Obtenção de sal de metformina e ácido ferúlico com aumento de solubilidade aquosa e sua aplicação no desenvolvimento de comprimidos

Abstract

Solid-state modification technologies can be represent by salts and cocrystals, which are 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 in literature shows a synergistic effect with AFE. Furthermore, dose-dependent undesirable effects of MT reduce adherence to DM treatment by patients. 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). After preformulation studies, 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 changes in their biopharmaceuticals properties 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, targeting in a pharmaceutical product in association.