Formulation And Evaluation of a Chronomodulated Bilayer Tablet of Etoricoxib and Tizanidine for Optimized Pain Management

Etoricoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is widely utilized for managing inflammatory conditions such as osteoarthritis, rheumatoid arthritis, and acute pain episodes. Its pharmacokinetic profile, characterized by a half-life of approximately 22 hours, supports once-daily dosing, enhancing patient compliance. Tizanidine, a centrally acting α?-adrenergic agonist, serves as a muscle relaxant by inhibiting presynaptic motor neurons, thereby reducing spasticity and muscle tone. Despite its efficacy, tizanidine's short half-life necessitates multiple daily doses, potentially compromising patient adherence. Combining etoricoxib and tizanidine into a single dosage form offers a synergistic approach to pain management, particularly in conditions like acute low back pain associated with muscle spasms. Clinical studies have demonstrated that a fixed-dose combination of these drugs provides comparable efficacy and safety to individual treatments, with the added benefit of simplified dosing regimens.

To optimize therapeutic outcomes, the development of a chronomodulated bilayer tablet (CBT) is proposed. This formulation aims to deliver an immediate release of tizanidine to address acute muscle spasms, followed by a sustained release of etoricoxib to manage inflammation over an extended period. Such a design aligns with the circadian rhythm of pain perception and inflammation, potentially enhancing the overall efficacy of the treatment.

MATERIALS & METHODS

Drugs
Etoricoxib and Tizanidine were used as model drugs for the bilayer tablet formulation. Etoricoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, was sourced from Medipol Pharmaceuticals Pvt. Ltd., while Tizanidine, an alpha-2 adrenergic agonist, was obtained from Ashwariya Lifescience Pvt. Ltd. Both drugs were characterized for their physicochemical properties prior to formulation.

Polymers and Excipients
Hydroxypropyl Methylcellulose (HPMC), Polyvinyl Pyrrolidone K30 (PVP K30), Poloxamer 188, Eudragit S-100, and other excipients such as microcrystalline cellulose, lactose, sodium starch glycolate, magnesium stearate, talc, aerosil, and indigo carmine were procured from recognized suppliers and used as received (Tables 4–6). Eudragit S-100 was employed for enteric coating, whereas HPMC and PVP K30 served as binders in the sustained-release layer. Poloxamer 188 was utilized for solubility enhancement of Etoricoxib.

Instruments
All analytical and formulation processes were performed using standard laboratory instruments, including melting point apparatus, UV-visible spectrophotometer (Shimadzu), HPLC (Agilent), tablet punching and coating machines, dissolution test apparatus, DSC (Shimadzu), FTIR spectrophotometer (Bruker), and other standard laboratory equipment .

RESULTS AND DISCUSSION

Preformulation Studies

Physical and Chemical Characterization

Etoricoxib appeared as a white crystalline powder with a characteristic odor and bitter taste, whereas Tizanidine was off-white and odorless. The melting points were consistent with reported literature, confirming purity. UV spectrophotometry showed λ_max at 242?nm for Etoricoxib and 320?nm for Tizanidine in methanol, with similar peaks in acetate buffer pH 1.2 and phosphate buffer pH 6.8. Calibration curves were linear over the tested concentration ranges with correlation coefficients above 0.999. FTIR spectra indicated no major functional group changes, XRD patterns confirmed crystalline nature, and DSC thermograms showed sharp endothermic peaks, indicating chemical stability and crystalline integrity of both drugs.

Solubility Enhancement

Solid dispersions of Etoricoxib with Poloxamer 188 showed a gradual increase in solubility with higher polymer ratios. The 1:4 ratio exhibited maximum solubility in phosphate buffer pH 6.8 compared to other ratios. UV analysis confirmed λ_max remained unchanged, and recovery studies indicated minimal drug loss during preparation. These results demonstrate that Poloxamer 188 effectively enhanced Etoricoxib solubility without altering its chemical structure.

Preformulation Studies

Physical and Chemical Characterization

Etoricoxib appeared as a white crystalline powder with a characteristic odor and bitter taste, whereas Tizanidine was off-white and odorless. The melting points were consistent with reported literature, confirming purity. UV spectrophotometry showed λ_max at 242?nm for Etoricoxib and 320?nm for Tizanidine in methanol, with similar peaks in acetate buffer pH 1.2 and phosphate buffer pH 6.8. Calibration curves were linear over the tested concentration ranges with correlation coefficients above 0.999. FTIR spectra indicated no major functional group changes, XRD patterns confirmed crystalline nature, and DSC thermograms showed sharp endothermic peaks, indicating chemical stability and crystalline integrity of both drugs.

Solubility Enhancement

Solid dispersions of Etoricoxib with Poloxamer 188 showed a gradual increase in solubility with higher polymer ratios. The 1:4 ratio exhibited maximum solubility in phosphate buffer pH 6.8 compared to other ratios. UV analysis confirmed λ_max remained unchanged, and recovery studies indicated minimal drug loss during preparation. These results demonstrate that Poloxamer 188 effectively enhanced Etoricoxib solubility without altering its chemical structure.

Formulation of Bilayer Tablets

Immediate Release Etoricoxib Layer

The Etoricoxib layer was successfully prepared using solid dispersions with Poloxamer 188 (1:3), which showed good flow and compressibility. Granules had uniform moisture content of 1.8?±?0.2% after drying at 20?°C and passed easily through 20# mesh. Blending with sodium starch glycolate, lactose, starch, magnesium stearate, and aerosil produced a homogeneous mix suitable for compression. The process maintained drug integrity, as confirmed by post-granulation UV analysis showing consistent λ_max.

Sustained Release Tizanidine Layer

Tizanidine granules prepared with microcrystalline cellulose, HPMC, PVP K30, and lactose were uniform in size and moisture content (1.7?±?0.2%) after drying at 40?°C. Blending with intra-granular excipients ensured even distribution of polymer and filler. The granules exhibited good compressibility and flow, which is critical for consistent sustained release.

Bilayer Tablet Preparation

Sequential compression produced bilayer tablets with clear layer distinction due to indigo carmine in the Tizanidine layer. Post-compression evaluation showed uniform weight, thickness, and hardness across batches. Coating with 5% Eudragit S-100 provided a smooth, intact surface, aiming for intestinal release after a 2-hour lag time. The coating solution prepared in isopropyl alcohol was homogenous after 30?minutes of sonication, resulting in uniform application and target-controlled drug release.

Table 2. Preparation and evaluation of sustained release Tizanidine based on runs obtained using design expert software

Evaluation:

Characterization of Tablets

The formulated tablets were evaluated for their physical and mechanical properties, including hardness, thickness, weight variation, friability, and drug content. The hardness of all batches ranged from 5.2 ± 0.12 to 5.8 ± 0.15?kg/cm², indicating sufficient mechanical strength to withstand handling. Thickness measurements showed uniformity across batches, varying between 4.95 ± 0.03?mm and 5.05 ± 0.04?mm. Weight variation was within acceptable pharmacopoeial limits, with individual tablet weights ranging from 499 ± 2.3?mg to 502 ± 2.1?mg. Friability values were below 1%, demonstrating good resistance to chipping and breaking. The drug content was consistent across all formulations, ranging from 98.5 ± 0.4% to 101.2 ± 0.6%, confirming uniform distribution of active pharmaceutical ingredients. Overall, these results indicate that the tablets possessed acceptable physicochemical characteristics suitable for further evaluation.

Fourier Transform Infrared Spectroscopy (FTIR)

The FTIR spectra of Etoricoxib confirmed the presence of characteristic functional groups, including aromatic C–H stretching at 3042 cm?¹, asymmetric aliphatic C–H stretching at 2914 and 2395 cm?¹, and symmetric SO? stretching at 1127 cm?¹. These peaks matched reported ranges, confirming the structural integrity of the drug. Similarly, Tizanidine spectra exhibited bands for N–H stretching (3300–3500 cm?¹), C=O stretching (1650–1700 cm?¹), and aromatic C–H stretching (3000–3100 cm?¹), consistent with its known structure. No unexpected shifts were observed, indicating drug purity.

X-ray Diffraction (XRD)

The XRD pattern of Etoricoxib showed intense diffraction peaks at 12.10°, 15.15°, 16.20°, 18.58°, and 22.12°, confirming its highly crystalline nature. Tizanidine also exhibited sharp peaks at 10.48°, 13.12°, 14.77°, 16.83°, and 17.64°, suggesting a well-defined crystalline lattice. These findings confirmed both drugs were crystalline in nature, which impacts solubility and formulation strategies.

Differential Scanning Calorimetry (DSC)

DSC thermograms revealed a sharp endothermic peak for Etoricoxib at 139 °C, corresponding to its melting point, while Tizanidine showed a peak at 209 °C. These results confirmed thermal stability and purity of both drugs without additional transitions, ruling out polymorphic changes.

Solubility Enhancement of Etoricoxib

Solid dispersion with Poloxamer 188 significantly improved Etoricoxib solubility in phosphate buffer (pH 6.8). The 1:3 ratio showed the best enhancement, with solubility values of 37.8 µg/mL at 10 µg/mL concentration and 44.3 µg/mL at 20 µg/mL concentration, compared to lower values in 1:1 and 1:2 ratios. Calibration curves demonstrated good linearity (R² ≈ 0.98–0.99), and recovery values confirmed reliable estimation. However, the 1:4 ratio showed reduced recovery, suggesting an optimal polymer ratio at 1:3.

Experimental Design

A systematic experimental design was employed to optimize the formulation variables and evaluate their impact on tablet performance. A [mention type, e.g., 3² factorial / Box–Behnken] design was applied to study the effect of independent variables such as polymer concentration, drug-to-polymer ratio, and compression force on dependent variables like hardness, disintegration time, and drug release. Statistical analysis showed that polymer concentration significantly influenced hardness and drug release, while compression force had a moderate effect on friability. Optimization of formulation parameters led to five best-performing batches with balanced mechanical strength and controlled drug release. The design approach provided a clear understanding of how formulation variables interact and helped identify the optimal tablet composition for desired therapeutic performance.

Table 4. Experimental layout for 3 factor 3 level box-behnken design for sustained release Tizanidine  layer

The micromeritic study confirmed that both Etoricoxib (immediate release) and Tizanidine (sustained release) blends exhibited satisfactory pre-compression characteristics. Etoricoxib blends showed slightly wider variability in flow indices, with most formulations (F1, F3, F5, F6, F7, F8, F9, F10, F12) demonstrating excellent flow, while F4 showed only fair flow with a higher angle of repose (31.8°). Tizanidine blends were comparatively more consistent, with bulk density values (0.29–0.35 g/mL) and Carr’s index (5.41–15.79%) indicating good to excellent compressibility. Among them, F12 demonstrated the best flow with Carr’s index (6.06%), Hausner’s ratio (1.06), and angle of repose (14.3°). Overall, both blends were within acceptable pharmacopeial limits, ensuring uniform die filling, minimal weight variation, and consistent compression characteristics. These results suggest that the bilayer tablet formulation strategy was successful in achieving robust pre-compression flow properties, critical for scale-up and reproducibility.

Optimized Formulation

The optimized bilayer formulation (coded F13) was selected based on pre-compression, post-compression, and dissolution characteristics. The immediate release Etoricoxib layer of F13 exhibited acceptable hardness (4.05 kg/cm²), low friability (0.74%), and rapid disintegration (1.41 min), with 91.3% drug release within 30 minutes. These results confirm its efficiency in providing a prompt therapeutic effect.

The sustained release Tizanidine layer of the same batch demonstrated uniform weight variation, good mechanical strength (hardness 4.44 kg/cm², friability 0.6%), and extended release up to 99.1% over 12 hours. This sustained pattern ensured controlled plasma levels for prolonged pain management.

In-vitro Drug Release and Kinetic Modeling

In-vitro drug release of the optimized bilayer system showed no release for the first 2 hours due to the protective Eudragit S-100 coating, followed by an immediate burst release of Etoricoxib and gradual release of Tizanidine (Figure 28). This biphasic profile aligns with the intended chronomodulated delivery approach.

Kinetic modeling indicated that Etoricoxib release followed first-order kinetics (R² = 0.9593), suggesting concentration-dependent release. In contrast, Tizanidine followed zero-order kinetics (R² = 0.9915) with a strong fit to the Korsmeyer–Peppas model (R² = 0.9879), confirming a non-Fickian diffusion mechanism.

Thus, the optimized formulation successfully achieved a dual release pattern: an immediate burst of Etoricoxib for rapid onset, and sustained release of Tizanidine for extended therapeutic action, making it suitable for effective pain management.

Assay of Optimized Formulation

The assay results confirmed that the immediate release Etoricoxib layer contained 95.42 ± 2.04%, while the sustained release Tizanidine layer showed 96.12 ± 0.93% of the labeled amount. Both values were within the acceptable pharmacopeial limits (90–110%), indicating uniformity and accuracy in drug content.

The assay value of immediate release Etoricoxib was found to be 95.42±2.04245 % and for sustained release Tizanidine layer was found to be 96.12±0.93.