A Greener Pathway to Enantiopurity: Mechanochemical Deracemization through Abrasive Grinding.

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.

Simultaneous Chiral Resolution of Two Racemic Compounds by Preferential Cocrystallization*.

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.

Ionic Co-Crystal Formation as a Path Towards Chiral Resolution in the Solid State.

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.

Simultaneously resolving BINOL and proline using a stoichiometric cocrystal switch.

We here highlight the importance of stoichiometry for simultaneous cocrystal resolution. Focusing on combining the racemates of binol and proline, we show that a 1 : 2 ratio leads to formation of a full racemic compound, whereas a 2 : 1 ratio, leads to conglomerate formation, with simultaneous resolution of both binol and proline. Playing on stoichiometry, one achieves a reversible switch between the racemic compound and conglomerate. This is the first investigation of such behavior combining two racemates.

Complexation: An Interesting Pathway for Combining Two APIs at the Solid State.

Combining different drugs into a single crystal form is one of the current challenges in crystal engineering, with the number of reported multi-drug solid forms remaining limited. This paper builds upon an efficient approach to combining Active Pharmaceutical Ingredients (APIs) containing carboxylic groups in their structure with APIs containing pyridine moieties. By transforming the former into their zinc salts, they can be successfully combined with the pyridine-containing APIs. This work highlights the successfulness of this approach, as well as the improvement in the physical properties of the obtained solid forms.

L-Proline, a resolution agent able to target both enantiomers of mandelic acid: an exciting case of stoichiometry controlled chiral resolution.

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.

Steps towards a nature inspired inorganic crystal engineering.

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.

Comparison of Antimicrobial and Antibiofilm Activity of Proflavine Co-crystallized with Silver, Copper, Zinc, and Gallium Salts.

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·AgNO3, proflavine·CuCl, ZnCl3[Proflavinium], [Proflavinium]2[ZnCl4]·H2O, and [Proflavinium]3[Ga(oxalate)3]·4H2O. 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.

Co-crystallization of antibacterials with inorganic salts: paving the way to activity enhancement.

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.

Solid-state chiral resolution mediated by stoichiometry: crystallizing etiracetam with ZnCl2.

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.

Smart urea ionic co-crystals with enhanced urease inhibition activity for improved nitrogen cycle management.

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.