In this work, for the first time, RESS, RESOLV, and ultrasonic-assisted RESOLV methods were applied to produce amiodarone hydrochloride (AMH) drug nanoparticles. Design of experiments was accomplished by Taguchi method (robust design) to obtain optimized process conditions. Water-soluble polymers, viz. polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC), were used to stabilize and control the size of the AMH nanoparticles. The results illustrated that the ultrasonic-assisted RESOLV (US-RESOLV) method outperforms conventional methods such as RESS and RESOLV. In order to characterize unprocessed and processed AMH particles, FTIR, DLS, FESEM, XRD, DSC and dissolution rate analyses were employed. DSC studies confirmed lower crystallinity of the AMH produced by US-RESOLV, as compared to original AMH. The US-RESOLV method could provide quasi-spherical particles of significantly smaller mean size (<50 nm) than unprocessed AMH particles (75.4 pm, on average). Moreover, the small particle size, the presence of polymers and ultrasonic waves increased the dissolution rate of the AMH in aqueous solutions by up to 13.2 folds. The combination of ultrasonication with RESOLV technique provided a method of large potentials for producing AMH nanoparticles. (C)0 2018 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.