Formulation and Evaluation of Azelnidipine-Loaded Nanosponges for Enhanced Solubility and Oral Bioavailability

Table 1 Representative Polymers and Cross-Linking Agents Used in Nanosponge Synthesis

Once formed, the resulting inclusion complexes between drug and nanosponge can be confirmed by thermo-analytical methods (DTA/DSC, in which broadening, shifting or the appearance/disappearance of thermal peaks provides evidence of complexation), by microscopic examination of particle morphology (SEM/TEM), and by spectroscopic techniques such as FTIR, which can reveal shifts in characteristic drug absorption bands upon complexation with the polymer matrix. The extent of complexation is additionally influenced by the method of drug loading, the degree of substitution on the polymer backbone, and process temperature, since elevated temperature can reduce the strength of the van der Waals and hydrophobic interactions that stabilize the drug–nanosponge complex.

D. Biopharmaceutical Classification System (BCS)

The Biopharmaceutical Classification System, first proposed by Amidon et al. in 1995, classifies drug substances into four classes on the basis of their aqueous solubility and intestinal permeability: Class I (high solubility, high permeability), Class II (low solubility, high permeability), Class III (high solubility, low permeability) and Class IV (low solubility, low permeability). For Class II drugs such as Azelnidipine, in-vivo dissolution rate is the rate-limiting step governing absorption, which makes solubility- and dissolution-enhancement technologies — including nanosponge-based carriers, solid dispersions and complexation approaches — particularly relevant formulation strategies.

The BCS framework also underpins regulatory biowaiver policy: for BCS Class I drugs, regulatory agencies may waive the requirement for in-vivo bioequivalence studies provided that in-vitro dissolution criteria are met, whereas BCS Class II drugs such as Azelnidipine are generally not eligible for such waivers because their absorption is dissolution-rate-limited and therefore more sensitive to formulation-dependent variability. This regulatory context reinforces the practical value of formulation strategies — such as the nanosponge-based approach investigated here — that directly target the dissolution-rate limitation of BCS Class II drugs, since a formulation that reliably improves and stabilizes the in-vitro dissolution profile is more likely to produce consistent in-vivo performance across batches and, potentially, to streamline the bioequivalence-demonstration pathway for follow-on or generic products.

E. Objectives of the Study

The specific objectives of the present study were as follows:

1. To formulate Azelnidipine-loaded nanosponges for enhancement of its solubility, dissolution and bioavailability.

2. To study and optimize the method of preparation of the nanosponges.

3. To characterize and evaluate the developed nanosponge delivery system, and to compress the optimized batch into tablets.

4. To assess the accelerated stability of the optimized formulation as per ICH guidelines.

The novelty of the present work lies in the combination of a systematic, factorial-design-driven optimization of the tablet formulation with a comprehensive in-vitro characterization package (particle size, zeta potential, SEM, FTIR, DSC, XRD, dissolution and accelerated stability) for Azelnidipine nanosponges — an approach that, at the time of this study, had received only limited prior attention in the published literature relative to the extensive body of work available for cyclodextrin-based nanosponges of other actives.

II. LITERATURE REVIEW

Several formulation strategies have historically been employed to improve the solubility and dissolution of BCS Class II drugs, including particle-size reduction (micronization and nanocrystallization), solid-dispersion technology, cyclodextrin complexation, self-emulsifying drug delivery systems (SEDDS), and polymeric nanocarriers such as nanosponges. Micronization and solid dispersions can improve dissolution rate but frequently suffer from physical instability (crystal growth, phase separation) on storage, while simple cyclodextrin inclusion complexes can be limited by relatively low drug-loading capacity and cost at manufacturing scale. Nanosponges, by contrast, combine a porous, high-surface-area matrix capable of accommodating a comparatively large drug payload with the mechanical robustness and processability of a solid particulate, and are reported to offer better physical stability than simple amorphous solid dispersions because the drug is retained within a rigid, cross-linked polymeric scaffold rather than a metastable amorphous film. This combination of attributes provides the rationale for evaluating nanosponges, rather than a solid dispersion or simple complexation approach, as the solubility-enhancement strategy for Azelnidipine in the present study.

A number of prior studies support the use of polymeric nanosponges for solubility and bioavailability enhancement of poorly water-soluble drugs. Ansari et al. formulated nanosponges by an emulsion solvent evaporation method using ethyl cellulose, Eudragit RS 100, polymethyl methacrylate and Poloxamer 188 as carriers with polyvinyl alcohol as the stabilizing agent, and reported that the resulting formulations produced sustained drug release across the batches studied. Deshpande et al. similarly prepared and evaluated cyclodextrin-based nanosponges of a poorly soluble statin, while other workers have used hydroxyethyl cellulose and polyvinyl alcohol in combination to obtain nanosponges with improved release characteristics, screening successive formulation batches to identify an optimized carrier ratio. Across these studies, the emulsion solvent evaporation/diffusion technique is consistently reported as an effective, scalable and relatively simple method for nanosponge synthesis, and increasing polymer concentration is repeatedly associated with an increase in particle size and a corresponding decrease in the rate and extent of drug release, consistent with the trends observed in the present investigation.

Selvamuthukumar et al. reviewed nanosponges as a novel drug delivery class and highlighted their high drug-loading capacity, biocompatibility and suitability for oral, topical, parenteral and inhalation delivery. Cyclodextrin- and polyester-based nanosponges have additionally been explored for the delivery of anticancer agents (camptothecin, paclitaxel, 5-fluorouracil), antifungal agents (econazole nitrate) and antioxidants (gamma-oryzanol), and have been shown to improve aqueous solubility, protect labile drugs from degradation and, in several cases, provide sustained or targeted release. Torne et al. reported that paclitaxel-loaded cyclodextrin nanosponges produced significantly enhanced oral bioavailability relative to the free drug, while Ansari et al. demonstrated improved in-vitro stability, reduced cytotoxicity and favourable permeation characteristics for resveratrol-loaded nanosponges, illustrating that the benefits of the platform extend across structurally diverse actives and are not limited to a single therapeutic class.

Additional work has examined the physicochemical basis of nanosponge performance in more depth. Sapino et al. showed that encapsulation of gamma-oryzanol within beta-cyclodextrin nanosponges preserved its antioxidant activity while conferring photostability, and Darandale and Vavia reported that curcumin nanosponges markedly improved the aqueous solubility and physicochemical stability of an otherwise poorly soluble polyphenol. Shende et al. compared different preparation techniques for cross-linked beta-cyclodextrin inclusion complexes and found that formulation method had a significant influence on complexation efficiency and drug release, a finding that parallels the process-parameter sensitivity (PVA concentration, polymer ratio) observed for the Azelnidipine nanosponges in the present work. Collectively, this body of literature provides strong support for the hypothesis that a nanosponge carrier system, prepared under optimized process conditions, can meaningfully enhance the solubility and dissolution profile of a BCS Class II drug such as Azelnidipine, while also indicating that formulation and process variables must be carefully optimized — as undertaken here through a systematic factorial design — to realize the full benefit of the platform.

III. MATERIALS AND METHODS

A. Drug and Polymer Profile

Azelnidipine is a 1,4-dihydropyridine calcium channel blocker (chemical formula C33H34N4O6; molecular weight 582.65; IUPAC name 3-[1-(diphenylmethyl)azetidin-3-yl] 5-propan-2-yl 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate), marketed in Japan by Daiichi-Sankyo Pharmaceuticals. It occurs as a pale-yellow to yellow crystalline powder with a melting point of 120–126 °C, is freely soluble in methanol, ethanol and dichloromethane, sparingly soluble at phosphate pH 7.4, and practically insoluble in water, consistent with its BCS Class II designation. Pharmacologically, Azelnidipine inhibits trans-membrane Ca²? influx through L-type voltage-dependent calcium channels in vascular smooth muscle, producing vasodilation and a gradual, sustained reduction in blood pressure without the reflex tachycardia typically associated with dihydropyridine calcium channel blockers. It undergoes rapid, dose-dependent oral absorption, is extensively bound to plasma proteins (90–91%), is metabolized predominantly by hepatic CYP3A4, and shows a plasma elimination half-life of approximately 16–28 h at typical daily doses of 8–16 mg. Its pronounced lipophilicity and high affinity for vascular smooth-muscle membranes, combined with its poor aqueous solubility, make it a suitable candidate for a solubility-enhancing nanocarrier approach such as the nanosponge system investigated here.

Ethyl cellulose, the polymer selected for nanosponge synthesis, is a water-insoluble cellulose ether that is soluble in esters, aromatic hydrocarbons, alcohols and ketones. It is supplied as a white powder with an ethoxyl content of approximately 48% (2.25–2.58 mol ethyl per mol cellulose), a glass transition temperature (Tg) of 120–124 °C, a density of about 1.14 g/mL at 25 °C and a refractive index of 1.47. Its film-forming ability, chemical inertness, biocompatibility and well-characterized permeability behaviour make it a widely used release-controlling polymer in oral solid-dosage formulation, and these properties underpin its selection as the matrix-forming polymer for the Azelnidipine nanosponges evaluated in this study.

Commonly reported adverse effects of Azelnidipine include dizziness, mild pyrexia, sore throat, joint pain and upper respiratory tract infection; the drug is typically administered at a once-daily oral dose of 8–16 mg and should be stored in a well-closed container below 25 °C. As Azelnidipine is metabolized by CYP3A4, co-administration with potent inhibitors or inducers of this enzyme should be undertaken with appropriate clinical caution. These practical handling and dosing considerations were taken into account during formulation development to ensure that the nanosponge-based delivery system remained compatible with the established clinical use profile of the drug.

B. Materials

Azelnidipine was used as the model drug. Ethyl cellulose was employed as the polymer for nanosponge synthesis, and polyvinyl alcohol (PVA) was used as the emulsifying/stabilizing agent. Dichloromethane served as the organic solvent for the dispersed phase. Avicel-102, Cross-Carmellose Sodium, lactose and magnesium stearate were used as tableting excipients. All other chemicals and reagents used were of analytical grade.

Table 2 Major Instruments Used in the Study

C. Preformulation Studies

The received sample of Azelnidipine was subjected to preformulation evaluation prior to formulation. Organoleptic properties (colour, odour and appearance) were recorded, and the melting point of the drug was determined by the capillary method. UV spectroscopic analysis was performed by preparing a 100 μg/mL stock solution of the drug in methanol and scanning over 200–400 nm on a UV-Visible double-beam spectrophotometer (Agilent Technologies, Cary 60) to determine λmax; a standard calibration curve was subsequently constructed using working solutions of 2, 4, 6, 8 and 10 μg/mL at 253 nm, with methanol as blank. An analogous procedure was used to determine λmax and construct a calibration curve in the first fluid specified by the Japanese Pharmacopoeia (7 mL HCl + 2 g NaCl made up to 1000 mL with water), where absorbance was measured at 269 nm. In both media the drug obeyed Beer–Lambert's law over the concentration range studied.

Solubility of Azelnidipine was determined in phosphate buffer pH 6.8, phosphate buffer pH 7.4, methanol, 0.01 N HCl and dimethyl formamide by adding an excess of drug to each solvent and shaking on an orbital shaker for 48 h at room temperature; the equilibrated supernatant was filtered and analyzed spectrophotometrically. For comparison of drug and nanosponge solubility, an excess of pure drug (30 mg) and of nanosponges (equivalent to 30 mg drug) were each added to 10 mL of pH 6.8 buffer in Teflon-capped vials and equilibrated for 48 h at 37 ± 0.5 °C on an orbital shaking incubator at 50 rpm; the filtered supernatant (0.45 μm membrane) was analyzed at 227.5 nm, and the drug-to-carrier ratio giving the best solubility enhancement was selected for further optimization. Drug–excipient compatibility was additionally assessed by FTIR spectroscopy, comparing the spectrum of the pure drug with that of the drug–polymer physical mixture (denoted AZEC, for Azelnidipine–Ethyl Cellulose) to rule out chemical incompatibility.

D. Preparation of Azelnidipine Nanosponges

A physical mixture of Azelnidipine and ethyl cellulose was first prepared by simple blending at drug:polymer ratios ranging from 1:1 to 1:4 for 10 min. Nanosponges were then synthesized by the emulsion solvent diffusion method. Briefly, the dispersed phase — ethyl cellulose and drug dissolved in 20 mL of dichloromethane — was slowly added to a defined concentration of polyvinyl alcohol in 100 mL of aqueous continuous phase. The resulting emulsion was stirred continuously at 1000 rpm for 2 h to allow solvent diffusion and particle hardening. The formed nanosponges were recovered by filtration, dried in a hot-air oven at 40 °C for 24 h, and stored in a vacuum desiccator to ensure complete removal of residual solvent. Trial batches (T1–T4) were first prepared to screen the drug:polymer ratio (100:100 to 100:400) at a fixed PVA concentration of 0.2% w/v, and a second series of batches (F1–F4) was then prepared at a fixed drug:polymer ratio of 100:200 while varying PVA concentration from 0.1–0.4% w/v, as summarized in Tables III and IV.

Table 3 Process Parameters for Trial Batches (T1–T4) of Nanosponges

Table 4 Process Parameters for Nanosponge Batches F1–F4 (Emulsion Solvent Diffusion Method)

E. Characterization of Nanosponges

The prepared nanosponge batches were characterized for percentage yield, particle size, zeta potential, surface morphology, drug content and in-vitro drug release. Percentage yield was determined by weighing the dried nanosponges relative to the theoretical total solid input. Drug content was estimated by dissolving 10 mg of powdered nanosponges in 10 mL methanol and measuring the UV absorbance at 253 nm. Particle size and zeta potential were determined to assess colloidal size distribution and physical stability of the dispersion, and surface morphology was examined by scanning electron microscopy (SEM). Swelling characteristics of the polymer were separately evaluated by hydrating 10 g of ethyl cellulose in a graduated cylinder for 24 h and calculating the swelling index from the initial and final bed heights.

In-vitro drug release from the nanosponges (F1–F4) was studied over 2 h using first fluid (simulated gastric fluid, SLS-containing) as the release medium at 37 ± 0.5 °C, with samples withdrawn at fixed intervals (5, 10, 15, 30, 45, 60, 90 and 120 min) using the USP paddle method at 50 rpm, and analyzed spectrophotometrically at 269 nm; an equal volume of fresh dissolution medium was replenished after each withdrawal to maintain sink conditions, and cumulative percentage release values reported are the mean of three replicate determinations. The dissolution testing parameters used for the powder (nanosponge) dissolution study are summarized in Table V.

Table 5 Dissolution Testing Parameters for Powder Dissolution Study of Nanosponges

F. Formulation of Nanosponge Tablets — Experimental Design

The optimized nanosponge batch was compressed into tablets using a 3² full-factorial experimental design (Design-Expert® software, version 7.0.0/8.0.4) to study the combined effect of two independent formulation variables — Avicel-102 (Factor A, low level 28 mg, high level 56 mg) and Cross-Carmellose Sodium (Factor B, low level 6 mg, high level 12 mg) — on percentage drug release as the dependent response. Nine formulation batches (F1–F9) were generated according to the design matrix, each containing 112 mg nanosponges (equivalent to 60 mg Azelnidipine), the specified levels of Avicel-102 and Cross-Carmellose Sodium, 13 mg lactose and 1 mg magnesium stearate, and were prepared by direct compression.

Avicel-102 (microcrystalline cellulose) and Cross-Carmellose Sodium were selected as the two independent formulation variables on the basis of their complementary functional roles in a direct-compression tablet: Avicel-102 acts primarily as a diluent/binder that contributes to tablet mechanical strength and powder flow, while Cross-Carmellose Sodium is a superdisintegrant that governs the rate of tablet breakup and, consequently, the rate at which the nanosponge-entrapped drug is exposed to the dissolution medium. Because these two excipients can influence drug release through partially independent (matrix integrity vs. disintegration-driven) mechanisms, and because their combined and quadratic effects on release were not assumed to be purely additive, a 3² factorial design was considered more appropriate than a simple one-factor-at-a-time screening approach for this optimization.

G. Evaluation of Tablets

Pre-compression parameters — angle of repose, bulk density, tapped density, Carr's compressibility index and Hausner's ratio — were evaluated for the powder blends to assess flow properties and compressibility. Post-compression evaluation of the compressed tablets included weight variation, hardness (kg/cm²), friability (%), thickness (mm) and drug content (%), each performed in accordance with pharmacopoeial (USP 30, 2007) limits. In-vitro dissolution of all nine tablet batches was carried out under first-fluid/SLS dissolution conditions at 37 ± 0.5 °C, and results were analyzed using the response-surface methodology of the factorial design, including ANOVA, normal-probability and 3-D surface/desirability plots, to identify the formulation offering the optimal balance of pre- and post-compression properties and drug release.

H. Release Kinetics and Stability Studies

Dissolution data for the optimized batch were fitted to four commonly used release models to identify the mechanism and order of drug release, based on the regression coefficient (R²) obtained for each model. In the zero-order model, cumulative percentage drug released is plotted against time, describing formulations that release the drug at a constant rate independent of concentration. In the first-order model, the logarithm of the cumulative percentage of drug remaining is plotted against time, describing concentration-dependent release. The Higuchi model plots cumulative percentage drug released against the square root of time and describes drug release from a matrix system governed by Fickian diffusion, while the Korsmeyer–Peppas model plots the logarithm of cumulative percentage drug released against the logarithm of time and is used to characterize the underlying release mechanism (Fickian diffusion, anomalous/non-Fickian transport, or case-II relaxation-controlled transport) from the value of the diffusional release exponent. The model giving the highest R² value was taken as best describing the release behaviour of the optimized formulation.

The optimized formulation was additionally subjected to accelerated stability studies as per ICH guidelines, with drug content and in-vitro drug release evaluated at baseline and after 30, 60 and 90 days of storage under elevated temperature and humidity conditions, in order to assess the physical and chemical robustness of the nanosponge tablet formulation under accelerated stress conditions representative of long-term storage.

I. Statistical Analysis

All characterization and evaluation experiments were performed in triplicate unless otherwise indicated, and results are reported as mean values. The response of percentage drug release from the 3² factorial design was analyzed by one-way analysis of variance (ANOVA) using Design-Expert® software; model terms with a p-value below 0.05 were considered statistically significant. Response-surface (3-D) and desirability plots were generated to visualize the combined influence of the two independent factors on drug release and to identify the formulation offering the maximum desirability score.

Table 6 List of Abbreviations

IV. RESULTS AND DISCUSSION

A. Percentage Yield of Nanosponges

The percentage yield of the nanosponge batches, determined after drying, ranged from 21.2% to 67.96% across the F1–F4 series (Table VI), with batch F2 giving the highest yield. Variation in PVA concentration was found to influence the efficiency of particle formation during emulsification, with an intermediate stabilizer concentration favouring more complete particle recovery.

Table 7 Percentage Yield of Nanosponge Batches F1–F4

B. Drug Content of Nanosponges

Drug content of the nanosponge batches, determined by UV spectrophotometry at 253 nm, ranged from 60.15% to 79.43%, with the maximum drug content observed for batch F1 (Table VII). The variation in drug content across batches reflects differences in the efficiency of drug entrapment as a function of stabilizer concentration during the emulsification process.

Table 8 Drug Content of Nanosponge Batches F1–F4

C. FTIR, DSC and XRD Characterization

FTIR spectra of the pure drug, pure polymer, physical mixture and optimized nanosponge formulation were recorded between 4000 and 650 cm?¹ to assess drug–polymer interaction. The principal characteristic absorption bands of Azelnidipine — including N–H (1681.5 cm?¹), C–H (1650.1 cm?¹), C=O (1522.6 cm?¹), CH? (1484.5 cm?¹) and C–O (1346.0 cm?¹) stretching/bending vibrations — were retained without significant shift in the nanosponge formulation (Table VIII), indicating that no chemical interaction occurred between drug and polymer and that any solubility enhancement observed arises from a physical rather than a chemical mechanism.

Table 9  Principal FTIR Absorption Frequencies of Azelnidipine Nanosponges

DSC thermograms of pure Azelnidipine showed a sharp endothermic peak at 240.10 °C, corresponding to its melting point, while pure ethyl cellulose exhibited a broad peak at 70.01 °C associated with the glass-transition relaxation of the polymer. The DSC thermogram of the optimized nanosponge formulation showed a broadened peak of reduced intensity with a small shift in melting point, attributable to the amorphous/glassy character imparted by the polymer matrix and to the formation of weak hydrogen bonding between drug and polymer — a phenomenon considered responsible, at least in part, for the observed solubility enhancement. XRD analysis provided complementary evidence of this transformation: the pure drug showed sharp, well-defined diffraction peaks at 2θ = 11.94°, 13.09°, 18.36° and 21.26° (with the most intense peak at 21.55°), consistent with a highly crystalline material, whereas the nanosponge formulation showed peaks at 2θ = 10.39°, 15.06° and 18.73° with the most intense peak at 18.73°, indicating a reduction in crystallinity. This partial amorphization is consistent with the improved apparent solubility of Azelnidipine observed in the nanosponge form relative to the pure crystalline drug.

D. Particle Size and Zeta Potential

The average particle size of the nanosponge batches ranged from approximately 46 nm to 97 nm, with formulation batch F2 exhibiting the minimum particle size and higher-polymer batches showing progressively larger particles. This trend indicates that increasing the concentration of ethyl cellulose in the dispersed phase increases the viscosity of the organic phase during emulsification, producing larger droplets and, consequently, larger nanosponge particles on solvent removal. Representative particle-size values for batches F1–F3 are summarized in Table IX. The zeta potential of the optimized Azelnidipine nanosponge formulation was found to lie in the range of −10 to −20 mV, a magnitude generally considered sufficient to provide electrostatic stabilization and prevent particle aggregation in the colloidal dispersion.

Table 10 Particle Size of Nanosponge Batches

Figure 1 Scanning electron micrograph (SEM) of Azelnidipine-loaded nanosponges showing a porous, spherical surface morphology

E. Solubility Studies

Solubility of pure Azelnidipine and of the drug-loaded nanosponges was compared across three media (Table X). The drug was essentially insoluble in distilled water, while nanosponge formulation markedly enhanced apparent solubility in the first fluid and in methanol relative to the pure drug, consistent with a reduction in effective crystal size to a nanocrystalline form and favourable drug–polymer interaction within the porous nanosponge matrix.

Table 11 Solubility of Azelnidipine in Different Media

F. In-Vitro Drug Release from Nanosponges (F1–F4)

Cumulative percentage drug release from batches F1–F4 over 120 min is presented in Table XI and Fig. 2. Batch F1 showed the fastest and most complete release profile (98.6% at 120 min), followed by F3, F4 and F2. Increasing PVA/polymer concentration was associated with a progressive decrease in the rate and extent of drug release, confirming that the diffusional resistance of the nanosponge matrix increases with polymer loading. On this basis, batch F1/F2 offered the most favourable balance between yield, drug content and release rate and was carried forward for tablet formulation.

Table 12 In-Vitro Cumulative Drug Release (%) from Nanosponge Batches F1–F4

Figure 2 Comparative in-vitro drug release profile of nanosponge batches F1–F4.

G. Pre-Compression Evaluation of Tablet Powder Blend

Angle of repose, bulk and tapped density, Carr's index and Hausner's ratio were determined for the pure drug and for the drug–nanosponge (1:1) powder blend (Table XII). The nanosponge-based blend showed a substantially lower angle of repose (27.74° vs. 33.42°), lower Carr's index (13.79% vs. 28%, 'good' vs. 'poor') and lower Hausner's ratio (1.16 vs. 1.38) than the pure drug, indicating markedly improved flow and compressibility. This improvement allowed the nanosponge blends to be directly compressed into tablets with good die-fill and content uniformity.

Table 13 Pre-Compression Evaluation of Powder Blends

H. Post-Compression Evaluation of Tablet Batches (F1–F9)

All nine factorial-design tablet batches complied with pharmacopoeial (USP 30, 2007) limits for weight variation, hardness, friability and thickness, with drug content ranging from 91.5% to 99.7% (Table XIII). Hardness values (3.5–4.4 kg/cm²) and friability values (0.51–0.63%) were within acceptable limits for all batches, confirming that the nanosponge-based tablet blends were mechanically robust despite the improved flow and compressibility of the granulation.

Table 14 Post-Compression Evaluation of Tablet Formulations F1–F9

I. Factorial Design Analysis and ANOVA

The 3² factorial design matrix (Table XIV) generated nine tablet batches by combining low, mid and high levels of Avicel-102 (28–56 mg) and Cross-Carmellose Sodium (6–12 mg). ANOVA of the percentage-drug-release response (Table XV) yielded a model F-value of 14.37 (p = 0.0263), confirming that the fitted model was statistically significant. Among the individual terms, the linear effect of Cross-Carmellose Sodium (B) and the quadratic effects of both Avicel-102 (A²) and Cross-Carmellose Sodium (B²) were significant model terms (p < 0.05), whereas the linear effect of Avicel-102 alone and the A×B interaction were not significant, indicating that drug release was governed predominantly by disintegrant level and by curvature (non-linear) effects of both factors rather than a simple additive relationship.

Table 15 Factorial Design Formulation Matrix (F1–F9)

Table 16 ANOVA for the Fitted Model (% Drug Release)

J. Optimized Batch and Comparison with Marketed Formulation

On the basis of desirability analysis, batch F2 (Avicel-102 ≈ 34–42 mg, Cross-Carmellose Sodium ≈ 9–10 mg) was selected as the optimized formulation, with a desirability value of 1.000. The optimized batch showed weight variation of 99.5 ± 0.4%, thickness of 3.10 ± 0.06 mm, hardness of 3.9 kg/cm², friability of 0.55% and drug content of 99.13% — all within pharmacopoeial limits. When compared with a marketed Azelnidipine tablet formulation (Table XVI, Fig. 3), the optimized batch showed a closely matching cumulative release profile, reaching 99.88% release at 12 h against 99.99% for the marketed product, indicating that the nanosponge-based formulation is in-vitro bioequivalent to the reference product.

Table 17 In-Vitro Drug Release: Optimized Batch (F2) vs. Marketed Formulation

Figure 3  In-vitro cumulative drug release of the optimized nanosponge tablet (F2) compared with the marketed Azelnidipine formulation.