A Systematic Approach to the Development of Cilostazol Nanosuspension by Liquid Antisolvent Precipitation (LASP) and Its Combination with Ultrasound

Abstract

Nanosizing is an approach to improve the dissolution rate of poorly soluble drugs. The first aim of this work was to develop nanosuspension of cilostazol with liquid antisolvent precipitation (LASP) and its combination with ultrasound. Second, to systematically study the effect of bottom-up processing factors on precipitated particles’ size and identify the optimal settings for the best reduction. After solvent and stabilizer screening, in-depth process characterization and optimization was performed using Design of Experiments. The work discusses the influence of critical factors found with statistical analysis: feed concentration, stabilizer amount, stirring speed and ultrasound energy governed by time and amplitude. LASP alone only generated particle size of a few microns, but combination with ultrasound was successful in nanosizing (d10 = 0.06, d50 = 0.33, d90 = 1.45 µm). Micro- and nanosuspension’s stability, particle morphology and solid state were studied. Nanosuspension displayed higher apparent solubility than equilibrium and superior dissolution rate over coarse cilostazol and microsuspension. A bottom-up method of precipitation-sonication was demonstrated to be a successful approach to improve the dissolution characteristics of poorly soluble, BCS class II drug cilostazol by reducing its particle size below micron scale, while retaining nanosuspension stability and unchanged crystalline form.