Formulation and Bioequivalence Evaluation of a Miniaturized Fexofenadine Hydrochloride Tablet

Abstract

Background: Fexofenadine hydrochloride (FEX) is widely used to treat allergic rhinitis. However, poor solubility, high cohesiveness, and risk of polymorphic transformation present significant formulation challenges. Conventional FEX tablet formulations are large and may pose swallowing difficulties for patients with dysphagia. Therefore, a miniaturized FEX tablet that maintained bioequivalence with the marketed product was developed. Methods: An organic solvent-based binder and porous carrier enhanced solubility, flowability, and process efficiency. The formulation was optimized using a design of experiments approach to assess the effects of tablet size and porous carrier incorporation on dissolution and residual solvent content. Scale-up feasibility was evaluated using Froude number-based process optimization, and stability studies were conducted under accelerated conditions (40 °C and 75% relative humidity) to ensure long-term formulation robustness. Results: The miniaturized tablet exhibited dissolution at pH 4.0 and pH 6.8 equivalent to that of the reference product, whereas a faster dissolution rate was observed at pH 1.2. No significant changes were observed in the dissolution rate, crystalline structure, or impurity levels over six months. An in vivo bioequivalence study demonstrated that the test formulation met the bioequivalence criteria, with 90% confidence intervals for the area under the curve and the C_max falling within the regulatory acceptance range. Conclusions: A miniaturized and commercially viable fexofenadine hydrochloride tablet was developed (44% weight reduction and 50% volume reduction compared to the marketed product). The organic solvent-based binder and porous carrier system improved manufacturing efficiency, stability, and solubility, thereby ensuring compliance with regulatory standards. These findings provide valuable insights into size reduction, solubility enhancement, and large-scale production strategies for the development of future pharmaceutical formulations.

Keywords: bioequivalence; miniaturized; organic solvent; porous carrier; scale-up.

Figure 1

Experimental formulation using the central composite design method: (A) central composite design; (B) formulation and design matrix.

Figure 2

The results of modeling the design of experiments: (A) dissolution rate contour plot for colloidal silicon dioxide and total weight, (B) residual solvent contour plot for colloidal silicon dioxide and total weight, (C) Pareto chart, and (D) optimization plot showing the effect of colloidal silicon dioxide and total weight. The red star represents the optimal point.

Figure 3

Dissolution results of RLD and F1–F7; (A) dissolution profiles of F1–F3 prepared using ethanol solutions of varying concentrations, (B) dissolution profiles of F4–F7 using different types and amounts of porous agents, and (C) dissolution rate at 30 min of prepared formulations (n = 4). All values are presented as mean ± standard deviation (SD). All values were statistically analyzed by one-way ANOVA with post hoc Dunnett’s test. ** p < 0.01; compared with RLD.

Figure 4

Dissolution results RLD, Lab-1 and -2, and Scale-Ups 1–3; (A) dissolution profiles of Lab-1 and -2 and Scale-Ups 1–3, and (B) dissolution rate at 30 min. All values are presented as mean ± standard deviation (SD). All values were statistically analyzed by one-way ANOVA with post hoc Dunnett’s test. ** p < 0.01; compared with RLD.

Figure 5

Photographs and dissolution profiles of manufactured formulation in different dissolution media: (A) picture of conventional fexofenadine tablets and coated Scale-Up 3 tablets, (B) dissolution profiles in pH 1.2, (C) dissolution profiles in pH 4.0, (D) dissolution profiles in pH 6.8 (n = 8).

Figure 6

PXRD stability test results: (A) fexofenadine HCl; (B) physical mixture; (C) initial; (D) 6 months accelerated. The red arrows indicate the characteristic peaks of fexofenadine HCl form I (2-theta: 12.3°, 14.3°, 18.5°, 19.6°, 20.1°, and 24.1°).

Figure 7

Pharmacokinetic profiles of manufactured formulation in humans (n = 60).