Development and Characterization of Celecoxib-Loaded Nanoemulgel for Enhanced Topical Delivery: Optimization, In Vitro Release, and Stability Assessment

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, represents a significant advancement in non-steroidal anti-inflammatory drug (NSAID) therapy, offering potent anti-inflammatory and analgesic effects with reduced gastrointestinal toxicity compared to non-selective NSAIDs. [1] Celecoxib functions by selectively inhibiting the COX-2 enzyme, which is predominantly expressed at sites of inflammation, while sparing the constitutive COX-1 enzyme that plays a protective role in gastric mucosa maintenance. [2] This selectivity confers a markedly improved gastrointestinal safety profile, making celecoxib a preferred therapeutic option for patients requiring long-term NSAID therapy. [3,4] The drug has received regulatory approval for the management of osteoarthritis, rheumatoid arthritis, acute pain, and familial adenomatous polyposis, demonstrating clinically meaningful efficacy across these diverse indications. [5,6]In clinical practice, celecoxib has consistently demonstrated a superior safety profile regarding gastric ulceration and bleeding complications when compared to traditional non-selective NSAIDs such as ibuprofen and naproxen. [7,8] However, oral administration of celecoxib is associated with significant limitations that compromise its overall therapeutic utility. [9] These limitations include a delayed onset of action typically requiring 3–4 hours to achieve meaningful plasma concentrations, extensive hepatic first-pass metabolism that substantially reduces the fraction of drug reaching systemic circulation, variable absorption profiles influenced by food intake and gastrointestinal motility, and dose-dependent cardiovascular risks that become increasingly concerning with long-term use. [10]The topical drug delivery system (TDDS) has emerged as a promising alternative to oral administration, offering distinct advantages that address many of the shortcomings inherent to the oral route. By delivering medication directly to the site of action through the skin, TDDS provides avoidance of hepatic first-pass metabolism, thereby preserving a greater proportion of the active drug for therapeutic effect. Additionally, topical delivery enables maintenance of steady plasma drug concentrations over extended periods, avoiding the sharp peaks and troughs characteristic of oral dosing regimens. [11,12,13] This delivery modality significantly reduces systemic side effects by limiting drug distribution to tissues beyond the target site, improves patient compliance particularly among elderly populations and those with swallowing difficulties, and provides the ability to terminate medication rapidly when necessary by simply removing the topica preparation from the skin surface. [14,15,16]Celecoxib exhibits poor aqueous solubility (approximately 3–7 μg/mL) and high lipophilicity (log P ~3.5), characteristics that result in low oral bioavailability (approximately 40%) and present substantial challenges in topical formulation development. [17,18,19] The Biopharmaceutics Classification System (BCS) categorizes celecoxib as a Class II drug (low solubility, high permeability), a classification that necessitates advanced formulation strategies to enhance both solubility and permeation across biological membranes. [20,21,22] Nanocarrier systems have revolutionized topical drug delivery by overcoming the formidable stratum corneum barrier through multiple sophisticated mechanisms including disruption of lipid bilayers, enhanced drug partitioning into deeper skin layers, controlled release kinetics that prolong therapeutic effect, and targeted delivery to specific skin layers. [23,24,25]Among these nanocarrier platforms, nanoemulsions have garnered particular attention due to their unique physicochemical properties. [26,27,28] Nanoemulsions are characterized by thermodynamic stability, a transparent or translucent appearance, and droplet sizes ranging from 20–200 nm, features that collectively contribute to enhanced drug loading capacity and improved skin interaction. [29,30] The incorporation of nanoemulsions into gel matrices, yielding what is termed a nanoemulgel, addresses the critical limitation of low viscosity associated with conventional nanoemulsions, providing suitable consistency for topical application while maintaining the penetration-enhancing properties of nanocarrier systems.[31]The development of celecoxib-loaded nanoemulgel requires systematic optimization of multiple formulation components including the oil phase, the surfactant-co-surfactant system, the aqueous phase, and appropriate gelling agents. [32] Modern formulation development increasingly employs Quality by Design (QbD) approaches to efficiently navigate the multidimensional formulation space and achieve optimal drug loading, particle size, zeta potential, viscosity, and permeation characteristics. [33] This study focuses on the systematic development, optimization, and characterization of a celecoxib-loaded nanoemulgel to overcome the solubility and permeability barriers of the drug.[34]

2. MATERIALS AND METHODS

2.1 MATERIALS SELECTED:

METHODOLGY

1 Preformulation Studies

Preformulation focused on establishing celecoxib’s physicochemical profile to guide rational formulation design.

•Organoleptic & Melting Point: Identity and purity were confirmed via visual inspection and the capillary method (Ref: 158–160°C).

•Solubility Screening: Equilibrium solubility was determined by vortexing excess drug in various oils (e.g., MCT), surfactants (Tween 80), and co-surfactants (Transcutol P) for 72 hours, followed by centrifugation and UV analysis.

•Analytical Method: λmax

was identified at 285 nm via UV scanning (200–400 nm). A standard calibration curve (2–12 µg/mL) provided the regression equation (y=mx+c

) for drug quantification.

 

•Compatibility & Partitioning: Drug-excipient compatibility was verified by FTIR (4000–400 cm⁻¹) using 1:1 physical mixtures. Lipophilicity was assessed via the shake-flask method (n-octanol/buffer) to determine log P.

•pH & Conductivity: Calibrated digital meters were used to measure the pH and electrical conductivity of 1% w/v dispersions.

2 Formulation Development

2.1 Nanoemulsion Optimization

•Phase Diagrams: Pseudo-ternary diagrams were constructed by titrating water into oil-Smix

 blends (ratios 1:1 to 4:1) under stirring. The largest transparent, isotropic region defined the optimal composition.

 

•Preparation: Celecoxib (1–2% w/w) was dissolved in oil at 40°C, mixed with Smix

, and spontaneously emulsified by dropwise aqueous titration under 500 rpm stirring.

 

2.2 Nanoemulgel Fabrication

•Gel Base: Carbopol 940 (0.5–1.5% w/w) was hydrated overnight and neutralized with triethanolamine to pH 6.0–6.5.

•Incorporation: The optimized nanoemulsion was stirred into the gel base at 500 rpm for 15 minutes, followed by the addition of preservatives (parabens) and antioxidants (BHT) in propylene glycol.

•QbD Approach: A 33

Factorial or Box-Behnken design optimized independent factors (Oil, Smix

, Carbopol) against critical responses (Size, Zeta, Viscosity, Release, Flux) using ANOVA and Response Surface Methodology.

 

2.3 Evaluation Parameters

1.Size & Zeta Potential: Measured via Dynamic Light Scattering (DLS) and Electrophoretic Light Scattering (ELS) after 1:100 dilution; $\pm$30 mV indicates stability.

2.Entrapment Efficiency: Determined by separating free drug via centrifugation (15,000 rpm) or ultrafiltration and analyzing the supernatant at 285 nm.

3.Stability & Type: Conductivity confirmed the o/w or w/o nature. Thermodynamic stability was verified through heating-cooling (4–45°C), freeze-thaw (−21–25°C), and centrifugation stress tests.

 

 

Figure 1: Simple Methodology of celecoxib nanoemulgel development

Table 3: Calibration Curve Data of Celecoxib in Phosphate Buffer pH 7.4 (λmax = 285 nm)

Concentration (µg/mL)	Absorbance ± SD (n = 3)
5	0.128 ± 0.004
10	0.255 ± 0.005
15	0.382 ± 0.006
20	0.510 ± 0.007
25	0.638 ± 0.008
30	0.765 ± 0.009
40	1.018 ± 0.011
50	1.272 ± 0.013

The correlation coefficient (r²) was found to be 0.999.

 

 

Figure 2: Calibration Curve of Celecoxib

 

 

Figure 3: FTIR Spectrum of Celecoxib

 

 

Figure 4: Differential Scanning Calorimetry (DSC) of Pure Celecoxib

 

 

Figure 5: XRD

Data of Pure Celecoxib

Table 5: Saturation Solubility of Celecoxib in Different Vehicles (n = 3)

Category	Vehicle	Solubility (mg/mL) ± SD
Oils	Medium Chain Triglycerides (MCT)	18.2 ± 0.4
	Isopropyl Myristate	15.6 ± 0.3
	Oleic Acid	12.4 ± 0.5
	Castor Oil	8.7 ± 0.2
	Soybean Oil	6.3 ± 0.4
Surfactants	Tween 80	22.5 ± 0.6
	Span 80	10.8 ± 0.3
Co-surfactants	Transcutol-P	28.7 ± 0.5
	Propylene Glycol	14.2 ± 0.4
	PEG 400	16.9 ± 0.3
	Ethanol	35.4 ± 0.7

 

 

 

Figure 6: Saturation Solubility of Celecoxib in Different Vehicles

Table 6: Aqueous Solubility of Celecoxib at Different pH Values (n = 3)

pH	Solubility (mg/mL) ± SD
4.0	0.002 ± 0.001
5.5	0.003 ± 0.001
6.5	0.004 ± 0.001
7.0	0.005 ± 0.001
7.4	0.006 ± 0.001
8.0	0.007 ± 0.001

 

 

Figure 7: Aqueous Solubility of Celecoxib at Different pH Values (n=3)

 

 

Figure 8: a) FTIR Spectroscopy of Drug-Excipient Mixture, b) DSC of Biliary Mixtures

 

 

Figure 9: Accelerated Stability of Drug-Excipient Physical Mixtures

 

 

Figure 10: Pseudo-Ternary Phase Diagrams

 

 

Figure 11: Nanoemulsion Region at Different Smix Ratios

Table 9: Composition and Characterization of Celecoxib-Loaded Nanoemulsions (n = 3)

Formulation	Oil (% w/w)	Smix (% w/w)	Water (% w/w)	Drug (% w/w)	Droplet Size (nm) ± SD	PDI ± SD	Zeta Potential (mV) ± SD	Drug Content (%) ± SD	Entrapment Efficiency (%) ± SD
NE1	5	45	50	1	38.5 ± 2.1	0.18 ± 0.02	-32.4 ± 1.2	97.2 ± 0.8	88.5 ± 1.2
NE2	10	45	45	1	52.3 ± 3.2	0.22 ± 0.03	-35.8 ± 1.5	96.8 ± 0.6	91.2 ± 1.0
NE3	15	45	40	1	78.6 ± 4.5	0.31 ± 0.04	-28.6 ± 1.8	95.4 ± 0.9	85.3 ± 1.5
NE4	10	30	60	1	65.4 ± 3.8	0.28 ± 0.03	-30.2 ± 1.4	94.6 ± 1.1	82.6 ± 1.8
NE5	10	50	40	1	45.2 ± 2.8	0.20 ± 0.02	-37.4 ± 1.3	97.8 ± 0.5	93.5 ± 0.8

Formulation NE5 exhibited droplet size of 45.2 ± 2.8 nm, PDI of 0.20 ± 0.02, zeta potential of -37.4 ± 1.3 mV, drug content of 97.8 ± 0.5%, and entrapment efficiency of 93.5 ± 0.8%.

 

 

Figure 12: Droplet Size & Entrapment Efficiency of Nanoemulsions

 

 

 

Table 10: Thermodynamic Stability Studies of Optimized Nanoemulsion (NE5) (n = 3)

Stability Test	Condition	Cycles	Droplet Size (nm) ± SD	PDI ± SD	Zeta Potential (mV) ± SD	Phase Separation
Initial	25 °C	-	45.2 ± 2.8	0.20 ± 0.02	-37.4 ± 1.3	None
Heating-Cooling	4–45 °C	6	47.8 ± 3.1	0.22 ± 0.03	-36.2 ± 1.5	None
Freeze-Thaw	-21–25 °C	3	49.5 ± 3.4	0.24 ± 0.03	-35.8 ± 1.6	None
Centrifugation	3500 rpm, 30 min	1	46.1 ± 2.9	0.21 ± 0.02	-36.9 ± 1.4	None

No phase separation, creaming, or cracking was observed in any of the stress tests.

 

 

Figure 13: Thermodynamic Stability of NE5 Formulation

 

 

Figure 14: Physical Properties of Nanoemulgels vs Gelling Agent Conc.

 

 

Figure 15: Rheological Behavior of NEG2

 

 

 

 

Figure 17: A) Zero-Order Release, B) First-Order Release, C) Higuchi Release and       D) Korsmeyer-Peppas Release

 

 

Figure 18: Accelerated Stability Data

DISCUSSION

The present study successfully developed and characterized a celecoxib-loaded nanoemulgel for topical delivery, addressing the persistent therapeutic hurdles associated with the drug's poor aqueous solubility and limited bioavailability. Preliminary organoleptic evaluation and melting point determination (158 ± 0.5 °C) confirmed the high purity, crystallinity, and chemical identity of the procured celecoxib sample. Further validation through UV spectrophotometric analysis demonstrated strict adherence to the Beer-Lambert law across the 5–50 µg/mL concentration range (λmax

 at 285 nm, r2=0.999

), establishing a reliable foundation for quantitative estimation. Advanced analytical techniques, including Fourier-transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction, provided convergent evidence of the drug's well-ordered crystal lattice without any evidence of degradation or amorphous conversion prior to formulation development.

Saturation solubility studies corroborated celecoxib's classification as a BCS Class II drug, exhibiting negligible aqueous solubility across the physiological pH range (4.0–8.0) due to its weakly acidic sulfonamide moiety. In stark contrast, solubility increased exponentially in lipidic and surfactant vehicles, with Medium Chain Triglycerides (MCT) emerging as the optimal oil phase due to favorable molecular volume and fluidity, while Transcutol-P and Tween 80 demonstrated superior solubilization and interfacial stabilization capacities. Compatibility studies via FTIR and differential scanning calorimetry confirmed the absence of deleterious drug-excipient interactions in binary physical mixtures, and four-week accelerated stability testing at 40 °C/75% RH demonstrated excellent retention of drug content (98.5%), thereby validating the selection of MCT, Tween 80, Transcutol-P, and Carbopol 940 for the final delivery system.

The construction of pseudo-ternary phase diagrams revealed that the extent of the nanoemulsion region is critically governed by the surfactant-to-co-surfactant (Smix

) ratio, with a 2:1 ratio yielding the widest compositional zone by achieving an optimal balance of interfacial film flexibility and low interfacial tension. Among the evaluated nanoemulsion systems, formulation NE5—prepared with 10% oil and 50% Smix

—proved optimal, exhibiting the smallest droplet size, a narrow polydispersity index below 0.3, a highly negative zeta potential (-28 to -37 mV) ensuring electrostatic stability against droplet coalescence, and a maximum entrapment efficiency of 93.5%. Rigorous thermodynamic stress testing, including heating-cooling cycles, freeze-thaw cycles, and centrifugation, confirmed genuine thermodynamic stability rather than mere kinetic stabilization, establishing NE5 as an ideal candidate for subsequent gel incorporation.

The incorporation of optimized nanoemulsion NE5 into Carbopol 940 gel bases resulted in concentration-dependent viscosity scaling, ranging from 12,450 cP to over 62,000 cP. Formulation NEG2, containing 0.75% Carbopol 940, achieved the optimal balance among mechanical structural integrity, spreadability, and tube extrudability, while maintaining a skin-compatible pH of 5.9–6.2. Rheological analysis established pseudoplastic, shear-thinning behavior with a flow behavior index of 0.62, which enhances storage stability by resisting droplet sedimentation while facilitating smooth, effortless skin application under shear. In vitro drug release studies demonstrated a controlled hierarchical profile where NE5 exhibited the fastest release, followed by nanoemulgel NEG2, whereas conventional gel lagged significantly behind with less than 50% cumulative release after 24 hours. Kinetic modeling identified the Korsmeyer-Peppas model as the best fit (n=0.58

), indicating that drug release from the nanoemulgel is governed by anomalous non-Fickian transport involving concurrent droplet diffusion and polymer network relaxation. Finally, six-month accelerated stability testing confirmed that NEG2 preserved its physicochemical, rheological, and release integrity under stressed storage conditions, supporting an extended shelf life and robust potential for topical clinical application.

CONCLUSION

The developed celecoxib-loaded nanoemulgel (NEG2) successfully addresses the challenges of poor aqueous solubility and limited bioavailability by integrating a stable nanoemulsion into a Carbopol 940 gel matrix. Characterized by a skin-compatible pH, optimal rheological behavior, and high entrapment efficiency, the formulation demonstrated a superior sustained-release profile (94.2% over 24 hours) compared to conventional gels, with kinetic modeling indicating a robust non-Fickian transport mechanism. Accelerated stability testing over six months further confirmed its physicochemical robustness, positioning this nanoemulgel as a promising, stable, and effective alternative for localized topical delivery in managing inflammatory conditions like osteoarthritis.

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