Isonicotinamide-4-methoxybenzoic acid co-crystal (1), C6H6N2O·C8H8O3, is formed through slow evaporation from methanol solution and it undergoes a first-order isosymmetry (monoclinic I2/a ↔ monoclinic I2/a) structural phase transition at Tc= 142.5 (5) K, which has been confirmed by an abrupt jump of crystallographic interaxial angle β from variable-temperature single-crystal XRD and small heat hysteresis (6.25 K) in differential scanning calorimetry measurement. The three-dimensional X-ray crystal structures of (1) at the low-temperature phase (LTP) (100, 140 and 142 K) and the high-temperature phase (HTP) (143, 150, 200, 250 and 300 K) were solved and refined as a simple non-disordered model with final R[F2> 2σ(F2)] ≃ 0.05. The asymmetric unit of (1) consists of crystallographically independent 4-methoxybenzoic acid (A) and isonicotinamide (B) molecules in both enantiotropic phases. Molecule A adopts a `near-hydroxyl' conformation in which the hydroxyl and methoxy groups are positioned on the same side. Both `near-hydroxyl' and `near-carbonyl' molecular conformations possess minimum conformational energies with an energy difference of
Understanding crystallization behaviors is of utmost importance for developing robust amorphous pharmaceutical solids. Herein, the crystal growth behaviors of amorphous anti-inflammatory drug nimesulide (NIME) are systemically investigated in the glassy and supercooled liquid state as a function of temperature. A sudden over-tenfold increase is observed in the bulk crystal growth of NIME on cooling below its glass transition temperature (Tg). This fast growth behavior is known as a glass-to-crystal (GC) mode and has been reported in some molecular glasses. Fast surface crystal growth of NIME can persist up to Tg + 57°C with a weak jump in its growth rates at 30-40°C. In addition, surface crystal growth and GC growth of NIME exhibit an almost identical temperature dependence, supporting the view that GC growth is indeed a surface-facilitated process. Moreover, the bubble-induced fast crystal growth of NIME is observed in the interior of its supercooled liquid with approximately the same growth kinetics as surface crystal growth. These findings are relevant for a full understanding of the surface-related crystallization behaviors and physical stability of amorphous pharmaceutical formulations.
Hexamethylenetetramine-benzoic acid (1/2) (HBA) and hexamethylenetetramine-4-methylbenzoic acid (1/2) (HMBA) co-crystals undergo order-disorder structural phase transition from a low-temperature monoclinic crystal structure to a high-temperature orthorhombic crystal structure at the transition temperatures of 257.5 (5) K (Pn ↔ Fmm2) and 265.5 (5) K (P21/n ↔ Cmcm), respectively, using variable-temperature single-crystal X-ray diffraction analysis. The observed phase transitions were confirmed to be reversible first-order transitions as indicated by the sharp endothermic and exothermic peaks in the differential scanning calorimetry measurement. The three-molecule aggregate of HBA and HMBA consists of a hexamethylenetetramine molecule and two benzoic acid or two 4-methylbenzoic acid molecules, respectively. The acid molecules are ordered at the low-temperature phase and are equally disordered over two positions, which are related by a mirror symmetry, at the high-temperature phase. The two-dimensional supramolecular constructs common to both co-crystals are formed by three-molecule aggregates via weak intermolecular C-H...O and C-H...π interactions into molecular trilayers parallel to the ac plane with small XPac dissimilarity indices and parameters. The PIXEL interaction energies of all corresponding molecular contacts were calculated and the results are comparable between HBA and HMBA co-crystals, resulting in similar lattice energies and transition temperatures despite their two-dimensional isostructural relationship. The observed phase transitions of these two energetically similar co-crystals are triggered by similar mechanisms, i.e. the molecular rotator ordering and structural order-disorder transformation, which induced non-merohedral twinning with similar twin matrices in the low-temperature crystal form of both co-crystals.