ESTUDO DFT DOS FÁRMACOS DAPSONA E RIFAMPICINA E DE SUAS INTERAÇÕES COM O COFORMADOR ÁCIDO OXÁLICO NA FORMAÇÃO DE DISPERSÕES SÓLIDAS

Abstract

Infectious diseases known as leprosy (HAN) and tuberculosis (TB) are caused by bacteria and still affect many Brazilians, and the drugs dapsone (DPS) and rifampicin (RIF) are used to treat these diseases. However, it was found in the study of these materials that they are drugs that have low solubility in water and are classified as Class II drugs of the Biopharmaceutical Classification System (SBC). Thus, solid dispersions of each of these drugs with the coformer oxalic acid (OXA) were developed in other studies, with the aim of increasing the bioavailability of these drugs in the body, with greater therapeutic efficacy. Therefore, it is necessary to develop a theoretical study, contributing to a better understanding of the formation and stability of the solid dispersions of the drug DPS with OXA coformer and of the drug RIF with the same coformer. In the present work, DFT calculations were initially performed with the DFT functional ωB97X-D in association with Pople basis sets, in geometry optimization and vibrational frequencies calculations, in the study of structural, thermodynamic and electronic properties of the drugs DPS and RIF, of the coformer OXA, as well as of the ions formed from this coformer and from both studied drugs DPS and RIF. Then, new calculations were also performed in the study of heterodimers, formed from the interaction between ions formed from the drug and the coformer, in each case. Each optimized geometry obtained in this work was confirmed as a minimum on the potential energy surface, through vibrational frequency calculations, since all calculated vibrational frequencies are positive. From these initial calculations, several parameters were determined in each case, such as dipole moment, electrostatic potential map, partial atomic charges, spectroscopic data, as well as the spatial distributions and energy values of molecular orbitals. All these parameters were determined for each of the RIF, DPS and OXA species, and were then considered in the construction of the initial geometries of the heterodimers, considered in the study of interactions in the formation of solid dispersions. Thus, in each case, the drug was positioned in a specific orientation in relation to the coformer, in order to favor intermolecular interactions, considering different possibilities, investigating intermolecular interactions from different sites of the drug and the coformer. From the results of the calculations, the interactions were then studied from the theoretically obtained thermodynamic and spectroscopic data, determining the most favorable interaction in each case. The values of ΔG 298 and ∆EZPVE obtained for the DPSH2+ -OXA2- interaction are -38.94 kcal/mol and -45.83 kcal/mol, while the values of these parameters for the RIF+ -OXAinteraction are -14.81 kcal/mol and -19.62 kcal/mol, respectively. Therefore, our results confirm that the starting compounds used in the preparation of solid dispersions are stable, also indicating that solid dispersions are stabilized mainly through hydrogen bonds between the drug and the coformer, in each of the solid dispersions, which contributes for the stability of the formed materials. These results also contribute to the understanding of the formation of new solid dispersions that may be studied.