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In this paper, we address the problem of antimicrobial resistance in the case of Helicobacter pylori with a crystal engineering approach. Two antibiotics of the fluoroquinolone class, namely, levofloxacin (LEV) and ciprofloxacin (CIP), have been co-crystallized with the flavonoids quercetin (QUE), myricetin (MYR), and hesperetin (HES), resulting in the formation of four co-crystals, namely, LEV∙QUE, LEV∙MYR, LEV2∙HES, and CIP∙QUE. The co-crystals were obtained from solution, slurry, or mechanochemical mixing of the reactants. LEV∙QUE and LEV∙MYR were initially obtained as the ethanol solvates LEV∙QUE∙xEtOH and LEV∙MYR∙xEtOH, respectively, which upon thermal treatment yielded the unsolvated forms. All co-crystals were characterized by powder X-ray diffraction and thermal gravimetric analysis. The antibacterial performance of the four co-crystals LEV∙QUE, LEV∙MYR, LEV2∙HES, and CIP∙QUE in comparison with that of the physical mixtures of the separate components was tested via evaluation of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). The results obtained indicate that the association with the co-formers, whether co-crystallized or forming a physical mixture with the active pharmaceutical ingredients (API), enhances the antimicrobial activity of the fluoroquinolones, allowing them to significantly reduce the amount of API otherwise required to display the same activity against H. pylori.

Abstract 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 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.

Co-crystallization of kojic acid (HKA) with silver(I), copper(II), zinc(II), or gallium(III) salts yielded three 1D coordination polymers and one 0D complex in which kojic acid was present as a neutral or anionic terminal or bridging ligand. All reactions were conducted mechanochemically via ball milling and manual grinding, or via slurry. All solids were fully characterized via single-crystal and/or powder X-ray diffraction. As kojic acid is a mild antimicrobial compound that is widely used in cosmetics, and the metal cations possess antibacterial properties, their combinations were tested for potential antibacterial applications. The minimal inhibition concentrations (MICs) and minimal biocidal concentrations (MBCs) for all compounds were measured against standard strains of the bacteria P. aeruginosa, S. aureus, and E. coli. All compounds exerted appreciable antimicrobial activity in the order of silver, zinc, copper, and gallium complexes.

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.

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.

Ionic co-crystals (ICCs) are constituted of inorganic salts and organic molecules. These crystals combine ionic interactions with classical supramolecular bonding such as hydrogen and dipole-bonding interactions. Such is the case of the hydrogen bonds between N–H and CO dipoles in primary and secondary amides when these cocrystallize with an ionic material such as CaCl2. Here, we report our results of the preparation and characterization of a series of ICCs in which the molecular component is an active pharmaceutical ingredient (API) or a precursor of APIs, namely, barbituric acid, diacetamide, malonamide, nicotinamide, and piracetam, while the inorganic salt coformer is CaCl2. CaCl2has been chosen, inter alia, for its nontoxicity and potential applications in the pharmaceutical field. Preparative methods include conventional crystallizations from solution, as well as slurry and solid state techniques (grinding and kneading). All crystal structures reported herein were determined either from single crystal diffraction data or from powder diffraction data, using simulated annealing procedures. Crystalline products were analyzed by differential scanning calorimetry, thermogravimetric analysis, and variable temperature X-ray powder diffraction. Intrinsic dissolution rate measurements were also performed on nicotinamide and piracetam ICCs. [ABSTRACT FROM AUTHOR]

Reaction in solution and in the solid state of 18-crown[6] with Cs2CO3and 5-substituted isophthalic acids yields the new organic–inorganic complexes 18-crown[6]·Cs[OH-isoH] (2), 18-crown[6]·Cs[CH3-isoH] (3), 18-crown[6]·Cs[Br-isoH] (4), 18-crown[6]·Cs[OCH3-isoH] (5), 18-crown[6]·Cs[NO2-isoH] (6) and 18-crown[6]·Cs[tert-Butyl-isoH] (8), which have all been characterized by X-ray diffraction. All compounds except the latter are isomorphous, in spite of the size, shape and chemical nature of the substituent and its ability to form hydrogen bonds. [ABSTRACT FROM AUTHOR]

Solid-state reactions of copper(i) iodide with 1,4-diazabicyclo[2.2.2]octane (DABCO) and piperazine in different conditions (kneading, vapour digestion, thermal treatment) resulted in the formation of four new luminescent systems, which have been characterized viaX-ray diffraction and photo-luminescence spectroscopy. At room temperature all compounds exhibit a bright emission in the solid state that markedly shifts bathochromically on cooling to 77 K. The luminescence of the almost isostructural 2D-coordination polymers [Cu2I2(L)2]∞(L = DABCO, piperazine) exhibits an unusually long lifetime (125 and 53 μs, respectively), which becomes even longer (609 and 420 μs, respectively) at 77 K. [ABSTRACT FROM AUTHOR]

Solid-state adducts (co-crystals and molecular salts) of 1,4-diazabicyclo-[2.2.2]-octane (DABCO) with aromatic polycarboxylic acids (isophthalic acid, isoH2, dinicotinic acid, dinH2and dipicolinic acid, dipH2) were prepared in the solid state by grinding and kneading techniques, and fully characterized viaX-ray diffraction. The polycarboxylic acids differ for the presence/absence and position of a nitrogen atom in the aromatic ring; the extent of proton transfer, from the carboxylic groups on the acids to the nitrogen atoms on DABCO, reflects the trend of solution acidity of the three polycarboxylic acids. [ABSTRACT FROM AUTHOR]

In this communication we describe the solid-state preparation and structural characterization of the coordination and hydrogen bonding networks formed by the antibiotic 4-aminosalicylic acid and the nootropic drug piracetam with silver and nickel cations, respectively; the silver complex formed viasolid-state reaction is anhydrous, while from solution its hydrated phase is obtained. [ABSTRACT FROM AUTHOR]

18-Crown[6] has been used to prepare new organic–inorganic complexes with Cs2CO3and aromatic mono-, di- and tricarboxylic acids (benzoic, isophthalic, terephthalic and trimesic acid). The complexes 18-crown[6]·Cs[trimH2] (1), 18-crown[6]·Cs[isoH] (2), 18-crown[6]·Cs2[isoH]2·2H2O (3), (18-crown[6])3·Cs3[trim]·9H2O (4), 18-crown[6]·Cs[ben]·H2O (5) and (18-crown[6])6·Cs4[tereH]2[tere]·5H2O (6) have been characterized by single-crystal X-ray diffraction. The thermal behaviour of 1, 2and 4has been investigated by a combination of solid-state techniques including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and variable temperature X-ray powder diffraction (VT-XRPD); in the case of 2hot stage microscopy was used to clarify its thermal behaviour. [ABSTRACT FROM AUTHOR]

The reaction of trans-1,4-diaminocyclohexane and piperazine with hydrochloric acid in dimethylsulfoxide or water led to new co-crystals and chloride salts, namely trans-1,4-diammoniocyclohexane dichloride dimethylsulfoxide 1, trans(ammonio-4-amino)cyclohexane monochloride 2, and piperazinium dichloride hemihydrate 3. The crystal structures show unexpected similarities to already noted organic and metal–organic derivatives. Furthermore, hot-stage microscopy, variable-temperature X-ray diffraction studies, and thermoanalytical measurements revealed decomposition reactions, solvent-free reaction pathways, and phase transition at temperatures between 160 and 210 °C. [ABSTRACT FROM AUTHOR]

A range of crystallisation experiments seeking to investigate the chloro/methyl structural similarity of o-toluic acid (o-methylbenzoic acid) and o-chlorobenzoic acid, including heterogeneous seeding experiments, has produced single crystals of both acids, and a 1 : 1 co-crystal (1) in which the chlorine atom and methyl group are disordered. All structures are characterized by the same hydrogen bonded ribbons, but they are not isostructural because of significant differences in the packing of the ribbons. Additional polymorphs of o-toluic acid were detected: microcrystalline form II, and form III with a large unit cell. The observed structures were compared with computationally generated isomorphs and ordered models, and alternative low energy structures generated in computational searches. These calculations show that the structures generated by interchanging the chloro and methyl groups are slightly less stable than the experimentally observed forms. The small energy differences associated with interchanging the two functional groups and between alternative packing arrangements of the hydrogen-bonded ribbons is consistent with the polymorphism of o-toluic acid and the observed disorder in the co-crystal. [ABSTRACT FROM AUTHOR]

The reactions of solid 1,3-dimethylbarbituric acid (DMBA) with vapours of NH3 and of the volatile amines NH2(CH3) and NH(CH3)2 have been investigated. The barbiturate salts (DMB) [NH4]DMB (1), [NH3(CH3)]DMB (2) and [NH2(CH3)2]DMB (3) have been characterized by X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis. The solid–gas reactions were monitored by UV–Vis spectroscopy in the solid state. Single crystal X-ray diffraction was used to characterize compounds 1, obtained by recrystallization from methanol, and 3, obtained by direct reaction of DMBA with aqueous NH(CH3)2. In the case of 3, recrystallization from methanol yields the salt [NH2(CH3)2][DMB]·2[DMBA] (3a), while recrystallization of 2 yields both the dimerization product [NH3(CH3)][(C6O3N2H6)2-OH]·2H2O (2a) and the hydurilate salt [NH3(CH3)]2[(C6O3N2H6)2] (2b), i.e. the product 2 is only accessible via the solid–gas reaction. [ABSTRACT FROM AUTHOR]

A new class of organic−inorganic complexes has been prepared by reaction in solution or by mechanical mixing of 15-Crown-5 or 18-Crown-6 ethers with MSO4(M Mn2, Cd2, Pb2) and/or H2SO4in stoichiometric amount. The complexes (15-Crown-5)Mn(H2O)2(HSO4)2(1), (15-Crown-5)Cd(H2O)2(HSO4)2(2), (15-Crown-5)(H7O3)(HSO4)2·H2O (3), (18-Crown-6)Pb(HSO4)2(4), and (18-Crown-6)(H5O2)(HSO4) (5) have been characterized by single-crystal X-ray diffraction. Compounds 1and 2undergo reversible water release−uptake processes, accompanied by a change in coordination at the metal centers; the dehydration and phase-transition processes have been investigated by DSC, TGA, and variable-temperature X-ray powder diffraction. [ABSTRACT FROM AUTHOR]

The cis−transisomerization of (5-C5H5)Fe(-CO)(CO)2, well known in solution, has been studied also in the solid state. The solid-state process has been investigated on polycrystalline samples by 13C CPMAS NMR spectroscopy and variable-temperature powder diffraction (VTXPD). It has been shown that an irreversible isomerization takes place at 80 °C. The reaction was also monitored by heating the sample at four different temperatures for periods of time and by determining the conversions by a 13C CPMAS spectrum. The transformation has been shown to obey a first-order Avrami−Erofe'ev rate law typical of a nucleation and growth mechanism. By the Sharp−Hancock plot of the isotherms it has been demonstrated that the process is not isokinetic, and the Avrami exponentials indicate that it passes from a one- to a three-dimensional growth. An activation energy of 164 ± 7 kJ/mol for the isomerization process has been found. [ABSTRACT FROM AUTHOR]

Co-crystals of dextro-(R,R), levo-(S,S), meso-(R,S) and racemic(R,R–S,S)-tartaric acid with pyrazine were obtained by manual kneading and slurry experiments; subsequent reactions in the solid state between these co-crystals and the various forms of tartaric acid in the solid state and viaslurry show that co-former exchange takes place according to the sequence of stability [(R,S)-ta]2·py > (S,S/R,R)-ta·py > (R,R)-ta·py or (S,S)-ta·py. [ABSTRACT FROM AUTHOR]

A crystal engineering approach affords the novel crystalline coordination polymer [C3H7N6]6[Yb(C2O4)4][NO3] (1) based on the interaction between the monomeric building-block [Yb(C2O4)4]5−and melamine creating a new structural motif in lanthanide chemistry with prospects for electromagnetic properties. [ABSTRACT FROM AUTHOR]

The polymorphism study of dibenzylsquaramide reveals the appearance of two forms sharing a solid–solid transition at the same temperature towards the highest melting polymorph. [ABSTRACT FROM AUTHOR]

In this communication we describe the solid-state preparation and structural characterization of the first two coordination complexes of the neuroleptic drug gabapentin, obtained by grinding together solid gabapentin and the inorganic salts ZnCl2 and CuCl2·2H2O. [ABSTRACT FROM AUTHOR]

On heating the hydrated complexes 18-Crown[6]·M[H2PO4]·xH2O (x= 2 for M = K, Rb; x= 1.5 for M = Cs), quantitatively prepared by mechanical mixing of crystalline 18-Crown[6] and M[H2PO4], to ca. 60 °C, water loss takes place, accompanied by the extrusion of the crown ether from the crystalline complex and followed by reconstruction of the inorganic phase M[H2PO4](M = K, Rb, Cs); the resulting solid mixture reverts to 18-Crown[6]·M[H2PO4]·xH2O (x= 2 for M = K, Rb; x= 1.5 for M = Cs) upon grinding in air. [ABSTRACT FROM AUTHOR]