Development and Evaluation of Carvedilol Nanosuspension by Acid Base Neutralization Method

Abstract

This study aimed to improve the solubility and dissolution rate of the biopharmaceutics classification system (BCS) 2 candidate carvedilol through nanoformulation using the design of experiments (DoE) approach. Nanosuspensions were prepared via acid-base neutralization using sodium hydroxide and hydrochloric acid at various molar ratios, with poloxamer 407 as a stabilizer, followed by ultrasonication. The drug content, solubility, particle size distribution, and zeta potential of the formulations were evaluated. The optimized formula was determined using a custom experimental design with JMP version 11 software. The formula was freeze-dried and characterized using X-ray, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and stability measurements. The nanosuspensions had particle sizes ranging from 292.0 nm to 622.5 nm and a polydispersity index (PDI) of 0.147-1.6. Drug release ranged from 72.46 ± 1.3% to 95.83 ± 1.2% after 5 h. The optimized formulation had a maximum desirability of 76.13, remained discrete without aggregation, and had a particle size of 292 nm, PDI of 0.615, and zeta potential of 45 mV. Comparative drug release profiles indicated that the plain drug suspension released 12.3% ± 0.12, the marketed formulation released 60.26% ± 0.56%, and the optimized formula released 95.83 ± 1.3% of the drug at 5 h respectively. X-ray analyzis revealed more evident peaks in the pure drug pattern, whereas the optimized formula displayed more randomized peaks. A shift in the endotherm from 124.68 °C to 80 °C suggests the amorphization of the drug in the nanosuspension. Pharmacokinetic studies in Wistar rats showed a 48-fold increase in the bioavailability of nanosuspensions compared to that of carvedilol. Carvedilol formulated as a nanosuspension via acid-base neutralization demonstrated enhanced solubility, dissolution, stability, and bioavailability.