OBTENÇÃO E CARACTERIZAÇÃO DE COAMORFOS DO ANTI-HIPERTENSIVO OLMESARTANA MEDOXOMILA PARA A PRODUÇÃO DE NOVAS FORMULAÇÕES FARMACÊUTICAS

Abstract

The low aqueous solubility limits the absorption of orally administered drugs. Solid drug dispersions (SDDs), such as coamorphous systems, represent an alternative to increase the water solubility of these materials. Olmesartan medoxomil (OLM) is an antihypertensive drug with low aqueous solubility and high membrane permeability, belonging to Class II of the Biopharmaceutical Classification System (BCS), which limits its absorption in the body, leading to the need for higher doses of the drug and intensifying of its adverse effects. Tromethamine (TRIS) is a compound with high aqueous solubility and high membrane permeability, classified as Class I of the BCS, and is used as a coformer in the preparation of SDDs. This study aimed to obtain and characterize coamorphous of OLM using TRIS as a conformer. Initially, molecular modeling of the starting compounds (OLM and TRIS) was performed using computational calculations based on density functional theory (DFT). For this purpose, the ωB97X-D functional, the 6-311++G(d,p) basis set, and the integral equation formalism of the polarizable continuum model (IEFPCM) solvation method were used. The OLM-TRIS coamorphous systems were prepared by slow solvent evaporation (SSE). Subsequently, they were characterized by powder X-ray diffraction (PXRD); Fourier transform infrared spectroscopy (FT-IR); simultaneous thermogravimetry, derivative thermogravimetry, and differential thermal analysis (TG/DTG-DTA); and differential scanning calorimetry (DSC). The aqueous solubility and in vitro dissolution profile of free crystalline base OLM (OLMFCB), the coamorphous systems, and the physical mixtures (PMs) were also determined. The DFT study of the starting compounds revealed that the imidazole, tetrazole, and ester functional groups of OLM, and the hydroxyl and amine groups of TRIS, were the most likely to engage in intermolecular interactions via hydrogen bonding. PXRD results showed that the binary mixtures of OLM-TRIS formed amorphous materials at ratios of 2:1, 1:1, 1:2, 1:3, and 1:4 after undergoing SSE. Time-dependent PRXD analysis demonstrated that the OLM-TRIS coamorphous systems (2:1), (1:1), (1:2), (1:3), and (1:4) maintained the coamorphous state for at least 392, 392, 269, 250, and 7 days, respectively. FT-IR spectra of the obtained coamorphous systems showed evidence of hydrogen bonding between the ester groups of OLM and the hydroxyl and amine groups of TRIS, as suggested by the DFT study. TG/DTG curves indicated that the coamorphous systems in the studied molar ratios exhibites good thermal stability up to 115.9; 117.6; 121.9; 120.2 and 138.1 oC (Tonset), respectively. DTA and DSC curves of these materials showed no melting events, confirming their amorphous nature. DSC curves of the OLM-TRIS coamorphous systems (2:1), (1:1), and (1:2) exhibited glass transition events (Tg) at 65.7, 96.8, and 97.2 °C (Tonset), respectively. Solubility assays showed that the OLM present in the coamorphous exhibited an increase in its aqueous solubility of at least 61-fold compared to OLMFCB. In vitro dissolution tests of OLM in OLM-TRIS (2:1), (1:1) and (1:2) revealed that the drug exhibited dissolution efficiency values (DE30 and DE60) at least 4.4 and 2.7 times higher than those of OLMFCB. Therefore, the materials obtained in this study are very promising promising for the development of more effective pharmaceutical formulations for the treatment of hypertension, as they significantly improved the solubility and dissolution rate of OLM.