Solid State Investigation and Characterization of a Nepadutant Precursor: Polymorphic and Pseudopolymorphic Forms of MEN11282

MEN11282 (<b>1</b>) is a precursor of nepadutant (MEN11420), a potent and selective antagonist at the human tachykinin NK-2 receptor (hNK-2), that has been evaluated in clinical trials for different therapeutic indications. Three crystalline forms of <b>1</b> were identified and characterized by both single crystal and powder X-ray diffraction (SCXRD and XRPD): a monohydrate (<b>1</b>·<b>H</b>_<b>2</b><b>O</b>, SCXRD) and two different anhydrous forms, namely, <b>1_α</b> and <b>1_β</b> (XRPD). Because of the relevance that the solid form of a substance of pharmaceutical interest plays during the manufacturing process, variable temperature powder X-ray diffraction (VT-XRPD) in conjunction with differential scanning calorimetry were used to investigate the behavior of the different solid forms of <b>1</b>. The rationale for the dehydration and hydration process involving <b>1·H</b>_<b>2</b><b>O</b> and <b>1_α</b> and the stability of <b>1_β</b> toward water uptake is provided based on their crystal packings

Similar but Different: The Case of Metoprolol Tartrate and Succinate Salts

The solid-state structure and behavior of tartrate (MT-o) and succinate (MS-m) metoprolol salts have been studied with a combined experimental (X-ray diffraction by both single crystal and microcrystalline powder and differential scanning calorimetry) and modeling approach (molecular dynamics and molecular orbital calculations). In spite of their close similarity at the molecular level in the corresponding crystal lattices, calorimetric data suggest for MS-m a slightly greater cohesive energy. In addition and more importantly, they show significantly different “macroscopic” behaviors: MS-m undergoes a reversible anisotropic lattice expansion/contraction upon temperature change and once melted quickly recrystallizes to the starting crystal phase. On the other hand, MT-o expands/contracts isotropically, and upon cooling from the melt gives an amorphous solid, which, at ambient conditions, takes 6 days to completely revert to the starting crystal form. Both findings are relevant in the field of the pharmaceutical drug development; i.e., when the phase purity of these active pharmaceutical ingredients is assessed, discussed, and possibly related to drug product formulations and manufacturing methods

Solid–Solid Transition between Hydrated Racemic Compound and Anhydrous Conglomerate in Na-Ibuprofen: A Combined X‑ray Diffraction, Solid-State NMR, Calorimetric, and Computational Study

A combined X-ray diffraction (XRD), solid state nuclear magnetic resonance (SSNMR), differential scanning calorimetry (DSC), and modeling approach has been applied to study the solid–solid transition of ibuprofen sodium salt between the hydrated racemic compound (RS-H) and the anhydrous conglomerate (RS-A). For comparison, the dihydrate → anhydrous transformation of the sodium salt of the pure S-enantiomer of ibuprofen was also investigated by means of SSNMR and DSC. All the solid state studies indicate that the RS-H → RS-A transition is fully reversible under different experimental conditions [temperature, pressure (ambient and vacuum), and type of atmosphere (N₂, air, and static dry by P₂O₅)]. The static and dynamic disorder affecting the isobutyl fragment in RS-H, already observed by SSNMR, has been further investigated by single crystal XRD and computational techniques. On these grounds, a model for the dihydrate → anhydrous solid–solid transformations is proposed

Structural insights into a versatile macrocyclic family based on 2,5-diphenyl[1,3,4]oxadiazole: a combined X-ray diffraction and computational study

<p>By means of X-ray diffraction analysis the solid state structure of the diprotonated species of the ligand <b>L1_Me</b> (9,12-Dimethyl-9,12,27,28-tetraaza-15,18-dithia-29-oxatetracyclo[24.2.1.0^2,7.0^20,25]-enneicosa-2,4,6,20,22,24,26,28¹-octaene), a macrocycle containing a <i>mixed</i> sulfur-nitrogen set of donor atoms decorated with the PPD signaling group, and of its dinuclear platinum complex was investigated . The information retrieved were used as starting point for a deep computational study. Then, with the aim to get hints for the design of possibly improved strictly related receptors, the molecular modeling study was extended to the <i>all</i>-nitrogen ligand <b>L2_H</b> which, at variance with <b>L1_Me,</b> has four nitrogen atoms as donors. Finally, to complete the modeling investigation we design the related ligands <b>L1_H</b>, <b>L2_Me</b> and <b>L3_H</b> on which computational studies were performed. The aim was to investigate and try to rationalise the parameters affecting the overall shape of the host-guest adducts.</p

New Aryl α‑Diimine Palladium(II) Catalysts in Stereocontrolled CO/Vinyl Arene Copolymerization

The effect of the catalyst structure on the stereoselectivity of CO/vinyl arene copolymerization has been studied with the aim of developing catalytic systems able to improve the yields while maintaining the high degree of copolymer isotacticity previously obtained using achiral nitrogen ligands. Aryl α-diimine ligands having extended aromatic rings (Ar)₂DABMe₂, with Ar = 1-C₁₀H₇ (<b>e</b>), 1-C₁₄H₉ (<b>f</b>), 9-C₁₄H₉ (<b>g</b>), have been synthesized, and α-diimine coordination to cationic methylpalladium complexes has been investigated in solution, by means of NMR spectroscopy, and in the solid state for [Pd­(Me)­(NCMe)­((9-C₁₄H₉)₂DABMe₂)]­[PF₆] (<b>2g</b>). The performance of these catalysts in CO/vinyl arene copolymerization, under mild conditions, was analyzed in terms of productivity and degree of stereoregularity of the resulting polyketones. In comparison with previous results, a remarkable enhancement in the yield of isotactic copolymer was observed using the new achiral 9-anthryl α-diimine ligand <b>g</b>, confirming that the ortho disubstitution and the extended aromatic rings play key roles in obtaining good stereoselectivity and good productivity. To perform a structural analysis of the first steps of the CO/<i>p</i>-methylstyrene copolymerization, complex [Pd­(Me)­(CO)­((9-C₁₄H₉)₂DABMe₂)]­[BAr′₄] (<b>3g</b>) was used as a starting point: NMR investigation reveals the stereoselective formation of the olefin/CO/olefin insertion product (<b>6g</b>), which prevalently exists in solution in only one diastereoisomeric form, thus justifying the observed high polymer isotacticity

New Aryl α‑Diimine Palladium(II) Catalysts in Stereocontrolled CO/Vinyl Arene Copolymerization

The effect of the catalyst structure on the stereoselectivity of CO/vinyl arene copolymerization has been studied with the aim of developing catalytic systems able to improve the yields while maintaining the high degree of copolymer isotacticity previously obtained using achiral nitrogen ligands. Aryl α-diimine ligands having extended aromatic rings (Ar)₂DABMe₂, with Ar = 1-C₁₀H₇ (<b>e</b>), 1-C₁₄H₉ (<b>f</b>), 9-C₁₄H₉ (<b>g</b>), have been synthesized, and α-diimine coordination to cationic methylpalladium complexes has been investigated in solution, by means of NMR spectroscopy, and in the solid state for [Pd­(Me)­(NCMe)­((9-C₁₄H₉)₂DABMe₂)]­[PF₆] (<b>2g</b>). The performance of these catalysts in CO/vinyl arene copolymerization, under mild conditions, was analyzed in terms of productivity and degree of stereoregularity of the resulting polyketones. In comparison with previous results, a remarkable enhancement in the yield of isotactic copolymer was observed using the new achiral 9-anthryl α-diimine ligand <b>g</b>, confirming that the ortho disubstitution and the extended aromatic rings play key roles in obtaining good stereoselectivity and good productivity. To perform a structural analysis of the first steps of the CO/<i>p</i>-methylstyrene copolymerization, complex [Pd­(Me)­(CO)­((9-C₁₄H₉)₂DABMe₂)]­[BAr′₄] (<b>3g</b>) was used as a starting point: NMR investigation reveals the stereoselective formation of the olefin/CO/olefin insertion product (<b>6g</b>), which prevalently exists in solution in only one diastereoisomeric form, thus justifying the observed high polymer isotacticity

A Biphenol-Based Chemosensor for Zn^II and Cd^II Metal Ions: Synthesis, Potentiometric Studies, and Crystal Structures

We synthesized and characterized the ligand <i>N</i>,<i>N</i>′-bis­[(2,2′-dihydroxybiphen-3-yl)­methyl]-<i>N</i>,<i>N</i>′-dimethylethylenediamine (<b>L</b>), which contains two biphenol moieties linked as side arms to an <i>N</i>,<i>N</i>′-dimethylethylenediamine scaffold. The ligand is highly soluble in a 50/50 (v/v) water/ethanol mixture and, in its deprotonated form H_–2<b>L</b>^2–, is able to coordinate transition-metal ions such as Ni^II, Zn^II, Cu^II, Cd^II, and Pd^II. The crystal structures of [Ni­(H_–2<b>L</b>)·2<i>n</i>-BuOH], [Ni­(H_–2<b>L</b>)·2MeOH], [Cd­(H_–2<b>L</b>)·2DMF], [Cu­(H_–2<b>L</b>)­(DMF)], and [Pd­(H_–2<b>L</b>)­(DMF)] were also determined and described. Potentiometric titrations were carried out in a mixed solvent with Zn^II, Cu^II, and Ni^II metal ions to determine the acid–base and stability constants. <b>L</b> was highly fluorescent in the visible range (400 nm). Moreover, its emission intensity increased upon the addition of Zn^II or Cd^II ions in an ethanol/water solution and behaved as a chemosensor for the presence of these ions in the solution

Synthesis, Basicity, Structural Characterization, and Biochemical Properties of Two [(3-Hydroxy-4-pyron-2-yl)methyl]amine Derivatives Showing Antineoplastic Features.

The <i>N</i>,<i>N</i>′-bis­[(3-hydroxy-4-pyron-2-yl)­methyl]-<i>N</i>,<i>N</i>′-dimethylethylendiamine (malten) and 4,10-bis­[(3-hydroxy-4-pyron-2-yl)­methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (maltonis) were synthesized and characterized. The acid–base behavior, structural characterizations, and biochemical studies in aqueous solution were reported. Each compound contains two 3-hydroxy-2-methyl-4-pyrone units (maltol) symmetrically spaced by a polyamine fragment, the 1,4-dimethylethylendiamine (malten), or the 1,7-dimethyl-1,4,7,10-tetraazacyclododecane (maltonis). They are present at physiological pH 7.4 in the form of differently charged species: neutral but in a zwitterion form for malten and monopositive with an internal separation of charges for maltonis. Malten and maltonis are both able to alter the chromatin structure inducing the covalent binding of genomic DNA with proteins, a feature consistent with the known antiproliferative activity exerted by this class of molecules. Solid-state results and MD simulations in water show that malten, because of its molecular topology, should be more prone than maltonis to act as a donor of H-bonds in intermolecular contacts, thus it should give a better noncovalent approach with the negatively charged DNA. Crystal structures of [H₂malten]²⁺ and [H₂maltonis]²⁺ cations were also reported

Modulating the Sensor Response to Halide Using NBD-Based Azamacrocycles

Ligand <b>L</b> (2,6-bis­{[7-(7-nitrobenzo­[1,2,5]­oxadiazole-4-yl)-3,10-dimethyl-1,4,7,10-tetraazacyclododeca-1-yl]­methyl}­phenol) is a fluorescent sensor that is useful for detecting Cu­(II), Zn­(II), and Cd­(II). Some of the complexes formed are able to sense the presence of halides in solution. <b>L</b> passes through the cellular membrane, becoming fluorescent inside cells. The H_<i>–</i>1<b>L</b>^<i>–</i> species is able to form dinuclear complexes with [M₂H_<i>–</i>1<b>L</b>]³⁺ stoichiometry with Cu­(II), Zn­(II), and Cd­(II) ions, experiencing a CHEF effect upon metal coordination in an acetonitrile/water 95:5 (v/v) solution. In all three of the complexes investigated, the metal cations are coordinatively unsaturated and can therefore bind secondary ligands as anionic species. The crystal structure of [Cd₂(H_<i>–</i>1<b>L</b>)­Cl₂]­(ClO₄)·4H₂O is discussed. The Zn­(II) complex behaves as an OFF–ON sensor for fluoride and chloride anions

Modulating the Sensor Response to Halide Using NBD-Based Azamacrocycles

Ligand <b>L</b> (2,6-bis­{[7-(7-nitrobenzo­[1,2,5]­oxadiazole-4-yl)-3,10-dimethyl-1,4,7,10-tetraazacyclododeca-1-yl]­methyl}­phenol) is a fluorescent sensor that is useful for detecting Cu­(II), Zn­(II), and Cd­(II). Some of the complexes formed are able to sense the presence of halides in solution. <b>L</b> passes through the cellular membrane, becoming fluorescent inside cells. The H_<i>–</i>1<b>L</b>^<i>–</i> species is able to form dinuclear complexes with [M₂H_<i>–</i>1<b>L</b>]³⁺ stoichiometry with Cu­(II), Zn­(II), and Cd­(II) ions, experiencing a CHEF effect upon metal coordination in an acetonitrile/water 95:5 (v/v) solution. In all three of the complexes investigated, the metal cations are coordinatively unsaturated and can therefore bind secondary ligands as anionic species. The crystal structure of [Cd₂(H_<i>–</i>1<b>L</b>)­Cl₂]­(ClO₄)·4H₂O is discussed. The Zn­(II) complex behaves as an OFF–ON sensor for fluoride and chloride anions