The objective of this study was to screen and prepare cocrystals of the poorly soluble drug nitrofurantoin (NTF) with the aim of increasing its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. Manual LAG and reaction crystallization (RC) experiments were carried out to confirm and scale-up the hits. Seven hits were confirmed to be cocrystals. The cocrystals were characterized by PXRD, Raman and IR spectroscopy, thermal analysis (DSC and TGA) and liquid-state NMR or elemental analysis. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1:1 stoichiometric ratio with urea (1), 4-hydroxybenzoic acid (2), nicotinamide (3), citric acid (4), l-proline (5) and vanillic acid (6). In addition, NTF forms a 1:2 cocrystal with vanillin (7). All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming cocrystals have a higher solubility than the NTF hydrate under these conditions. The crystal structures of 1:1 NTF-citric acid (4) and 1:2 NTF-vanillin (7) were solved by single-crystal X-ray diffraction. The crystal structures of these two cocrystals were analyzed in terms of their supramolecular synthons.

The aim of this work was to study the crystal structures of 1:1 and 2:1 urea-succinic acid (U-SA) cocrystals and to investigate the role of solution chemistry in the formation and stability of different stoichiometric cocrystals. The structural diversity of other urea-dicarboxylic acid cocrystals is also discussed. The 1:1 U-SA cocrystal was stabilized by an acid-amide heterosynthon while acid-amide heterosynthons and amide-amide homosynthons stabilized the 2:1 cocrystals. The hydrogen bonding motifs in 1:1 and 2:1 U-SA cocrystals were consistent with other urea-dicarboxylic acid systems with similar stoichiometries. The 1:1 cocrystals were transformed to 2:1 cocrystals upon slurrying in various solvents at 25 °C. The phase solubility diagram was used to define the stability regions of different solid phases in 2-propanol at 25 °C. While no phase stability region for 1:1 cocrystal could be found, the stable regions for the 2:1 cocrystals and their pure components were defined by eutectic points. The solubility of the 2:1 cocrystals was dependent on the concentration of the ligand in the solution and explained by the solubility product and 1:1 solution complexation. The mathematical models predicting the solubility of the 2:1 cocrystals were evaluated and found to fit the experimental data

Hydrogen bond competition was studied in 21 X-ray crystal structures of N-X-phenyl-N′-p-nitrophenyl urea compounds (X = H, F, Cl, Br, I, CN, C≡CH, CONH2, COCH3, OH, Me). These structures are classified into two families depending on the hydrogen bond pattern: urea tape structures contain the well-known α-network assembled via N-HO hydrogen bonds; however, in nonurea tape structures the N-H donors hydrogen bond with NO2 groups or solvent O acceptor atoms. Surprisingly, the urea CO hardly accepts strong H bonds in nonurea type structures sustained by ureanitro and ureasolvent synthons. The carbonyl group accepts intra- and intermolecular C-HO interactions. The molecular conformation and H bonding motifs are different in the two categories of structures: the phenyl rings are twisted out of the urea plane in the tape motif, but they are coplanar in the nonurea category. Even though hydrogen bond synthon energy and urea carbonyl acceptor strength favor the N-HO tape structure, the dominant pattern in electron-withdrawing aryl urea crystal structures is the ureanitro/ureasolvent synthon and persistence of intramolecular C-HO interactions. Remarkably, the presence of functional groups that can promote specific C-IO or C-HO interactions with the interfering NO2 group, for example, when X = I, C≡CH, NMe2, and Me, steers crystallization toward the N-HO urea tape structure, and now the diaryl urea molecule adopts the metastable, twisted conformation. Molecular conformer energy calculations and difference nuclear Overhauser enhancement NMR experiments show that the planar, trans-trans-N,N′-diphenyl urea conformation is more stable than the N-Ph twisted rotamer. However, the urea CO is a better hydrogen bond acceptor in the twisted conformer compared to the planar one, based on electrostatic surface potential (ESP) charges. These diaryl ureas together with previously reported crystal structures provide a global structural model to understand how functional groups, molecular conformation, hydrogen bonding, and crystal packing are closely related and influence each other in subtle yet definitive ways. Our strategy simultaneously exploits weak, soft intermolecular interactions and strong, hard hydrogen bonds [supramolecular hard and soft acid-base (HSAB) principle] in the crystal engineering of multifunctional molecules.

The title compound, [Zn(C44H28N4)(C7H7NO)], is a square-pyramidal five-coordinate zinc-porphyrin complex with γ-acetyl­pyridine as the apical ligand. The inter­molecular packing involves van der Waals forces, close π-π stacking and C-Hπ contacts, revealing an inter­esting pairing of adjacent mol­ecules related by inversion.

Self-assembly of functionalized tetraarylporphyrins into 2-D and 3-D supramolecular arrays may exhibit structural isomerism when carried out in different experimental conditions. This study shows that the open 2-D hydrogen bonding quadrangular grid networks of free-base tetra(4-carboxyphenyl)porphyrin (TCPP) form an interweaved crystalline architecture, in addition to the non-interweaved offset-stacked porous arrangement observed before. In the two structures the individual arrays are similarly stabilized by multiple cyclic-dimeric (COOH)2 hydrogen bonding synthons, differing slightly in the grid shape. The Mn-metalled TCPP building blocks afford in a lipophilic environment 2-D coordination polymers by direct Mn-OOC/HOOC association between the tetra-acid metalloporphyrin units, without incorporation of any external bridging auxiliaries. This polymerization is further enforced by interporphyrin O-HO hydrogen bonding within and between the 2-D arrays, yielding a solvent-free 3-D architecture. The latter is related to an isomeric crystalline organization of similar layered Mn-TCPP coordination polymers obtained earlier from hydrophilic crystallization mixtures, wherein intercalated solvent separates the layered polymeric arrays. The non-acidic Mn(Cl)-TOHPP compound yields a chiral 3-D assembly sustained by multiple inter-porphyrin hydrogen bonding. Its formation is promoted by the non-centrosymmetric (axially polarized) shape of this porphyrin unit, as well as by the directional hydrogen bonding interactions, and it involves coordination of an additional axial ligand to the manganese ion. Effects of competing solvation, which interfere with the supramolecular aggregation of the TCPP scaffolds into network arrays, are demonstrated also by structures obtained from solvent mixtures containing dimethylsulfoxide.

Self-assembly of functionalized tetraarylporphyrins into 2-D and 3-D supramolecular arrays may exhibit structural isomerism when carried out in different experimental conditions. This study shows that the open 2-D hydrogen bonding quadrangular grid networks of free-base tetra(4-carboxyphenyl)porphyrin (TCPP) form an interweaved crystalline architecture, in addition to the non-interweaved offset-stacked porous arrangement observed before. In the two structures the individual arrays are similarly stabilized by multiple cyclic-dimeric (COOH)2 hydrogen bonding synthons, differing slightly in the grid shape. The Mn-metalled TCPP building blocks afford in a lipophilic environment 2-D coordination polymers by direct Mn-OOC/HOOC association between the tetra-acid metalloporphyrin units, without incorporation of any external bridging auxiliaries. This polymerization is further enforced by interporphyrin O-HO hydrogen bonding within and between the 2-D arrays, yielding a solvent-free 3-D architecture. The latter is related to an isomeric crystalline organization of similar layered Mn-TCPP coordination polymers obtained earlier from hydrophilic crystallization mixtures, wherein intercalated solvent separates the layered polymeric arrays. The non-acidic Mn(Cl)-TOHPP compound yields a chiral 3-D assembly sustained by multiple inter-porphyrin hydrogen bonding. Its formation is promoted by the non-centrosymmetric (axially polarized) shape of this porphyrin unit, as well as by the directional hydrogen bonding interactions, and it involves coordination of an additional axial ligand to the manganese ion. Effects of competing solvation, which interfere with the supramolecular aggregation of the TCPP scaffolds into network arrays, are demonstrated also by structures obtained from solvent mixtures containing dimethylsulfoxide.

Reactions of free-base tetra(4-carboxyphenyl)porphyrin with lanthanide ions as Pr3+, Dy3+, and Nd3+ led to open metal-organic framework solids sustained by polynuclear metal-carboxylate clusters. Their three-dimensional structures are characterized by channel voids accessible to other guest components (e.g., water, small organics). Crystalline solids obtained by the hydrothermal synthesis with Dy3+ and Nd3+ reagents reveal remarkable stability and represent the first example of hybrid porphyrin-lanthanide single framework architectures.

This study relates to the self-assembly of the free-base 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP), six-coordinate manganese-5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin with molecules of water or methanol as axial ligands [MnIII(H2O)2-TCPP or MnIII(CH3OH)2-TCPP, respectively], and manganese chloride-5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin [MnIII(Cl)-TOHPP] into multiporphyrin hydrogen-bonding "polymers". In the first case, the porphyrin units hydrogen bond directly to each other through their carboxylic acid functions. The two-dimensional (2D) square-grid polymeric arrays thus formed are sustained by characteristic intermolecular cyclic dimeric (COOH)2 hydrogen-bond synthons between a given porphyrin unit and four other neighboring species along the equatorial directions. They stack tightly one on top of the other in an offset manner along the normal direction, yielding channeled lattice architecture. In an aqueous basic environment insertion of MnIII into the porphyrin core involves deprotonation of one of the carboxylic groups, to balance the charge, and attraction of two water molecules as axial ligands. The MnIII(H2O)2-TCPP units hydrogen bond, however, directly to one another through their carboxylic/carboxylate functions in the equatorial plane in a catemeric (rather than cyclic dimeric) manner. The 2D networks that form in this case are interconnected in the normal direction by additional hydrogen bonds through the axial water ligands, yielding a three-dimensional (3D) hydrogen-bonding architecture. In a methanolic solution of H3PO4, the methanol molecules replace water as axial ligands to the metal ion. The phosphate anions balance the extra positive charge of the trivalent metal, and they act also as effective bridges between adjacent MnIII(CH3OH)2-TCPP moieties by interacting as proton acceptors with the peripheral carboxylic functions of four different porphyrins. This affords open square-grid-type layers with alternating porphyrin and phosphate components. The 2D arrays stack in an offset manner, interconnecting to one another through hydrogen bonds involving the methanol axial ligands. The Mn(Cl)-TOHPP building blocks arrange in a unique tetragonal structure around axes of 4-fold rotation and self-assemble through multiple O-HCl- attractions between neighboring units into a single-framework hydrogen-bonding polymer. The directional asymmetry introduced to them by the Cl-axial ligand, which is amplified by the preferred hydrogen-bonding scheme, induces the formation of a noncentrosymmetric crystal structure. The nanoporous nature of TCPP-based multiporphyrin assemblies and the chirality of the Mn(Cl)-TOHPP structure are highlighted.