title: Identification of a potential conformationally disordered mesophase in a small molecule: experimental and computational approaches.
abstract: GNE068, a small organic molecule, was obtained as an amorphous form (GNE068-A) after isolation from ethanol and as a partially disordered form (GNE068-PC) from ethyl acetate. On subsequent characterization, GNE068-PC exhibited a number of properties that were anomalous for a two phase crystalline-amorphous system but consistent with the presence of a solid state phase having intermediate order (mesomorphous). Modulated DSC measurements of GNE068-PC revealed an overlapping endotherm and glass transition in the 135-145 °C range. ΔH of the endotherm showed strong heating rate dependence. Variable temperature XRPD (25-160 °C) revealed structure loss in GNE068-PC, suggesting the endotherm to be an "apparent melt". In addition, gentle grinding of GNE068-PC in a mortar led to a marked decrease in XRPD peak intensities, indicating a "soft" crystalline lattice. Computational analysis of XRPD data revealed the presence of two noncrystalline contributions, one of which was associated with GNE068-A. The second was a variable component that could be modeled as diffuse scattering from local disorder within the associated crystal structure, suggesting a mesomorphous system. Owing to the dominance of the noncrystalline diffuse scattering in GNE068-PC and the observed lattice deformation, the mesomorphous phase exhibited properties consistent with a conformationally disordered mesophase. Because of the intimate association of the residual solvent (ethyl acetate) with the lattice long-range order, loss of solvent on heating through the glass transition temperature of the local disorder caused irrecoverable loss of the long-range order. This precluded the observation of characteristic thermodynamic mesophase behavior above the glass transition temperature.
authors.affiliation: Small Molecules Pharmaceutical Sciences, Genentech, Inc. , 1 DNA way, South San Francisco, California 94080, United States. chakravarty.paroma@gene.com
authors.forename: Paroma
authors.initials: P
authors.lastname: Chakravarty
authors.forename: Simon
authors.initials: S
authors.lastname: Bates
authors.forename: Leonard
authors.initials: L
authors.lastname: Thomas
mesh_terms: D002152:Calorimetry, Differential Scanning; D019295:Computational Biology; D050866:Liquid Crystals; D009930:Organic Chemicals / Q000737:chemistry*; D013059:Spectrum Analysis, Raman; D013696:Temperature; D013818:Thermogravimetry
chemical_list: D009930:Organic Chemicals