pH independent controlled release of verapamil hydrochloride using HPMC-alginate matrices & organic acids

Background: Verapamil HCl, a weakly basic drug, exhibits pH-dependent solubility that limits sustained-release formulation efficacy. This study developed controlled-release matrix tablets using HPMC, sodium alginate, and organic acids to achieve pH-independent drug release. Methodology: Sixteen formulations (F1-F16) were prepared using a 2⁴ factorial design with varying concentrations of organic acids (citric/fumaric: 50-75 mg), sodium alginate (50-80 mg), and HPMC K4M (30-50 mg). Evaluations included pre- and post-compression studies, dissolution testing under a two-stage pH protocol (pH 1.2 for 2 hours, then pH 6.8 for 10 hours), microenvironmental pH monitoring, and kinetic modeling. Results and Discussion: All formulations met pharmaceutical standards, with hardness of 6.88-7.55 kg/cm², friability <0.55%, and drug content of 98.65-99.68%. Fumaric acid formulation F8 achieved superior performance with 89% drug release and the highest pH-independence (f₂ = 91.2) compared to control F1 (72% release, f₂ = 85.3). Microenvironmental pH monitoring revealed that F8 maintained sustained acidification (pH 4.10-4.75) for 12 hours, whereas citric acid formulations showed premature acid depletion. All formulations fitted the Korsmeyer-Peppas model (R² > 0.99), with F8 exhibiting diffusion-controlled release (n = 0.512). Statistical optimization identified fumaric acid as the most significant factor (F-value = 26.30, p = 0.0003). Conclusion: Incorporating 75 mg fumaric acid in HPMC-alginate matrices provides robust, pH-independent sustained release through maintained microenvironmental acidification, offering a validated solution for weakly basic drugs in sustained-release formulations.