Conformational and crystal energetics of a polymorphic cyclized product of Napafenac: The Z′ and crystal stability correlation

We report the single crystal diffraction study of a dimorphic 7-benzoyl-1,3-dihydroindol-2-one system and evaluate its stability relationships through thermal, grinding and slurry methods. Computational methods are invoked to understand the stability relationships. The form I crystallizes in the triclinic space group PI with two molecules in the asymmetric unit (Z' = 2), whereas, form II crystallizes in the monoclinic space group P-21/c with a single molecule in the asymmetric unit (Z' = 1). The molecules exhibit subtle conformational variations along the bond connecting the phenyl and indole rings and adopt different crystal packing. While both polymorphs show similar amide dimer of N-H center dot center dot center dot O interactions, they do differ significantly in the way the amide dimers are packed. The Differential Scanning Calorimetry (DSC), phase transformation studies and lattice energy calculations clearly established the greater stability of high Z' form over low Z' form, which contradicts the widely accepted notion that Z' > 1 structures are usually kinetic (or metastable). The choice of two different orientations of phenyl rings in form I enforces shorter it it interactions and additional C-H center dot center dot center dot pi contacts to result in the extra stabilization energy over form II crystal packing with a single conformer. The Z' and stability correlation is established in 83 reported polymorphic systems which indicate that the number of stable crystal structures decrease as the Z' value increases. However, the polymorphic systems with Z' similar or equal to 1 and 2 combinations are more frequently observed than any other combinations. (C) 2013 Elsevier B.V. All rights reserved.