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Understanding the process of prenucleation clustering at supersaturating stage is of significant importance to envisage the polymorphism in crystalline materials. Preferential formation of a thermodynamically stable crystal form suggests energetically favored patterns of interactions which control molecular aggregation during nucleation. Introduction of additives during crystallization is sometimes used as a suitable strategy to obtain metastable polymorphs in cases where it is not easy to capture the same by conventional crystallization methods. Comparative analysis of energy relationships and intermolecular interactions between thermodynamically stable and metastable crystal forms provides valuable clues about the nature of growth synthons at prenucleation clustering and preferential crystallization of the thermodynamic form. Conformationally flexible sulfonamide/sulfoester derivatives constituting electron rich and electron-deficient aromatic rings were synthesized to study the interplay between π-stacking and hydrogen bonding synthons. We have identified and characterized the thermodynamically stable and metastable elusive polymorphs of aromatic sulfonamides 1 and 2 and sulfoesters 3 and 4. However, these compounds eluded polymorphism during crystallization from various common solvents/conditions and only produced thermodynamically stable crystals forms (form I crystals). Surprisingly, exploitation of pyrazinamide as an additive in different stoichiometric ratios during crystallization gave elusive polymorphs [three for 1 (form 1II, form 1III, and form 1IV) and one each for 2 (form 2II), 3 (form 3II), and 4 (form 4II)]. Molecules in stable crystal forms of these compounds are linked via extended chains of parallel displaced π···π stacking interactions that seem to play a vital role in driving the self-assembly of molecules and subsequently governing the nucleation process. In contrast, molecules in metastable polymorphs are devoid of such extended π-stacking assemblies. Interestingly, differential scanning calorimetry, hot stage microscopy, and X-ray crystallographic studies confirmed the thermal crystal-to-crystal transition of all three metastable polymorphs of 1 (form 1II, form 1III, and form 1IV) to its thermodynamically stable crystal form (form 1I). Conformational analysis of molecule 1 using density functional theory calculations also validated higher stability for syn conformation (observed in Form 1I crystals) over anti and midway conformations (seen in metastable polymorphs). Melt crystallization of form 1I crystals of 1 on the larger face (001) of δ-pyrazinamide and lattice matching analysis (GRACE) revealed that the layered arrangement of molecules of δ-pyrazinamide (on 001 face) during heterogeneous nucleation acts as a template (heteroepitaxy) to provide a preferential site for the nucleation of new metastable polymorphs by selectively inhibiting the most preferred crystal form from growing into the nucleus. Solution state one- and two-dimensional (NOESY) ¹H NMR, scanning electron microscopy, and a Cambridge Structural Database survey were conducted to substantiate the role of additives during crystallization. [ABSTRACT FROM AUTHOR]

Furosemide (FS), a loop diuretic drug commonly used for the treatment of hypertension and edema, exhibited color cocrystal polymorphism with coformer 4,4'-bipyridine (4BPY) in the stoichiometry 2:1, albeit both the API and the cocrystal former are colorless. Crystallization from ethanol, isopropanol, ethanol-water (v/v, 1/1) mixture, and acetonitrile yielded pale yellow (form 1I, thin needles) and orange (form 1II, blocks) cocrystals concomitantly. Needles appeared from solution within a day, while the blocks were obtained after 1-2 days from the same flask, indicating that yellow needles were formed faster and the orange blocks were perhaps formed under thermodynamic conditions. Form 1I cocrystals could also be produced from the variety of common solvents. Cocrystallization of FS with 2,2'-bipyridine (2BPY) and 4-aminopyridine (4AP) gave colorless cocrystals 2 and 3, respectively, and did not exhibit polymorphism. The single-crystal X-ray structures, powder X-ray diffraction, photophysical characterization, differential scanning calorimetry, hot stage microscopy studies, and density functional theory (DFT) calculations provide insight into the structure-property relationship. The common structural features observed in all of the structures is the formation of sandwich motifs comprising FS and pyridines through p-stacking interactions. These motifs are linked differently through hydrogen bonding interactions in all three directions. The significant color difference between the two cocrystals dimorphs could be attributed to the different p-stacking patterns and hydrogen bonding interactions between molecules of FS and 4BPY in their cocrystal structures. Investigation on the origin of the color difference using DFT calculations revealed the decrease in HOMO-LUMO gap for form 1II cocrystals (orange) compared to form 1I crystals (light yellow). The crystal-to-crystal thermal transformation of form 1I crystals to form 1II crystals of 1 suggests the role of p-stacking assemblies in driving the self-assembly. [ABSTRACT FROM AUTHOR]