INTRODUCTION:

The skin serves as an insulation to shield internal organs from the external environment and covers the bulk of the body. There are three distinct layers of skin. The dermis, subcutaneous, as well epidermis are the main three layers that make up the structure of the skin. The topmost layer of the skin, the epidermis, is made up of many cell layers. The stratum corneum, stratum granulosum, stratum spinosum, and stratum basale (sometimes called the stratum greminativum) are the primary layers that run from outer to inner. The epidermis contains specialized cells such as Langerhans cells, CD8+ T-cells, and melanocytes. Defense, controlling temperature, sense of touch, vitamin D production, waste removal, and immune system activity are some of the several functions of skin.^1,2

The 1991 discovery of Solid Lipid Nanoparticles (SLN) exemplifies common colloidal transport agents such liposome emulsions, polymeric as well as micro, and nanoparticles. Improving drug penetration capability, a robust release profile, and controlled drug delivery with superior physical stability along with minimal degradability are all related with the modern SLN method. Because of its non-toxic and non-skin-irritating lipid content, SLN is suitable for usage on inflammatory skin in addition to serving as an alternate carrier. It is indeed possible to turn SLN into hydrogels. Good tolerability, physical stability, biodegradability, high accessibility, safeguarding responsible pharmaceuticals from decay, simplicity of production, and low toxicity are some of its characteristics that make it a new drug delivery system (NDDS). SLNs often have a spherical form. Based on the means of administration, level of biological degradation, etc., nano carrier-based systems for drug delivery may be divided into several subcategories.^3,4

An optimal medication delivery method using nanoparticles demonstrates A minimum immune reaction, tissue aiming for, controlled dissolution kinetics, maximum bioavailability of the drug, the ability to deliver medications that are often challenging to administer, such lipophiles, amphiphiles, and biomolecules, enough drug loading capacity, and good patient compliance. Gels are a "semisolid phenomenon where a fluid phase is hindered in a matrix of polymers, which produces an elevated level of chemical and physically cross-linking".⁵

Etodolac is a very powerful analgesic, non-steroidal anti-inflammatory, as well anti-rheumatoid arthritis medication (structure in figure 1). Its usage in treatment regimens is restricted because of its substantial gastrointestinal side effects and several unattractive physicochemical characteristics, such as its low solubility.

Because of its high sophistication in capacity for loading drug, limited number of excipients, steady stability of drugs, lower toxicity, and ease of scaling up along with processing, nano formulation has seen exponential expansion in the pharmaceutical industry in recent years.^6,7 Finding the ideal gel composition for Etodolac packed SLN was the aim of the current study.

Figure 1: Etodolac Structural Formula

MATERIAL AND METHODS:

Reagents and chemicals: The supplier of Etodolac was SMS Pharmaceuticals, India. We bought Carbopol 934, Steric acid, and Surfactant Tween 80 from Sigma Aldrich. From a local approved dealer, we bought methanol, ethanol, sodium hydroxide, n-octanol, disodium hydrogen orthophosphate as well potassium dihydrogen orthophosphate. Every reagent that was purchased was of analytical quality.

Preformulation studies:

Determination of the absorption maximum of Etodolac: By pouring (1, 2, 0.5, 3, 4, 5 ml) of Etodolac base solution (100 ppm) to a succession of dry and thoroughly cleaned 10 ml volumetric flasks, standard solutions of Etodolac in the strength range of 5 g/ml and 10 g/ml to 50 g/ml were produced. Etodolac's solution was examined at wavelengths between 200 and 400nm. At 279nm, the spectrum was captured.⁸

Determination of Etodolac Solubility: Etodolac's water solubility was established using the saturation shake-flask technique. Etodolac was shown to be soluble in dynasan 114, stearic acid, prectrol, and n-octanol solvents. By entering the value into the calibration curve calculation, the quantity of medication that was dissolved was determined.

Fourier Transform Infrared (FTIR) Spectroscopy: The Win-IR spectrophotometer was used to do the spectrum analysis for stearic acid and etodolac, both independently and in combination. Each sample is mixed with the potassium bromide solution before being observed spectroscopically in the 4000–400 cm−1 range.

Preparations of Etodolac loaded SLN: With minor adjustments, the solvent diffusion method's cited methodology was used to prepare the SLN. Following successful coding of each produced group of SLN (table 1), the percentage entrapment of the active moiety was measured spectrophotometrically at 279nm. Etodolac-high entrapment SLN was selected as the optimal SLN and moved on for more analysis.

Table 1: Different Etodolac SLN Formulations

Formulations	Stearic acid % (w/v)	Etodolac % (w/v)	Tween 80 % (w/v)
F1	0.5	1	1
F2	0.7	1	1
F3	1.5	1	1
F4	2	1	1
F5	1	1	0.5
F6	1	1	0.7
F7	1	1	1.5
F8	1	1	2

Evaluation of drug loaded SLNs:

Evaluation of entrapment efficiency (EE): EE was calculated using the following formula:

W(added drug) − W(free drug)

EE percentage = ––––––––––––––––––––––––––––

W(added drug) 100.

where W (free drug) is the amount of drug that is free identified in the remaining fluid upon centrifugation, and W (added drug) is the amount of drug given during SLN manufacture.

Physicochemical property: pH, odor, Color and SLN dissolution in aqueous media were the physicochemical characteristics of SLN dispersions.

Particle size and zeta potential: With minor adjustments, the specified procedure was followed to estimate the average particle size along with zeta potential.

Preparation of gel: A specified amount of carbopol 934P was dissolved in distilled water while being continuously stirred at 600 rpm. Additionally, as preservatives, methyl paraben sodium (0.02% w/v) along with propyl paraben sodium (0.1% w/v) were included while being constantly stirred. For thirty minutes, the gentle stirring continued. The already created gel base was left for a full day. Following constant agitation at 1000 rpm and 30 minutes of churning, SLN F5 formulation in a determined amount dispersed in propylene glycol (5% w/w) and 1% ethanol (20% w/w), was transferred to this carbopol gel basis. Tri-ethanol amine (TEA) was then added to stabilize the medication while keeping the pH between 5.5 and 6.5. The mixture was carefully agitated to produce transparent gels (table 2).

Table 2: Preparation of different Gel formulations of SLNs

Formulation code	Carbopol 934 % (w/v)
G1	0.5
G2	1
G3	1.5
G4	2

Characterization of gel:

Determination of pH: To measure the pH of the gel, the glass electrode of a pH meter was submerged in the ideal SLN gel composition then rotated.

Determination of viscosity: After evaluating the obtained SLN gel's visual characteristics, the Brookfield viscometer was used to measure the gel's viscosity.

Spreadability: Improved composition 500mg were placed in the middle of the acrylic plate, with a second plate positioned concentrically above it. Diameter of the circle where the principal breadth of the gel spread is determined. For a few minutes, a weight of around 500g was placed on the plate above. Gel's spread ability is calculated based on the diameter increases brought about by gel dispersion and the measured diameter of the dispersed gel.

In-vitro drug release study: Using the approach of dialysis bag, in-vitro drug dissolution profiling techniques were used to assess the drug release characterization of the improved formulation (SLN G2) gel.

Scanning Electron Microscopy: A small SLN gel sample was put on a glass tube then dried under vacuum. Following that, the sample was placed in a stub and placed inside a gold-palladium-coated SEM chamber. The sample was then examined under a microscope at an acceleration voltage of 10 kV.

Stability study: The kind of lipids employed and the kind of emulsifier utilized in the composition have a significant impact on the mechanical strength of lipid nanoparticle suspensions. After a month, the durability of hydrogels containing SLN was assessed using the ICH Q1A (R2) guideline in comparison to the fresh formulation.

RESULT AND SUMMARY:

Preformulation study of drug:

Determination of the absorption maximum of Etodolac: Plotting the curve for calibration along with the absorbing capacity of the resulting solutions at 279 nm opposed to the solvent mixture as a blank was done. In the amount range of 5,10 to 50μg/ml near 279 nm for etodolac, Lambert-Beer's Law showed a linear appearance. Table 3 and Figure 2 present the findings. The coefficient along with regression equation were determined to be 0.9973 and 0.0234x + 0.015, respectively. The aforementioned range has high linearity, as shown by the correlation value of 0.9973.

Table 3: Absorbance of Etodolac at different concentration

S. No.	Concentration	Absorbance
1	5	0.139
2	10	0.279
3	20	0.495
4	30	0.698
5	40	0.942
6	50	1.152

Figure 2: Standard Calibration curve of Etodolac

Solubility profile: Research was done to assess the hydrophilic along with lipophilic compliance of etodolac. Etodolac's dissolution potential when mixed with water was 0.00675 ± 0.283 mg/ml, according to the results. Etodolac was shown to be soluble in prectrol, stearic acid, and dynasan 114 at 19.325± 0.94, 24.764±0.46, plus 23.857±0.31 mg/ml, correspondingly. Additionally, Etodolac's non-aqueous dissolution in n-octanol was 18.945 ± 0.53 mg/ml. Etodolac had log10P values of 3.40, 3.98, 3.97, and 3.85 in prectrol, stearic acid, dynasan 114, and n-octanol, correspondingly. Table 4 lists the results.

Table 4: Solubility of Etodolac in different solvents

Solvents	Solubility in mg/ml	Log₁₀ P of Etodolac
Water	0.00675 ± 0.283 mg/ml	<1
Stearic acid	24.764±0.46	3.98
Prectrol	19.325± 0.94	3.40
Dynasan 114	23.857±0.31	3.97
n-Octanol	18.945 ± 0.53	3.85

Stearic acid was shown to have the greatest capacity to dissolve ETD from the fatty acid group (23.754±0.47 mg/ml) out of every solvent that were chosen. For this reason, stearic acid is being used in future research.^9,10

FTIR analysis: Before and after formation, the most prominent moiety's compliance was examined using FTIR. The wavenumber range in which the investigations were conducted was 4000 cm^-1 to 500 cm^-1. Figure 3 displays the Etodolac FTIR spectrum. Etodolac's primary infrared absorption peaks were located at 3338.41 cm^-1, which indicated an amine group; 1739.48 cm^-1, which indicated aldehydes as well as ketones; 1407.81 cm^-1, which indicated nitrogen compounds; 1031.68 cm^-1, which indicated ether groups; and 748.34 cm^-1, which indicated an alkane functional group. These identified primary peaks validated Etodolac's validity and purity in accordance with the cited study.

Stearic acid's principal infrared peak absorbance values were found in the high-frequency area at about 2919 and 2848 cm⁻¹, respectively. Also, these were ascribed to symmetric as well as asymmetric vibrations of stretching in the −CH₂−band. The −COOH group from stearic acid is responsible for the peak at 1701 cm⁻¹ in the low-frequency domain (figure 4).

Figure 4: FTIR spectra of stearic acid

Further, SLN gel synthesis may continue as there was not any chemical incompatibilities between Etodolac with Polymer, as shown by the appearance of all the distinctive Etodolac FTIR peaks in the mixture FTIR spectrum of the combination of Etodolac and Polymer (as shown in Figure 5).

Figure 5: FTIR spectra of Mixture of Etodolac with polymer

Evaluation of SLN:

Evaluation of entrapment efficiency of SLN: The percentage EE of etodolac was calculated after the successful creation of several batches of nanoparticles. At 279nm, the percentage of EE was measured using spectrophotometry. According to the results, SLN F5 and SLN F2 had the greatest and lowest percentages of EE of SLN loaded with etodolac, respectively, at 85.50 ± 1.50 and 62.90 ± 1.90. Ige et al. referenced a research that stated that the greatest percentage of EE was between 85 and 90 percent.¹¹ The results are displayed in figure 6 below and summarized in table 6.

Table 6: Entrapment Efficiency of various SLN formulations of Etodolac

Formula	Entrapment efficiency(%±SD)
F1	83.50±1.50
F2	62.90±1.90
F3	80.80±1.68
F4	70.50±1.50
F5	85.50±1.50
F6	82.50±1.50
F7	65.00±0.50
F8	74.50±1.50

Figure 6: Percentage entrapment efficiency of Etodolac in SLN

Physicochemical property: The physicochemical properties of SLN reveal that it is white and transparent, with a smooth and consistent texture, emits a pleasant aromatic scent, and maintains a stable pH of 7.4. The average water solubility of SLN across eight formulations is 0.2736 ± 0.265 mg/ml, which is significantly greater than that of pure Etodolac. For comprehensive details, please refer to table 7.

Table 7: Physicochemical characterization of the prepared SLN formulations

S. No.	Physicochemical properties	Outcomes
1	Color	White transparent
2	Surface Feel	Homogeneous, being uniform
3	Smell	Aromatic
4	Average pH	7.3
5	Average solubility in water	0.2736 ± 0.265 mg/ml

Zeta potential, particle size and size distribution: The SLN formulations exhibit a range of characteristics that are crucial for their stability and performance. The formulations have negative zeta potential values ranging from -33.62±0.93 to -63.61±0.28 mV. This indicates a high stability of the nano system, as the negative charge causes particles to repel each other, reducing aggregation. The particle sizes range from 168±0.15 nm to 334±0.21 nm, showing a broad distribution. Despite the range, the unimodal size distribution suggests a single peak, which is preferable for consistent behavior. Poly Dispersity Index (PDI) values range from 0.258±0.14 to 0.364±0.13.

Table 8: Particles size, PDI, Zeta Potential of Etodolac SLNs Formulations

Formula	Particle size (d/nm)	PDI	Zeta potential (mV)
F1	314±0.06	0.297±0.12	-35.06±0.63
F2	309±0.12	0.364±0.13	-46.83±0.71
F3	249±0.31	0.351±0.21	-48.67±0.68
F4	192±0.14	0.263±0.10	-39.54±1.34
F5	168±0.15	0.258±0.14	-63.61±0.28
F6	334±0.21	0.265±1.23	-33.62±0.93
F7	198±0.12	0.294±1.31	-35.16±1.53
F8	256±0.17	0.324±1.20	-48.58±0.64

Evaluation of SLN gel:

Evaluation of pH, Viscosity, Spreadability and Visual appearance: Here in this case, the gel G2 has a relatively high viscosity (369cP) and yet has good spreadability. This indicates that there's a balance between thickness and ease of spreading, possibly achieved through the formulation's ingredients, like the type of gelling agent or additives. This outcome is similar to the gel viscosity as reported by Jana et al with pH being near to that of skin i.e. 6.12±0.255.¹³ Further in spreadability evaluation, spreadability factor of prepared SLN gel found to be 4.5. Overall, this data suggests that the G2 gel has desirable properties for a topical formulation: it's thick enough to stay in place but spreads easily, and its pH is close to the skin's natural pH, making it gentle and compatible. The inclusion of SLNs indicates it's likely designed for effective drug delivery, making it a promising candidate for various topical applications.

Table 9: Evaluation of various physicochemical parameters studied

S. No.	Formulation	pH	Viscosity (cP)	Spreadability (cm²)
1	G1	5.64 ± 0.05	460 ± 7.20	4.28 ± 0.11
2	G2	6.12 ± 0.255	369± 3.70	4.5± 0.42
3	G3	5.59 ± 0.03	461 ± 2.30	3.78 ± 0.21
4	G4	5.67 ± 0.06	386 ± 3.30	3.98 ± 0.33

In vitro drug release study: Figure 7 and Table 10 show how the de-solvation percentages of Etodolac from SLN rose over time. Evidence from release profiles indicates that the developed SLN is capable of releasing the medication in a controlled way. Homogeneous drug entrapment across systems is the basis for the slow release of the leading moiety from the majority of SLN forms. The similar idea is stated by Ekambaram et al., who assert that when a drug is evenly dispersed across a lipid matrix, a regulated drug de-solvation profile may be achieved.¹⁴

Table 10: Percentage drug release profile of G3 and control gel

S. No.	Time in hours	G3	Control gel
1	0	0	0
2	1	20.01±0.1	17.01±0.1
3	2	38.23±0.2	29.23±0.2
4	4	49.02±0.2	41.02±0.2
5	6	57.53±0.2	52.5±0.2
6	8	63.31±0.1	60.31±0.1
7	10	74.1±0.1	70.85±0.1
8	12	88.6±0.2	82.3±0.2

Figure 7: In-vitro drug release profile of SLN gel and control gel

Scanning electron microscopy: According to SEM pictures, Carbopol offered a uniform network that included SLN dispersions filled with etodolac. The constant hold of the dispersions in the system may have been made possible by the uniform and stable Carbopol network. This indicated that Carbopol was essential in creating a solid framework with Etodolac-loaded nanoparticles, which would help with Etodolac's long-term dermal delivery.

Figure 8: SEM analysis of G2 gel

Stability Study: Even within intermediary and fast settings, the recovery of drugs coming from formulation was close to full for both medicines all through the investigation (Table 11), indicating the SLN formulations' physical resilience. The drug recovery variability, which was likely caused by the size of the batch, remained within the range of 100±5%. Every formulation exhibited shear-thinning behavior, which means that its consistency dropped as the transmitted shear strength increased. This feature makes the formulation more spreadable when a force is applied, which makes it perfect for topical administration. A hydro-alcoholic gel containing 5% (w/w) etofenamate for topical application showed similar outcomes.¹⁵

Therefore, it is evident from the aforementioned study that the topical gel based on solid lipid nanoparticles had a superior release profile for the API Etodolac NSAID. Additionally, the formulation complied with the guidelines for safe and efficient gel compositions.

CONCLUSION:

In the current study, we have created solid lipid nanoparticles (SLN) that encapsulate Etodolac in order to improve skin penetration and regulate drug release at the intended location. We have also integrated these SLNs into a topical gel of carbopol 934 that has an acceptable skin retention duration. There is not any chemical interaction between Etodolac and excipients, even according to spectroscopic research. SEM analysis of the gel revealed a homogeneous distribution of SLN inside the gel with well-organized drug release kinetics. Therefore, it can be said that SLN gel offers regulated drug release, also these systems may be used as drug delivery systems, bioavailability enhancers for medications that are poorly soluble in water by nanoparticles, and drug carriers for lipophilic pharmaceuticals.

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Received on 25.04.2025 Revised on 13.05.2025

Accepted on 28.05.2025 Published on 19.06.2025

Available online from June 23, 2025

Asian J. Research Chem.2025; 18(3):167-173.

DOI: 10.52711/0974-4150.2025.00027

This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License.

	Storage conditions 30 ±2 ⸰C/60 ± 5% RH			Storage conditions 40 ± 2 ⸰C/75 ± 5% RH
Time in months	% Drug Release	pH	Viscosity	% Drug Release	pH	Viscosity
0	102.11±2.21	4.99±0.04	47,121±2.89	100.27±3.74	5.64±0.57	47,200±8.2
1	97.36±0.81	4.41±0.07	45,133±1.34	96.07±5.56	4.42±0.07	46,133±4.2