title: Crystal structure and physicochemical characterization of ambazone monohydrate, anhydrous, and acetate salt solvate.
abstract: The crystal structures of the monohydrate and anhydrous forms of ambazone were determined by single-crystal X-ray diffraction (SC-XRD). Ambazone monohydrate is characterized by an infinite three-dimensional network involving the water molecules, whereas anhydrous ambazone forms a two-dimensional network via hydrogen bonds. The reversible transformation between the monohydrate and anhydrous forms of ambazone was evidenced by thermal analysis, temperature-dependent X-ray powder diffraction and accelerated stability at elevated temperature, and relative humidity (RH). Additionally, a novel ambazone acetate salt solvate form was obtained and its nature was elucidated by SC-XRD. Powder dissolution measurements revealed a substantial solubility and dissolution rate improvement of acetate salt solvated form in water and physiological media compared with ambazone forms. Also, the acetate salt solvate displayed good thermal and solution stability but it transformed to the monohydrate on storage at elevated temperature and RH. Our study shows that despite the requirement for controlled storage conditions, the acetate salt solvated form could be an alternative to ambazone when solubility and bioavailability improvement is critical for the clinical efficacy of the drug product.
authors.affiliation: National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca R-400293, Romania.
authors.forename: Marieta
authors.initials: M
authors.lastname: Muresan-Pop
authors.affiliation: Dipartimento di Chimica G. Ciamician, Università di Bologna 40 126, Bologna, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Braga
authors.affiliation: National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca R-400293, Romania.
authors.forename: Mihaela M
authors.initials: MM
authors.lastname: Pop
authors.affiliation: National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca R-400293, Romania.
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Borodi
authors.affiliation: National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca R-400293, Romania.
authors.forename: Irina
authors.initials: I
authors.lastname: Kacso
authors.affiliation: Dipartimento di Chimica G. Ciamician, Università di Bologna 40 126, Bologna, Italy. Electronic address: l.maini@unibo.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Maini
mesh_terms: D000085:Acetates / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006813:Humidity; D006860:Hydrogen Bonding; D007700:Kinetics; D008935:Mitoguazone / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D033362:Powder Diffraction; D011208:Powders; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D014867:Water / Q000737:chemistry
chemical_list: D000085:Acetates; D011208:Powders; D014867:Water; C037931:1,4-benzoquinone guanylhydrazone thiosemicarbazone; D008935:Mitoguazone
keywords: X-ray diffractometry; acetate salt solvate; ambazone; antimicrobial; crystal structure; dissolution rate; polymorphism; proton transfer; stability