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In the field of crystallization-based chiral resolution, preferential crystallization is particularly interesting. In recent work, we showed how the simultaneous resolution of two racemic compounds can be realized through the formation of chiral conglomerate cocrystals. The crystallization of a compound as a conglomerate is a rather rare phenomenon. In this study, we decided to test the probability of multi-component conglomerate formation between two racemic compounds by cocrystallizing racemic compounds with each other. Specifically, racemic proline, mandelic acid and etiracetam were cocrystallized with 14 racemic coformers. The analysis of XRPD patterns upon grinding revealed 16 potential cocrystals, four of which have been already published. The crystal structures of all new cocrystals were determined by single crystal diffraction. The crystal structure elucidation showed 13 cocrystals were racemates and 3 were conglomerates. All conglomerates are isomorphous as they were formed between etiracetam and mandelic acid or its 2-fluoro- and 2-chloro-derivatives. Simultaneous resolution through preferential cocrystallization of racemic compounds, therefore, is limited to very specific systems. In parallel, our results did, however, highlight a striking success rate of DL-proline in the context of cocrystallization as 11 out of 14 cocrystallization experiments were successful.

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.

Combining active pharmaceutical ingredients (APIs) with sweeteners through crystal engineering is an attractive way to mask the bitter taste of drugs. However, traditional methods such as salt or cocrystal formation still suffer some major limitations. Herein, racetams, a series of normally bitter drugs, cannot be combined with the popular sweetener saccharin through either salt or cocrystal formation. We here, however, show how these compounds can be combined when zinc saccharinate is used rather than saccharin. The obtained complexes can either be identified starting from a binary target API/Zn saccharinate or a ternary API/ZnO/saccharin combination. This work opens up novel pathways to couple two compounds of interest through a crystal engineering approach.

We present a thought-provoking development in chiral resolution. Using a resolving agent of a given handedness, L-proline, we show that both R- and S-enantiomers of mandelic acid can be resolved from a racemic mixture simply by varying the stoichiometry. We are the first to report this specific feature, achieved by the existence of stoichiometrically diverse cocrystal systems between R- and S-mandelic acid and L-proline.

We report the first case of mechanochemical deracemization by using liquid-assisted abrasive grinding. The target molecule is a precursor of Paclobutrazol, an important fungicide and plant growth inhibitor. Using mechanochemical deracemization, we are even able to transform a 10 % ee scalemic mixture of this latter in an enantioenriched product of 97 % ee in a couple of hours. This is substantially shorter compared to solution-based deracemization methodologies. The present paper thus introduces an efficient and greener process to enantiopure material.

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.

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.

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).

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.

We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization.We highlight how the two racemic compounds RS-mandelic acid (MAN) and RS-etiracetam (ETI) can be combined together as enantiospecific R-MAN:R-ETI and S-Man:S-ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee>98%) and mandelic acid (ee~95%) enantiomers

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.

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

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.

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.

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.

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 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.

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.

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.

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.