Zusammenfassung
Ethionamide (ETH), a Biopharmaceutics Classification System class II
drug, is a second-line drug manufactured as an oral dosage form by
Pfizer to treat tuberculosis. Since its discovery in 1956, only one
reformulation was proposed in 2005 as part of the efforts to improve its
solubility. Due to the limited scientific research on active
pharmaceutical ingredients (APIs) for the treatment of neglected
diseases, we focused on the development of an approachable and green
supramolecular synthesis protocol for the production of novel solid
forms of ETH. Initially, three salts were crystal engineered and
supramolecular synthesized via slow evaporation of the solvent: a
saccharinate, a maleate and an oxalate. The crystal structures of all
salts were determined by single crystal X-ray diffraction. In sequence,
mechanochemical protocols for them were developed, being the scale-up
production of the maleate salt successfully reproducible and confirmed
by powder X-ray diffraction. Finally, a more complete solid-state
characterization was carried out for the ETH maleate salt, including
thermal analysis, infrared spectroscopy, scanning electron microscopy
and equilibrium solubility at different dissolution media. Although ETH
maleate is thermodynamically less stable than ETH, the equilibrium
solubility results revealed that this novel salt is much more soluble in
purified water than ETH, thus being a suitable new candidate for future
formulations. (C) 2015 Published by Elsevier B.V.
Nutzer