Novas formas sólidas cristalinas de Acetazolamida e de Benzoilmetronidazol e caracterização físico-química e biofarmacêutica de sólidos multicomponentes de Benzoilmetronidazol

Abstract

The acquisition of Active Pharmaceutical Ingredients (APIs) with appropriate physicochemical and mechanical characteristics for drug production is one of the main challenges faced by the pharmaceutical industry. Over 80 % of the drugs produced are in solid form due to greater stability and therapy adherence. Strategies based on solid-state concepts, such as Crystal Engineering and polymorphism screening, have proven efficient in optimizing various unfavorable properties of APIs, particularly solubility and dissolution, which have a direct impact on their bioavailability. The APIs acetazolamide (ACTZ) and benzoylmetronidazole (BZMD) belong to Class IV of the biopharmaceutics classification system (BCS), with low solubility and permeability, making them excellent candidates for the application of these strategies aimed at improving their properties. Thus, the objective of this work was to apply previously mentioned solid-state concepts to obtain new solid forms from these drugs. The slow evaporation method was used to synthesize new solid forms of BZMD and ACTZ. Singlecrystal X-ray diffraction was employed for their structural elucidation. Complementary characterization of 14 multicomponent crystalline solids of BZMD was carried out using infrared (FT-IR) and Raman vibrational spectroscopy, as well as thermal analyses by differential scanning calorimetry (DSC) and thermogravimetry (TG). Dissolution profiles were also performed to compare the solubilities of the different crystalline forms of BZMD in relation to the API. Two novel cocrystals, ACTZPZA and BZMD2,4DBA, and one polymorph, BZMDII, were obtained using the slow evaporation technique, highlighting the relevance of solid-state concepts applied to drugs. Regarding the characterization of the solid forms derived from BZMD, spectroscopic (FT-IR and Raman) and thermal (DSC and TG) studies revealed changes in molecular vibrations and differences in thermal stability of the solid forms, respectively, contributing to the understanding and application of these structures. The dissolution profiles did not show significant differences between the solid forms of BZMD and the API. Despite this, the findings reinforce the potential of multicomponent solid forms for the development of drugs with improved physicochemical characteristics.