Dispersões sólidas e complexos de inclusão como estratégia para o incremento da solubilidade de amiodarona

• Ano de defesa: 2016
• Autor(a) principal: Rubim, Alexandre Machado
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Santa Maria; Brasil; Farmacologia; UFSM; Programa de Pós-Graduação em Ciências Farmacêuticas; Centro de Ciências da Saúde
• Palavras-chave em Português: Dispersão sólida; Complexo de inclusão; Comprimidos; Perfil de dissolução; Cloridrato de amiodarona; Solid dispersion; Inclusion complex; Tablets; Dissolution profile; Amiodarone hydrochloride; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: http://repositorio.ufsm.br/handle/1/17958

This study aimed to develop solid dispersions (SD) and inclusion complex (IC) using as carriers hydrophilic polymers (polyethylene glycol PEGs 1500, 4000 and 6000) and cyclodextrins (CDs) (β–cyclodextrin, metil-β-cyclodextrin and hydroxypropy-β-cyclodextrin), respectively, in order to verify the influence of each technological approach in the solubility of Amiodarone Hydrochloride (AMH). SD was prepared in the proportion AMH:PEGs of 1:1 and 1:10 (w/w) by the fusion and kneading techniques. IC were prepared by co-evaporation, freeze-drying and spray-drying methods, and the proportion AMD: CD of 1:1 (w/w) was used. For both approaches, AL-type solubility diagrams and thermodynamic approaches favorable to the formation of this new solid entity were obtained. The AMH solubility in different physiological media (acid buffer pH 1.2, acetate buffer pH 4.5 and phosphate buffer pH 6.8 and water) showed a strong dependence of its ionization due to the presence of amine chemical, which ionizes itself in a greater proportion in more acid means, below the AMH pKA (6.56). In order to characterize SD and CI, different techniques were used, such as X-Ray Diffraction (XRD), Forrier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Scanning Electronic Miscroscopy (SEM), Proton Nuclear Magnetic Resonance (RMN), determination of Specific Surface Area of the particles (SBET) and studies about Molecular Modeling (MM), as well as the determination of dissolution profiles between pure AMH and the solid products obtained. From the DRX, FT-IR and DSC analysis, it was possible to verify a strong interaction in a molecular level between AMH and the studied carriers. With the aid of SEM and SSA analysis, it was diagnosed a morphological alteration on the AMH crystals after the IC formation, as well as an increase of the superficial area of the particles in relation to pure AMH. For the determination of each portion of AMH molecule that is inside the cyclodextrin cavity, RMN and MM were used. RMN spectra showed strong evidence that the complexation process with methyl-β-cyclodextrin occurred by the lipophilic side, constituted by a diethylamide group. MM was used from an IC containing AMH and methyl-β-cyclodextrin in order to determine the binding energy, amount of charge transferred and the distances between the principal atoms. According to the results, it was determined a strong interaction between the diethylamide group of AMH with the methyl-β-cyclodextrin cavity, compounding a stable complex with the binding energy of 0.76 eV, confirming the results found by RMN. The obtained dissolution profiles showed to suffer a great influence of SD and CI, as well as the preparation methods of these products. It was also developed three formulations for the obtainment of immediate release tablets containing 10 mg de AMH complex with methyl-β-cyclodextrin by direct compression. The batches were submitted to tests of quality control, and the formulation 1 presented friability superior to 1.5%, which rendered this formulation improper for the execution of dissolution profiles and continuation of the studies. The tablets obtained from the F2 and F3 formulations presented satisfactory results in relation to the tests of variation of weigh, hardness, friability, disintegration time and AMH content. These two formulations were selected for the execution of dissolution profiles using water and acetate buffer pH 4.5. For both evaluated mediums, there was an increase in the dissolved amount of AMH from the tablets in relation to the pure AMH, demonstrating that IC can be useful strategies in the pharmacotechnical developments of new solid oral pharmaceutical ways.