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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.

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.

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.

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.

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.