CRISTAIS MULTICOMPONENTES FARMACÊUTICOS DE CARVEDILOL COMO ESTRATÉGIA PARA MELHORAR A ESTABILIDADE TÉRMICA

Abstract

Understanding and manipulating the physicochemical properties of the solid state of Active Pharmaceutical Ingredients (APIs) are crucial for the development of new drugs. Among the relevant properties of a drug, solubility, intrinsic dissolution, permeability, and bioavailability stand out. In this context, crystal engineering of pharmaceutical compounds emerges as an essential tool. It enables rational planning and the development of new solid forms through the strategic use of supramolecular synthons. Carvedilol (CVD), an antihypertensive drug belonging to the beta-blocker class, is used to treat cardiovascular diseases. This API falls into Class II of the Biopharmaceutical Classification System (BCS), exhibiting low solubility and high permeability. Based on a literature search and a detailed analysis of molecular interaction, crystals were successfully obtained using the following acids: nitric, maleic, benzoic, and p-toluenesulfonic. The salts were prepared via evaporative crystallization methods, and the resulting phases were characterized using single-crystal X-ray diffraction and thermal analysis, complemented by powder X-ray diffraction data. Four Carvedilol salts were obtained: Carvedilol Nitrate (CVD-NO3), Carvedilol Maleate (CVD-MAL), Carvedilol Benzoate (CVD-BZN), and Carvedilol Tosylate (CVD-TOS). The crystal structures of the nitrate and maleate salts are isostructural. Both crystallize in the triclinic space group P1 ̅ and present as hydrates due to the incorporation of water molecules into the crystal lattice. CVD-TOS also presents as a hydrate, crystallizing in the Fdd2 space group. In contrast, CVD-BZN crystallizes in the triclinic space group P1 ̅ with an anhydrous structure. Thermal analyses confirm that the CVD-BZN salt is the most thermally stable, with degradation occurring at 160 ºC. For CVD-MAL, dehydration occurs at 75.6 ºC and degradation at 171 ºC, indicating lower stability. Therefore, the results presented in this work provide important and innovative scientific contributions, particularly concerning the possibility of improving the biopharmaceutical properties of the studied APIs.