OBTENÇÃO DE SAL DE METFORMINA E ÁCIDO FERÚLICO COM AUMENTO DE SOLUBILIDADE AQUOSA E SUA APLICAÇÃO NO DESENVOLVIMENTO DE COMPRIMIDOS
ferulic acid; metformina; salt; aqueous solubility; dissolution;
Solid-state modification technologies such as salts and cocrystals represent
multicomponent systems that allow improvement of physical-chemical properties of
drugs, such as stability and aqueous solubility. Ferulic acid (FEA) is a molecule with
high antioxidant and hypoglycemic potential, but with limited aqueous solubility, which
may imply low bioavailability. Metformin (MT) is a consolidated hypoglycemic agent in
the treatment of type 2 diabetes mellitus (DM), which showed a synergistic effect with
AFE. The objective of this study is to develop and characterize multicomponent
systems with AFE and MT with improved aqueous solubility, as well as to incorporate
them into a solid pharmaceutical form. For this, a recrystallization process
demonstrated high reproducibility and yield (91.3 ± 0.8%). After a series of
experiments, it was possible to develop a multicomponent system between FEA and
MT in a 1:1 molar ratio, characterized as a salt, SFM (metformin ferulate, by X-ray
diffraction techniques, thermal techniques, infrared spectroscopy and microscopy.
FEA in SFM showed an increase of at least 740 fold in its aqueous solubility (643 ± 18
mg/mL). Tablets were developed with the SFM, which met the quality control
requirements for this dosage form. From in vitro dissolution tests with SFM tablets with,
a superior dissolution efficiency was calculated, in relation to a control formulation, of
95.4 ± 0.5% and 42.1 ± 0.5%, respectively. The FEA and MT contents were determined
using a high-performance liquid chromatography method, which was properly
developed and validated. Finally, in a stability study at 40 ºC for 3 months, no physical
or chemical changes were found, for both the SFM raw material and tablets. Thus, the
developed product emerges as a technological innovation to be applied in the
treatment of DM.