Nanosuspension with improved saturated solubility and dissolution rate of cilostazol and effect of solidification on stability

The aim of the study was to formulate cilostazol containing nanosuspension by top-down wet milling method in order to increase the in vitro solubility and dissolution rate of this substance. The investigation of formulation parameters (emulsifier type, concentration, and combination of surface-active agents) on the milling efficiency was also brought into focus. The wet-milled and unmilled suspensions were applied onto solid carriers, and matrix pellets were prepared by extrusion/spheronization method.

Highlights

Preparation of Cilostazol (CLZ) nanosuspension to improve its solubility.

Composition of the nanosuspension and the milling parameters were optimized by DoE.

Solidification of nanosuspension to perform matrix pellets.

Size reduction and amorphization increased dissolution rate of CLZ.

Solid state characterization of matrix pellets via DSC and PXRD.

The reconstitution of nanoparticles from solid dosage forms was successful. Particle size reduction had a major impact on maximal thermodynamic solubility of cilostazol at pH = 1.2 and demonstrated a two times improvement compared to raw, unmilled surfactant dispersion. A significant effect on the highest dissolution rate constants at pH = 1.2 compared to raw, unmilled surfactant dispersion. Solid-state characterization of pulverized matrix pellets with differential scanning calorimetry and powder X-ray diffractometry indicated the transition of cilostazol Form A to amorphous form due to the extrusion process. More on Nanosuspension with improved saturated solubility and dissolution rate of cilostazol and effect of solidification on stability

Keywords:  Cilostazol, Wet milling, Nanosuspension solidification, Extrusion/spheronization, PXRD, Amorphous transition, polysorbate80 (Tween 80), sodium laurylsulphate, macrogolglycerol hydroxystearate (Kolliphor® RH40), Dimethylpolysiloxane (Foamsol) , MCC (Vivapur® 105), isomalt (galenIQ™ 800)