CONICET | Buscador de Institutos y Recursos Humanos

The solubility bioavailability and processability of crystalline drugs can be improved converting them into an amorphous state. However, a particular issue related to amorphous solids is that they are high-energy states and therefore metastable. In this work, the stability of the amorphous binary system formed by the H2 receptor antagonist (famotidine, FMT) and a NSAID (ibuprofen, IBU) in 1:1 molar ratio was studied. The sample was prepared by cryo-milling process; its amorphous nature was confirmed by the lack of the diffraction peaks and the appearance of a Tg (transition glass) signal. This sample was physically stable when stored for 60 days at different temperatures. The high stability is due to a solid state interaction, confirmed by FTIR analysis, between the guanidine group of FMT and carboxylic acid of IBU forming a heterodimer trough the heterosynthon N-H?O. This intermolecular interaction was studied by DFT and QTAIM calculations. Two heterodimer were proposed and the lowest energy conformer was determined, moreover, the presence of bond critical point confirms this interaction. Besides, molecular dynamics simulations have been conducted to investigate the thermal properties (Tg), hydrogen bonding distributions and molecular diffusion, since these properties are important to justify the physical stability of metastable material. The estimated Tg is in good agreement with the experimental one. In addition, the radial distribution functions suggest that the heterosynthon N-H?O is found in this amorphous sample. Taking into account these results, the high stability observed in this amorphous sample is due to a strong interaction (N-H?O) between both drugs as was confirmed by FTIR and DFT calculations. Moreover, molecular simulations could be employed to predict properties and justify the stability of amorphous compound.