title: Difluprednate: more than meets the eye.
abstract: Difluprednate, a FDA approved topical corticosteroid indicated for the treatment of inflammation and pain associated with ocular surgery, affords three polymorphic crystal forms (one hexagonal, sg. P65, and two distinct orthorhombic, both sg.'s P212121, phases), whose preparation, thermal stability ranges, crystal structures and stereochemical preferences are here reported. Using DSC, single-crystal structural analysis and less conventional ab-initio X-ray powder diffraction methods, the rich structural and thermal behavior of three difluprednate polymorphs have been clarified, and the validity of previous complex and sometimes contradicting literature reports has been challenged. Complementary solution state NMR provided (1)H, (13)C and (19)F chemical shifts full assignment of the corresponding signals. These results allow us to precisely describe the selective isolation pathways toward three distinct crystal phases, and to define their structural and analytical data necessary for identification and easy and accurate quantification, by modern Rietveld analysis, of complex difluprednate polymorphic mixtures, often obtained as a result of poorly controlled (co)-precipitation methods.
authors.affiliation: Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell'Insubria, via Valleggio 11, 22100 Como, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giacobbe
authors.affiliation: Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell'Insubria, via Valleggio 11, 22100 Como, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palmisano
authors.affiliation: Dipartimento di Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2/3, 28100 Novara, Italy.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Giovenzana
authors.affiliation: Dipartimento di Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2/3, 28100 Novara, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Giovannelli
authors.affiliation: Dipartimento di Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2/3, 28100 Novara, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Negri
authors.affiliation: Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell'Insubria, via Valleggio 11, 22100 Como, Italy. Electronic address: norberto.masciocchi@uninsubria.it.
authors.forename: Norberto
authors.initials: N
authors.lastname: Masciocchi
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D005477:Fluprednisolone / Q000031:analogs & derivatives* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D014961:X-Ray Diffraction
chemical_list: D005477:Fluprednisolone; C015808:difluprednate
keywords: Crystal structure; Difluprednate; Phase transitions; Polymorphism; Powder diffraction