title: Conformational polymorphism in aripiprazole: Preparation, stability and structure of five modifications.
abstract: Five phase-pure modifications of the antipsychotic drug aripiprazole were prepared and characterized by thermal analysis, vibrational spectroscopy and X-ray diffractometry. All modifications can be produced from solvents, form I additionally by heating of form X degrees to approximately 120 degrees C (solid-solid transformation) and form III by crystallization from the melt. Thermodynamic relationships between the polymorphs were evaluated on the basis of thermochemical data and visualized in a semi-schematic energy/temperature diagram. At least six of the ten polymorphic pairs are enantiotropically and two monotropically related. Form X degrees is the thermodynamically stable modification at 20 degrees C, form II is stable in a window from about 62-77 degrees C, and form I above 80 degrees C (high-temperature form). Forms III and IV are triclinic ($P\overline 1$), I and X degrees are monoclinic (P2(1)) and form II orthorhombic (Pna2(1)). Each polymorph exhibits a distinct molecular conformation, and there are two fundamental N-H$\cdots$O hydrogen bond synthons (catemers and dimers). Hirshfeld surface analysis was employed to display differences in intermolecular short contacts. A high kinetic stability was observed for three metastable polymorphs which can be categorized as suitable candidates for the development of solid dosage forms.
authors.affiliation: Institute of Pharmacy, University of Innsbruck, Innrain 52, 6020 Innsbruck, Austria.
authors.forename: Doris E
authors.initials: DE
authors.lastname: Braun
authors.forename: Thomas
authors.initials: T
authors.lastname: Gelbrich
authors.forename: Volker
authors.initials: V
authors.lastname: Kahlenberg
authors.forename: Richard
authors.initials: R
authors.lastname: Tessadri
authors.forename: Josef
authors.initials: J
authors.lastname: Wieser
authors.forename: Ulrich J
authors.initials: UJ
authors.lastname: Griesser
mesh_terms: D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D000068180:Aripiprazole; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013055:Spectrophotometry, Infrared; D013059:Spectrum Analysis, Raman; D013816:Thermodynamics
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D012997:Solvents; D000068180:Aripiprazole