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Síntese e Caracterização de Co-cristais com Interesse para a Indústria Farmacêutica
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Resumo(s)
Fumaric acid and alkyl fumarates have demonstrated a wide spectrum of effects and potential therapeutic applications. Dimethyl fumarate (DMF) is one of the main examples, being used for the treatment of diseases such as multiple sclerosis or psoriasis. Monomethyl fumarate (MMF) is the active metabolite of DMF. It was approved in April 2020 by the FDA under the tradename Bafiertam, for the treatment of relapsing forms of multiple sclerosis. Monoethyl fumarate (MEF) is one of the APIs (active pharmaceutical ingredient) present in the formulation Fumaderm, together with DMF, used for the treatment of psoriasis. This work focused on the improvement of solubility of the mentioned APIs (mainly MMF), in order to improve their bioavailability, and study the thermodynamic stability of the co-crystals of these compounds. For this, pharmaceutical co-crystals were prepared through mechanochemistry, with the APIs MMF and MEF and GRAS (generally recognized as safe) co-formers: nicotinamide (NIC), picolinamide (PIC), L-alanine (ALA), and L-proline (PRO). The solubilities of the MMF:NIC, MMF:ALA and MMF:PRO co-crystals were determined through the dynamic method, in which the co-crystal solubility was higher in the first two cases and similar in the last one, when compared with that of the pure API. The studies were then focused on the MMF:NIC co-crystal. The structure of the MMF:NIC co-crystal was determined by Single Crystal X-Ray Diffraction. Solubility in equilibrium was determined, using HPLC, in water and biologically relevant mediums, in which an increase of at least two times was observed in relation to pure MMF. Thermodynamic stability was assessed in terms co-crystal decomposition into its precursors, conjugating solubility and dissolution enthalpy measurements. The Gibbs energy of this process (ΔrGmo) was positive, indicating thermodynamic stability of MMF:NIC. Finally, lattice enthalpy (ΔlatHmo) was determined, with the obtained data being consistent with the obtained stability results.
Descrição
Tese de mestrado, Química (Química), 2026, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Co-crystals API Fumarates Solubility Stability