Bosentan Monohydrate Nanosuspension by Media Milling Technique: Formulation, Optimization, and Pharmacokinetic Study

Bosentan monohydrate is a class II drug according to the Biopharmaceutical Classification System (BCS) which has a dissolution rate limiting absorption and thus has low oral bioavailability (50%). Poor aqueous solubility is the main constraint for scientists working on oral drug delivery systems. The present work aimed to develop Bosentan monohydrate nanosuspension to enhance its dissolution and to optimize the process and formulation variables by 32 factorial design. The media milling method was utilized to prepare nanosuspension. A preliminary study was performed to screen the factors like size of zirconium oxide beads, the amount of zirconium oxide beads, stirring time, stirring speed, and type of stabilizer. 32 factorial design applied to optimize processing and formulation variables. The result indicated that the stirring speed and the concentration of the stabilizer have a significant effect on dependent response variables. The size particles were in the 233-550-nm range, saturation solubility was in the 0.044-0.17 mg/ml range, percentage drug release at 30 min ranges from 79.85 to 99.33%, the and zeta potential was in - 10.54 to - 32.35 mv range. Scanning electron microscopy study revealed the presence of nearly spherical, nano-sized particles. The stability study under accelerated conditions indicates the formulation was stable against crystal growth and polymorphic changes. The pharmacokinetic study in rats showed a significant increase in AUC compared to the drug. The study concluded that the nanosuspension of Bosentan monohydrate prepared by media milling method can be a promising formulation to overcome its dissolution and bioavailability problem.