Obtenção e caracterização de dispersões sólidas de fármacos para a produção de formulações farmacêuticas antibacterianas

Abstract

Pyrazinamide (PZA) and ethambutol hydrochloride (ETH) are antibiotics used in the treatment of leprosy. Obtaining solid dispersions (SDs) can increase the aqueous solubility of these drugs and, consequently, their therapeutic efficacy. This study aimed to obtain and characterize SDs of these drugs. Initially, molecular modelling of the starting compounds was performed by density functional theory (DFT) using the ωB97X-D functional with a set of 6-311++(d,p) basis functions. Resulting, it was possible to prepare a eutectic mixture composed of acetylsalicylic acid (ASA) and PZA by the liquid-assisted grinding (LAG) method; an eutectic of PZA and ETH by solvent evaporation (ES); and an eutectic mixture of mefenamic acid (MFA) with PZA

also by ES. The characterization of the materials obtained in this study was performed using X- ray diffraction techniques by the powder method (DRXP); Fourier transform infrared

spectroscopy (FT-IR); Raman spectroscopy of the eutectic mixture of ASA-PZA (2:1); simultaneous thermogravimetry, derivative thermogravimetry and differential thermal analysis (TG/DTG-DTA) and differential scanning calorimetry (DSC). The aqueous solubility of the eutectics ASA-PZA (2:1) and MFA-PZA (1:1) was tested. The DFT study allowed the determination of dipole moment vectors, HOMO and LUMO energies, reactivity index values, and the electrostatic potential map (EPM) for each molecule, indicating the regions favorable for the establishment of intermolecular interactions. For the ASA-PZA (2:1) eutectic mixture, the DRXP, FT-IR, and Raman results showed a characteristic profile for this type of DS, with no evidence of intermolecular interactions. The TG/DTG curves of this material showed that it is thermally stable up to 134 °C, and its DTA and DSC curves showed a single melting event with a lower temperature than the melting events of the starting compounds (ASA and PZA). From the phase diagram and Tamman triangle obtained for this eutectic, it was possible to determine the stoichiometric ratio (ASA:PZA) as χASA = 0.67. It was also possible to observe an increase in the aqueous solubility of ASA and PZA present in this eutectic mixture of 1.62 and 1.86 times, respectively. The DRXP and FT-IR results of the binary mixture of PZA-ETH (1:1) showed results of a simple physical mixture, resulting in the formation of a eutectic-type DS. This material demonstrated good thermal stability up to 130 °C. In this study, it was also possible to obtain a eutectic mixture of MFA-PZA (1:1). The drugs present in this DS showed an increase in their water solubility rates of 48.95 (MFA) and 1.86 times (PZA) compared to the starting compounds. The TG/DTG curves showed that this eutectic is thermally stable up to 133 °C. Thus, the results obtained in this study confirmed the achievement of three eutectic mixtures. These new materials are promising for use in the production of more effective drugs for the treatment of tuberculosis.