Estudo DFT de propriedades de hipoglicemiantes orais e de suas dispersões sólidas com a trometamina

Abstract

Theoretical chemistry studies performed with the use of computational resources have promoted great advances in the development of materials with applications in many areas. The basis of this powerful combination, beyond of other existing methods, is supported in Density Functional Theory (DFT). The employment of theoretical chemistry foundations in the development of compounds with pharmacological applications allow the study of important physical-chemistry properties and promote, among other advantages, the resources saving in experimental studies. In co-amorphous materials two or more different compounds are combined, in order to obtain a new material with different physical-chemistry properties. The preparation of co-amorphous materials has been one of the most promising strategies to promote an increase in the bioavailability of drugs, with the obtention of these new materials from drugs with low solubility in water with a coformer compound with higher solubility in water. Oral hypoglycemiant drugs derived from sulfonylurea are used for the treatment of diabetes mellitus type II. These drugs have low aqueous solubility and, consequently, low bioavailability in human organism, directly impacting their therapeutic efficacy. In this work, a theoretical study was performed, from the use of the DFT in the investigation of properties of the oral hypoglycemic drugs chlorpropamide (CLP) and tolbutamide (TBM), as well as of interactions of each of these drugs with the coformer tromethamine (TRIS). The study was conducted employing the DFT functional ωB97x-D in association with the 6-311++G(d,p) basis set, as implemented in Gaussian16 software, considering also the use of the continuum solvation model Integral Equation Formalism Polarizable Continuum Model (IEFPCM), for analysis of solvation effects. Geometry optimization calculations, followed by vibrational frequencies calculations, were performed for each one of the compounds and for the systems corresponding to drug-coformer interactions, confirming each optimized geometry as a minimum in potential energy surface, since all vibrational frequencies calculated are positive. Structural, electronic, and thermodynamic properties, as well as reactivity indices were calculated for each compound and the most favorable interactions were identified with a basis on interaction energy values calculated. Hydrogen bonds between drug and coformer were elucidated, in each case, from structural parameters analysis and through theoretical FTIR and Raman spectra, with attribution of the main vibrational modes, confronting these data with experimental results available in the literature. The theoretical findings confirmed the stability of the co-amorphous materials obtained from the hipoglicemiant oral drugs CLP and TBM, using TRIS as a coformer, and contributed for a better understanding of the formation of the co-amorphous materials CLP-TRIS (1:1) and TBM-TRIS (1:1).