Thermal study, process optimization, and water solubility improvement of a freeze-dried artemether nanosuspension for malaria treatment

Abstract

This study aims to develop nanocrystals for improving the water solubility of artemether, an antimalarial drug substance. A compatibility study of the artemether and excipients was performed by differential scanning calorimetry and thermogravimetry to select an adequate stabilizer system. Soluplus® proved to be the most stable excipient evaluated. Artemether nanosuspension was prepared by miniaturized wet bead milling, using Soluplus® as a stabilizer. The process parameters were optimized firstly by a full 2³ factorial experimental design and then by response surface with axial points. The final composition of artemether nanosuspension provided a hydrodynamic diameter below 350 nm. The lyophilization process was developed by determining the glass transition, eutectic, and collapse temperature. Solid artemether nanocrystal presented an elegant cake appearance by visual inspection, and the hydrodynamic diameter practically did not change after water reconstitution. Differential scanning calorimetry and thermogravimetry revealed that the final artemether nanocrystal formulation and its components were thermally stable. The formulation presented an increase in water saturation solubility and pH 2.5–7.2 ranges, which was 3-fold higher in pH 7.2 than micronized artemether. These promising results present an excellent perspective for malarial treatment.