title: Solid-state supramolecular synthesis based on the N-H…O heterosynthon: an approach to solve the polymorphism problem in famotidine.
abstract: Famotidine (FMT), a histamine H2 -receptor antagonist, is a drug commonly used in treatments of gastroesophageal diseases that presents solid-state polymorphism (A and B forms), the marketed form being the metastable polymorph B. A new stable salt was obtained by combination of FMT and maleic acid as coformer. FMT maleate (FMT-MLT) was prepared either by solvent evaporation or comilling methods. Single-crystal X-ray diffraction reveals that (FMT)(+) in FMT-MLT adopts an extended conformation that is stabilized by classical and nonclassical H-bonds. The three-dimensional packing consists of tapes along the axis b that further develop a columnar array based on H-bonds involving (FMT)(+) side chain. Nonconventional π-stacking interactions between adjacent tapes were also identified. Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, polarized light thermal microscopy, and scanning electron microscopy were employed to characterize the multicomponent complex. According to the solubility values in water and simulated gastric fluid, FMT-MLT exhibits such a performance that improves on the solubility of the commercially available polymorph. Finally, the higher stability of FMT-MLT regarding both FMT forms, as well as its easy preparation from either A or B forms or a mixture of them, also allows to consider this salt as a valuable alternative to avoid the polymorphism issue in marketed formulations containing FMT.
authors.affiliation: Química Inorgánica - INTEQUI. Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis 5700, Argentina.
authors.forename: Marcos G
authors.initials: MG
authors.lastname: Russo
authors.affiliation: Química Inorgánica - INTEQUI. Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis 5700, Argentina.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Brusau
authors.affiliation: Physics Institute of São Carlos, University of São Paulo, São Carlos, São Paulo, CP 369, 13560-970, Brazil.
authors.forename: Javier
authors.initials: J
authors.lastname: Ellena
authors.affiliation: Química Inorgánica - INTEQUI. Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis 5700, Argentina. Electronic address: gnarda@unsl.edu.ar.
authors.forename: Griselda E
authors.initials: GE
authors.lastname: Narda
mesh_terms: D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D018360:Crystallography, X-Ray; D004355:Drug Stability; D015738:Famotidine / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D005750:Gastric Juice / Q000737:chemistry; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008298:Maleates / Q000138:chemical synthesis*; D008855:Microscopy, Electron, Scanning; D008859:Microscopy, Polarization; D008958:Models, Molecular; D015394:Molecular Structure; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D013818:Thermogravimetry
chemical_list: D006635:Histamine H2 Antagonists; D008298:Maleates; D015738:Famotidine; C030272:maleic acid
keywords: FTIR; crystal structure; physicochemical properties; solid state; solubility; thermal analysis