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A family of salts of R-(+)-(3)-hydroxyquinuclidinium [QH]+, with SO42−, BPh4−, BF4− and PF6− counter-anions, have been prepared by the metathesis of [QH]Cl and metal salts of the corresponding anions. Solid solutions of formula [QH](PF6)x(BF4)1−x for x = 0.9, 0.8, 0.7 have also been obtained. The crystalline materials have been investigated by a combination of solid-state techniques, including variable temperature XRD, thermal analyses, multinuclear (11B, 13C, 15N, 19F, and 31P) solid-state NMR spectroscopy, variable temperature wideline 19F T1 relaxation measurements, and micro-Raman spectroscopy to investigate their thermal stability and phase transition behaviors. It has been shown that the salts [QH]PF6 and [QH]BF4 undergo an order–disorder solid–solid phase transition to plastic phases, whereas [QH]2SO4·H2O and [QH]BPh4 do not display any plastic phase transition. Doping [QH]BF4 into the [QH]PF6 lattice up to 30% results in the formation of a solid solution that is plastic in an expanded thermal range, thanks to a phenomenon that we describe here for the first time as “reordering frustration”.

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.

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.

The boronic acid derivatives 4-pyridinylboronic acid (4-pyBA) and pyrimidine-5-boronic acid (pyrBA) have been reacted with the oxocarbon rhodizonic acid or with sodium rhodizonate both in solution and in the solid state. Four novel condensation adducts have been isolated as hydrates, namely C16H16B2N2O12•xH2O (1a•xH2O; x = 2 or 4), C16H14B2N2O10•3H2O (2a•3H2O), C14H14B2N4O12•2.5H2O (1b•2.5H2O), and C14H12B2N4O10•3H2O (2b•3H2O), and fully characterized by X-ray single crystal and powder diffraction. Their thermal stability and behavior upon dehydration have also been investigated by TGA and single-crystal to single-crystal X-ray diffraction experiments. It has been shown that the boronic acid derivatives 4-pyridinylboronic acid and pyrimidine-5-boronic acid react with rhodizonic acid in a similar way producing two distinct products, the so-called “axle” compounds (1a and 1b) and “tweezer” compounds (2a and 2b), depending on the experimental conditions and preparation method. With both boronic acids, the “tweezer” compound is the only product of the mechanical mixing of the reactants. Both “axle” and “tweezer” compounds are in the zwitterionic form with the boronate ion being neutralized via protonation on the pyridinyl and pyrimidine N-terminus.

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

The structures and solid-state dynamics of the supramolecular salts of the general formula [(12-crown-4)2 ⋅DABCOH2 ](X)2 (where DABCO=1,4-diazabicyclo[2.2.2]octane, X=BF4 , ClO4 ) have been investigated as a function of temperature (from 100 to 360 K) and pressure (up to 3.4 GPa), through the combination of variable-temperature and variable-pressure XRD techniques and variable-temperature solid-state NMR spectroscopy. The two salts are isomorphous and crystallize in the enantiomeric space groups P32 21 and P31 21 . All building blocks composing the supramolecular complex display dynamic processes at ambient temperature and pressure. It has been demonstrated that the motion of the crown ethers is maintained on lowering the temperature (down to 100 K) or on increasing the pressure (up to 1.5 GPa) thanks to the correlation between neighboring molecules, which mesh and rotate in a concerted manner similar to spiral gears. Above 1.55 GPa, a collapse-type transition to a lower-symmetry ordered structure, not attainable at a temperature of 100 K, takes place, proving, thus, that the pressure acts as the means to couple and decouple the gears. The relationship between temperature and pressure effects on molecular motion in the solid state has also been discussed.

α-Aminophosphonates are an important class of biologically active compounds, attracting considerable attention in medicinal chemistry, by inhibiting enzymes involved in amino acid metabolism. Herein, the Kabachnik–Fields domino reaction was investigated by mechanochemistry for the first-time preparation of α- aminophosphonate derivatives in high yields and with full selectivity, outperforming comparable solution procedures. The reaction occurs without the addition of any external catalyst, possibly via a metal-mediated process occurring on the surface of the jar (zirconium oxide was used as the milling media). The mechanism of the mechanochemical reaction was also investigated by in situ Raman spectroscopy, and the kinetic behavior was disclosed. The solid- state structures of two representative compounds have been determined by single- crystal X-ray diffraction.

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.

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 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

The reaction of squaric acid (H2SQ) with three pyridine-appended boronic acid derivatives (BA), viz. 4-pyridinylboronic acid (1BA), 3-pyridinylboronic acid (2BA), and (4-(pyridin-4-yl)phenyl)boronic acid (3BA), leads to the formation of supramolecular zwitterions of the general formula [SQ(BAH)2]·xH2O generated by proton transfer from the squaric acid to the pyridine sites. The zwitterion [SQ(1BAH)2]·2H2O can further react with the neutral molecule bipyridine (bpy) leading thus to a ternary system of the general formula [SQ(1BAH)2]·bpy.

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.

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.

In this highlight, the reasons for the widespread interest generated by ionic co-crystals, namely those formed by a neutral molecule and a salt, are addressed. In particular, the class of compounds obtained by co-crystallization of neutral organic molecules and inorganic salts (e.g. alkali and alkaline earth halides, sulfates, phosphates etc.) is discussed with the focus on their applications in diverse areas, such as pharmaceuticals, food and fertilizers, and also in chiral resolution. It is argued that, in terms of structure and intermolecular bonding features, these compounds do not differ from classical coordination compounds (complexes) and that their popularity arises from the effectiveness of the organic–inorganic assembly to enhance thermal stability, improve particle size and morphology and change significantly the solubility and dissolution rate with respect to those of the pure active ingredients.

The solid-state photoreactivity of 4-aminocinnamic acid (1) and molecular salts [1H]ClO4 and [1H]HSO4 has been investigated, and structural changes have been monitored by X-ray diffraction techniques and FTIR spectroscopy. While the parent compound 1 and its perchlorate salt [1H]ClO4 are photoinert, irradiation of [1H]HSO4 single crystals results in partial single-crystal to single-crystal (SCSC) [2 + 2] photodimerization, with formation of a {[1H]HSO4}0.36·{[12H2][HSO4]2}0.64 solid solution. If crystalline powders of [1H]HSO4 are irradiated, however, the formation of a monomer/dimer solid solution is followed by “extrusion” and recrystallization of both the phodimerization product [12H2]HSO4 and unreacted [1H]HSO4 as nonisomorphous crystal phases. The outcome of the UV irradiation of [1H]HSO4, therefore, is influenced by the crystal size of the reacting monomer and changes dramatically if the irradiated sample is in the form of single macrocrystals or microcrystalline powder.

The new molecular salt [1H]Br (1 = 4-amino-cinnamic acid) was obtained in two polymorphic modifications, forms A and B. While mechanical stress induces transformation of form A into form B, an unexpected effect of UV irradiation is observed on form A, i.e., a single crystal to single crystal (SCSC) transformation to a third polymorph, form C. Form B, on the contrary, responds to UV irradiation by undergoing a stepwise SCSC [2 + 2] photodimerization to α-[12H2]Br2, via formation of a solid state solutions in the whole compositional range. All transformations were followed by a combination of solid-state techniques, i.e., single crystal and powder X-ray diffraction, FTIR, and FT-Raman, and by solution 1H NMR. All structural changes also resulted in variations in crystal morphology/texture, and these were monitored via SEM analysis.

The bottom-up preparation of mixed crystals, co-crystals and photoreactive materials starting from molecular building blocks across the borders of organic, organometallic and metal–organic chemistry is described., The conceptual relationship between crystal reactivity, stability and meta­stability, solubility and morphology on the one hand and shape, charge distribution, chirality and distribution of functional groups over the molecular surfaces on the other hand is discussed, via a number of examples coming from three decades of research in the field of crystal engineering at the University of Bologna. The bottom-up preparation of mixed crystals, co-crystals and photoreactive materials starting from molecular building blocks across the borders of organic, organometallic and metalorganic chemistry is recounted.

The potent natural hydrophilic antioxidant l-carnosine has been reacted with a number of organic acids belonging to the “generally regarded as safe” (GRAS) group, resulting in the preparation of 11 new crystalline salts, which were characterized by X-ray powder diffraction and thermal analysis; the structures of six of them were determined from powder data, and one was fully characterized via single crystal data. The reaction with folic acid resulted in an amorphous folate salt, which was characterized by a combination of thermal methods and Raman spectroscopy; the solubility of the folate salt was also measured and found to be comparable to that of the commercial sodium folate.

The enantiomers of a previously reported naphthalimide derivative are shown in this study to form a solid solution; furthermore, on the basis of the knowledge of solid solution structural aspects other naphthalimide derivatives have been synthesized and shown to lack the enantioselectivity in the solid state. The structural origin of solid solution formation is the same as observed in most of the cases in the literaturequasi-centrosymmetric structures form at nonracemic compositions where the most abundant enantiomer adjusts its conformation to mimic the absent one. Such solid solutions belong to the type showing some enantioselectivity. An extended single crystal X-ray diffraction study of the crystals of different enantiomeric compositions reveals the nature of the disorder in studied solid solutions. Intermolecular interactions are analyzed in terms of Hirshfeld surfaces and by means of density functional theory calculations to explore the differences of isostructural quasi-centrosymmetric (enantiopure) and genuine centrosymmetric (racemic) packings to shed light on the energetic aspects of solid solution formation as well as to explain the origin of partial enantioselectivity. Furthermore, lattice energy calculations explain why two structurally distinct solid solutions (around the racemic and near the pure enantiomer regions) form as found for one of the studied compounds.

Ionic co-crystals (ICCs) of L- and DL-histidine with CaCl2, CaBr2 and CaI2 were prepared by mechanochemical and solution methods and were structurally characterized by either single crystal or powder X-ray diffraction methods. The L-histidine molecules bridge Ca2+ cations forming enantiopure ribbons in the homochiral crystals (L-His)2·CaX2·nH2O (X = Cl and Br n = 3, X = I n = 4), as well as in the partial dehydration product of (L-His)2·CaI2·4H2O, namely (L-His)2·CaI2·3H2O. In the racemic (DL-His)2·CaX2·4H2O cases (X = Cl, Br, X = I), molecules of both chiralities are accommodated in the coordination sphere of the Ca2+ cation forming ribbons with homochiral rims as in the enantiopure crystals. Intrinsic dissolution rate measurements show that the histidine-CaCl2 co-crystals have a much higher IDR with respect to both enantiopure and racemic histidine solids.

A personal view of nearly four decades of structural chemistry is presented. The rise of molecular crystal engineering as an independent cross-disciplinary field of research at the intersection of crystallography with supramolecular chemistry and solid-state reactivity is discussed in light of the development of theoretical and instrumental tools and the need for novel molecular materials. The exchange of ideas and experience within the structural chemistry community has played a fundamental role in reaching the present high level of understanding of the factors that control crystal formation and stability. Crystal-oriented synthetic strategies, including solvent-free mechanochemical methods, have been developed, as well as screening methods and computational approaches. Some drawbacks and limitations are also discussed. The wealth of multiple crystal forms, from single-molecule crystals to solvates, co-crystals, salts and ionic co-crystals, and their polymorphs, is both an open challenge to the crystal engineering paradigm and a source of discovery and innovation.

Anhydrous ionic co-crystals (ICCs) of cyanuric acid (CA) with sodium and lithium chlorides have been prepared by solid state methods and structurally characterized from X-ray powder diffraction data (XRPD). Complete encapsulation of the Li+Cl− ion pair by the organic molecules is observed in CA·LiCl, while the solid-state solvation of piles of Na+ cations in CA·NaCl results in the markedly increased dissolution rate (ca. 5 times) and solubility (ca. 20 times) in water with respect to pure CA.

This Article reports the solvent-free synthesis and characterization of a number of different crystal forms of niclosamide (HNic), which is an API belonging to the Salicilamide class. The synthesized compounds are four new salt cocrystals (KNic.HNic.H2O, KNic.HNic.3H(2)O, NaNic.HNic.3H(2)O, NaNic.HNic.2H(2)O), a classic cocrystal with imidazole (IM) (HNic.IM), and two sodium salts, (NaNic.DMSO.H2O and NaNic.DMSO.2H(2)O). The peculiarity of these salt cocrystals is the APIs concomitant presence as both a neutral component and as a salt coformer and the fact that they interact via hydrogen bond formation. HNics poor aqueous solubility makes the enhancement of its dissolution rate via the modulation of its physical properties extremely important. All samples have been investigated using a combination of solid-state experimental techniques which provide complementary information on powdered samples. These techniques are X-ray powder diffraction, solid-state NMR, IR, and Raman. Single crystals were only obtained for KNic.HNic.H2O and NaNic.DMSO.2H(2)O. The nature of the adducts (whether salt or cocrystal), their stoichiometry and the presence of independent molecules in the unit cell of the other samples were thus all determined by means of solid-state NMR and the comparative analysis of C-13 and N-15 CPMAS (Cross-Polarization Magic Angle Spinning) and 1H MAS spectra. Furthermore, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate measurements completed the characterization and enabled us to evaluate the effects of microscopic changes (molecular packing, weak interactions, conformations, etc.) on the macroscopic properties (thermal stability and bioavailability) of the multicomponent forms. The results obtained indicate that the formation of salt cocrystals provides a reliable method with which to improve the HNic intrinsic dissolution rate.

Post-synthesis (de)hydration techniques were used here to explore further hydrated forms of ionic co-crystals (ICCs) of nicotinamide with CaCl2. Humidity is shown to be a crucial factor for ICCs, which cannot be ignored for a complete polymorph screening of this class of compounds. The exposure of nicotinamide[middle dot]CaCl2[middle dot]H2O obtained by kneading reaction to a controlled relative humidity of 75% led to the formation of a new hydrated phase: nicotinamide[middle dot]CaCl2[middle dot]4H2O. When nicotinamide[middle dot]CaCl2[middle dot]H2O was exposed to a relative humidity between 32% and 54%, nicotinamide2[middle dot]CaCl2[middle dot]2H2O was obtained. The anhydrous form was achieved as the result of overnight dehydration of nicotinamide[middle dot]CaCl2[middle dot]H2O at 150 [degree]C. The tetrahydrate form cannot be obtained as a first product for kinetic (or thermodynamic) reasons. Control of the relative humidity has proven to be an efficient way to selectively isolate and stabilize powders of pure hydrous ICC phases, which is fundamental for industrial applications. Crystalline structures of nicotinamide[middle dot]CaCl2[middle dot]4H2O and anhydrous nicotinamide[middle dot]CaCl2 were determined by powder diffraction.

Condensation reactions between 1,8-naphthalic anhydride and racemic 3-aminoquinuclidine or chiral (S) or (R)-(-)-3-aminoquinuclidine allowed preparation of three novel racemic and enantiopure aza-donor ligands, namely NMiABCO (1), (S)NMiABCO (2a), and (R)NMiABCO (2b). Racemic NMiABCO (1) crystallizes in the monoclinic space group P2(1)/c, Z' = 1, while enantiopure (S)NMiABCO (2a) and (R)NMiABCO (2b) crystallize in the chiral monoclinic space group P2(1), Z' = 2, and show significant pseudocentrosymmetry, being pseudo-isomorphous with racemic NMiABCO (1). Reactivity of both racemic and enantiopure NMiABCO toward iodine and interhalogen IBr was also investigated as a way to remove the pseudoisomorphism, yielding the three new molecular adducts [NMiABCO center dot I-2] (3), [(S)NMiABCO center dot I-2]center dot xCHCl(3) (4), [(S)NMiABCO center dot IBr]center dot xCHCl(3) (5) and the molecular salt [HNMIABCO][1Br(2)] (6). Synthesis of complexes 3 and 4 was also carried out in the solid state via kneading and vapor digestion techniques. All compounds were fully characterized via single crystal and powder X-ray diffraction and Raman spectroscopy.

Organo-copper(I) halide complexes with a Cu4I4 cubane core and cyclic amines as ligands have been synthesized and their crystal structures have been defined. Their solid state photophysical properties have been measured and correlated with the crystal structure and packing. A unique and remarkably high luminescence quantum yield (76%) has been measured for one of the complexes having the cubane clusters arranged in a columnar structure and held together by N-H...I hydrogen bonds. This high luminescence quantum yield is correlated with a slow radiationless deactivation rate of the excited state and suggests a rather strong enhancement of the cubane core rigidity bestowed by the hydrogen bond pattern. Some preliminary thin film deposition experiments show that these compounds could be considered to be good candidates for applications in electroluminescent devices because of their bright luminescence, low cost and relatively easy synthesis processes.

The isomorphous hydrated ionic co-crystals (ICCs) of barbituric acid (BA) of the formula BA·MBr·2H2O (M = Na, K, Rb) can be easily dehydrated to the corresponding anhydrous ICCs BA·MBr (M = Na, K, Rb). The three anhydrous crystals possess different structures that revert to the isomorphous crystals upon hydration. Only BA·RbBr is stable in air, making it possible to determine its crystal structure from single-crystal X-ray diffraction. BA·NaBr and BA·KBr rapidly absorb water from air and convert to the hydrated form. The crystal structures of BA·NaBr and BA·KBr have been determined by X-ray powder diffraction in sealed capillaries. Solid-state NMR spectroscopy was fundamental in determining the number of independent molecules in the asymmetric unit for the structural determination of the ICC BA·NaBr. The dehydration process was characterized by variable temperature X-ray powder diffraction, DSC and TGA.

Alloying isomorphous crystals of barbituric acid (BA) and thiobarbituric acid (TBA) yields solid solutions of general formula BAxTBA1-x (x < 0.8); for x = 0.5 the stable co-crystal BA0.5TBA0.5, isomorphous with the parent keto forms, is observed, which melts at 265 °C, i.e. ca. 10 and 20 °C higher than the melting points of BA and TBA, respectively. While the BAxTBA1-x solid solutions with x > 0.5 are stable, those with x < 0.5 convert, with time or temperature, to the BA0.5TBA0.5 co-crystal.

Ionic cocrystals (ICC) of l- and dl-histidine with lithium halides (LiCl, LiBr, LiI) have been prepared by solid state and solution methods, and structurally characterized in order to compare the behavior of enantiopure and racemic crystals in the interaction with inorganic salts. It has been shown that the lithium cations interact selectively with enantiomers of one handedness only, to the extent that the crystals obtained with racemic dl-histidine can be described as a special type of cocrystals made of enantiopure l-histidine and d-histidine chains of the same type as those obtained with enantiopure l-histidine. This chiral preference is even more noticeable in the ICC obtained from dl-histidine and LiI, which is actually a conglomerate of l- and d-ICCs. It is also reported that attempts to prepare ICCs with other alkali/alkaline earth halides invariably yield crystals of the less stable polymorph of l-histidine.

Four lidocaine molecular salts of dicarboxylic acids (oxalic, fumaric, malonic, and succinic) were synthesized and characterized by a combined use of X-ray power and single-crystal diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy (FT-IR), and solid-state NMR (H-1 MAS and CRAMPS, and C-13 and N-15 CPMAS); all molecular salts show a dramatic increase in their melting point with respect to both lidocaine and lidocaine hydrochloride, and a higher dissolution rate and thermodynamic solubility in physiological solution with respect to the free base.

In this study we have purposely altered the solid state luminescence properties of 2-(1,8-naphthalimido)ethanoic acid (NEaH) (0) via molecular salts formation with cyclic amines such as 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine (ABCO), 3-quinuclidinol (OH-ABCO), and piperazine (PIP). All crystalline materials have been characterized in the solid state via single-crystal and variable temperature powder X-ray diffraction and thermal methods; luminescence spectra in the solid state have been recorded. Exciton interactions have been determined with quantum-chemical calculations for all molecular organic salts, and tuning of their magnitude in response to changes in the crystal packing has been demonstrated. It is suggested that the variations in photoluminescence can be interpreted on the basis of the different excitonic interactions amongst the naphthalimide moieties.

Grinding of solid brivaracetam (BRV) and seletracetam (SEL) with inorganic lithium salts yields original ionic co-crystals (ICCs) characterized by markedly different thermal properties with respect to pure racetams; solid products have been characterized by single crystal crystallography. It is suggested that co-crystallizing lithium with some racetams could lead to a pharmacologically relevant synergetic association and to development of an original drug substance.

none 7 no The quinoline urea derivatives 1,3-di(quinolin-5-yl) urea (DQ5U), 1-phenyl-3-(quinolin-6-yl) urea (PQ6U), 1-(isoquinolin-5-yl)-3-phenylurea (PiQ5U) and 1-phenyl-3-(3,5-bis(pyrid-2-yl)-1,2,4-triazol-4-yl) urea (PPT4U) have been synthesised and structurally characterized by powder and single crystal X-ray diffraction. Their gelator behaviour in the formation of Ag-complexes has been explored. Compound DQ5U proved capable of gelating the mixed solvent EtOH-DMF 1:2 (v/v) when mixed with 1 equivalent of AgNO3. In the case of PQ6U, two polymorphic forms of the complex [Ag(PQ6U)(2)]NO3, plus the solvated form [Ag(PQ6U)(2)]NO3 center dot CH3CN, were crystallized. Photophysical characterization of the ligands has been conducted in solution, while fluorescence microscopy has been used to examine the microstructure and photophysical properties of the gels formed by PQ5U and DQ5U with AgNO3. Dario Braga;Simone d'Agostino;Eros D'Amen;Fabrizia Grepioni;Damiano Genovese;Luca Prodi;Massimo Sgarzi Dario Braga;Simone d'Agostino;Eros D'Amen;Fabrizia Grepioni;Damiano Genovese;Luca Prodi;Massimo Sgarzi

L-Serine and DL-serine have been treated with oxalic acid under different experimental conditions, e. g. crystallization from solution and slurry, kneading and dry mixing, yielding the molecular salts [L-serH](2)[ox]center dot 2H(2)O forms I and II, [L-serH][Hox] and [DL-serH](2)[ox]center dot 2H(2)O, all fully characterized by powder or single crystal X-ray diffractions; the relationship between the different crystal forms, relative thermal stability, dependence on relative humidity and possible interconversions have all been explored.

Molecular crystal engineering, i.e. the design and synthesis of solid state molecular materials with predefined properties, is used here to exploit non-covalent interactions to pre-arrange buiding blocks in their crystalline state for properties modification and specific applications, all involving the absorption of UV radiation. Depending on the chemical complexity and/or application, crystals of appropriate size and purity are required for characterization, chemical reactivity and applicative processes. Three cases will briefly be presented here: (i) single crystal to single crystal photodimerization of cinnamic acid derivatives and the effect of crystal size on the solid-state reactivity; (ii) cocrystallization as a tool to switch from fluorescence to phosphorescence in the solid state, and the necessity of obtaining single crystals following a mechanochemical synthesis; (iii) molecular crystals for dye-sensitized solar cells applications, and the single crystal vs. polycrystalline material requirements on passing from characterization to photophysical measurements and to thin-film deposition.