Abstract
Benznidazole, the primary drug used in Chagas' disease treatment, has
known side effects, which may limit its widespread use. Its low
solubility could negatively interfere in the bioavailability, even
accentuating the toxic effects. Cocrystals have been extensively used to
modify and optimize physicochemical properties, but, as single-component
raw materials, they are susceptible to the phenomenon of polymorphism.
In this work, we report a trimorphic cocrystal containing a 1:1 ratio of
benznidazole and salicylic acid. The crystalline structures of three
polymorphs were elucidated by single-crystal X-ray diffraction.
Moreover, several isostructural solvates were also synthesized and
analyzed. The same carboxylic acid-imidazole supramolecular
heterosynthon is present in the four forms, but the main structural
feature is an extended column based on amide-amide hydrogen bonds. On
the basis of the crystalline structures, the trimorphic system was
classified as conformational and packing polymorphism. Furthermore, the
dissolution profiles of the stable forms were determined and showed a
significant solubility improvement over the raw material.
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