Salts and Cocrystals of Furosemide with Pyridines: Differences in π‑Stacking and Color Polymorphism

Furosemide (FS), a loop diuretic drug, exhibits polymorphism not only in pure entity, but also in cocrystal/salt forms. In continuation of our previous report of color cocrystals polymorphism of FS and 4,4′-bipyridine (4BPY), FS was further screened for color cocrystals by cocrystallization with other pyridines using a slow evaporative solution crystallization method. Interestingly, 2:1 molecular salt of FS and 1,2-bis­(4-pyridyl)­ethylene (4BPE) displayed color polymorphism in isopropanol yielding an orange (form <b>1</b>I, plates) and the yellow (form <b>1</b>II, blocks) crystals concomitantly. The yield of orange crystals, which appeared within 10–15 h, has always been more compared to the later formed yellow crystals, thus signifying the preference for orange crystals. The cocrystallization experiment once also yielded a yellow-colored 2:3 molecular salt (form <b>1</b>III); however these crystals could not be reproduced later. Further, cocrystallization of FS and 4BPE from THF, dioxane, and their mixture produced comparatively unstable solvates, form <b>1</b>IV, form <b>1</b>V, and form <b>1</b>VI crystals, respectively. Cocrystallization of FS with other pyridines like 1,2 bis­(4-pyridyl)­ethane (4BPA), 1,2 bis­(4-pyridyl)­propane (4BPP), 1,2 bis­(2-pyridyl)­ethylene (2BPE), and 1,10-phenanthroline (Phen) also gave colorless molecular salts <b>2</b>, <b>4</b> and cocrystals <b>3</b> and <b>5</b> respectively. The single crystal structure analysis revealed the formation of a common sandwich motif between FS and pyridines through varying geometry π-stacking interactions in all the crystals. The significant color difference between the polymorphs could be attributed to the different levels of conjugation generated by dissimilar π-stacking patterns between the two components. Investigation on the origin of the color difference using density functional theory calculations revealed the decrease in the highest occupied molecular orbital–lowest unoccupied molecular orbital gap for orange crystals compared to yellow crystals

Furosemide Cocrystals with Pyridines: An Interesting Case of Color Cocrystal Polymorphism

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 <b>1</b>I, thin needles) and orange (form <b>1</b>II, 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 <b>1</b>I 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 <b>2</b> and <b>3</b>, 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 π-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 π-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 <b>1</b>II cocrystals (orange) compared to form <b>1</b>I crystals (light yellow). The crystal-to-crystal thermal transformation of form <b>1</b>I crystals to form <b>1</b>II crystals of <b>1</b> suggests the role of π-stacking assemblies in driving the self-assembly

Additive Mediated <i>Syn-Anti</i> Conformational Tuning at Nucleation to Capture Elusive Polymorphs: Remarkable Role of Extended π‑Stacking Interactions in Driving the Self-Assembly

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 <b>1</b> and <b>2</b> and sulfoesters <b>3</b> and <b>4</b>. 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 <b>1 </b>(form <b>1</b>II, form <b>1</b>III, and form <b>1</b>IV) and one each for <b>2</b> (form <b>2</b>II), <b>3 </b>(form <b>3</b>II), and <b>4 (</b>form <b>4</b>II)]. 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 <b>1</b> (form <b>1</b>II, form <b>1</b>III, and form <b>1</b>IV) to its thermodynamically stable crystal form (form <b>1</b>I). Conformational analysis of molecule <b>1</b> using density functional theory calculations also validated higher stability for <i>syn</i> conformation (observed in Form <b>1</b>I crystals) over <i>anti</i> and <i>midway</i> conformations (seen in metastable polymorphs). Melt crystallization of form <b>1</b>I crystals of <b>1</b> on the larger face (001) of <i>δ-</i>pyrazinamide and lattice matching analysis (GRACE) revealed that the layered arrangement of molecules of <i>δ-</i>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