title: Mechanochemistry applied to reformulation and scale-up production of Ethionamide: Salt selection and solubility enhancement.
abstract: 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.
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, CP 369, 13560-970 São Carlos, SP, Brazil; Departamento de Física, Universidade Federal do Ceará, CP 6030, 60440-900 Fortaleza, CE, Brazil.
authors.forename: Cristiane C
authors.initials: CC
authors.lastname: de Melo
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, CP 369, 13560-970 São Carlos, SP, Brazil.
authors.forename: Cecilia C P
authors.initials: CC
authors.lastname: da Silva
authors.affiliation: Faculdade de Ciências Médicas, Universidade Estadual de Campinas, CEP 13083-887 Campinas, SP, Brazil.
authors.forename: Carla C S S
authors.initials: CC
authors.lastname: Pereira
authors.affiliation: Faculdade de Ciências Médicas, Universidade Estadual de Campinas, CEP 13083-887 Campinas, SP, Brazil.
authors.forename: Paulo C P
authors.initials: PC
authors.lastname: Rosa
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, CP 369, 13560-970 São Carlos, SP, Brazil. Electronic address: javiere@ifsc.usp.br.
authors.forename: Javier
authors.initials: J
authors.lastname: Ellena
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D005000:Ethionamide / Q000737:chemistry*; D008298:Maleates / Q000737:chemistry; D019815:Oxalic Acid / Q000737:chemistry; D012439:Saccharin / Q000737:chemistry; D012492:Salts / Q000737:chemistry; D012995:Solubility
chemical_list: D000995:Antitubercular Agents; D008298:Maleates; D012492:Salts; C030272:maleic acid; D019815:Oxalic Acid; D012439:Saccharin; D005000:Ethionamide
keywords: Ethionamide salts; Mechanochemical synthesis; Powder X-ray diffraction; Single-crystal X-ray diffraction; Solubility improvement; Thermal analysis; Tuberculosis