A screening design of experiments has been applied to the supercritical antisolvent precipitation of ampicillin (APC) using carbon dioxide (CO2) and N-methylpyrrolidone (NMP) as antisolvent and solvent, respectively. The proposed design of experiment (DOE) is useful for identifying the key factors involved in the SAS process in just a few runs at an early stage of experimentation. Seven factors were studied, and two levels were assigned to each. A fractional factorial design with 2 − experiments plus two additional runs to calculate the accuracy of the estimates was used. The mean particle size (PS) and particle size distribution (PSD) of the processed ampicillin were chosen as responses to evaluate the process performance. Within the range of operating conditions investigated, concentration, temperature, and nozzle diameter proved to be the key factors having the greatest effect on both PS and PSD and, thus, the most important factors for controlling the formation of submicrometer particles of ampicillin by the SAS technique.

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The Supercritical AntiSolvent (SAS) technique (which is also referred to as ASES, PCA, or SEDS in the literature) is a promising means of overcoming the low bioavailability found in some active pharmaceutical compounds (APIs). By determining the thermodynamic properties of the phases involved in the process, and applying empirical equations (operations with dimensionless numbers), it has been possible to estimate the different disintegration regimes of the jet when an N-methyl-pyrrolidone (NMP)-ampicillin solution is injected into the CO 2 -pressurized chamber under pressure (P), temperature (T), and flow rate (Q L ) conditions in the following ranges: P ) 80-180 bar, T ) 308-328 K, Q L ) 1-5 mL/min. The application of the empirical hydrodynamics model highlights the existence of significant mechanisms that stabilize the liquid jet, and it shows that there are limiting hydrodynamic conditions that must be overcome to direct the process toward the formation of uniform spherical nanoparticles and the achievement of higher yields.

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