyrene²², non-toxic polymer solvents such as polyethylene glycol (PEG)^23,24, and ionic liquids offer safer, thermally stable, and low-vapor-pressure alternatives that minimize hazardous solvent use²⁵. Techniques like nanoprecipitation and salting-out utilize safer antisolvents or aqueous phases, effectively eliminating chlorinated solvents and enhancing environmental and biological safety²⁶.

In this study, we investigate the use of a eutectic solvent mixture as a non-toxic alternative for dissolving PCL (molecular weight 45,000) in the preparation of diclofenac-loaded nanoparticles. Employing both emulsification solvent evaporation and spontaneous emulsification solvent diffusion methods, we aim to leverage the biodegradable and biocompatible properties of PCL for sustained drug release while mitigating the risks associated with traditional toxic solvents. This approach aspires to advance safer and more effective nanoparticle-based delivery systems for diclofenac, with potential applications in long-term anti-inflammatory and anticancer therapies.

2. MATERIALS:

Lutrol F68 (Sigma-Aldrich, Germany), Polycaprolactone (Sigma-Aldrich), Sodium diclofenac (ChemPifine Chemicals, India), Ethanol, absolute, ≥99.8% (Sigma-Aldrich), Acetone, HPLC grade (ACROS Organics), Acetonitrile, HPLC grade (Scharlau), Water, HPLC grade, Acetic acid (HPLC grade) was purchased from Riedel-de Haën (Honeywell Research Chemicals, Seelze, Germany), Menthol from Anhui Herrman IMPEX, Camphor from Suzhou Youhe Science and Technology JSGC.

3. CHARACTERIZATION:

3.1. Characterization of nanoparticles:

3.1.1. Scanning electron microscopy (SEM):

To identify the shape of the nanoparticles, a small amount of each sample was placed as a thin layer onto a copper grid that was covered with an amorphous carbon film and left to dry at ambient temperature. Once dried, the samples were further coated with a thin conductive carbon layer using an EMITECH K975x carbon coater. The nanoparticle morphology was then analyzed using a Tescan Vega2 XMU scanning electron microscope, operated at an accelerating voltage of 30kV.

3.1.2. Dynamic Light Scattering (DLS):

Particle size analysis was conducted using dynamic light scattering (DLS) with a Zetasizer Nano-ZS device (Malvern Instruments, UK) maintained at 25°C. This technique assesses the temporal variations in scattered light intensity resulting from the Brownian motion of particles suspended in a medium. From these fluctuations, the translational diffusion coefficient is determined, which is then applied in the Stokes-Einstein equation to calculate the hydrodynamic diameter. The instrument’s software computed the average particle size along with the polydispersity index (PdI), indicating the breadth of the particle size distribution. Additionally, zeta potential measurements were carried out on the same instrument at 25°C using disposable folded capillary cells. These measurements were repeated three times on samples highly diluted with 1mM NaCl, and the zeta potential values were derived from electrophoretic mobility data.

3.1.3. Analytical Method:

Diclofenac was assayed by high-performance liquid chromatography (HPLC) following the protocol proposed by Guterres et al., with slight modifications²⁷. The concentration of diclofenac acid released into the medium was quantified using a JASCO LC-NETII/ADC system equipped with ChromNAV software. Separation was achieved on a Zorbax Eclipse XDB C18 column (4.6 × 150mm, 5μm) under isocratic conditions, with a mobile phase consisting of acetonitrile and quadruple-distilled water (65:35, v/v), adjusted to pH 4.0 with glacial acetic acid. The flow rate was set at 0.6mL/min, the column oven temperature at 25°C, and detection was performed at 278nm. The calibration curve was linear over the concentration range of 0.03–40 μg/mL, with a correlation coefficient (R²) of 0.999.

3.1.4. Determination of Encapsulation Efficiency:

The samples underwent ultrafiltration and centrifugation using Amicon Ultra-15 tubes (Millipore, 10,000 MWCO) at 8,228 × g for a duration of 30minutes. The filtrates obtained were then examined through high-performance liquid chromatography (HPLC). The encapsulation efficiency was subsequently determined using the following formula:

Encapsulation Efficiency (%) = (Amount of drug encapsulated in nanoparticles) × 100/Initial amount of drug used in the process.

3.1.5. Release Kinetics Experimental Setup:

A 0.5mL portion of the diluted nanoparticle suspension was mixed into 9mL of phosphate buffer at pH 6.8 and then incubated in a temperature-controlled shaking water bath maintained at 37±0.5°C, with shaking occurring at roughly 30 strokes per minute. At specific time intervals, aliquots were collected and processed via ultrafiltration and centrifugation using Amicon Ultra-15 filtration devices (Millipore, 10,000 MWCO). The centrifugation was carried out at 8,228 × g for 30 minutes. To maintain uniformity across samples, this method was repeated for multiple tubes at each designated sampling time.

To investigate the release behavior of diclofenac from PCL nanoparticles, the release patterns were tracked for 66 hours and analyzed using five standard mathematical models²⁸.

Zero order equation:

where F stands for the fraction of drug released up to time t and ko is the zero-order release rate constant

First order equation:

where k1 stands for first-order release rate constant

Higuchi’s equation:

Where k_H represents the Higuchi release rate constant

Hixson–Crowell model:

Where k_HC stands for Hixson–Crowell release rate constant

Korsmeyer–Peppas model:

Where k_KPis a constant corresponding to the geometric and structural characteristics of the device and “n” is the release exponent which determined the mechanism of the drug release^29–31.

3.2. Statistical Analysis:

All experiments were performed in triplicate. Data are presented as mean±SD. Statistical significance was assessed using Student’s t-test (p<0.05).

4. METHODS:

4.1. Preparation of Diclofenac Acid from Diclofenac Sodium Solution:

To prepare diclofenac acid, 5mL of 1N hydrochloric acid was added to each 100mL of a 1% (w/v) aqueous solution of diclofenac sodium. The mixture was stirred for 40minutes, or until the precipitation of diclofenac acid crystals was complete. The precipitated crystals were collected by filtration and washed three times with 100 mL portions of quadruple-distilled water to remove residual sodium and chloride ions. The crystals were subsequently dried in an oven at 45°C for 72 hours. The dried product was then purified twice by recrystallization using 200mL of an ethanol/quadruple-distilled water mixture (80:20, v/v). Finally, the purified diclofenac acid crystals were dried and stored in a tightly sealed, light-resistant container¹⁴.

4.2. Investigation of PCL Solubility in the Eutectic Mixture:

Solutions of 5% and 10% PCL (molecular weight 45,000) in a eutectic mixture of Menthol/Camphor with a ratio 1:1.25 were prepared by heating to 43℃. Both solutions remained clear for at least 14 days after cooling to room temperature.

4.3. Preparation Methods for Pharmaceutical Nanoparticles Using Polycaprolactone (Mn 45,000):

4.3.1. Solvent Evaporation from an Emulsion

4.3.1.1. Organic Phase:

A 4mL solution containing diclofenac acid (0.001g/mL) and polycaprolactone (Mn 45,000; 0.01g/mL) dissolved in Menthol/Camphor 1:1.25.

4.3.1.2. Aqueous Phase:

40mL of an aqueous Poloxamer 68 solution at a concentration of 1.5% (w/v).

4.3.1.3 Temperature Conditions:

The organic phase is maintained at 30°C, while the aqueous phase is kept at 5°C.

4.3.2. Solvent Diffusion from a Spontaneous Emulsion:

4.3.1.2 Organic Phase:

A 4mL solution containing diclofenac acid (0.001g/mL) and polycaprolactone (Mn 45,000; 0.01g/mL) dissolved in a 1:1 mixture of acetone and a mixture of Menthol/Camphor 1:1.25.

4.3.2.2. Aqueous Phase: 40mL of an aqueous Poloxamer 68 solution at a concentration of 1.5% (w/v).

4.3.2.3.Temperature Conditions:

The organic phase is maintained at 30°C, while the aqueous phase is kept at 5°C.

Emulsification and Solvent Removal Procedures:

· The organic phase is added to the aqueous phase under continuous stirring for 30 minutes using a high-shear homogenizer (Ultra Turrax® T25, Ika) at 21,400 rpm.

· The resulting emulsion is subsequently stirred with a mechanical impeller (marine propeller) at 600rpm for 1.5hours.

· Complete removal of the organic solvent is achieved using a rotary evaporator under reduced pressure.

5. RESULTS:

5.1. Investigation of PCL Solubility in the Eutectic Mixture:

Solutions of 5% and 10% PCL14,000 in a eutectic mixture of Menthol/Camphor with a ratio 1:1.25 remained clear for at least 14 days after cooling to room temperature.

5.2. Physicochemical Properties of Particles:

5.2.1. Particle size:

As shown in Table 1 and Figure 4, nanoparticles prepared by spontaneous solvent diffusion were smaller (103.7±2.0nm) than those prepared by solvent evaporation/extraction (115.5±1.15nm).

5.2.2 Polydispersity index (PDI):

As shown in Table 1 and Figure 4, both methods produced moderately monodisperse particles with similar PDI values (~0.26–0.29).

5.2.3. Zeta potential:

As shown in Table 1 and Figure 5, nanoparticles from solvent evaporation/extraction exhibited a higher negative surface charge (-12.07±1.6mV) than those from spontaneous solvent diffusion (-3.41±1.83mV).

5.2.4. Shape:

As shown in Figure 3, all nanoparticles were spherical.

5.2.5. Encapsulation efficiency:

Slightly lower encapsulation efficiency was observed with spontaneous solvent diffusion (73.49±0.6%) compared to solvent evaporation/extraction (76.09±0.53%).

As shown in Table 2, differences in size, zeta potential, and encapsulation efficiency between methods were statistically significant (p<0.05), except for PDI.

As shown in (Table 3), (Figure 1) and (Figure 2), the drug release profiles of formulations prepared by Spontaneous Emulsification Solvent Diffusion and Emulsification Solvent Evaporation/Extraction methods were analyzed using various kinetic models. The Korsmeyer-Peppas model showed the best fit with R² values of 0.967 and 0.995, respectively. The release exponent 'n' was 0.5273 for the former, indicating anomalous (non-Fickian) diffusion, while the latter exhibited an 'n' value of 0.9057, suggesting Case II transport mechanisms. The cumulative drug release was 39.07% and 36.97% over 66 hours for the respective methods.

SEM results:

A B

C D

Figure 3: SEM Results of the Nanoparticles Prepared by: Left. A and B. Spontaneous Emulsification Solvent Diffusion. Right. C and D. Emulsification Solvent Evaporation/Extraction.

Figure 4: DLS Results of Nanoparticles Prepared by: Left. Spontaneous Emulsification Solvent Diffusion. Right. Emulsification Solvent Evaporation/Extraction.

Figure 5: Zeta Potential Results of Nanoparticles Prepared by: Left. Spontaneous Emulsification Solvent Diffusion. Right. Emulsification Solvent Evaporation/Extraction.

6. DISCUSSION:

This study successfully demonstrates the preparation of diclofenac acid-loaded PCL nanoparticles using a novel green solvent system.

Both emulsification solvent evaporation/extraction and spontaneous solvent diffusion methods produced nanoparticles with desirable physicochemical properties for drug delivery.

6.1. Nanoparticle Size and Size Homogeneity:

The studies refer that size range (between 100nm and 300nm) is optimal for enhanced permeability and retention (EPR) in tumor tissues³². The low PDI values indicate uniformity, which is critical for reproducible biological performance.

6.2. Surface Charge:

The nanoparticles exhibited zeta potentials of -12.1±1.6 mV (evaporation/extraction) and -3.4±1.8mV (spontaneous diffusion), indicating low to moderate electrostatic stability. These relatively low values may be attributed to the use of the non-ionic surfactant Poloxamer 68, which limits surface charge development. The more negative charge observed with the evaporation/extraction method suggests enhanced stability, potentially improving circulation time by reducing aggregation and clearance.

Studies have shown that diclofenac-loaded polycaprolactone (PCL) nanoparticles stabilized with Pluronic F-68 primarily achieve stability through steric hindrance^33–35. Pluronic F-68 forms a hydrophilic polyethylene oxide (PEO) layer on the nanoparticle surface, preventing aggregation and protein adsorption ^33,34, thereby maintaining stability even in high ionic strength environments (up to 2.5 M NaCl)³⁴. This steric stabilization complements electrostatic repulsion, resulting in robust colloidal stability. Additionally, the non-ionic nature of Pluronic may facilitate interactions with cellular membranes, potentially enhancing drug delivery efficiency³⁵. Furthermore, the slight negative surface charge reduces clearance by the reticuloendothelial system, improving blood compatibility and tumor targeting³⁶.

6.3. Encapsulation Efficiency:

Both methods achieved high encapsulation efficiencies (>70%), indicating the suitability of the green solvent system for effective drug encapsulation.

6.4. Sustained Release Profile:

In vitro release studies demonstrated sustained diclofenac release over 66hours, with a cumulative release approaching 40%. The release kinetics of nanoparticles prepared by both methods were best described by the Korsmeyer-Peppas model. For one formulation, the release exponent (n = 0.5273) indicated anomalous (non-Fickian) transport, which is desirable for controlled drug delivery, as it suggests that drug release is governed not only by diffusion but also by polymer relaxation or erosion mechanisms³⁷, In contrast, the other formulation exhibited an n value of 0.9057, corresponding to super case II transport. This implies that drug release is predominantly controlled by polymer swelling and erosion processes rather than diffusion alone by the expansion and erosion of the polymer structure, rather than solely by diffusion³⁸.

6.5. Green Solvent Advantage:

A key innovation of this study is the use of a green solvent for dissolving PCL and diclofenac acid. This addresses a major limitation of conventional nanoparticle preparation methods, which often rely on toxic organic solvents. The green solvent approach enhances the safety profile of the final product and aligns with regulatory and environmental requirements.

6.6. Comparison of Methods:

Both methods yielded comparable results in terms of size, encapsulation, and release profile, suggesting flexibility in manufacturing approaches. The spontaneous solvent diffusion method, with a slightly smaller particle size and higher cumulative release, may offer advantages for applications requiring faster drug release.

6.7. Interpretation of Results:

The findings demonstrate that green solvent-based fabrication of PCL nanoparticles is an effective and environmentally friendly method for producing high-quality drug delivery vehicles. The nanoparticles exhibit optimal physicochemical properties, including size and surface charge, for tumor targeting via the EPR effect, with steric stabilization enhancing colloidal stability. Their sustained release profile benefits diclofenac by potentially reducing dosing frequency and minimizing systemic toxicity. Overall, this approach maintains excellent drug encapsulation and release performance, making it a promising strategy for anticancer nanomedicine development.

7. CONCLUSION:

This study convincingly establishes that diclofenac acid-loaded polycaprolactone (PCL) nanoparticles can be effectively prepared using an innovative green solvent system, employing both emulsification solvent evaporation/extraction and spontaneous solvent diffusion techniques. The nanoparticles produced exhibit optimal physicochemical characteristics—including a size range of 100–300nm conducive to enhanced permeability and retention (EPR) in tumor tissues, low polydispersity indices indicating uniformity, and surface charges that confer adequate colloidal stability through a combination of steric hindrance and moderate electrostatic repulsion. Notably, the use of Poloxamer 68 (Pluronic F-68) as a non-ionic surfactant enhances steric stabilization, reducing aggregation and clearance, thus potentially improving circulation time and tumor targeting. Both methods achieved high encapsulation efficiencies (>70%) and demonstrated sustained diclofenac release over an extended period, with release kinetics governed by Korsmeyer-Peppas models indicative of controlled, anomalous transport mechanisms beneficial for drug delivery. The green solvent approach addresses critical safety and environmental concerns associated with conventional organic solvents, aligning with regulatory expectations for biocompatible nanomedicines. Comparable performance between the two fabrication methods suggests manufacturing flexibility, with the spontaneous solvent diffusion method offering advantages for applications requiring faster release profiles. Overall, this work highlights a robust, environmentally friendly platform for producing safe and high-quality diclofenac-loaded PCL nanoparticles with promising implications for anticancer therapy, combining effective drug encapsulation, sustained release, and expected favorable stability and targeting properties to enhance therapeutic outcomes.

The green solvent strategy overcomes a significant barrier to clinical translation by eliminating toxic solvent residues. These findings support further preclinical evaluation of this platform for safe and effective cancer therapy.

8. AUTHOR CONTRIBUTIONS:

S. A. S contributed to study design, sample preparation, sample analysis, data analysis, and manuscript writing.

A. A. contributed by supervising the research work, providing technical support, and reviewing the manuscript.

9. FUNDING:

This research is funded by Damascus University

10. CONFLICT OF INTERESTS:

The authors have no conflict of interest in the present manuscript.

11. ACKNOWLEDGEMENTS:

We gratefully acknowledge the technical support provided by the Atomic Energy Commission of Syria and Professor.Wassim Abdel wahed from the University of Aleppo.

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Received on 30.06.2025 Revised on 13.10.2025

Accepted on 29.12.2025 Published on 20.05.2026

Available online from May 25, 2026

Research J. Pharmacy and Technology. 2026;19(5):2358-2366.

DOI: 10.52711/0974-360X.2026.00338

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Method	R² Zero Order	R² First Order	R² Higuchi	R² Korsmeyer-Peppas	R² Hixson Crowell	'n' Exponent (Korsmeyer-Peppas)	Cumulative Release (%) and Duration
Spontaneous Emulsification Solvent Diffusion	0.947	0.944	0.916	0.967	0.945	0.5273	39.07 % release over 66 hours
Emulsification Solvent Evaporation/Extraction	0.963	0.964	0.93	0.995	0.964	0.9057	36.97% release over 66 hours

Method

Z Average(nm) by intensity (radius.nm)

PDI

Zeta Potential (mv)

shape

Encapsulation efficiency %

Emulsification Spontaneous solvent diffusion

103.7 ± 2.007

0.263 ± 0.061

-3.41 ± 1.83

Spherical

73.49±0.6

Emulsification solvent evaporation/extraction

115.5 ±1.153

0.29 ± 0.07

-12.07 ± 1.6

Spherical

76.09± 0.53

Method

P value of Z Average (nm) by intensity

P value of PDI

P value of Zeta Potential (mv)

P value of Encapsulation efficiency %

Emulsification Spontaneous solvent diffusion

0.0009

0.0035

0.0050

Emulsification solvent evaporation/extraction

Method

Spontaneous Emulsification Solvent Diffusion

0.947

0.944

0.916

0.967

0.945

0.5273

39.07 % release over 66 hours

Emulsification Solvent Evaporation/Extraction

0.963

0.964

0.93

0.9057

36.97% release over 66 hours