Formas sólidas dos ingredientes farmacêuticos ativos (IFA) doxazosina e fluconazol e seu impacto em propriedades farmacêuticas

Abstract

This doctoral thesis addressed the challenges and opportunities in the pharmaceutical field provided by the different supramolecular arrangements that an Active Pharmaceutical Ingredient (API) can adopt in the solid state, including the amorphous, mono and multicomponent crystalline forms and their polymorphs. This work aimed to study some of the doxazosin (DXZ) and fluconazole (FLU) API solid forms, constituents of medicines used in the treatment of benign prostatic hyperplasia and fungal infection, respectively. These API has been chosen due to the significant number of crystalline forms, including polymorphs, hydrates and salts, reported in the literature, and some of these, without reported crystal structure and/or without evaluation of their physicochemical properties of pharmaceutical interest. In the case of DXZ, the crystal structure of DXZ free base (DXZ-FB) was first determined here, which had its equilibrium solubility carried out in different aqueous media compared to two known polymorphs of DXZ mesylate (DXZM) (form used in DXZ medicines). The results showed that the three DXZ forms are insoluble or poorly soluble at neutral to slightly acidic pH ranges. DXZ-FB showed the higher solubility in the acid medium, but lower than the values obtained for DXZM-H and DXZM-A, which justifies the need to use the saline form to improve the drug solubility. It was also shown, by comparing its solubilities and melting point (established by differential exploratory calorimetry (DSC)), that DXZM-A is more stable than DXZM-H, which suggests that DXZM-A as the most suitable polymorph for solid formulations. For FLU, it has been shown that the raw materials (API) and some FLU formulations studied are/contain binary physical mixtures consisting of polymorph 5 (FLU-5), and the FLU monohydrate form (FLU-H2O). Long-term stability studies (IVb zoneBrazil) showed that the raw material and drug products that contain FLU-5 or FLU-5 + FLU-H2O (binary mixture) converted to FLU-H2O. From this result, a thermal study starting by the pure FLU-H2O was evaluated. The mechanical grinding (mechanochemical) assisted by adding solvent (water) was used for the obtention of the pure FLU-H2O. The thermal study confirmed that the anhydrate formed from the FLU-H2O dehydration was the FLU-5, which melts without decomposition. The solidification of the molten FLU generated an amorphous solid (FLUamorphous) which converted into FLU-5 again upon further heating and recrystallization. The transitions temperatures were established by DSC and the phases were identified by powder X-ray diffraction (PXRD). In addition, the formation of a metastable anhydrous crystalline phase of FLU (a new polymorph, FLU-10) was observed from the crystallization of the amorphous FLU, which has isomorphic structure to FLU-H2O (except for presence of water). Finally, a study comparing the equilibrium solubility values of the raw material of FLU (MP-FLU = FLU-5 + FLU-H2O), pure FLU-5, pure FLU-H2O and FLU-amorphous showed no significative difference in the same medium. It has also been shown that all studied forms converted in FLU-H2O during the solubility experiment. These results suggest that both FLU-5 and FLU-H2O or a mixture thereof may be used to prepare or be present in FLU formulations, considering the expected bioavailability of the drug.