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In order to form a solid solution with its prodrug cortisone, hydrocortisone (cortisol) must violate Etter’s rule of hydrogen bonding. The preparation of a uniform product with the desired composition, which is hindered under a thermodynamic regime, can be achieved by supercritical assisted spray drying. The new phase enables fine-tuning of the phase’s composition as well as a higher dissolution rate for hydrocortisone., Multidrug products enable more effective therapies and simpler administration regimens, provided that a stable formulation is prepared, with the desired composition. In this view, solid solutions have the advantage of combining the stability of a single crystalline phase with the potential of stoichiometry variation of a mixture. Here a drug–prodrug solid solution of cortisone and cortisol (hydrocortisone) is described. Despite the structural differences of the two components, the new phase is obtained both from solution and by supercritical CO2 assisted spray drying. In particular, to enter the solid solution, hydrocortisone must violate Etter’s rules for hydrogen bonding. As a result, its dissolution rate is almost doubled.

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”.

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.

Four different structural models, which all fit the same X-ray powder pattern, were obtained in the structure determination of 4,11-di-fluoro-quinacridone (C

Among all possible NMR crystallography approaches for crystal-structure determination, crystal structure prediction - NMR crystallography (CSP-NMRX) has recently turned out to be a powerful method. In the latter, the original procedure exploited solid-state NMR (SSNMR) information during the final steps of the prediction. In particular, it used the comparison of computed and experimental chemical shifts for the selection of the correct crystal packing. Still, the prediction procedure, generally carried out with DFT methods, may require important computational resources and be quite time-consuming, especially if there are no available constraints to use at the initial stage. Herein, the successful application of this combined prediction method, which exploits NMR information also in the input step to reduce the search space of the predictive algorithm, is presented. Herein, this method was applied on mebendazole, which is characterized by desmotropism. The use of SSNMR data as constraints for the selection of the right tautomer and the determination of the number of independent molecules in the unit cell led to a considerably faster process, reducing the number of calculations to be performed. In this way, the crystal packing was successfully predicted for the three known phases of mebendazole. To evaluate the quality of the predicted structures, these were compared to the experimental ones. The crystal structure of phase B of mebendazole, in particular, was determined de novo by powder diffraction and is presented for the first time in this paper.

Ketoprofen–l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we studied deeply the solid-state characteristics of KLS to possibly identify new polymorphic drugs. Conducting a polymorph screening study and combining conventional techniques with solid-state nuclear magnetic resonance, we identified, for the first time, a salt/cocrystal polymorphism of the ketoprofen (KET)–lysine (LYS) system, with the cocrystal, KET–LYS polymorph 1 (P1), being representative of commercial KLS, and the salt, KET–LYS polymorph 2 (P2), being a new polymorphic form of KLS. Interestingly, in vivo pharmacokinetics showed that the salt polymorph has significantly higher absorption and, thus, different pharmacokinetics compared to commercial KLS (cocrystal), laying the basis for the development of faster-release/acting KLS formulations. Moreover, intrinsic dissolution rate (IDR) and electronic tongue analyses showed that the salt has a higher IDR, a more bitter taste, and a different sensorial kinetics compared to the cocrystal, suggesting that different coating/flavoring processes should be envisioned for the new compound. Thus, the new KLS polymorphic form with its different physicochemical and pharmacokinetic characteristics can open the way to the development of a new KET–LYS polymorph drug that can emphasize the properties of commercial KLS for the treatment of acute inflammatory and painful conditions.

Among GRAS molecules, α-amino acids have been extensively used to produce molecular salts and cocrystals of APIs thanks to their nontoxicity, ready availability, cheapness, and their zwitterionic n...

We demonstrate that liquid additives can exert inhibitive or prohibitive effects on the mechanochemical formation of multi-component molecular crystals, and report that certain additives unexpectedly prompt the dismantling of such solids into physical mixtures of their constituents. Computational methods were employed in an attempt to identify possible reasons for these previously unrecognised effects of liquid additives on mechanochemical transformations., Liquid additives can exert catalytic, inhibitive or prohibitive effects on the mechanochemical formation of multi-component molecular crystals.

Two new solvates of the widely used anthelminthic Praziquantel (PZQ) were obtained through mechanochemical screening with different liquid additives. Specifically, 2-pyrrolidone and acetic acid gave solvates with 1:1 stoichiometry (PZQ-AA and PZQ-2P, respectively). A wide-ranging characterization of the new solid forms was carried out by means of powder X-ray diffraction, differential scanning calorimetry, FT-IR, solid-state NMR and biopharmaceutical analyses (solubility and intrinsic dissolution studies). Besides, the crystal structures of the two new solvates were solved from their Synchrotron-PXRD pattern: the solvates are isostructural, with equivalent triclinic packing. In both structures acetic acid and 2-pyrrolidone showed a strong interaction with the PZQ molecule via hydrogen bond. Even though previous studies have shown that PZQ is conformationally flexible, the same syn conformation as the PZQ Form A of the C=O groups of the piperazinone-cyclohexylcarbonyl segment is involved in these two new solid forms. In terms of biopharmaceutical properties, PZQ-AA and PZQ-2P exhibited water solubility and intrinsic dissolution rate much greater than those of anhydrous Form A.

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A.

In the continuous search for multimodal systems with combined diagnostic and therapeutic functions, several efforts have been made to develop multifunctional drug delivery systems. In this work, through a covalent approach, a new class of fluorinated poly(lactic-co-glycolic acid) co-polymers (F-PLGA) were designed that contain an increasing number of magnetically equivalent fluorine atoms. In particular, two novel compounds, F

Herein is presented a rare example of salt/cocrystal polymorphism involving the adduct between ethionamide (ETH) and salicylic acid (SAL). Both the salt and cocrystal forms have the same stoichiometry and composition and are both stable at room temperature. The synthetic procedure was successfully optimized in order to selectively obtain both polymorphs. The two adducts' structures were thoroughly investigated by means of single-crystal X-ray diffraction, solid-state NMR spectroscopy, and density functional theory (DFT) calculations. From the solid-state NMR point of view, the combination of mono- and multinuclear experiments (1H MAS, 13C and 15N CPMAS, 1H-{14N} D-HMQC, 1H-14N PM-S-RESPDOR) provided undoubted spectroscopic evidence about the different positions of the hydrogen atom along the main N···H···O interaction. In particular, the 1H-14N PM-S-RESPDOR allowed N-H distance measurements through the 1H detected signal at a very high spinning speed (70 kHz), which remarkably agree with those derived by DFT optimized X-ray diffraction, even on a natural abundance real system. The thermodynamic relationship between the salt and the cocrystal was inquired from the experimental and computational points of view, enabling the characterization of the two polymorphs as enantiotropically related. The performances of the two forms in terms of dissolution rate are comparable to each other but significantly higher with respect to the pure ETH.

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.

In the continuous search for multimodal systems with combined diagnostic and therapeutic functions, several efforts have been made to develop multifunctional drug delivery systems. In this work, through a covalent approach, a new class of fluorinated poly(lactic-co-glycolic acid) co-polymers (F-PLGA) were designed that contain an increasing number of magnetically equivalent fluorine atoms. In particular, two novel compounds, F3 -PLGA and F9 -PLGA, were synthesized and their chemical structure and thermal stability were analyzed by solution NMR, DSC, and TGA. The obtained F-PLGA compounds were proven to form in aqueous solution colloidal stable nanoparticles (NPs) displaying a strong 19 F NMR signal. The fluorinated NPs also showed an enhanced ability to load hydrophobic drugs containing fluorine atoms compared to analogous pristine PLGA NPs. Preliminary in vitro studies showed high cell viability and the NP ability to intracellularly deliver and release a functioning drug.

The formation of a codrug, a cocrystal formed by two active pharmaceutical ingredients (APIs), between theophylline (THEO) and pyridoxine·HCl (PyrH+Cl–) is reported. The THEO PyrH+Cl– drug–drug cocrystal could turn out to be interesting in the pharmaceutical field because these two APIs are concurrently administered for asthma treatment. The codrug was characterized by a combined experimental and computational investigation by means of single crystal X-ray diffraction (SCXRD), solid-state NMR (SSNMR), and density functional theory (DFT) calculations. An exhaustive SSNMR study was performed to unravel the complex network of hydrogen bond interactions which was poorly defined by SCXRD. Several advanced two-dimensional SSNMR spectra such as 1H DQ MAS, 13C–1H HETCOR, 14N–1H J- and D-HMQC were acquired, taking advantage of the resolution and sensitivity improvement provided by indirect detection pulse sequences and very fast MAS at 70 kHz. These experiments, supported and completed by DFT calculations, were fu...

The system Ca(BH4)2–Mg2NiH4 is used as a model to prove the unique possibility to fully reverse the borohydride decomposition process even in cases where the decomposition reaction leads to undesired stable boron containing species (boron sinks). The formation of MgNi2.5B2 directly from Ca(BH4)2 or from CaB12H12 and amorphous boron allows an unexpectedly easy transfer of the boron atoms to reversibly form Ca(BH4)2 during rehydrogenation. In addition, to the best of our knowledge, the mutual destabilisation of the starting reactants is observed for the first time in Ca(BH4)2 based Reactive Hydride Composite (RHC) systems. A detailed account of dehydrogenation and rehydrogenation reaction mechanisms as the function of applied experimental conditions is given.

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

Heterogenization of catalytically important homogeneous catalysts on solid supports has become an expanding area of research. PNN and PONOP ruthenium pincer complexes were immobilized on a silica poly(allylamine) composite, BP-1 by a two-step Mannich reaction. The complexes on BP-1 were characterized by solid state NMR, FT-IR, elemental analysis, and metal digestion studies. Model solution experiments were carried out to determine the site of electrophilic substitution on the pyridine ring of the pincer complexes and revealed substitution in both the meta- and para-position. The catalytic reactivity of immobilized (PNN)RuH(Cl)(CO) and (PONOP)RuH(Cl)(CO) on BP-1 was studied for the dehydrogenative coupling of alcohols to esters with the liberation of H2. Moderate to good ester yields were realized with both immobilized systems without using the base required for the homogeneous reaction and also in the presence of KOH. The homogeneous model reactions required a base for ester formation. The amine functionality on BP-1 served as the base to generate the active pincer catalyst on the BP-1 surface. Both immobilized catalysts were recycled for multiple alcohol reaction cycles. Four-step control experiments were carried out using an alcohol and both immobilized systems. The results revealed the heterogeneity of the alcohol catalysis by both BP-1-Ru-PNN and BP-1-Ru-PONOP systems. This study has opened a new catalytic methodology for reactions where base is required for catalyst activation, by using a solid support with basic functionality.

In recent years many efforts have been devoted to the screening and the study of new solid-state forms of old active pharmaceutical ingredients (APIs) with salification or co-crystallization processes, thus modulating final properties without changing the pharmacological nature. Salts, hydrates/solvates, and cocrystals are the common solid-state forms employed. They offer the intriguing possibility of exploring different pharmaceutical properties for a single API in the quest of enhancing the final drug product. New synthetic strategies and advanced characterization techniques have been recently proposed in this hot topic for pharmaceutical companies. This paper reviews the recent progresses in the field particularly focusing on the characterization challenges encountered when the nature of the solid-state form must be determined. The aim of this article is to offer the state-of-the-art on this subject in order to develop new insights and to promote cooperative efforts in the fascinating field of API salt and cocrystal forms.

The Li-5(BH4)(3)NH complex hydride, obtained by ball milling LiBH4 and Li2NH in various molar ratios, has been investigated. Using X-ray powder diffraction analysis the crystalline phase has been indexed with an orthorhombic unit cell with lattice parameters a = 10.2031(3), b = 11.5005(2), and c = 7.0474(2) angstrom at 77 degrees C. The crystal structure of Lis(BH4)(3)NH has been solved in space group Pnma, and refined coupling density functional theory (DFT) and synchrotron radiation X-ray powder diffraction data have been obtained for a 3LiBH(4):2Li(2)NH ball-milled and annealed sample. Solid-state nudear magnetic resonance measurements confirmed the chemical shifts calculated by DFT from the solved structure. The DFT calculations confirmed the ionic character of this lithium-rich compound. Each Li+ cation is coordinated by three BH4- and one NH2- anion in a tetrahedral configuration. The room temperature ionic conductivity of the new orthorhombic compound is close to10(-6) S/cm at room temperature, with activation energy of 0.73 eV.

In this work we investigated in detail the effects of nitric acid on the surface chemistry of two carbons, activated by steam and by phosphoric acid, meant to identify the nature and the concentration of the oxidized surface species. To this aim, the oxidized carbons were characterized by means of a large number of complementary techniques, including micro-Raman spectroscopy, N2 physisorption, Boehm titration method, 13C solid state nuclear magnetic resonance, X-ray photoelectron spectroscopy, diffuse reflectance infrared and inelastic neutron scattering spectroscopy. Carboxylic and carboxylate groups are mainly formed, the latter stabilized by the extended conjugation of the π electrons and being more abundant on small and irregular graphitic platelets. We demonstrated that the presence of oxygen-containing groups acts against the palladium dispersion and causes the appearance of an appreciable induction time in hydrogenation reactions. The carbon with more oxygenated surface species (and in particular more carboxylate groups) must be chosen in the hydrogenation of polar substrates, while it is detrimental to the hydrogenation of nonpolar substrates.

Vinpocetine is a poorly water soluble weakly basic drug (pKa = 7.1) used for the treatment of several cerebrovascular and cognitive disorders. Because existing formulations exhibit poor bioavailability and scarce absorption, a dosage form with improved pharmacokinetic properties is highly desirable. Cocrystallization represents a promising approach to generate diverse novel crystal forms and to improve the aqueous solubility and in turn the oral bioavailability. In this article, a novel ionic cocrystal of vinpocetine is described, using boric acid as a coformer, and fully characterized (by means of differential scanning calorimetry, solid-state nuclear magnetic resonance, powder and single-crystal X-ray diffraction, and powder dissolution test). Pharmacokinetic performance was also tested in a human pilot study. This pharmaceutical ionic cocrystal exhibits superior solubilization kinetics and modulates important pharmacokinetic values such as maximum concentration in plasma (Cmax), time to maximum concentration (tmax), and area under the plasma concentration-time curve (AUC) of the poorly soluble vinpocetine and it therefore offers an innovative approach to improve its bioavailability.

The combination of a phase-modulated (PM) saturation pulse and symmetry-based dipolar recoupling into a rotational-echo saturation-pulse double-resonance (RESPDOR) sequence has been employed to measure

Four metal halides of the (tBuPCN)NiX family [X = F (1), Cl (2), Br (3), or I (4); PCN = 1-[3-[(di-tertbutylphosphino) methyl]phenyl]-1H-pyrazole] have been prepared through a direct reaction of the corresponding anhydrous NiX2 salts and the unsymmetrical PCN pincer ligand. Structural information from single-crystal X-ray data, 19F solution nuclear magnetic resonance, and combined electrochemical results [cyclic voltammetry (CV) and in situ electron paramagnetic resonance spectro-electrochemistry] reveal that the fluoride complex 1 is different from the other halides 2-4 in terms of electro-oxidation behavior (presence of three anodic peaks instead of one in the CV profile). 1 is also different from its symmetrical analogue (tBuPCP)NiF in terms of halogen-bonding capability toward the halogen-bond donor, iodopentafluorobenzene (C6F5I, IPFB). The positive ?S° value for the formation of the 1···IPFB adduct inferred from the van't Hoff plots is in agreement with the existence of (1·H2O) aggregates in solution, not present in 2-4. The high nucleophilicity of the fluoride ligand and the simultaneous presence of electrophilic (acidic) protons on the sidearm of the pyrazole ligand are at the origin of the observed phenomena.

The possible existence of mixed methylammonium (MA)/dimethylammonium (DMA) lead bromide hybrid perovskites of general formula MA1–xDMAxPbBr3 (0 ≤ x ≤ 1) was investigated. A combined X-ray diffraction and solid-state nuclear magnetic resonance approach indicates that DMA can be incorporated up to about x = 0.30 while retaining the cubic lattice of MAPbBr3. By increasing the DMA content (x), the absorption shows a progressive blue shift and the band gap moves from about 2.17 eV (x = 0) to about 2.23 (x = 0.30) with a concomitant slightly faster recombination in the mixed cation powders.

The possible existence of mixed methylammonium (MA)/dimethylammonium (DMA) lead bromide hybrid perovskites of general formula MA

Chemical shift anisotropy (CSA) is a sensitive probe of electronic environment at a nucleus, and thus, it offers deeper insights into detailed structural and dynamic properties of different systems, for example, chemical, biological, and materials. Over the years, massive efforts have been made to develop recoupling methods that reintroduce CSA interaction under magic angle spinning (MAS) conditions. Most of them require slow or moderate MAS (≤20 kHz) and isotopically enriched samples. On the other hand, to the best of the authors' knowledge, no

Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a versatile characterization technique that can provide a plethora of information complementary to single crystal X-ray diffraction (SCXRD) analysis. Herein, we present an experimental and computational investigation of the relationship between the geometry of a halogen bond (XB) and the SSNMR chemical shifts of the non-quadrupolar nuclei either directly involved in the interaction (15 N) or covalently bonded to the halogen atom (13 C). We have prepared two series of X-bonded co-crystals based upon two different dipyridyl modules, and several halobenzenes and diiodoalkanes, as XB-donors. SCXRD structures of three novel co-crystals between 1,2-bis(4-pyridyl)ethane, and 1,4-diiodobenzene, 1,6-diiodododecafluorohexane, and 1,8-diiodohexadecafluorooctane were obtained. For the first time, the change in the 15 N SSNMR chemical shifts upon XB formation is shown to experimentally correlate with the normalized distance parameter of the XB. The same overall trend is confirmed by density functional theory (DFT) calculations of the chemical shifts. 13 C NQS experiments show a positive, linear correlation between the chemical shifts and the C-I elongation, which is an indirect probe of the strength of the XB. These correlations can be of general utility to estimate the strength of the XB occurring in diverse adducts by using affordable SSNMR analysis.

In this paper, Li2(BH4)(NH2) and Li4(BH4)(NH2)3 compounds were prepared through different synthesis approaches (ball milling, annealing treatment and liquid quenching) and characterized by X-ray diffraction and solid-state NMR. The thermal analysis of samples with various (LiBH4)1−x(LiNH2)x compositions (0 ≤ x ≤ 1) have been performed by High Pressure DSC. Lattice constants, chemical shifts and relative phase stability obtained by DFT turned out in good agreement with experimental data. On the basis of a combination of ab-initio calculations and experimental data, a thermodynamic assessment of the LiBH4 LiNH2 system has been obtained using the Calphad method. Li2(BH4)(NH2) has been identified as a metastable phase and a peritectic melting of Li4(BH4)(NH2)3 compound has been established.

We provide a review of the state-of-the-art of solid-state nuclear magnetic resonance (SSNMR) spectroscopy applied to the study of the halogen bond interaction. The SSNMR approach yields a wealth of information complementary or alternative to X-ray crystallography, thus providing similar, yet different insight into the halogen bond. Indeed, SSNMR parameters can be used to probe powders at both the molecular and crystal structure level, without needing highly crystalline samples or special preparations. This Highlight article serves as a tutorial example of the SSNMR strategies to characterize the halogen bond, and is based on a comprehensive literature survey and the discussion of relevant NMR parameters. Unresolved problems and future directions in the field are also summarized.

The industrial synthesis of perinone results in a mixed crystal containing an isomer mixture of trans- and cis-perinone. The isomers are separated by treatment with alcoholic KOH, which leads to a pale yellow precipitate and a yellow solution. The precipitate is subsequently hydrolyzed to produce pure trans-perinone (Pigment Orange 43). The yellow solution is treated with dilute acids to give cis-perinone (Pigment Red 194). The chemical structure and the stoichiometry of the intermediate pale yellow precipitate has never been determined, although this intermediate has been produced on a multi-ton scale for more than 80 years. The intermediate was assumed to be a “potassium hydroxide addition compound”. X-ray single-crystal analyses reveal that this assumption is wrong. The KOH/ethanol treatment actually causes a double ring-opening of the perinone. This results in the tetra-potassium salt of 4,8-bis(benzimidazolato)-naphthalene-1,5-dicarboxylate. Two phases were isolated: The α-phase, K4[C26H12N4O4]·3C2H5OH·6H2O, from the industrial synthesis and the β-phase, 1.5(K4[C26H12N4O4])·5C2H5OH·4H2O, from a recrystallization in KOH/ethanol. The molecular and crystal structures are confirmed by solid-state NMR spectroscopy through combination of 13C CPMAS and MAS experiments, which revealed that the solvent layers in the crystals show a highly dynamic solvent disorder in the solid state. The intermediate of cis-perinone, which is formed in the isomer separation step, has been isolated as well. Also this intermediate has a ring-opened molecular structure, as revealed by single-crystal X-ray diffraction.

A series of halogenated imidazo[1,5-a]pyridines was prepared and their structural and optical properties investigated. The products were characterized by spectroscopic techniques and their optical properties discussed in relation to their chemical structure. We were able to triplicate the luminescence quantum yields (φ) in solution for three different imidazo[1,5-a]pyridine derivatives, depending on the halogen nature of the substituent on the imidazo[1,5-a]pyridine moiety. The effect of the halogen and of the geometrical and chemical characteristics of the molecular skeleton on the crystal packing was studied in the solid state by single crystal X-ray diffraction. At the same time, the possible presence of halogen bonds was evaluated through solid-state NMR analysis.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Praziquantel is the only available drug to treat Schistosomiasis. However, its utilization is limited by many drawbacks, including the high therapeutic dose needed, resulting in large tablets and capsules difficult to be swallowed, especially from pediatric patients. In this study, an alternative option to overcome these disadvantages is proposed: to switch to a novel crystalline polymorph of racemic compound praziquantel. The preparation of the crystalline polymorph was realized via a neat grinding process in a vibrational mill. The new phase (Form B) was chemically identical to the starting material (as proved by HPLC, 1H NMR, and polarimetry), but showed different physical properties (as evaluated by SEM, differential scanning calorimetry, thermogravimetry, ATR-FTIR spectroscopy, X-ray powder diffraction, and solid-state NMR). Furthermore, the crystal structure of the new phase was solved from the powder synchrotron X-ray diffraction pattern, resulting in a monoclinic C2/c cell and validated by DFT-D calculation. Moreover the simulated solid-state NMR 13C chemical shifts were in excellent agreement with the experimental data. The conversion of original praziquantel into Form B showed to affect positively the water solubility and the intrinsic dissolution rate of praziquantel. Both the in vitro and in vivo activity against Schistosoma mansoni were maintained. Our findings suggest that the new phase, that proved to be physically stable for at least one year, is a promising product for designing a new praziquantel formulation.

Solid-state NMR (SSNMR) techniques yield a wealth of information complementary to, or alternative to, X-ray crystallography, thus providing similar yet different insights into the investigation of supramolecular systems. Indeed, SSNMR parameters can be used to probe powders at both the molecular and crystal structure level, without needing highly crystalline samples or special preparations. This chapter aims to provide an overview of the recent literature, paying particular attention to the study of weak interactions such as hydrogen and halogen bonds, in supramolecular systems through solid-state NMR investigations. Selected systems will be also discussed.

The crystal structure of a mixed amide-imide phase, RbMgND2ND, has been solved in the orthorhombic space group Pnma (a = 9.55256(31), b = 3.70772(11) and c = 10.08308(32) Å). A new metal amidehydride solid solution, Rb(NH2)xH(1−x), has been isolated and characterized in the entire compositional range. The profound analogies, as well as the subtle differences, with the crystal chemistry of KMgND2ND and K(NH2)xH1−x are thoroughly discussed. This approach suggests that the comparable performances obtained using K- and Rb-based additives for the Mg(NH2)2-2LiH and 2LiNH2− MgH2 hydrogen storage systems are likely to depend on the structural similarities of possible reaction products and intermediates.