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In situ monitoring of mechanochemical reactions between dicyandiamide (DCD) and CuX2 salts (X = Cl-, NO3-), for the preparation of compounds of agrochemical interest, showed the appearance of a number of phases. It is demonstrated that milling conditions, such as the amount of water added in wet grinding and/or the milling frequency, may affect the course of the mechanochemical reactions, and drive the reaction towards the formation of different products. It has been possible to discover by in situ monitored experiments two novel crystalline forms, namely the neutral complexes [Cu(DCD)(2)(OH2)(2)(NO3)(2)] (2) and [Cu(DCD)(2)(OH2)Cl-2]center dot H2O (4), in addition to the previously known molecular salt [Cu(DCD)(2)(OH2)(2)] [NO3](2)center dot 2H(2)O (1, DIVWAG) and neutral complex [Cu(DCD)(2)(OH2)Cl-2] (3, AQCYCU), for which no synthesis conditions were available. Compounds 2 and 4 were fully characterized via a combination of solid-state techniques, including X-ray diffraction, Raman spectroscopy and TGA.

Here, we exploit our mechanochemical synthesis for co-crystallization of an organic antiseptic, proflavine, with metal-based antimicrobials (silver, copper, zinc, and gallium). Our previous studies have looked for general antimicrobial activity for the co-crystals: proflavine center dot AgNO3, proflavine center dot CuCl, ZnCl3[Proflavinium], [Proflavinium](2)[ZnCl4]center dot H2O, and [Proflavinium](3)[Ga(oxalate)(3)]center dot 4H(2)O. Here, we explore and compare more precisely the bacteriostatic (minimal inhibitory concentrations) and antibiofilm (prevention of cell attachment and propagation) activities of the co-crystals. For this, we choose three prominent "ESKAPE" bacterial pathogens of Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus. The antimicrobial behavior of the co-crystals was compared to that of the separate components of the polycrystalline samples to ascertain whether the proflavine-metal complex association in the solid state provided effective antimicrobial performance. We were particularly interested to see if the co-crystals were effective in preventing bacteria from initiating and propagating the biofilm mode of growth, as this growth form provides high antimicrobial resistance properties. We found that for the planktonic lifestyle of growth of the three bacterial strains, different co-crystal formulations gave selectivity for best performance. For the biofilm state of growth, we see that the silver proflavine co-crystal has the best overall antibiofilm activity against all three organisms. However, other proflavine-metal co-crystals also show practical antimicrobial efficacy against E. coli and S. aureus. While not all proflavine-metal co-crystals demonstrated enhanced antimicrobial efficacy over their constituents alone, all possessed acceptable antimicrobial properties while trapped in the co-crystal form. We also demonstrate that the metal-proflavine crystals retain antimicrobial activity in storage. This work defines that co-crystallization of metal compounds and organic antimicrobials has a potential role in the quest for antimicrobials/antiseptics in the defense against bacteria in our antimicrobial resistance era.

Mechanochemical mixing of cyanuric acid and alkali halides, which show extreme differences in solubility, is a viable, solvent-free method to quantitatively prepare ionic cocrystals (ICCs) of cyanuric acid (CA) with halide salts of alkali metals. In this paper, we report the preparation and structural characterization of a series of new compounds, namely, CA2·MCl (M= Rb, Cs), CA·MBr (M= Na, K, Rb, Cs), and CA·RbI, and of the two hydrates CA·NaBr·2H2O and CA·KI·H2O. Crystal structures were determined directly from X-ray powder diffraction data in all cases with the exception of CA·KI·H2O, for which single crystals were obtained. The effect of cation size on the stoichiometry as well as on the architecture of the ICCs has been discussed.

We report on the mechanochemical synthesis of inclusion complexes obtained by reacting the neutral crystalline herbicide bentazon (HBtz) with native cyclodextrins (CDs). The reaction of HBtz with γ-CD resulted in the formation of the inclusion complexes [β-CD·HBtz]·6H2O and [γ-CD·HBtz]·8H2O, which were characterized via a combination of X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy, and calorimetric measurements. No complexation, on the contrary, was achieved upon the reaction of HBtz with α-CD. The salt NaBtz·1.75H2O, widely used as a water-soluble salt of bentazon for the manufacturing of agrochemicals, was also synthesized and structurally characterized, and its solubility and dissolution properties were compared to those of neutral HBtz and of the β-CD and γ-CD inclusion complexes. It was found that the behavior of [β-CD·HBtz]·6H2O and [γ-CD·HBtz]·8H2O in water is similar, with dissolution rates of 28.4 ng·L-1·min-1and 39.8 ng·L-1·min-1, respectively, and is intermediate between those of NaBtz·1.75H2O (228 ng·L-1·min-1) and neutral bentazon (3.5 ng·L-1·min-1). These results were also compared with those of the dehydrated inclusion complexes, which displayed intermediate dissolution rates between hydrous complexes and NaBtz·1.75H2O. All findings indicate that the inclusion of HBtz in β-CD and γ-CD might represent a viable alternative for the preparation of environmentally friendly agrochemicals with controlled bentazon release to be used in the formulation of herbicides.

crystal engineering, cocrystals, chirality The coordination mode to lithium, magnesium, calcium and zinc cations of racemic vs. enantiopure amino acids and racetam APIs is analysed and its effect on chiral selection critically reviewed. It is shown that chiral resolution in the solid state can be obtained via cocrystallization of racemic compounds with an achiral inorganic salt coformer, such as LiX (X=Cl, Br, I) or ZnCl2, which favour tetrahedral coordination in the solid state. The chiral selection may take the form of conglomerate crystal formation or of selective homochiral aggregation in racemic crystals. When cocrystallization involves alkaline earth metal cations, such as Ca2+ and Mg2+, which favour octahedral coordination, heterochiral complexation is observed in most cases, with formation of racemic crystals.

The hydrophobic dl-amino acids alanine, valine, leucine, and isoleucine have been cocrystallized with LiCl via solid-state and solution methods, and the effect of preparation conditions and solvent choice on the racemic versus conglomerate formation has been investigated. For the sake of comparison, enantiopure l-amino acids have also been reacted with LiCl in the same experimental conditions. With dl-alanine only, a racemic ionic cocrystal of formula dl-alanine·LiCl·H2O is obtained, irrespective of the preparation conditions, while the amino acids dl-valine and dl-leucine undergo spontaneous chiral resolution when MeOH is used in ball milling conditions, yielding monohydrated conglomerates, which at ambient conditions convert over time into the racemic ionic cocrystals dl-Val·LiCl·H2O and dl-Leu·LiCl·1.5H2O; these racemic ionic cocrystals (ICCs) are otherwise obtained in a single step if water is employed instead of MeOH, both in ball milling and solution conditions. dl-Isoleucine behaves differently, and product characterization is complicated by the presence of dl-alloisoleucine (dl-aIle) in the commercial starting material; solution crystallization in the presence of excess LiCl, however, unexpectedly results in the formation of the alloisoleucine conglomerate d-aIle·LiCl·H2O and l-aIle·LiCl·H2O, together with unreacted dl-isoleucine. Solid-state syntheses of the ionic cocrystals proceed in most cases via formation of intermediate metastable polymorphs; phase identification and structural characterization for all ICCs have been conducted via single crystal and/or powder X-ray diffraction.

Ionic cocrystals (ICCs) of racemic RS-oxiracetam and of its active S-enantiomer of pharmaceutical interest with the pharmaceutically acceptable salts calcium and magnesium chloride were synthesized and structurally characterized. The cocrystallization of RS-oxiracetam with MgCl2 resulted in chiral resolution with formation of an S-OXI·MgCl2·5H2O/R-OXI·MgCl2·5H2O conglomerate. Ternary phase diagrams of RS-oxiracetam/inorganic salt/solvent were constructed to determine the overall compositions for which the ICCs are the only stable phases in suspension. In addition, single crystals of S-oxiracetam were grown, and its structure was determined.

Co-crystallization between the polycyclic aromatic hydrocarbons anthracene (A) and 9-methylanthracene (MA) with 1,4-diiodotetrafluorobenzene (I2F4) afforded three novel co-crystals, viz. A·(I2F4)2 and an unexpectedly complex system with two distinct compositions, namely MA·I2F4 and (MA)4·I2F4, which can be mechanochemically interconverted by a change in the stoichiometry of the reactive mixtures. Interestingly, all co-crystals are dual-emissive materials and exhibit different mechanisms of emission. A·(I2F4)2 and MA·I2F4 fluoresce from isolated molecules, whereas the luminescence of (MA)4·I2F4 is dominated by excimer emission. In all cases, phosphorescence at RT (RTP) is observed and interpreted as a direct consequence of the interactions between the iodine atoms of the I2F4 co-former and the π-electron density of the anthracene aromatic rings. Furthermore, [4 + 4] photoactivity within (MA)4·I2F4 was also investigated by means of FTIR/NMR spectroscopy and PXRD. The photophysical and photochemical behaviors of all solids are discussed and rationalized based on their structural features.

This review is aimed to provide to an “educated but non-expert” readership and an overview of the scientific, commercial, and ethical importance of investigating the crystalline forms (polymorphs, hydrates, and co-crystals) of active pharmaceutical ingredients (API). The existence of multiple crystal forms of an API is relevant not only for the selection of the best solid material to carry through the various stages of drug development, including the choice of dosage and of excipients suitable for drug development and marketing, but also in terms of intellectual property protection and/or extension. This is because the physico-chemical properties, such as solubility, dissolution rate, thermal stability, processability, etc., of the solid API may depend, sometimes dramatically, on the crystal form, with important implications on the drug’s ultimate efficacy. This review will recount how the scientific community and the pharmaceutical industry learned from the catastrophic consequences of the appearance of new, more stable, and unsuspected crystal forms. The relevant aspects of hydrates, the most common pharmaceutical solid solvates, and of co-crystals, the association of two or more solid components in the same crystalline materials, will also be discussed. Examples will be provided of how to tackle multiple crystal forms with screening protocols and theoretical approaches, and ultimately how to turn into discovery and innovation the purposed preparation of new crystalline forms of an API.

We report here the preparation and structural characterization of a series of new crystalline materials obtained by mechanochemical mixing of cyanuric acid (CA) and alkali halides (LiI, NaI, and KI) in the presence of molecular iodine, namely, the isomorphous catena-poly[tetra(cyanuric acid)·lithium tetraiodide], n[CA4·LiI4], and catena-poly[tetra(cyanuric acid)·sodium tetraiodide], n[CA4·NaI4], featuring three-dimensional (3D) cationic frameworks able to segregate linear, infinite n[I4-] chains in their squared open channels and the layered solid [CA·KI3]2·I2·2H2O characterized by alternating sheets of (i) hydrated potassium cations and CA molecules and (ii) I3- anions and discrete I2 molecules. The combination of X-ray diffraction (XRD), Raman spectroscopy, and thermal analyses allowed us to elucidate the compound's structural features and to discuss the effect of cation size on the stoichiometry and architecture of the three ionic cocrystals (ICCs).

The environmental sustainability of soil nitrogen fertilization is essential for the primary production of food for an expanding human population. In this framework, the control of soil enzymatic activities that impact the release of N-based compounds either in the atmosphere or in the underground waters is critical. The two enzymes that act as key players in the biogeochemical cycle of nitrogen are urease and ammonia monooxygenase (AMO), respectively, nickel- and copper-dependent enzymes. This article reveals the high efficacy of three molecules of the thiurams family, namely, thiram (tetramethylthiuram disulfide, TMTD), disulfiram (tetraethylthiuram disulfide, TETD), and tetraisopropylthiuram disulfide (TIPTD) as inhibitors of both the activities of jack bean (Canavalia ensiformis) urease (JBU) and Nitrosomonas europaea AMO. The water solubility of these compounds was significantly improved by the preparation of three novel inclusion complexes of beta-cydodextrin with TMTD, TETD, and TIPTD by mechanochemical synthesis, using green technology. The resulting beta-CD.thiuram complexes beta-CD.TMTD, (beta-CD)(2)-TETD, and (beta-CD)(2).TIPTD were all characterized by powder X-ray diffraction, thermogravimetric analysis, and solid-state NMR. A conformational polymorph of TIPTD was also detected and isolated via hot stage microscopy, and structurally characterized by single-crystal X-ray diffraction. Biological tests of enzymatic inhibition performed on JBU and AMO with the beta-CD.thiuram complexes showed the same inhibition efficacy as the isolated molecules, suggesting that the active species is, in all cases, the free thiuram, likely in equilibrium with the adduct in solution. These results have a great potential for improving the nitrogen use efficiency of soil fertilizers for a greener environment.

This Perspective outlines the results obtained at the University of Bologna by applying crystal engineering strategies to develop nature inspired organic-inorganic materials to tackle challenges in the health and environment sectors. It is shown by means of a number of examples that co-crystallization of inorganic salts, such as alkali and transition metal halides, with organic compounds, such as amino acids, urea, thiourea and quaternary ammonium salts, can be successfully used for (i) chiral resolution and conglomerate formation from racemic compounds, (ii) inhibition of soil enzyme activity in order to reduce urea decomposition and environmental pollution, and (iii) preparation of novel agents to tackle antimicrobial resistance. All materials described in this Perspective have been obtained by mechanochemical solvent-free or slurry methods and characterized by solid state techniques. The fundamental idea is that a crystal engineering approach based on the choice of intermolecular interactions (coordination and hydrogen bonds) between organic and inorganic compounds allows obtaining materials with collective properties that are different, and often very much superior to those of the separate components. It is also demonstrated that the success of this strategy depends crucially on cross-disciplinary synergistic exchange with expert scientists in the areas of bioinorganics, microbiology, and chirality application-oriented developments of these novel materials.

Three structurally similar antibiotics of the cephalosporin (CEPH) class, namely, cephalexin (CPX), cephradine (CFD), and cefaclor (CFC), have been co-crystallized with thymol (THY) via different preparation techniques, yielding the hydrated co-crystals CPX·THY·2.5H2O form I and form II, CFD·THY·2.5H2O, and CFC·THY·4H2O. All co-crystals were structurally characterized by single crystal and/or powder X-ray diffraction. In all co-crystals, except in the case of the elusive metastable form I of CPX·THY·2.5H2O, the CEPH molecules interact with thymol only via water bridges; i.e., there is no direct hydrogen bonding between CEPH molecules and THY. Preliminary antimicrobial experiments via measurements of minimal inhibitory concentration (MIC) provide clear-cut evidence that the association with thymol increases the resistance of both Gram-negative and Gram-positive bacteria to the antibiotic with respect to pure CEPH as well as to physical mixtures of CEPH with thymol.

The antimicrobial activity of the novel coordination polymers obtained by co-crystallizing the amino acids arginine or histidine, as both enantiopure L and racemic DL forms, with the salts Cu(NO3)2 and AgNO3 has been investigated to explore the effect of chirality in the cases of enantiopure and racemic forms. The compounds [Cu·AA·(NO3)2]CPs and [Ag·AA·NO3]CPs (AA = L-Arg, DL-Arg, L-His, DL-His) were prepared by mechanochemical, slurry, and solution methods and characterized by X-ray single-crystal and powder diffraction in the cases of the copper coordination polymers, and by powder diffraction and by solid-state NMR spectroscopy in the cases of the silver compounds. The two pairs of coordination polymers, [Cu·L-Arg·(NO3)2·H2O]CP and [Cu·DL-Arg·(NO3)2·H2O]CP, and [Cu·L-Hys·(NO3)2·H2O]CP and [Cu·DL-His·(NO3)2·H2O]CP, have been shown to be isostructural in spite of the different chirality of the amino acid ligands. A similar structural analogy could be established for the silver complexes on the basis of SSNMR. The activity against the bacterial pathogens Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus was assessed by carrying out disk diffusion assays on lysogeny agar media showing that, while there is no significant effect arising from the use of enantiopure or chiral amino acids, the coordination polymers exert an appreciable antimicrobial activity comparable, when not superior, to that of the metal salts alone.

The use of the gallium oxalate complex [Ga(ox)3]3− as a building block in the formation of a drug-drug salt with the antimicrobial agent proflavine (PF) as its proflavinium cation (HPF+), namely [HPF]3[Ga(ox)3]·4H2O, is reported together with the preparation of the potassium salt K3[Ga(ox)3] and the novel dimeric gallium(III) salt K4[Ga2(ox)4(μ-OH)2]·2H2O. All compounds have been characterized by solid state methods, and their performance as antimicrobial agents has been evaluated by disk diffusion assay against the bacteria strains Pseudomonas aeruginosa ATCC27853, Staphylococcus aureus ATCC25923, and Escherichia coli ATCC25922. While the [HPF]3[Ga(ox)3]·4H2O drug-drug salt is effective against all three strains, the gallium oxalate salt K3[Ga(ox)3] showed impressive selectivity towards P. aeruginosa, with little to no antimicrobial activity against the other two organisms. This work presents novel breakthroughs towards Ga based antimicrobial agents.

The polycyclic aromatic hydrocarbon (PAH) triphenylene (TP) has been reacted with halo-pentafluorobenzene (XF5, X = Br, I) and 1,4-dihalo-tetrafluorobenzene (X2F4, X = Br, I) to yield the corresponding cocrystals TP center dot BrF5, TP center dot Br2F4, TP center dot IF5, and TP center dot I2F4 form I. These materials have been synthesized by dissolving TP into an excess of liquid or molten coformer, and single crystals have been grown via seeding chloroform solutions. They have been fully characterized by a combination of techniques including X-ray diffraction, Raman spectroscopy, and luminescence spectroscopy in the solid state. TP center dot I2F4 form I was found to undergo a single-crystal to single-crystal (SCSC) polymorphic phase transition induced by temperature (when cooled down to 100 K) leading to the new form TP center dot I2F4 form II, which is transformed back into the first structure when brought again at RT. This behavior was confirmed also by Raman spectroscopy. Upon cocrystallization and as a result of the external heavy atom effect, all crystalline materials exhibited bright room temperature phosphorescence clearly visible by the naked eye. The latter was almost exclusive for cocrystal TP center dot I2F4, whereas for TP center dot Br2F4 both fluorescence and phosphorescence were detected. In TP center dot Br2F4, the phosphorescence lifetime was on the order of 200 ms, and with the visual outcome of an orange phosphorescence lasting for a couple of seconds upon ceasing the excitation, that makes this compound classifiable as an ultralong organic phosphorescent (UOP) material. The results evidenced the role of the nature of the heavy atom in governing the phosphorescence output from organic cocrystals.

The [4 + 4] photoreactivity of the anthracene derivative 9-(methylaminomethyl)anthracene (MAMA) has been investigated in solution, gel medium and in the solid state. While quantitative formation of the cyloaddition photoproduct was achieved upon irradiation at λ = 365 nm of ethanol solutions of MAMA, only partial and slow conversion was detected in gels of low molecular weight gelators, and solid-state reactivity was not observed due to the unfavourable relative orientation of the anthracene moieties in the crystal. In hexafluorophosphate, tetrafluoroborate and nitrate silver(I) complexes, however, 9-(methylaminomethyl) anthracene exhibits a more favourable mutual orientation for the aromatic fragments, and [4 + 4] photoreactivity resulted. All compounds were structurally characterized via single crystal and/or X-ray powder diffraction and by Raman spectroscopy; this last technique proved effective in detection of the photoproduct in all solid state complexes.

A striking variety of anhydrous and hydrated ionic cocrystals (ICCs) of the enantiopure antiepileptic drug (AED) levetiracetam and of its racemic intermediate etiracetam with the pharmaceutically acceptable salts CaCl 2 and MgCl 2 was synthesized and structurally characterized. The difference in the interaction of enantiopure and racemic compounds of interest with the inorganic salts was investigated. Variable-temperature X-ray powder diffraction (VT-XRPD) and calorimetric analyses (TGA and DSC) of all obtained ICCs showed a significant improvement in thermal stability with respect to pure racetams.

Crystallization of rifaximin from 2-(2-ethoxyethoxy)ethanol (Transcutol®, DEGME or DEGEE), an inactive ingredient approved by the FDA and a solvent commonly used in the pharmaceutical and cosmetic fields, affords a crystalline form of the API with better solubility properties with respect to the known crystalline hydrates, which are characterized by a very low solubility in water and in buffered solutions. The new form, named rifaximin τ, is an anhydrous solvate, fully characterized by single crystal X-ray diffraction, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Solubility properties were also investigated and compared with known forms of rifaximin. Rifaximin τ combines a high dissolution rate, comparable to that of amorphous rifaximin, with a high storage stability, as in its solid form it is not affected by exposure to humidity.

Co-crystallization of the antibacterial agent proflavine (PF) with the inorganic salt ZnCl2 by mechanochemical and solution methods results in the formation of novel compounds ZnCl3(HPF) (1) and [HPF]2[ZnCl4]·H2O (2), both containing the proflavinium cation (HPF)+. Both compounds show a 50–125% enhanced antimicrobial activity with respect to a reference standard of AgNO3, and a 25–50% enhancement to the behaviour of the separate components against pathogen indicator strains of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. In terms of crystal structure, both compounds ZnCl3(HPF) and [HPF]2[ZnCl4]·H2O are characterized by extensive π-stacking interactions between the proflavine moieties. The same interaction is predominant in the previously unknown crystal structures of neutral proflavine (PF), as well as in that of its dihydrated monochloride salt, [HPF]Cl·2H2O, which are also described in this paper.

We propose the use of solid solutions for the modulation of the kinetic in [2+2] photocycloaddition. Solid solutions with general formula [1H]BrxCl1‒x (1 = 4-amino-cinnamic acid; 0 < x < 1) were prepared via mechanochemical methods, structurally characterized, and found to undergo a single-crystal-to-single-crystal [2+2] photodimerization. The effect of the solid solutions composition on the kinetics was successfully investigated via a combination of FTIR and Principal Component Analysis (PCA), and the results were compared with those obtained for the parent materials [1H]Cl and [1H]Br. All systems follow the same nearly first-order law, and the overall reaction kinetics is influenced by a subtle interplay of structural and electronic factors as well as other processes regulating the formation and lifetime of the reacting excimer.

Co-crystallization of the antibacterial agents proflavine and methyl viologen with the inorganic salts CuCl, CuCl2 and AgNO3 results in enhanced antimicrobial activity with respect to the separate components.

The amino acids alanine, valine, proline, isoleucine, serine, asparagine, tyrosine, and threonine in their racemic forms have been reacted with ZnCl2 under different preparative conditions (grinding and LAG, both manual and ball milling, and co-crystallization from solvent). In most cases, relatively stable (from days to months) oils were obtained; only in those cases for which single crystals could grow from oils, structural characterisation was possible via X-ray diffraction. Aim of the work has been the investigation of the occurrence of chiral selectivity upon the formation of tetrahedral metal coordination complexes or polymers. It has been shown that co-crystallization reactions lead, in the majority of cases, to crystals of racemic-AA2ZnCl2, formed by 0D homochiral complexes of formula l-AA2ZnCl2 and d-AA2ZnCl2. With the dl-amino acid threonine, however, crystals of meso-AA2ZnCl2 have also been obtained, made of 0D heterochiral complexes of formula dl-AA2ZnCl2. With dl-proline, both the known racemic and the new meso-AA2ZnCl2 solids were obtained. Formation of 1D coordination polymers has been observed in the cases of dl-asparagine and dl-tyrosine with alternating d and l amino acids along the polymeric chain. This journal is

We report on the mechanochemical synthesis of inclusion complexes obtained by reacting β-cyclodextrin (β-CD) with two widely used sunscreens, namely, avobenzone (AVO) and octinoxate (OCT). Formation of crystalline inclusion complexes was confirmed via a combination of solid-state techniques, including X-ray diffraction (XRD), Raman, and ATR-FTIR spectroscopies. A new, metastable polymorph of avobenzone was also isolated and characterized. NMR spectroscopy and thermal analyses (TGA and DSC) allowed us to evaluate the host/guest ratio and the water content (ca. 8H2O) in crystalline (β-CD)2·AVO and (β-CD)3·OCT2. Photodegradation of the two sunscreens upon inclusion in the hydrophobic cavity of β-CD was evaluated in solution via mass spectrometry (ESI-MS) and UV-vis spectroscopy and found to be sharply reduced. All findings indicate that the inclusion of AVO and OCT in β-CD might represent a viable route for the preparation of environmentally friendly sunscreens with improved photostability to be used in formulations of sun creams.

Herein we report that 4-pyridinylboronic acid (1) in the solid state self-assembles into tetrameric macrocycles via B–N bond formation. The tetramers are linked via O–H···O bonds resulting in a material that can be exfoliated via sonication to give thinner sheets as we demonstrate via Fourier transform infrared spectroscopy, transmission electron microscopy, selected area electron diffraction, and atomic force microscopy experiments. For comparison, the structure of the related compound 4-(pyridin-4-yl) phenylboronic acid (2) is also discussed.

The investigation of the factors responsible for the stability of the diverse crystal forms that a given molecule can adopt in the solid state (polymorphs, hydrates, cocrystals, etc.) requires an appreciation of the relationship between static and dynamic behavior of atoms and molecules about equilibrium and far from equilibrium positions in the crystal structure. This is particularly relevant when dealing with molecules that are structurally nonrigid at ambient conditions in other media (solution, gas phase). The ease of motion of molecules in molecular crystals depends on the distribution of first neighboring molecules and on the network of intermolecular interactions, which are, in turn, also responsible for the relative thermodynamic stability of solid phases. The knowledge of the intermolecular interactions and of their interplay with the ionic charges commonly present in inorganic, coordination polymers and organometallic compounds is indispensable the application of crystal engineering strategies in the inorganic chemistry area. This microreview article describes, with numerous examples coming mainly from the authors' work, the scientific route that has led from early studies on dynamical processes taking place in the solid state to the design and preparation of novel molecular aggregates involving, inter alia, hydrogen bonded organometallic molecules, charged coordination complexes and metal organic frameworks. The use of solvent-free mechanochemical mixing of reactants as a method of choice for preparing supramolecular aggregates and hybrid organic–inorganic cocrystals will be discussed.

Indigo [2,2′-bis(2,3-dihydro-3-oxoindolyliden)], a commonly used natural dye, has been shown to exhibit a highly promising semiconducting behavior, allowing for the realization of ambipolar devices. Nevertheless, up to date, it is still unclear which crystal structure is present in the thin films, a piece of information relevant for device applications. In this work, we address this issue by an in-depth characterization of the polymorphs of Indigo in the bulk and in drop-cast films. To do this, X-ray diffraction (XRD) and micro-Raman spectroscopy have been employed jointly, with the support of state-of-the-art density functional theory calculations in the solid state. Structural and spectroscopic characterizations have established that the two known A and B polymorphs grow as concomitant in the bulk under most of the experimental conditions adopted in this work. In the drop-cast films, XRD cannot unambiguously identify the structure, but Raman spectroscopy is effective in establishing that only the B form is present. The calculations augment the experiments, providing valuable insights into the relative thermodynamic stability of the two forms as a function of temperature. They also allow for a more comprehensive characterization of the Raman modes.

The order-disorder phase transition associated with the uprise of reorientational motion in (DABCOH2)2+ , in the supramolecular salts of general formula [1⋅(DABCOH2 )]X2 (where 1=12-crown-4, DABCO=1,4-diazabicyclo[2.2.2]octane, and X=Cl- or Br- ), has been investigated by variable temperature X-ray diffraction on single crystals and powder samples, as well as by DSC and solid-state NMR spectroscopy (SSNMR). The two compounds undergo a reversible phase change at 292 and 290 K, respectively. The two crystalline materials form solid solutions [1⋅(DABCOH2 )]Cl2x Br2(1-x) in the whole composition range (0 < x

This contribution was prompted in response to the recent Perspective by Desiraju and Nangia (hereafter DN).1 The somewhat unconventional format used here is consistent with scientific discourse in general and the nature of an Editorial comment. Following an initial exchange of views the four authors opted on adopting a format historically employed in written discourse−namely, presenting the views of various commentators together in the same textual offering. Likewise, each of the authors of this contribution wishes to comment individually on the DN Perspective, but we wish to contain the comments in one publication to be read, considered, and cited together rather than individually. As a result, each comment is self-contained, with its own text and references cited at the end.

New binary and ternary solid solutions formed by p-chlorobenzyl alcohol (p-ClBA), p-bromobenzyl alcohol (p-BrBA) and their quasi-isostructural compound p-methylbenzyl alcohol (p-MeBA) have been prepared and characterized by DSC and powder X-ray diffraction. The binary and ternary solid solutions were synthesized by co-melting of p-MeBA/p-ClBA, p-MeBA/p-BrBA and p-ClBA/p-BrBA and by co-melting of p-MeBA/p-ClBA/p-BrBA in various molar ratios. By varying the relative concentrations, it has been possible to observe the consequent variations of the melting points of the solid solutions. For the binary 1 : 1 p-MeBA/p-BrBA and p-ClBA/p-BrBA compounds, single crystals were grown from solution and their structures were investigated by X-ray diffraction.

Chiral resolution of racemic etiracetam was achieved via co-crystallization with ZnCl2. Depending on the amount of ZnCl2 either a stable racemic compound or a stable conglomerate can be obtained. Excess ZnCl2 triggers the quantitative conversion of the racemate into the conglomerate solid; this unprecedented behaviour was investigated through a racetam/ZnCl2/solvent phase diagram.

Two co-crystals of melatonin with piperazine and (1,4-diazabicyclo[2.2.2]octane), DABCO, and a hydrated ionic co-crystal with CaCl2 were obtained directly in the solid-state via kneading of the solid mixtures with a few drops of ethanol. The structure of the DABCO co-crystal, mel2·DABCO, was determined by single crystal X-ray diffraction, while those of the piperazine co-crystal, mel2·pip, isomorphous with the DABCO one, and the ionic co-crystal, mel2·CaCl2·2H2O, were determined from powder data. In the case of the ionic co-crystal with CaCl2, solubility measurements indicate that melatonin solubility in water increases by an order of magnitude with respect to the pure substance.

Ionic cocrystals (ICCs) of LiCl with levodopa and its biological precursors l-tyrosine and l-phenylalanine, namely, l-phe·LiCl·nH2O, l-tyr·LiCl, and l-dopa·LiCl·H2O, were synthesized by mechanochemical mixing of the reactants in the presence of a small quantity of ethanol. In the case of l-dopa, a polymorph of l-dopa·LiCl·H2O was also obtained from solution crystallization. All compounds were investigated by solid state methods, and the structures were determined either from single crystal or from powder diffraction data.

The mechanochemical reaction of urea and catechol affords the quantitative formation of a 1:1 urea·catechol (URCAT) cocrystal that can act simultaneously as a urease inhibitor and as a soil fertilizer. The novel compound has been characterized using solid-state methods, and its environmental activity has been assessed using the inhibition of Canavalia ensiformis urease and water vapor sorption experiments at room temperature. The urea molecules within the cocrystal were organized in hydrogen-bonded dimers bridged by two catechol molecules, with the OH groups interacting via hydrogen bonds with the urea carbonyl groups. The inhibition of jack bean urease enzyme by URCAT led to the complete loss of urease activity after a 20 min incubation period. A large difference of water vapor adsorption was observed between urea and URCAT, with the latter adsorbing 3.5 times less water than urea. Our results suggested that cocrystal engineering strategies can be successfully applied to tackle sustainability problems at the food–energy–water nexus.

The novel ternary Zn(II)-thiourea–urea ionic cocrystal [Zn(thiourea)(urea)Cl₂], (ZnTU) has been prepared by both solution and mechanochemical processes and structurally characterized by solid-state methods. ZnTU exhibited improved response properties to water as relative humidity as inherited from thiourea. The results of enzymatic activity measurements provide evidence that ZnTU is effective in modulating urea hydrolysis both in vitro (negatively impacting on the activity of isolated urease) and in vivo (decreasing the ureolytic activity of Sporosarcina pasteurii, a widespread soil bacterium), and that Zn(II) is the component of the cocrystal acting as the actual urease inhibitor. Concomitantly, the analysis of the ammonia monooxygenase (AMO) enzymatic activity in Nitrosomonas europaea, taken as a representative of soil ammonia-oxidizing bacteria, in the presence of ZnTU reveals that thiourea is the only component of ZnTU able to inhibit ammonia conversion to nitrite. It has also been shown that ZnTU maintains these capabilities when applied to bacterial cultures containing both S. pasteurii and N. europaea working in tandem. The compound can thus act both as a fertilizer via urea and via the Zn(II) and thiourea components, as a dual action inhibitor of the activities of the enzymes urease and AMO, which are responsible for the negative environmental and economic impact of the agricultural use of urea as soil fertilizer. These results indicate that ZnTU should be considered a novel material to improve N fertilization efficiency, toward a more environment-friendly agricultural practice.

The structure of folic acid dihydrate has been investigated in the solid state by means of a synergistic approach combining Raman spectroscopy, X-ray powder diffraction, and cutting-edge calculation methods. The comparison of the computed and measured Raman spectra was used to support the finding of a new crystalline form. Crystalline folic acid·2H2O has also been used in the preparation, via solvent free methods, of amorphous multicomponent materials and salts by reacting folic acid with LiOH, NaOH, Na2CO3, and Ca(OH)2, which were also investigated by X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and intrinsic dissolution rate, and this has been compared with the values of the native vitamin. The preparation and characterization of the amorphous, hydrated adduct with LiCl is also reported.

A set of molecular salts with general formula [1H]nA·xH2O (1 = 4-amino-cinnamic acid, A(n-) = NO3(-), BF4(-), PF6(-), SO4(2-), x = 0, 1) was prepared and structurally characterized. [1H]Cl and [1H]2SO4·H2O(II) were found to undergo an SCSC stepwise [2+2] photodimerization, which was followed by X-ray diffraction; a kinetic analysis was performed on single crystals of both salts. In the case of [1H]Cl the photoreaction was also studied on polycrystalline materials.

The relevance of co‐crystals for pharmaceutical development is demonstrated by the constant growth of the number of papers and patents published in the two last decades. Co‐crystallization appears to be an efficient means to modulate the solid state properties of a pharmaceutical active ingredient (API) within the crystalline state. It is also a crystal engineering approach enabling to prepare original materials, including co‐drugs. Co‐crystallization is therefore a route to innovation and opens perspectives to patent protection. Alternatively, co‐crystal formation may represent an undesired or unexpected outcome of molecular complexation, for example in the drug product. This observation underlines the importance of a detailed study on the solid state chemistry not only of the pure API, but also of its combinations with the individual components in the formulation.

Chiral resolution of racemic etiracetam was achieved via co-crystallization with ZnCl2. Depending on the amount of ZnCl2 either a stable racemic compound or a stable conglomerate can be obtained. Excess ZnCl2 triggers the quantitative conversion of the racemate into the conglomerate solid; this unprecedented behaviour was investigated through a racetam/ZnCl2/solvent phase diagram.

The preparation and characterization of a whole family of hydrated ionic co-crystals formed by both enantiopure l-proline and racemic dl-proline with LiX (X=Cl, Br, I) are reported. The chiral preference of the lithium cation for homochiral coordination, both in the formation of crystalline conglomerates (with Cl and Br) and racemates (with Cl and I), in which molecules of opposite chirality are confined to distinct crystal layers, is discussed. Dehydration processes for all hydrated crystals have also been investigated.

A smart ionic co-crystal of urea with KCl and ZnCl2 has been obtained in two polymorphic modifications via mechanochemical and solution methods and proven to be a very efficient urease inhibitor while, simultaneously, able to provide soil nutrients to complement N supply.