We describe a nonporous organic crystal that exhibits a single-crystal-to-single-crystal (SCSC) desolvation. The crystal is based on a boron host that contains an azopyridyl linker. The molecules in the single crystal exhibit novel rotisserie-like movement upon guest release (i.e. benzene) that involves (i) rotation and (ii) stretching of the azopyridyl axle, and (iii) tilting of a boronic ester wheel. A crystalline intermediate isolated supports the rotisserie-style movement of the host.

Chlorthalidone (CTD), a BCS class IV antihypertensive racemic drug, presents poor aqueous solubility and low absorption in the gastrointestinal tract, limiting its oral bioavailability. A novel 1:2 cocrystal of CTD with the coformer isonicotinamide (INA), having improved dissolution properties, was obtained and comprehensively characterized. The cocrystal structure was elucidated via single-crystal X-ray diffraction (SCXRD) and further examined by Hirshfeld surface analysis, revealing a unique supramolecular architecture sustained by a network of heterosynthons, distinct from all known solid forms of CTD. Complementary solid-state characterization was performed using powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The cocrystal presented solid-state stability under accelerated stress conditions. Dissolution studies under nonsink conditions revealed a sustained pH-independent 2-fold increase in drug concentration compared to CTD Form I. The enhancement is originated by a cocrystal dissolution-supersaturation-precipitation (DSP) process toward the more soluble CTD Form II. As a result of spontaneous chiral resolution, CTD-INA features as a common element with CTD Form II, the presence of a physical mixture of crystals containing the R and S enantiomers. CTD-INA is a rare example of a conglomerate cocrystal. The phase transformation of the cocrystal in solution to CTD Form II is attributed to a fast DSP occurring at the particle surface that releases the coformer and originates the conglomerate form of CTD. The results reveal that cocrystals can constitute a pathway for generating a metastable API polymorphic form, thereby providing access to a solid form with a significant and sustained dissolution advantage.

Separation of mixtures containing low-molecular-weight hydrocarbons using sustainable and less energy-intensive processes is one of the grand challenges facing the chemical sciences. In this work, we report the peculiar ability of molecular crystals containing boron-based receptors A1 assembled through dative B←N bonds between 2-(naphthalen-1-yl)naphtho[2,3-d][1,2,3]dioxaborolane and 3,6-di(pyridin-4-yl)-1,2,4,5-tetrazine (BiPyTz), to readily capture and separate small molecules of great industrial interest like benzene (Bz) and cyclohexane (Cy) via the formation of stoichiometric solvates A1·2Cy and A1·2Bz with high conversions. Sorption in mixtures Bz/Cy 1:1 (v/v) showed high selectivity (≥99%) for Bz over Cy in liquid-solid experiments and up to 96% in vapor-solid tests. The dynamics of the vapor-solid sorption process revealed a transient formation of A1·2Cy that gradually converts to the more stable A1·2Bz. Recyclability of the sorbent materials was accomplished without heating through the reversible transformation of A1·2Bz toward the unsolvated form of A1 or A1·MeCN. Receptor A1 is prone to crystallize with MeCN in various stoichiometric ratios with noncentrosymmetric conformations displaying syn orientation of the naphthylboronic fragments, whereas crystals of A1 containing Bz or Cy exhibited a more stable conformation with antiparallel disposition of the aromatic substituents and crystallographic inversion symmetry. Computational studies of adduct-adduct and solvent-adduct interaction energies in the crystals of A1·MeCN, A1·2MeCN, and A1·2Bz confirmed a favorable solid phase transformation toward the Bz solvate due to two factors: (i) the conformational adaptability of receptor A1 to optimize adduct-adduct aromatic interactions, accounting for the major contribution to the crystal stability, and (ii) a larger attachment energy of Bz over MeCN. Overall, our studies demonstrate the potential of receptor-based molecular crystalline materials containing flexible and adaptive acyclic B←N adducts to effectively separate a very challenging hydrocarbon solvent system under gentle conditions and with recycling capabilities.

The presence of refractory aromatic sulfur compounds in fossil fuels needs to be eliminated or reduced to minimize the emissions of sulfur oxides that cause serious environmental and health problems. In this work, we investigated the ability of three crystalline adducts A1, A2, and A3, constituted of phenyl, 1-naphthyl, or 2-naphthyl boronic esters linked to 3,6-di(pyridin-4-yl)-1,2,4,5-tetrazine (BiPyTz) through dative B <- N bonds, to generate cocrystals with refractory aromatic sulfur compounds such as dibenzothiophene (DBT), 4-methyldibenzothiophene (4MDBT), and 4,6-dimethyldibenzothiophene (46DMDBT). Only compound A2 crystallized into the corresponding (1:1) cocrystal with 4MDBT and 46DMDBT (i.e., A2 & centerdot;4MDBT and A2 & centerdot;46DMDBT). Furthermore, crystalline A2 effectively removed 46DMDBT in batch sorption experiments with a single-component solution in isooctane, where quantitative conversion of A2 to A2 & centerdot;46DMDBT occurs within 2 h at 25 degrees C. In a three-component model fuel solution, uptake was particularly successful for the bulkier derivative 46DMDBT, and the efficiency followed the trend 46DMDBT > 4MDBT >> DBT. The X-ray crystal structure of A2 & centerdot;46DMDBT exhibits a binding pocket assembled with four neighboring adducts, anchoring the guest molecule by using multiple noncovalent interactions with BiPyTz (C-pi & centerdot;& centerdot;& centerdot;C-pi, S & centerdot;& centerdot;& centerdot;N, N & centerdot;& centerdot;& centerdot;C-pi), and with the aromatic moieties of the boronic ester (C-H & centerdot;& centerdot;& centerdot;C-pi and C-H & centerdot;& centerdot;& centerdot;O). Computational analysis of model A2-guest complexes showed bond critical points (AIM) for these reciprocal donor-acceptor aromatic interactions, and computation of the energies confirmed the greater stability of the complex A2-46DMDBT. Thus, the superior molecular recognition ability of the receptor-based crystal A2 is sustained using electron-deficient BiPyTz to incite significant donor-acceptor interactions with the electron-rich guest, accompanied by the adaptive behavior of the B <- N receptor leading to subtle conformational changes to engage the 1-naphthyl moiety in the assembly of the binding pocket to effectively remove methylated refractory sulfur compounds from fuels under friendly conditions.

Ciprofloxacin is a potent antibiotic used for the treatment of bacterial infections located mainly in the urinary and pulmonary tracts. In this work, we report the formation of ionic cocrystals of ciprofloxacin hydrochloride (CiHCl) in combination with phenolic acid derivatives like 2,3-dihydroxybenzoic acid (23DBA), 2,4-dihydroxybenzoic acid (24DBA), 2,5-dihydroxybenzoic acid (25DBA), 3,4-dihydroxybenzoic acid (34DBA), 3,5-dihydroxybenzoic acid (35DBA), and gallic acid (GAL). This series of phenolic acids was selected to systematically explore the impact on the biopharmaceutical properties of CiHCl originating from the formation of ionic cocrystals with species containing phenolic groups in different numbers and symmetry. The solids were obtained by solution-based crystallization (viz., slurry, reaction crystallization, solvent evaporation) and mechanochemical methods (LAG), and they were fully characterized by PXRD, TG, DSC, IR, NMR, and elemental analysis. Single-crystal X-ray diffraction studies were performed for anhydrous CiHCl and CiHCl23DBA. Structural comparison by Hirshfeld surface and fingerprint analysis of the anhydrous and hydrated forms (CiHCl and CiHClH2O) with the ionic cocrystals (CiHCl4HBA, CiHCl23DBA, and CiHCl35DBAH2O) revealed that changes in the hydrogen bonding and pi-pi interactions play a fundamental role in the supramolecular organization in the solid state and the successful establishment of cocrystals. In the anhydrous salt, the chloride ion coordination environment is determined by two [N-H]+Cl- and C-HCl- hydrogen bonds. In CiHClH2O, CiHCl4HBA, CiHCl23DBA, and CiHCl35DBAH2O, these interactions are partially or entirely replaced by [N-H]+O, O-HCl- and O-HO hydrogen bonds with water and coformer molecules, respectively, mostly at the expense of C-HCl- interactions. The presence of two available hydrogen bonding donors in the phenolic acids is essential in the formation of cocrystals, and therefore, coformers compromised in intramolecular O-HO hydrogen bonds, such as 2HBA and 26DBA, were not successful. In most cases, dissolution rates and solubilities of the cocrystals were lower than for CiHClH2O, covering overall a range of an order of magnitude. The trend found for these parameters correlates with the solubility of the coformers. The cocrystal with the most soluble coformer (35DBA) showed phase transformation, the highest dissolution rate constant, and its solubilization surpasses that of the reference salt (CiHClH2O), demonstrating the utility of cocrystallization for generating a portfolio of ionic cocrystals with tailored properties.

The natural anthraquinone Damnacanthal ( 1 ) was isolated from the roots of Morinda panamensis and used as a building block in the construction of five fluorescent boronate derivatives ( 4a -4e ). The novel compounds were obtained in moderate yields by the condensation of 1 , anthranilic acid ( 2 ) and diverse phenylboronic acids ( 3a -3e ) in acetonitrile. Boronate derivatives were fully characterized by 1 H, 13 C, 11 B and 2D nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV-vis), and high-resolution mass spectrometry (HR-MS). The photo -physical properties were evaluated in tetrahydrofuran revealing that the optical band gap (Egopt) values increase from 2.54 eV for 4a to 2.65 eV for 4d . The maximum emission wavelength and fluorescence quantum yield ( OF ) of the boron complexes were found to be sensitive to the substituents on the phenyl group attached to the boron atom. The resulting derivatives 4a -4c presented emission bands at approx-imately 522 nm ( OF = 0.41, 0.13 and 0.37%, respectively); while derivatives 4d and 4e presented broad emission bands with maxima at 676 nm ( OF = 6.27%) and 614 nm ( OF = 0.78%), respectively. The molec-ular geometry, electronic properties and intramolecular non-covalent interactions of the new molecules were evaluated using density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) methods. The value of the energy gap between the HOMO and LUMO increases from 2.89 eV for 4b , 2.96 eV for 4c , 3.04 eV for 4e , 3.08 eV for 4a to 3.32 eV for 4d . Furthermore, compound 4d showed a higher rotational energy barrier (3.33 kcal/mol) at the dihedral angle N1/B1/C24/C25 than its analogs, due to the F center dot center dot center dot zr and F center dot center dot center dot O interactions.(c) 2022 Elsevier B.V. All rights reserved.

The self‐assembly of 1,3‐diaminopropane (DAP), 2‐formylphenylboronic acid (FPBA) and 2,3,6,7,10,11‐hexahydroxytriphenylene (HHTP) into a trigonal‐prismatic molecular cage through reversible iminoboronate ester motifs is reported. The organic cage generates solvates with acetonitrile and nitrobenzene, exhibiting vapochromic behavior. Single‐crystal X‐ray diffraction analysis evidenced the inclusion of nitrobenzene within the cage cavity. The resulting host‐guest complex is stabilized by donor‐acceptor‐donor interactions between the nitrobenzene guest and the π electron‐rich HHTP units of the cage.

Two novel cocrystals of the pharmaceutically active enantiomer R-Praziquantel (R-PZQ) were formed with glutaric acid (R-PZQ/GA) and succinic acid (R-PZQ/SA) in a 1:1 stoichiometric ratio by liquid-assisted mechanical grinding. The characterization of the cocrystals by structural and physicochemical methods revealed properties distinct from the cocrystal analogues with racemic PZQ, i.e., RS-PZQ/GA and RS-PZQ/SA, reported previously in the literature. However, all four cocrystals exhibit improved intrinsic dissolution rates in a medium simulating the physiological conditions of the gastric fluid (pH 1.2) compared to the solid phases of the pristine drug (R-PZQ.0.5H2O and RS-PZQ). Nonsink powder dissolution tests showed that the cocrystals with R- and RS-PZQ can generate transient supersaturated solutions with solubility advantages of 1.3-to 2.2-fold compared to the pristine drugs. In the presence of predissolved hydrophobic polymers such as MC60HG and HPC 80,000, the supersaturation state is prolonged for 20-30 min providing solubility advantages of up to 2.7-fold and an even larger advantage compared to the pristine forms of Praziquantel.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

A cocrystal of the antihypertensive drug chlorthalidone (CTD) with caffeine (CAF) was obtained (CTD-CAF) by the slurry method, for which a 2:1 stoichiometric ratio was found by powder and single-crystal X-ray diffraction analysis. Cocrystal CTD-CAF showed a supramolecular organization in which CAF molecules are embedded in channels of a 3D network of CTD molecules. The advantage of the cocrystal in comparison to CTD is reflected in a threefold solubility increase and in the dose/solubility ratios, which diminished from near-unit values for D0D to 0.29 for D0CC. Furthermore, dissolution experiments under non-sink conditions showed improved performance of CTD-CAF compared with pure CTD. Subsequent studies showed that CTD-CAF cocrystals transform to CTD form I where CTD precipitation inhibition could be achieved in the presence of pre-dissolved polymer HPMC 80–120 cPs, maintaining supersaturation drug concentrations for at least 180 min. Finally, dissolution experiments under sink conditions unveiled that the CTD-CAF cocrystal induced, in pH-independent manner, faster and more complete CTD dissolution when compared to commercial tablets of CTD. Due to the stability and dissolution behavior of the novel CTD-CAF cocrystal, it could be used to develop solid dosage forms using a lower CTD dose to obtain the same therapeutic response and fewer adverse effects.

Nanoconfinement is a recent strategy to enhance solubility and dissolution of active pharmaceutical ingredients (APIs) with poor biopharmaceutical properties. In this work, we combine the advantage of cocrystals of racemic praziquantel (PZQ) containing a water-soluble coformer (i.e., increased solubility and supersaturation) and its confinement in a mesoporous silica material (i.e., increased dissolution rate). Among various potential cocrystalline phases of PZQ with dicarboxylic acid coformers, the cocrystal with glutaric acid (PZQ-GLU) was selected and successfully loaded by the melting method into nanopores of SBA-15 (experimental pore size of 5.6 nm) as suggested by physical and spectroscopic characterization using various complementary techniques like N2 adsorption, powder X-ray diffraction (PXRD), infrared spectroscopy (IR), solid-state NMR (ss-NMR), differential scanning calorimetry (DSC), and field emission-scanning electron microscopy (FE-SEM) analysis. The PZQ-GLU phase confined in SBA-15 presents more mobility according to ss-NMR studies but still retains its cocrystal-like features in the IR spectra, and it also shows depression of the melting transition temperature in DSC. On the contrary, pristine PZQ loaded into SBA-15 was found only in the amorphous state, according to the aforementioned studies. This dissimilar behavior of the composites was attributed to the larger crystal lattice of PZQ over the PZQ-GLU cocrystal (3320.1 vs 1167.9 Å3) and to stronger intermolecular interactions between PZQ and GLU, facilitating the confinement of a more mobile solid-like phase in the constrained channels. Powder dissolution studies under extremely nonsink conditions (SI = 0.014) of the confined PZQ-GLU and amorphous PZQ phases embedded in mesoporous silica showed transient supersaturation behavior when dissolving in simulated gastric fluid (HCl pH 1.2 at 37 ± 0.5 °C) in a similar fashion to the bare cocrystal PZQ-GLU. A comparison of the area under the curve (AUC0-90 min) of the dissolution profiles afforded a dissolution advantage of 2-fold (p < 0.05) of the new solid phases over pristine racemic PZQ after 90 min; under these conditions, the solubilized API reprecipitated as the recently discovered PZQ hemihydrate (PZQ-HH). In the presence of a cellulosic polymer, sustained solubilization of PZQ from composites SBA-15/PZQ or SBA-15/PZQ-GLU was observed, increasing AUC0-90 min up to 5.1-fold in comparison to pristine PZQ. The combination of a confined solid phase in mesoporous silica and a methylcellulose polymer in the dissolution medium effectively maintained the drug solubilized during times significant to promote absorption. Finally, powder dissolution studies under intermediate nonsink conditions (SI = 1.99) showed a fast release profile from the nanoconfined PZQ-GLU phase in SBA-15, which reached rapid saturation (95% drug dissolved at 30 min); the amorphous PZQ composite and bare PZQ-GLU also displayed an immediate release of the API but at a lower rate (69% drug dissolved at 30 min). In all of these cases, a large dissolution advantage was observed from any of the novel solid phases over PZQ.

Refractory aromatic sulfur compounds present in gasoline, diesel, and jet fuels cause serious environmental problems and must be removed to minimize the emissions of SOx, according to environmental regulations worldwide. Herein, we present a novel approach for the removal of organosulfur compounds from model liquid fuel solutions employing a nonporous host crystalline material (A1) that undergoes transformation into cocrystals with aromatic sulfur compounds like benzothiophene (BT) and dibenzothiophene (DBT) (i.e., A1 superset of BT and A1 superset of DBT). In experiments using a single component in cydohexane solutions, crystalline A1 reached a quantitative uptake of DBT after 12 h at 25 degrees C with equimolar or slightly increased molar ratios of DBT over A1 (e.g., 1.45 +/- 0.05 mmol of S/g of A1, which is equivalent to 267.3 +/- 9.3 mg of DBT/g of A1 at C-0 = 3000 ppmwS). The crystalline material A1 can be recycled from cocrystal A1 superset of DBT by a two-step process: (i) the generation of the solid A1 Dtoluene upon extraction of DBT in toluene and (u) the subsequent thermal treatment at 150 degrees C for desolvation to recover microcrystalline A1; after four recycling processes, the uptake capacity of A1 is maintained at 97.5%. In competitive experiments using a fivecomponent equimolar cydohexane solution containing BT, DBT, 4,6-dimethyldibenzothiophene (DMDBT), fluorene (FLUO), and naphthalene (NAPH), the uptake efficiency of A1 after 12 h at 25 degrees C followed the trend: DBT > FLUO > NAPH > BT > DMDBT. The selective uptake of DBT in these model fuel solutions is explained by matching of the pi-electron rich guest with pi-electron deficient diamine linkers and concomitant CH-pi interactions within the enclosed cavities of the double-tweezer B <- N host A1, as exhibited in the X-ray crystal structure. Size fitting is important for guest selectivity because attempts to isolate cocrystals with DMDBT were unsuccessful. Crystal-to-cocrystal is a solution mediated phase transformation that competes favorably in the removal of DBT with several examples of high-surface nano/microporous materials and composites used in batch adsorption experiments, and A1 can be recycled without compromising efficiency. Thus, crystal-to-cocrystal transformation emerges as a remarkable methodology for the quantitative removal of aromatic organosulfur compounds from liquid fuels because it can be extended to many other aromatic fuel contaminants by using the appropriate host molecule to coctystallize with it.

The thermodynamic stability of 1 : 1 and 2 : 1 boron-nitrogen (B←N) adducts formed between aromatic boronic esters with mono- and diamines was studied in solution by NMR and UV-vis spectroscopy with association energies (ΔG°) ranging from -11 to -28 kJ mol-1 . The effect of different substituents in the boronic ester, the nature of the diamine linker, and the effect of the solvent was explored. Stable 2 : 1 B←N adducts with diamines such as 1,3-diaminopropane were produced in solutions of hydrogen-bonding acceptor solvents (acetonitrile and ethyl acetate), which can be isolated in the solid state as crystalline solvates, whereas the use of noncoordinating solvents such as 1,2-dichloroethane afforded mainly 1 : 1 B←N adducts. In suitable combinations, aromatic bis-pyridyl diamines produced stable 2 : 1 B←N adducts that were isolated either as solvent-free solids, solvates, or cocrystals. In these crystalline forms, double-tweezer hosts were observed with an exceptional syn/anti conformational guest-adaptability driven by simultaneous donor-acceptor and C-H⋅⋅⋅π interactions in the tweezer cavities, resembling preorganized covalent tweezer hosts. Interestingly, cocrystals with electron-rich guests such as tetrathiafulvalene and pyrene showed non-centrosymmetric crystal lattices with infinite π-stacked donor-acceptor columns.

The Cover Feature shows the self-assembly of arylboronic esters and diamines into 1 : 1 and 2 : 1 boron–nitrogen adducts in solution, and the formation of host–guest complexes with aromatic molecules such as pyrene in the solid state. The rhythm of these processes is dictated by the equilibrium constant K, which determines the proportion of each species in solution. A glimpse of these events in solution was made possible by NMR and UV/Vis spectroscopic studies and the final pictures were taken from single crystal X-ray diffraction analysis. More details can be found in the full paper by H. Höpfl, H. Morales-Rojas, and co-workers on page 548 in Issue 3, 2020 (10.1002/cplu.201900717).

We report on B←N coordination to support a single-crystal-to-single-crystal reaction in the solid state. A [2 + 2] photodimerization is achieved with face-to-face π-stacks of monotopic B←N adducts composed of a phenylboronic acid catechol ester and an alkene with a terminal thiophene group. The photoreaction generates a ditopic B-adduct involving a head-to-tail cyclobutane regio- and stereoselectively. The photodimerization is accompanied by an increase in the tetrahedral character of the B atom. The resulting boron enables channel confinement of chloroform upon recrystallization.

The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others.

Cocrystallization of a nonconductive, boron-based host with aromatic guests generates conductive cocrystals. Carrier mobilities of the cocrystals with either pyrene or tetrathiafulvalene were measured using conducting probe atomic force microscopy. The incorporation of the pi-electron-rich aromatic guests results in electrically conductive cocrystals. The cocrystal with tetrathiafulvalene as a guest shows an approximately seven times higher charge carrier mobility than the cocrystal with pyrene.

B←N coordination supports a [2+2] photodimerization in the solid state. The bond is defined by an orthogonal interaction between stilbazole and a phenylboronic ester to enable a stereocontrolled and rapid photoreaction. The cyclobutane photoproduct affords a novel diboron bis-tweezer adduct that is used to separate a mixture of benzene and thiophene upon crystallization.