Preparação e caracterização de dispersões sólidas de deferasirox obtidas por extrusão a quente para aumento da solubilidade

Abstract

Deferasirox (DFX) is an oral iron chelator potent used worldwide as first-line therapy for iron overload related to blood transfusion in adult and pediatric patients (2 years of age or older). Commercial DFX has low solubility and slow dissolution rates in water that limit the attainment of an adequate oral bioavailability. Thus, it is observed the need to find new alternatives that promote improvement in the solubility of DFX, as well as its dissolution rate. Hot melt extrusion is a widely used solid dispersion manufacturing technology to mitigate problems related to solubility. The polymer Soluplus® (SLP) was selected for the study, based on its ability to prevent the recrystallization of the active pharmaceutical ingredient (API) and mainly by the low glass transition temperature, which allows the API to be submitted to lower process temperatures, avoiding degradation. This excipient is designed to be used in hot melt extrusion, solubilizing poorly water-soluble actives, with consequent increase in its bioavailability. Initially, the individual components were characterized by thermal, physicochemical and optical analysis. Physical mixtures of the drug and polymer were prepared and subjected to a study to evaluate the solubility capacity between DFX and SLP by means of the film casting technique in order to choose the best proportions for testing in the extruder. The proportions 90:10, 75:25 and 60:40 (polymer: active) were subjected to the hot melt extrusion (HME) process, conducted in a twin screw extruder. The extruded material was characterized by thermal, physical-chemical, instrumental and optical analysis. The proportion 75:25 (DFXHME 75:25) obtained the best results, both in process and in the analytical stages. Therefore, dissolution tests and quantitative assessment of the solubility between DFX and DFXHME 75:25 were performed, indicating improvement of solubility in potassium phosphate buffer (PPB) pH 6.8. In the dissolution tests, the release percentage of DFXHME 75:25 reached approximately 95% (~23.6 mg) in 10 minutes, while pure DFX was only 43.2% (~10.8 mg). Already in the test for quantitative assessment of solubility, the difference between DFXHME 75:25 and pure DFX was 2.047 mg/mL, representing ~98% increase in API solubility when extruded. Additionally, this proportion was evaluated by X-Ray diffractometry after 9 months of stability at room temperature and 6 months under accelerated conditions, obtaining positive results regarding the amorphization of the drug. Thus, the HME technology with SLP proved to be a viable and efficient alternative to provide increased solubility and dissolution rate of DFX by obtaining a stable amorphous solid dispersion.