title: Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids.
abstract: Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.
authors.affiliation: Transform Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts 02421-3102, USA. jremenar@transformpharma.com
authors.forename: Julius F
authors.initials: JF
authors.lastname: Remenar
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Morissette
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Peterson
authors.forename: Brian
authors.initials: B
authors.lastname: Moulton
authors.forename: J Michael
authors.initials: JM
authors.lastname: MacPhee
authors.forename: Héctor R
authors.initials: HR
authors.lastname: Guzmán
authors.forename: Orn
authors.initials: O
authors.lastname: Almarsson
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D003998:Dicarboxylic Acids / Q000737:chemistry*; D017964:Itraconazole / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D012995:Solubility
chemical_list: D000935:Antifungal Agents; D003998:Dicarboxylic Acids; D017964:Itraconazole