Tailoring the particle microstructures of gefitinib by supercritical CO2 anti-solvent process

Abstract

Supercritical CO2 anti-solvent (SAS) process is a green and effective method to produce particles with designated microstructures. In this study, the particle microstructures of gefitinib, a potent anticancer agent, are tailored by the SAS process to improve its aqueous solubility. The dichloromethane/ethanol (1:4, v/v) was selected as the suitable solvent from typical solvents used in the SAS process at first. Then, the effects of other SAS operating parameters, i.e., the flow rate of gefitinib solution (F), the concentration of gefitinib in the solution (C), the precipitation pressure (P) and the temperature (T), on the gefitinib particle size were investigated in detail. Lower F, lower C, higher P and suitable T were recommended for the formation of gefitinib particles with small particle size. The properties of the raw material and SAS processed samples of gefitinib were characterized by different methods. The results showed that a new polymorphic form (Form β) of gefitinib, which present different physicochemical properties, i.e., smaller particle size, narrower particle size distribution and higher solubility, with raw gefitinib (Form 1), was captured after the SAS process. The predicted structures of gefitinib crystals, which were consistent with the experiments, were performed from their experimental XRD data by the direct space approach using the Reflex module of Materials Studio. Meanwhile, the SAS processed gefitinib particles showed much higher solubility and faster dissolution rate than that of raw gefitinib, which had the potential to improve its bioavailability and decrease the dose-related adverse effects.