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

• Published in: Journal of molecular structure 2014-12, Vol.1078, p.133-145
• Main Authors: Nanubolu, Jagadeesh Babu, Ravikumar, Krishnan, Sridhar, Balasubramanian, Sreedhar, Bojja
• Format: Article
• Language: English
• Subjects: Amides; Asymmetric unit; Asymmetry; Correlation; Crystal structure; Crystallization; Crystals; Intermolecular potential; Metastable; Multiple molecules; Phenyls; Polymorph Z; Stability; Stable
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2013.10.061

A cluster of four molecules showing five strongest intermolecular potentials (kcalmol−1) in two polymorphs is depicted. Form I with two different conformations exhibits stronger intermolecular potentials than form II with a single conformation. [Display omitted] •Single crystal diffraction analysis and thermal study of a new polymorphic system.•The high Z′ form is interestingly more stable than its low Z′ form.•Conformer energies and intermolecular potentials in two polymorphs are discussed.•Collective weak interactions are stronger than the conventional N–H⋯O bonds.•The Z′ and crystal stability correlation is established in 83 polymorph sets. 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 P1¯ with two molecules in the asymmetric unit (Z′=2), whereas, form II crystallizes in the monoclinic space group P21/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 NH⋯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 π⋯π interactions and additional CH⋯π 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′=1 and 2 combinations are more frequently observed than any other combinations.