Conformational polymorphism in aripiprazole: Preparation, stability and structure of five modifications

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° to ∼120°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° is the thermodynamically stable modification at 20°C, form II is stable in a window from about 62–77°C, and form I above 80°C (high-temperature form). Forms III and IV are triclinic (), I and X° are monoclinic (P21) and form II orthorhombic (Pna21). Each polymorph exhibits a distinct molecular conformation, and there are two fundamental N–H⋯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. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2010–2026, 2009 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° to ∼120°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° is the thermodynamically stable modification at 20°C, form II is stable in a window from about 62–77°C, and form I above 80°C (high-temperature form). Forms III and IV are triclinic (), I and X° are monoclinic (P21) and form II orthorhombic (Pna21). Each polymorph exhibits a distinct molecular conformation, and there are two fundamental N–H⋯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. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2010–2026, 2009