Síntese e caracterização de novas formas sólidas de atazanavir a partir de misturas binárias

Abstract

The present work aimed to investigate new solid forms of the antiretroviral atazanavir (ATV) from its binary mixture with the coformers mannitol (MAN), citric acid (ACT), nicotinamide (NC), nicotinic acid (ACN), mandelic acid (ACM), erythritol (ERT) and xylitol (XLT) using mechanical, thermal and slow solvent evaporation methods. The drug belongs to the class of protease inhibitors that inhibits the maturation of the HIV virus and, like all molecules in this class, ATV has poor aqueous solubility, and consequently, low bioavailability. Based on this context, the research planned to modify the solid form of ATV through the synthesis of pharmaceutical cocrystals to optimize its physicochemical properties. Most of the products obtained at the end of each methodology resulted in physical interactions, amorphization or in some other type of chemical interaction different from the one sought. However, the use of thermoanalytical techniques allowed not only to investigate results obtained through the solvent and mechanochemical-assisted method, but also to obtain a solid dispersion (SD) through cyclic DSC. The SD was obtained by means of simultaneous melting using the differential scanning calorimetry (DSC) and this same technique was indispensable for the determination of its stoichiometry. The thermogravimetric technique (TG) provided information on the thermal stability of ATV in a hydrophilic matrix (MAN) that increased by approximately 17ºC compared to pure ATV. The complementary techniques, spectroscopy in the infrared region (FTIR) and X-ray powder diffraction (XRD), provided evidence of the SD formation which ATV is amorphized by comparing the absorption bands and the values of the diffraction peaks between the binary system and components of the mixture. Sample of ATV+MAN SD was subjected to solubility and dissolution tests under physiological pH and temperature conditions, and the results showed that SD was able to increase aqueous solubility by approximately 6-fold at a pH that simulates the stomach environment (pH 1.4), by 55-fold at pH that represents the duodenum (4.5 and 6.8) and by approximately 23-fold at pH that simulates blood pH, compared to ATV free base. Compared to ATV Sulfate (ATVs), the solubility was higher at pH 4.5, 6.8 and 7.5 by approximately 30, 10 and 36-fold, respectively. The dissolution test, performed using the USP II method, showed that DS exhibited a release rate according BCS criteria (>85% within 30 minutes) at pH 1.4. Thus, the ATV+MAN SD obtained in this work can be an alternative to other solid forms available of ATV.