Difluprednate: More than meets the eye

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 102; pp. 305 - 313
• Main Authors: Giacobbe, Carlotta, Palmisano, Giovanni, Giovenzana, Giovanni B., Giovannelli, Lorella, Negri, Roberto, Masciocchi, Norberto
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 05-01-2015
• Subjects: Calorimetry, Differential Scanning; Crystal structure; Crystallization; Difluprednate; Fluprednisolone - analogs & derivatives; Fluprednisolone - chemistry; Magnetic Resonance Spectroscopy; Phase transitions; Polymorphism; Powder diffraction; X-Ray Diffraction; Powder diffraction; Difluprednate; Phase transitions; Polymorphism; Crystal structure
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2014.09.028

The rich structural and thermal behavior of three difluprednate polymorphs has been clarified, and the validity of previous complex and sometimes contradicting literature reports (patents and scientific papers) has been challenged.
•Three distinct polymorphs of difluprednate have been selectively isolated.•Stability ranges and phase interconversions were assessed.•Stereochemical preferences have been determined.•Contradicting literature reports are now clarified.
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 1H, 13C and 19F 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.