Controlled submicro particle formation of ampicillin by supercritical antisolvent precipitation

A supercritical antisolvent (SAS) technique has been used in the precipitation of ampicillin (APC), one of the world's most widely prescribed antibiotics, to control its particle size (PS) and particle size distribution (PSD). The influences of different solvents and pressure on morphologies, PS and PSD have been investigated. Three different solvents: N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), and ethyl alcohol (EtOH) have been assayed. Experimental conditions (150 bar, 313 K, 20 mg/mL and ratio of CO2 flow rate/liquid flow rate equal to 15, on a mass basis at the process operating conditions) were kept constant throughout the course of this investigation. Through simply changing the APC–liquid solvent system we observed large variations in PS and PSD, accompanied by different particles morphologies. The APC–NMP proved to be the best system for controlling the precipitation of ampicillin; both compact particles and spherical microparticles (mean diameter = 0.26 μm and standard deviation = 0.08 μm) were obtained. In a second study, ampicillin has been successfully processed in the range of 80–150 bar using NMP as liquid solvent under constant experimental conditions. A change from 80 to 100 bar led to a large reduction of the mean PS and PSD, and no significant differences were found at pressures higher than 100 bar. Conversely, an increase in pressure produced better sphericity in particle shape.