Development of an amorphous nanosuspension by sonoprecipitation-formulation and process optimization using design of experiment methodology

Abstract

A Design of Experiment (DoE) methodology was adopted to investigate and optimize process parameters and formulations variables for preparing an amorphous clotrimazole (CLT) nanosuspension by sonoprecipitation technique. The amorphous nanosuspension can provide a synergistic effect of increase in dissolution velocity and kinetic solubility which can be advantageously used to improve bioavailability of low-solubility drugs. A Box-Behnken design was utilized to study the effect of formulation parameters (drug concentration, polymer concentration, and surfactant concentration) and process parameter (antisolvent: solvent ratio) on particle size, polydispersibility index (PDI), and zeta potential of amorphous CLT nanoparticles. Soluplus® and poloxamer 407 were incorporated in the formulation for steric and electrostatic stabilization respectively. The optimized formulation predicted by the developed model was validated experimentally. The micronized amorphous suspension, micronized crystalline suspension and nanocrystalline suspension were prepared as controls. The optimized amorphous nanosuspension and controls were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and polarized light microscopy (PLM) techniques. Additionally, in-vitro dissolution studies were performed. The drug concentration, polymer concentration and antisolvent:solvent ratio were found to be statistically significant in impacting critical quality attributes (CQAs) of drug product. The model developed for zeta potential was insignificant at a 95% confidence interval. The DSC, XRPD and PLM results confirmed the amorphization of CLT by sonoprecipitation process. The DSC thermogram did not show any characteristic endothermic peak, XRPD diffractogram showed amorphous halo pattern whereas PLM images did not illustrate birefringence for amorphous CLT nanosuspension. The in-vitro drug dissolution studies demonstrated relatively higher drug dissolution for amorphous CLT nanosuspension compared to controls at both the dissolution media (de-ionized water and pH 7.2 buffer). The sonoprecipitation process was successfully used to produce a stable amorphous nanosuspension with notably enhanced dissolution velocity by evaluating and optimizing critical process and formulation parameters.

Keywords: Design of Experiment; amorphous nanosuspension; analysis of variance (ANOVA); dissolution rate; optimization; sonoprecipitation; statistical analysis.