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INTRODUCTION
The Transdermal Drug Delivery System (TDDS) has gained interest for administering drugs through the skin, targeting localized skin conditions and delivering drugs into systemic circulation (Prajapati et al., 2011). Transdermal delivery is an easy-to-use option suitable for all ages. This method improves drug bioavailability in the bloodstream, outperforming traditional drug delivery methods (Alkilani et al., 2022). Transdermal patches effectively bypass hepatic first-pass metabolism, allowing the drug to enter systemic circulation through the skin directly (Ramadon et al., 2022).
The transdermal drug delivery system delivers lipophilic, hydrophilic, and amphiphilic drugs to targeted sites for therapeutic action (Akhtar et al., 2020). TDDS minimizes the risk of side effects, including nausea, emesis, and gastrointestinal irritation (Fong Yen et al., 2015).
Osteoarthritis is the most common form of chronic degenerative disease, characterized by pain, inflammation, and reduced joint function. It negatively impacts the patient’s quality of life (Singh et al., 2024). It primarily affects the knee joints, leading to significant disability and morbidity that diminishes the quality of life for individuals suffering from a condition known as knee osteoarthritis (Sin et al., 2025). This pain is accompanied by fatigue, restlessness, sensations with a needle-like quality, and dull pain (Törnblom et al., 2024). According to a comprehensive Global Burden of Disease (GBD) assessment conducted in 2021, approximately 607 million individuals worldwide were estimated to be affected by Osteoarthritis (OA) across all joint sites. Furthermore, evidence from an extensive meta-analysis indicates that the global prevalence of knee osteoarthritis is roughly 16% among individuals aged 15 years and older, with the rate increasing to nearly 23% in populations aged 40 years and above. The burden of knee osteoarthritis is growing each day, projected to increase by 74.9% by 2050 due to various factors, including obesity, inactivity, a sedentary lifestyle, and poor diet habits (Cui et al., 2020; Zhu et al., 2024).
Diclofenac sodium is classified as a Non-Steroidal Anti-Inflammatory Drug (NSAID) within the phenylacetic acid derivative class. It is commonly prescribed for treating pain and inflammation related to conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis (Brogden et al., 1980). Diclofenac inhibits COX-1 and COX-2 enzymes, which produce prostaglandins involved in inflammation and fever. Diclofenac sodium is the first-line therapy for knee osteoarthritis. While topical forms of diclofenac sodium and ketoprofen are common, diclofenac sodium is the main treatment choice (Wolff et al., 2021). Diclofenac sodium possesses suitable physicochemical attributes for transdermal delivery, including a molecular weight of 318.13 g/mol, log P ≈ 4.0, and pKa ≈ 4.0, ensuring balanced solubility and permeability. Its high melting point (≈283°C) provides thermal stability for patch fabrication. These properties support its use in controlled-release transdermal systems that sustain plasma levels and provide localized anti-inflammatory action. Transdermal delivery also avoids first-pass metabolism, minimizes gastrointestinal effects, and, owing to the drug’s short half-life (1-2 hr), enables prolonged therapeutic action and improved patient adherence in chronic arthritis management (Adamiak-Giera et al., 2025).
The present study aims to design and optimize controlled-release transdermal patches of diclofenac sodium using a synergistic blend of semisynthetic and synthetic polymers to achieve sustained drug delivery for long-term pain management in osteoarthritis. The formulation is engineered to provide extended drug release through a diffusion-controlled mechanism, facilitating efficient percutaneous absorption while minimizing dosing frequency. Incorporation of permeation enhancers is intended to further augment transdermal flux and bioavailability. Comprehensive in vitro physicochemical and performance evaluations will be conducted to assess patch uniformity, mechanical integrity, drug content, release kinetics, and skin compatibility. The proposed transdermal system is expected to deliver prolonged analgesic and anti-inflammatory effects, reducing systemic adverse reactions and overcoming the limitations of conventional oral NSAID therapy, thereby improving therapeutic efficacy and patient adherence in osteoarthritis management.
MATERIALS AND METHODS
Materials
Diclofenac sodium (C₁₄H₁₀Cl₂NNaO₂; CAS No. 15307-79-6) was used as the model drug. The polymeric matrix was formulated using Hydroxypropyl Methylcellulose (HPMC; CAS No. 9004-65-3) and Polyvinylpyrrolidone K-30 (PVP K-30; CAS No. 9003-39-8) as film-forming polymers. Polyethylene Glycol 6000 (PEG 6000; CAS No. 25322-68-3) was incorporated as a plasticizer to enhance elasticity and homogeneity of the films. Sodium Lauryl Sulfate (SLS; CAS No. 151-21-3) acted as a permeation enhancer and surfactant, facilitating diffusion of the drug through the stratum corneum by modifying lipid bilayer permeability. Distilled water served as the solvent for uniform dissolution of the active and excipient components. All materials were of analytical and pharmaceutical grade (≥ 99% purity), procured from Sigma-Aldrich (Germany), and used without further modification.
Methods
Transdermal patches of diclofenac sodium were prepared following the method reported by Singh et al., with minor modifications to optimize polymer compatibility and film uniformity. Accurately weighed quantities of Diclofenac Sodium (DS), PVP K-30, PEG-6000, HPMC, and Sodium Lauryl Sulfate (SLS) were obtained using a calibrated analytical balance, and each material was handled under controlled storage conditions to maintain integrity. The polymers were individually dissolved in 10 mL of distilled water to form uniform solutions. Because PVP K-30 and PEG-6000 exhibit limited solubility in cold water, while HPMC tends to form gels in hot water, the dissolution process was conducted at a carefully optimized temperature range to ensure complete polymer solubilization and to prevent premature gelation. Separately, diclofenac sodium (130 mg) and sodium lauryl sulfate (100 mg) were dissolved in 10 mL of distilled water each. PEG-6000 was then incorporated into the PVP K-30 solution, followed by the gradual addition of HPMC with continuous mild stirring to avoid clump formation. The drug and SLS solutions were subsequently added to the polymer blend and stirred gently to achieve homogeneity while minimizing air entrapment. The resulting degassed polymeric dispersion was poured into pre-prepared aluminum-lined Petri dishes and tapped gently to ensure uniform layer distribution. The films were dried in a hot-air oven at 45°C until complete solvent evaporation. Dried patches were carefully peeled from the aluminum backing and cut into uniform squares (4.5 × 4.5 cm). A total of nine formulations were developed in accordance with the established Standard Operating Procedures (SOPs). The composition of each formulation is presented in Table 1 (Singh & Bali, 2016).
| Formulation | HPMC (g) | PVP (g) | PEG (g) | Drug (g) | SLS (g) |
|---|---|---|---|---|---|
| F1 | 1.5 | 1 | - | 0.13 | 0.1 |
| F2 | 1.5 | - | 1 | 0.13 | 0.1 |
| F3 | 1 | 1 | 0.5 | 0.13 | 0.1 |
| F4 | 1 | 1.5 | - | 0.13 | 0.1 |
| F5 | - | 1.5 | 1 | 0.13 | 0.1 |
| F6 | 0.5 | 1.5 | 0.5 | 0.13 | 0.1 |
| F7 | 1 | - | 1.5 | 0.13 | 0.1 |
| F8 | - | 1 | 1.5 | 0.13 | 0.1 |
| F9 | 1.5 | 0.5 | 0.5 | 0.13 | 0.1 |
CHARACTERIZATION
Physical Appearance of the Patch
The patches were evaluated for organoleptic properties, including colour, surface texture and smoothness and clarity (Abdullah et al., 2023).
Patch Thickness
A screw gauge was employed to measure the thickness accurately, and multiple measurements were made along the length of the patch (Alkilani et al., 2015).
Percentage Elongation Break Test
The initial length of the patch was measured using a calibrated scale. A gradually increasing force was applied until rupture, and the final length was recorded. The percentage elongation at break was calculated using the standard formula (Shailesh T et al., 2011).
Weight Variation
Weight uniformity was determined by cutting each patch into three equal segments (2 × 2 cm), weighing them individually, and expressing the results as the mean ± standard deviation (Mamatha et al., 2020).
Flatness Study
Flatness was evaluated by cutting three longitudinal strips from each patch (one central and two peripheral). The length of each strip was measured, and any deviation in flatness was quantified as percentage constriction using the established formula (Kumar et al., 2013).
Folding Endurance
Each patch was folded repeatedly at the same spot until it tore, and the number of folds before breaking was measured as folding endurance (Singh & Bali, 2016).
Swelling Index
Swelling Index (SI) was evaluated by immersing pre-weighed patches in phosphate buffer (pH 5.8) for 24 hr, followed by reweighing after excess surface fluid was removed (Subedi & MeenakshiKandwal). The swelling index was calculated using this formula.
Percentage Moisture Content
Each patch was accurately weighed, stored in a CaCl₂ desiccator at room temperature for 24 hr, and reweighed until a constant weight was achieved. The percentage of moisture content was calculated using the following formula (Zhang et al., 2014).
Surface pH
Patches were equilibrated in 0.5 mL of distilled water for 1 hr, and the surface pH was measured by gently placing a glass electrode on the swollen surface after 1 min of stabilization (Singh & Bali, 2016).
Standard Calibration Curve
A stock solution of diclofenac sodium (1 mg/mL) was prepared by dissolving 100 mg in 100 mL of distilled water. Serial dilutions were analyzed using UV spectrophotometry at 276 nm to construct the calibration curve (Abdul, 2025).
Drug Content Analysis
Each patch was cut into 1 × 1 cm sections and immersed in 100 mL of phosphate buffer (pH 7.4) with continuous stirring for 12 hr to extract the drug. The solution was sonicated for 20 min, filtered through Whatman filter paper, and an aliquot of 3 mL was suitably diluted. The drug content was determined spectrophotometrically at 276 nm, using a placebo patch extract as the blank. Quantification was performed using the standard calibration curve equation of diclofenac sodium. The equation used is as follows (Subedi & MeenakshiKandwal).
Fourier Transform Infrared Spectroscopy (FTIR) Analysis
FTIR spectroscopy was performed for pure diclofenac sodium, drug-loaded, and placebo patches using a standard FTIR spectrophotometer (Cary-630, Agilent Technologies). Samples of appropriate particle size were prepared and analyzed over a wavelength range of 4000–500 cm⁻¹ with a transmittance range of 30–100% to identify possible drug–polymer interactions and confirm chemical compatibility within the formulation (Shafique et al., 2021).
Scanning Electron Microscopy (SEM)
The surface morphology and structural features of the patches were examined using a Scanning Electron Microscope (EVO LS 10, Zeiss, Germany). Prior to imaging, samples were mounted on aluminum stubs using double-sided conductive adhesive tape and sputter-coated with a thin layer of gold under vacuum to enhance surface conductivity and image resolution (Nayak et al., 2011).
Thermal Analysis
Thermal characterization was performed using a Q600 TA Instruments (USA) system. For DSC, approximately 2.5–5 mg of each sample was sealed in an aluminum crucible and heated from room temperature to 500°C at 10°C/min under nitrogen. For TGA, about 3 mg of sample was heated over the same temperature range at 5°C/min. Thermal transitions and weight-loss profiles were recorded to assess thermal stability and drug–excipient compatibility within the formulations (Tudja et al., 2001).
In vitro Drug Release/Drug Permeation Study
Drug release from the transdermal patches was evaluated using a Franz diffusion cell equipped with a semi-permeable cellophane membrane. The receptor compartment was filled with phosphate buffer (pH 5.8) and maintained at 37 ± 2°C using a thermostatically controlled water jacket and magnetic stirrer to ensure uniform mixing. The patch was mounted on the membrane with the drug-loaded side facing the receptor medium. At predetermined intervals, aliquots were withdrawn and immediately replaced with fresh buffer to maintain sink conditions. Samples were analyzed spectrophotometrically at 276 nm to quantify the cumulative drug release across the membrane over time (Subedi & MeenakshiKandwal).
Release Kinetics
The release kinetics were analyzed using data from the in vitro drug release studies processed through the DD-Solver add-in for Microsoft Excel. The release mechanism was evaluated by fitting the data to zero-order, first-order, Higuchi, and Korsmeyer–Peppas kinetic models to determine the best-fit equation and elucidate the drug-release mechanism (Mustafa et al., 2024).
Skin Compatibility Study
The dermal safety of the optimized diclofenac sodium transdermal patches was evaluated in six healthy albino rats weighing 200-250 g, divided equally into control (n = 3) and test (n = 3) groups. All procedures were approved by the Institutional Animal Ethics Committee and conducted in compliance with ARRIVE guidelines with Approval No. FOPS-DP/0145; 19 November 2024). The dorsal surface of each rat's thigh of each rat was shaved 24 hr before dosing. A patch (2 × 2 cm²) containing diclofenac sodium was applied to the shaved region and secured with hypoallergenic adhesive tape and gauze to maintain occlusion. Blank patches served as controls. Patches were removed after 24 hr, and the application sites were examined visually at 1, 24, 48, and 72 hr post-removal. Erythema and edema were scored using the Draize scale (0–4), and the Primary Irritation Index (PII) was calculated as the mean of all scores (Abdul Rasool et al., 2021).
RESULTS
Standard calibration curve
The standard dilutions were observed at 276 nm using a UV spectrophotometer. Figure 1 represents the calibration curve of diclofenac sodium.
Physicochemical Analysis
The physicochemical properties of all nine formulations (F1–F9) are summarized in Table 2, including physical appearance, thickness, weight uniformity, flatness, folding endurance, moisture content, surface pH, drug content, tensile strength, and percentage elongation. All patches exhibited satisfactory physical appearance without cracks or air bubbles. The thickness ranged from 0.07 mm (F8) to 0.12 mm (F5), while the weight varied between 0.19 g and 0.29 g. Most formulations demonstrated 100% flatness, except F2 (70%), F5 (70%), and F8 (80%). Folding endurance exceeded 200, indicating good flexibility. Moisture absorption was minimal (0.003–0.005%), and all formulations exhibited a surface pH of 7, confirming skin compatibility. Drug content uniformity ranged from 95% to 97%, while tensile strength varied between 0.32 ± 0.05 kg/cm² (F5) and 1.89 ± 0.05 kg/cm² (F3), with percentage elongation from 22 ± 0.03% (F2) to 102 ± 0.03% (F3).
| Formulation | Physical Appearance | Thickness of Patch (mm) | Weight of Patch (kg) | Flatness (%) | Folding Endurance | Percent Moisture Content | pH of Patch | Drug Content (%) | Tensile Strength (kg/cm²) | Elongation at Break (mm²) |
|---|---|---|---|---|---|---|---|---|---|---|
| F1 | + | 0.10 ± 0.34 | 0.29 ± 0.13 | 100 ± 0.14 | >200 | 0.004 ± 0.0032 | 7 ± 0.12 | 96 ± 0.51 | 0.55 ± 0.15 | 90 ± 0.13 |
| F2 | + | 0.08 ± 0.51 | 0.23 ± 0.17 | 70 ± 0.65 | >200 | 0.003 ± 0.0046 | 7 ± 0.16 | 96 ± 0.53 | 0.34 ± 0.18 | 22 ± 0.05 |
| F3 | + | 0.09 ± 0.29 | 0.19 ± 0.24 | 100 ± 0.31 | >200 | 0.003 ± 0.0071 | 7 ± 0.14 | 97 ± 0.59 | 1.89 ± 0.12 | 102 ± 0.08 |
| F4 | + | 0.10 ± 0.75 | 0.28 ± 0.11 | 100 ± 0.29 | >200 | 0.003 ± 0.0049 | 7 ± 0.11 | 96 ± 0.52 | 0.99 ± 0.19 | 99 ± 0.11 |
| F5 | + | 0.12 ± 0.28 | 0.27 ± 0.19 | 70 ± 0.24 | >200 | 0.004 ± 0.0083 | 7 ± 0.19 | 95 ± 0.54 | 0.32 ± 0.11 | 44 ± 0.19 |
| F6 | + | 0.08 ± 0.44 | 0.28 ± 0.32 | 100 ± 0.83 | >200 | 0.005 ± 0.0027 | 7 ± 0.16 | 96 ± 0.58 | 0.87 ± 0.14 | 101 ± 0.10 |
| F7 | + | 0.09 ± 0.62 | 0.21 ± 0.19 | 100 ± 0.72 | >200 | 0.004 ± 0.0012 | 7 ± 0.11 | 97 ± 0.52 | 0.97 ± 0.09 | 99 ± 0.16 |
| F8 | + | 0.07 ± 0.49 | 0.27 ± 0.27 | 80 ± 0.69 | >200 | 0.003 ± 0.0046 | 7 ± 0.12 | 95 ± 0.54 | 0.45 ± 0.17 | 63 ± 0.04 |
| F9 | + | 0.09 ± 0.62 | 0.25 ± 0.15 | 100 ± 0.34 | >200 | 0.004 ± 0.0093 | 7 ± 0.14 | 96 ± 0.50 | 1.57 ± 0.08 | 96 ± 0.17 |
Fourier Transform Infrared Spectroscopy (FTIR) Analysis
FTIR analysis was performed on pure diclofenac sodium, as well as drug-loaded and unloaded patches, using standard FTIR equipment. The resulting FTIR spectra are shown in Figures 2, 3, and 4.
Thermal Analysis
The DSC (differential scanning calorimetry) thermograms are presented as a blue line in Figure 2 (II). As seen in the Figure 2(II)(a), diclofenac sodium demonstrates two sharp endothermic peaks at temperatures of 80ºC and 285ºC, immediately followed by an exothermic event at 320ºC. DSC analysis in the Figure 2(II)(b) of the unloaded patch shows an endothermic trough at 50ºC, an exothermic peak at 320ºC and a broad endothermic peak centred at 420ºC. Lastly, in the Figure 2(II)(c) drug-loaded patch shows endotherm at 80ºC, an upward curve at 360ºC, representing an exothermic event and a small endothermic process at 435ºC. The TGA (thermogravimetric analysis) of the patches are depicted as green lines in Figure 2(I). The thermogravimetric curve for the drug, as in Figure 2(I)(c), represents initial weight loss (20%), ranging from 0-90ºC, a plateau region from 100-275ºC representing thermal stability, thermal degradation extending from 275ºC till 350ºC (25% weight loss) and completes at 500ºC. TGA studies of the unloaded patch, as in Figure 2(I)(b), show initial weight loss (15%), ranging from 0-130ºC, thermal stability region extending from 130ºC till 265ºC, thermal degradation (265-440ºC) resulting in 60% weight loss and concluding at 500ºC. Lastly, the diclofenac sodium-loaded patch thermogram, as in Figure 2(II)(a) reports an initial 15% weight loss up to 150ºC, a thermostable region (150-250ºC) and an extensive 70% weight loss due to thermolysis, ranging from 250-460ºC, reaching its endpoint at 500ºC.
Scanning Electron Microscopy (SEM)
The analysis focused on surface morphology, microstructure, and matrix of the prepared formulations. The matrix images obtained from SEM analysis are shown in Figures 4 (a) and (b).
In vitro Dissolution
In vitro dissolution testing was carried out using a standard dissolution apparatus for 9 hr. Table 4 presents the transdermal drug release data of formulations F1 to F9. The minimum and maximum drug release among all the formulations were 72.49% and 94.57%, respectively. The overall drug release duration was 9 hr. The transdermal drug release data are shown in Figure 5.
Release Kinetics
In the conducted experiment zero order kinetics exhibits high R² values ranging from (0.9313-0.989) compared to the first-order kinetics that ranges from (0.871 – 0.985) and the higuchi model ranging from (0.84 – 0.962). F4 showed the highest R² value (0.989) in the Zero-order model, suggesting it is independent of concentration which shows it follows zero order kinetics. The Higuchi model showed good fitting across all patches, highlighting a diffusion-controlled mechanism. Additionally, Korsmeyer–Peppas “n” values indicated non-Fickian diffusion for all formulations, meaning drug release occurs via both diffusion and polymer matrix erosion. Formulation F6, with an n value of 0.885, demonstrated the highest deviation toward polymer-controlled (Case II) transport. The corresponding data are provided in Table 3.
| Formulation | Zero Order | First Order | Higuchi | Korsmeyer | ||||
|---|---|---|---|---|---|---|---|---|
| KO | R(square) | K1 | R(square) | kH | R(square) | kKP | n | |
| F1 | 9.188 | 0.9774 | 0.148 | 0.985 | 23.172 | 0.962 | 17.966 | 0.645 |
| F2 | 9.917 | 0.9313 | 0.164 | 0.8661 | 24.818 | 0.9265 | 16.649 | 0.727 |
| F3 | 10.23 | 0.9556 | 0.17 | 0.8621 | 25.497 | 0.9112 | 15.662 | 0.776 |
| F4 | 10.865 | 0.989 | 0.192 | 0.8471 | 27.234 | 0.9307 | 18.88 | 0.708 |
| F5 | 11.012 | 0.9435 | 0.194 | 0.8417 | 27.506 | 0.9189 | 17.695 | 0.75 |
| F6 | 10.806 | 0.9822 | 0.182 | 0.9318 | 26.709 | 0.824 | 13.463 | 0.885 |
| F7 | 9.521 | 0.9544 | 0.15 | 0.9486 | 23.714 | 0.9019 | 14.221 | 0.789 |
| F8 | 9.56 | 0.9615 | 0.151 | 0.9485 | 23.759 | 0.8906 | 13.545 | 0.817 |
| F9 | 9.953 | 0.9411 | 0.164 | 0.9675 | 24.9 | 0.9318 | 16.558 | 0.731 |
Skin Compatibility Test
Only negligible erythema was observed in a few animals during the first 24 hr, which subsided without progressing to edema. Mean Draize scores for erythema and edema remained below 0.3 throughout the observation period, resulting in a Primary Irritation Index (PII) < 0.4 as described in Table 4. According to Draize classification, this indicates that the patches are non-irritant. Figure 6 shows the non-irritating outcome of patches.
| Time after patch removal (h) | Erythema (Mean ± SD) | Edema (Mean ± SD) | Primary Irritation Index (PII) |
|---|---|---|---|
| 1 hr | 0.2 ± 0.1 | 0.1 ± 0.0 | 0.15 |
| 24 hr | 0.3 ± 0.2 | 0.1 ± 0.1 | 0.2 |
| 48 hr | 0.1 ± 0.1 | 0.0 ± 0.0 | 0.05 |
| 72 hr | 0.0 ± 0.0 | 0.0 ± 0.0 | 0 |
DISCUSSION
All formulations demonstrated satisfactory physical attributes, featuring a smooth and homogenous surface. The thickness ranged from 0.07 mm (F8) to 0.12 mm (F5), and the weight varied from 0.19 g (F3) to 0.29 g (F1). These results align with Shailesh et al., (2011), who reported similar uniformity and film quality in repaglinide transdermal patches (Shailesh T et al., 2011). Most formulations (seven patches) had consistent strip dimensions before and after cutting, indicating 100% flatness. This absence of constriction enables maintenance of a uniform surface while application, promoting close contact and improved drug permeation. F8 had 80% flatness, while F2 and F5 showed 70% flatness, representing manufacturing inconsistencies. The folding endurance exceeded 200, exhibiting optimum flexibility and integrity with skin folding when applied, without brittleness. Minimal moisture absorption (0.003-0.005%) confirms stability and antimicrobial preservation. The neutral surface pH of 7 ensures excellent biocompatibility. Consistent drug loading across all formulations was confirmed by the drug content analysis, which ranged from 95% to 97%. Tensile strength was found to be in the range of 0.32 ± 0.05 kg/cm2 (F5) to 1.89 ± 0.05 kg/cm2 (F3) and % elongation between 22 ± 0.03% (F2) and 102 ± 0.03% (F3), Findings align with Kim and Choi (2021), confirming that optimal mechanical strength, flatness, and minimal moisture uptake ensure stable, flexible, and biocompatible transdermal patches (Zhang et al., 2014; Kim & Choi, 2021).
In the diclofenac sodium sample, the moderate-intensity peaks were observed at 3337.8 cm-1 (with 56.588 transmittances) and 1628.68 cm-1 (with 68.980 transmittances), respectively, interpreting the functional groups of COOH and C=C, respectively, as shown in Figure 2 (a). A study conducted in 2021 reported similar results for diclofenac sodium, confirming the presence of the COOH and C=C functional groups within the official range (Suhail et al., 2021). The strong intensity peaks of PEG 6000 were observed at 2881.2 cm-1 (with a transmittance of 41.295) for the C-H group and at 1097.7 cm-1 (with a transmittance of 7.630) for the C-O-C group, as shown in Figure 2 (b). These findings are consistent with those conducted in 2020, which demonstrated the presence of C-H and C-O-C groups (Bhatia & Devi, 2020). PVP K-30, a moderate intensity peak appeared at 3395.6 cm-1 (with 64.482 transmittance) for the N-H group at 1638.2 cm-1, the peak was strong (with 18.616 transmittance) and was attributed to the C=O group, as shown in Figure 2 (c). In the research conducted in 2020, similar peaks for C-O-C and C=O groups were reported, indicating that our findings fall within the limit (Febriyenti et al., 2020). The moderate intensity peak in the HPMC sample was observed at 3378.8 cm-1 (with 64.615 transmittance) for the -OH group and the strong intensity peak at 1049.2 cm-1 (with 27.640 transmittance) for the C-O-C group, as shown in Figure 2 (d). A study conducted in 2020 provides similar results, which proves the presence of the O-H group and the C-O-C functional group, both showed their peak intensities and transmittances at the points aligned with our research, and fall within the official limits (Alshehri et al., 2020). In the SLS, the sample strong stretching band for the C-H group is present at 2916.6 cm-1 with a transmittance of 44.820, and for the S=O group, a strong stretching band is present at 1217.0 cm-1 with a transmittance of 21.402, as shown in Figure 2 (e). In the SLS, the peaks and transmittances of the groups C-H and S=O are similar to the study considered as a reference here, conducted in 2021. Both studies' results are within the official standards (Kharroubi et al., 2021). In the unloaded transdermal patch, the stretching vibration of PEG 6000 is shown at 2885.0 cm-1 (C-H group), the peak of PVP K-30 is observed at 3386.3 cm-1 (N-H group), and the stretching band of HPMC is at 1058.6 cm-1 (ether group) in the patch, as shown in Figure 2 (f). The peaks of polymer in the loaded patch (containing diclofenac sodium) are slightly shifted due to the presence of the drug. The peaks of the drug, PEG 6000, PVP K-30, and HPMC in the loaded patch are present at 1653.1 cm-1, 2886.8 cm-1, 3388.2 cm-1, and 1060.4 cm-1, respectively, as shown in Figure 2 (g).
The DSC thermogram of diclofenac sodium in Figure 3(II)(a) exhibited two endothermic peaks at 80°C and 285°C, corresponding to polymorphic transition and melting, followed by an exothermic peak due to oxidative degradation, consistent with (Tita et al., 2009). In contrast, the unloaded patch in Figure 3(II)(b) showed a minor endotherm between 50–100°C from moisture loss of hygroscopic polymers (HPMC, PVP K-30, PEG-6000), and a broad exotherm at 320–420°C reflecting polymer decomposition, aligning with (Bolourchian et al., 2019; Krause et al., 2023; Mummidi & Jayanthi, 2013). The drug-loaded patch in Figure 3(II)(c) exhibited a similar initial endotherm (50–100°C) but lacked the sharp melting peak of diclofenac sodium, indicating amorphous dispersion and drug–polymer interaction. A broad exotherm near 360°C confirmed simultaneous degradation of the drug and polymer matrix.
TGA further supported these observations. Pure diclofenac sodium in Figure 3(I)(c) showed ~20% weight loss up to 90°C (moisture loss) and major degradation between 275–350°C, in agreement with (Tudja et al., 2001). The unloaded patch in Figure 3(I)(b) remained stable up to 265°C, with ~60 % weight loss from 265–440°C due to polymer breakdown as observed by (Redondo et al., 2022). The drug-loaded patch in Figure 3(I)(a) exhibited slightly lower onset stability but higher total weight loss (~70%) from 250–460°C, confirming combined decomposition and strong matrix integration. Collectively, the DSC and TGA profiles demonstrate multi-stage degradation typical of HPMC/PVP/PEG systems, verifying thermal compatibility, uniform dispersion, and formation of a stable amorphous drug–polymer matrix suitable for transdermal delivery.
SEM analysis confirmed uniform drug distribution within the polymeric matrix. DS-loaded patches (10 µm, 50×) showed a smooth, homogeneous surface with slight irregularities, indicating proper dispersion and facilitating easier drug release as the similar SEM scans were observed by (Arora & Mukherjee, 2002).
Within the first 3 hr, F1–F3 released 34.80%, 38.60%, and 35.45% of the drug, while F4–F6 showed slightly higher values (37.04%, 39.43%, 34.18%), and F7–F9 released 33.15%, 30.05%, and 34.38%. At 3 hr, F5 exhibited the highest cumulative release. Between 4–6 hr, F1–F3 reached 58.70–63.25%, F4–F6 64.72–70.12%, and F7–F9 54.82–60.45%, with F4 showing the fastest diffusion. At 9 hr, cumulative release rose to 72.94–83.68% (F1–F3), 89.54–94.57% (F4–F6), and 82.90–83.98% (F7–F9), with F5 achieving the maximum. The overall release order was F6 > F5 > F4 > F9 > F7 > F8 > F3 > F2 > F1. Formulations F5 and F6 showed superior, sustained release due to the synergistic HPMC–PVP polymer blend enhancing matrix integrity, hydration, and controlled diffusion (Jaber, 2023).
The comparison of R² values (Table 5) revealed that the zero-order kinetic model exhibited the strongest correlation with experimental data (R² = 0.9313–0.989), outperforming the first-order model (0.871–0.985). Among all, formulation F4 showed the highest R² (0.989) under the zero-order model, indicating a constant, concentration-independent release rate. This pattern aligns with the ideal behavior of transdermal systems, providing a steady and predictable delivery profile. Overall, these results confirm that diclofenac sodium release followed zero-order kinetics, enabling prolonged and controlled drug release, with F4 displaying the most favorable performance (Barros et al., 2015). A high R² values for Higuchi indicating that diffusion plays a key role in drug release from the polymeric matrix. Korsmeyer-Peppas model further supported this with n values between 0.645 and 0.885, confirming non-Fickian (anomalous) diffusion in all cases (Mustafa et al., 2024).
The diclofenac sodium transdermal patches demonstrated excellent dermal safety, as reflected by Draize scores consistently below 0.3 and a Primary Irritation Index < 0.4. These findings place the formulation in the non-irritant category, confirming the absence of clinically significant erythema or edema. The slightly transient erythema noted within the first 24 h may be attributed to occlusion or the adhesive material rather than the active formulation. These results align with Abdullah et al., (2023), who reported that diclofenac sodium transdermal patches caused no erythema or edema in rats, confirming their dermal safety and non-irritant nature (Abdullah et al., 2023). The results indicate that the developed diclofenac sodium patches are dermally safe and biocompatible.
CONCLUSION
This study establishes an optimized transdermal delivery platform for diclofenac sodium using a synergistic polymeric matrix of HPMC, PVP K-30, PEG-6000, and SLS. The films demonstrated excellent physicochemical uniformity, mechanical strength, and stability, reflecting formulation reliability. FTIR and DSC analyses confirmed drug–polymer compatibility, while SEM imaging revealed a uniform microstructure favorable for controlled diffusion. Sustained drug release was achieved for up to 9 hr, with formulation F6 showing the highest cumulative release (94.57%). Kinetic modeling indicated zero-order, non-Fickian behavior, suggesting a dual mechanism of diffusion and polymer relaxation. Dermal safety testing showed no erythema or edema, with Draize and PII scores confirming the system as non-irritant and biocompatible. Collectively, these findings highlight a clinically promising alternative to oral or injectable diclofenac therapy, capable of providing prolonged analgesic action, improved patient compliance, and reduced gastrointestinal risks. The developed transdermal system thus represents a significant step toward safer, more effective management of chronic musculoskeletal pain, warranting further in vivo and clinical validation for translational applications.