Preparação e caracterização de um novo co-amorfo de tolbutamida com trometamina

Abstract

Tolbutamide (TBM) is an oral antidiabetic drug used in the treatment of Type 2 Diabetes Mellitus (DMII). Although this drug has high membrane permeability, its water solubility is very low, which may reduce its bioavailability and its therapeutic efficacy. The synthesis of co-amorphous drugs is a promising alternative to increase the hidrosolubility of these active ingredients and hence the bioavailability and therapeutic efficacy of these compounds. This study aim to obtain and characterize a new co-amorphous TBM using tromethamine (TRIS). Initially, the TBM-TRIS co-amorphous preparation (1:1) was performed by the solvent evaporation method. The stoichiometry of the interaction of TBM with TRIS was investigated from preparation of material in different molar ratios of TBM and TRIS. Afterwards, the co-amorphous TBM-TRIS (1:1) was characterized by X-ray Diffraction by Powder Method (PXRD), Near Infrared Spectroscopy (NIR), Fourier Transform Infrared Spectroscopy (FTIR) and Spectroscopy Raman. The thermoanalytical study of the material synthesized by Thermogravimetry (TG) and Differential Thermal Analysis (DTA) and by Differential Exploration Calorimetry (DSC) was also carried out. In addition, the aqueous solubility test. The results obtained by PXRD indicated absence of well defined peaks in the TBM-TRIS material (1:1) characterizing formation of an amorphous phase in the equimolar proportion. While the diffractograms of the starting compounds and TBM-TRIS binary mixtures in the other molar ratios showed peaks characteristic of the crystalline forms of TBM.Rec an TRIS.Rec. The FTIR spectrum of the co-amorphous TBM-TRIS (1:1), compared to the spectral of the starting compounds, showed the band shift for the OH group of TRIS.Rec and NH of TBM.Rec for number of waves lower, indicating changes in structure due to the formation of hydrogen bonds in the material. The results obtained by Raman Spectroscopy showed disappearance of bands of the vibrational modes of the lattice, due to the fact that the material is amorphous and has no crystalline lattice, as well as the absence of bands related to carbonyl νs (C=O) and sulfonyl groups as sites of interaction of TBM.Rec with TRIS.Rec in the formation of these groups νas (SO2-) in 1160 cm-1 evidencing the performance of these groups as sites of interaction of TBM.Rec with TRIS.Rec in the formation of the co-amorphous. The DSC curve of the material obtained in this study did not present a melting event because it was an amorphous material and presented a glass transition at 84 ºC. Aqueous solubility assays have shown that the co-amorphous TBM-TRIS 1:1 is about twice as soluble as TBM. Thus, in this study it was possible to obtain, in an unprecedented way, a co-amorphous of the TBM using the TRIS as coformer. This new material has promising characteristics, such as good stability and possible higher solubility in water, since amorphous material are more water soluble than crystalline material. Thus, this material may present greater biovailability and greater therapeutic efficacy in the treatment of (DMII).