OBTENÇÃO E CARACTERIZAÇÃO DE UM NOVO CO-AMORFO DE RIFAMPICINA UTILIZANDO A TROMETAMINA COMO COFORMADOR

Abstract

Drugs are materials with bioactive properties, and most of them are developed to allow their oral administration. Many of these materials have low water solubility and, consequently, low bioavailability. Obtaining solid drug dispersions (SDDs), such as co-amorphous, has been an alternative for improving the aqueous solubility of these drugs. Rifampicin (RIF) is a bioactive material used as an oral antibiotic in the treatment of diseases such as tuberculosis and leprosy. This drug has low water solubility and high membrane permeability, therefore belonging to Class II of the Biopharmaceutical Classification System. This work aimed to obtain and characterize a new co-amorphous of RIF using a Tromethamine (TRIS) as a coformer, as well as to evaluate the aqueous solubility and its dissolution in vitro profile of this new material. Initially, a molecular modeling of the starting compounds (RIF and TRIS) was performed by the method based on the Density Functional Theory (DFT) to obtain the electrostatic potential map, energies of the HOMO, LUMO and gap orbitals, as well as the reactivity indices. A preparation of the DSF of RIF was carried out by the Slow Solvent Evaporation. Subsequently, the co-amorphous was characterized by X-Ray Diffraction using the Powder Method (PXRD), Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetry, Derivative Thermogravimetry and Differential Analysis (TG/DTG-DTA) and by Differential Scanning Calorimetry (DSC). The material stability was investigated by this PXRD, in time function. The solubility and dissolution in vitro profile tests of the RIF present in the SDD were also performed. The results obtained from the DFT study of the starting compounds are indicating a possible intermolecular interaction by hydrogen bonds between the available 4-hydroxyl and C=O groups of RIF and the hydroxyl and amino derived groups of TRIS. The data obtained from the analysis by DRXP determined the formation of a co-amorphous from the interaction of the RIF with a TRIS in the molar ratio of (2:1). The FTIR spectrum of the co-amorphous RIF-TRIS (2:1) indicated the formation of the new solid dispersion by the intermolecular interactions between the ketone groups of the RIF molecules (nucleophilic region) and the amino and hydroxyl groups of the TRIS molecule (electrophilic region), as observed in DFT study. The thermal behavior of the co-amorphous observed from the TG/DTG curves of this SDD showed that this material has good thermal stability up to 153°C. In addition, the DTA and DSC curves did not show a melting event, confirming its amorphous nature. The amorphous nature of this SDD proved to be stable for at least fifty (50) days. The aqueous solubility of the RIF present in this SDD is 5.5 times greater when compared to the solubility of the crystalline free base RIF (RIFBLC). This increase was also observed in the dissolution in vitro rate of RIF present in the co-amorphous. Thus, a SDD obtained in this study presents itself as a very promising alternative for an improvement in the treatment of leprosy and tuberculosis, since the increase in RIF's water solubility will favor the increase of its bioavailability and its therapeutic efficacy, as well as the reduction side effects.