Obtenção e caracterização de co-amorfos do candesartan cilexetila para a produção de medicamentos anti-hipertensivos

Abstract

Candesartan cilexetil (CAN) is a drug used to treat systemic arterial hypertension. It belongs to Class II of the Biopharmaceutical Classification System (BCS), presenting low water solubility, which contributed to the reduction of its bioavailability and therapeutic efficacy. Obtaining solid drug dispersions (SDDs), such as co-amorphous ones, is an alternative for improving the physicochemical properties of drugs, such as

increasing aqueous solubility. This work aimed to obtain and characterize co- amorphous CAN with tromethamine (TRIS), using the slow solvent evaporation

method. Initially, molecular modeling of the starting compounds (CAN and TRIS) was carried out based on computational calculations developed based on Density Functional Theory (DFT), using the ωB97X-D functional, basis set 6-31G(d,p) and the Integral Equation Formalism Polarizable Continuum Model (IEFPCM) continuous solvation method. After preparing binary CAN-TRIS mixtures in different molar ratios, they were characterized by X-ray powder diffraction (XRD); Fourier transform infrared spectroscopy (FT-IR); Raman spectroscopy (ER); thermogravimetry, derivative thermogravimetry and simultaneous differential thermal analysis (TG/DTG-DTA) and differential thermal analysis (DSC). Structural stability studies of the co-amorphous materials were carried out, as a function of time, by XRD, as well as solubility tests of these materials. The DFT study of the starting compounds indicated the regions most likely to participate in intermolecular interactions through hydrogen bonds, through the oxygen and nitrogen atoms present in the nucleophilic functional groups of CAN and TRIS. The data obtained by XRD showed that binary mixtures of CAN-TRIS in molar ratios of 1.5:1.0; 1.0:1.0; 1.0:1.5 and 1.0:2.0 are amorphous materials. The FT-IR spectra of the obtained co-amorphous showed the occurrence of intermolecular interactions between the functional groups present in the molecules, as indicated from the DFT study. The ER results of these solid dispersions showed the absence, displacements and broadening of some vibrational bands related to CAN, such as the asymmetric ester ν(C-O-C), carbonyl ν(C=O), ν(C-N), ν(N=N) aromatic and ν(C=N). For TRIS, most vibrational bands were absent, confirming the interaction between the compounds. The TG/DTG curves of the co-amorphous ones showed that these materials have good thermal stability up to 165.7; 170.0; 158.0 and 155.1 oC, respectively. The DTA and DSC curves of the co-amorphous materials did not show events related to the melting of these materials, confirming the amorphous nature of these compounds. Furthermore, it was possible to determine the glass transition (Tg) of the co-amorphous, in which the molar ratio of 1.0:2.0 presented a lower Tg temperature in relation to the other co-amorphous. Aqueous solubility tests of these co-amorphous showed an increase of 3.1; 3.6; 15.2 and 42.1 times the water solubility of CAN present in SDDs, respectively, in relation to the crystalline free base CAN, as amorphous materials tend to be more water-soluble than crystalline materials. Thus, these CAN-TRIS SDDs will contribute to increasing the dissolution rates, bioavailability and therapeutic efficacy of CAN. This indicates that these materials are attractive for the production of more effective medications for the treatment of hypertension, as well as for reducing the drug's side effects.