300 research outputs found
A crystallographic route to understand drug solubility: the case of 4- aminoquinoline antimalarials
No full textMost Active Pharmaceutical Ingredients (API) can be prepared in various crystalline forms [1] displaying largely different physical/chemical properties and bioavailability. Salt formation represents the most common and simplest chemical way to modify the overall features but also the toxicity and biopharmaceutical availability of a drug substance. However, it is often unclear how and why the chemical and crystallographic characters can cooperate in determining these changes. We here face the problem from the perspective of the antiplasmodial drug piperaquine (PQ, C29H32Cl2N6) [2]. Being highly lipophilic, both neutral PQ and its commercial hydrogen phosphate tetrahydrate salt are poorly soluble in water, resulting in a reduced oral bioavailability. We synthesized five novel PQ salts and characterized them by both single crystal X–ray diffraction methods and T-dependent (20 – 50 oC) UV–Vis spectroscopy. Our aim was to explore possible relationships among non-covalent interaction networks in the crystals and measured solubilities. We also estimated changes in thermodynamic state functions related to the solvation process by DFT simulations, both in vacuo and in the solid state. We found that solubilities of PQ salts conform in most cases to the Hard and Soft Acid and Bases (HSAB) rules, i.e. less soluble compounds bear ions of comparable hardness. Crystal packing plays a far less important role, even though disorder-related entropic effects can influence the response of solubility to temperature. A possible take-home message is that intensive thermodynamic properties stem from a non-trivial cooperation several physicochemical effects. A first-principle understanding of the drug solubility cannot rely just on the description of the crystal packing, but must take into account the explicit evaluation of interaction energetics and pertinent electronic factors. [1] R. Hilfiker and M. von Raumer, Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development. 2019, Wiley-VCH, Weinheim (Germany). ISBN: 978-3-527-34040-8. [2] P. Sacchi, L. Loconte, G. Macetti, S. Rizzato and L. Lo Presti Crystal Growth Des. 2019. 19, 139
LA RESPONSABILITA' DELLE PERSONE GIURIDICHE PER I REATI AMBIENTALI
No full textThe thesis tackles the problems related to environmental crimes which have emerged in recent years, moving from a preliminary analysis concerning the reforms introduced in this area and paying particular attention to the case of so-called eco-crimes introduced in 2015.
The research provides important insights regarding the introduction of the company’s liability in the environmental field. The work deals with the changes occurred recently and the first case law emerging in relation to the subject of work and environmental safety, examining in particular the objective indictment criteria provided in article 5 of the Legislative Decree n. 231/2001.
Finally, the present work provides the analysis of the supervisory body’s figure and of the characteristics required to the same in relation to environmental standards, and the identification of the necessary requirements to make the organizational, managerial and controlling model adopted by the entities suitable and effective in view of prevention of the environmental crimes
Neutrons in chemistry : contributions of single crystal neutron diffraction to coordination chemistry
No full text1. Introduction
Single crystal neutron diffraction is the technique of choice for unambiguously and accurately locating hydrogen atoms even in the presence of nearby “heavy atoms”. Recent advances in instrumentation and neutron sources are opening up new possibilities: in particular the use of fairly small crystals and short data collection times.
2. Results and Discussion
We will report three examples to illustrate the power of this technique in inorganic chemistry:
1) the first unambiguous structural evidence for non-conventional hydrogen bonding between a water molecule and a metal center in trans-[PtCl2(NH3)(N-glycine)]∙H2O.[1]
2) The coordination geometries of the binary platinum hydrides [Pt2(P-P)2(H)3]+ (P-P = dppb: 1,4–Bis(diphenylphosphino)butane and dpe: 1,2–Bis(diphenylphosphino)ethane).
3) The unambiguous location of deuterium atoms in the deuterated form of RuH2(η2-H2)2(PCyp3)2 (Cyp = cyclopentyl) complex as a proof of the metal-mediated C-H activation.[2]
3. References
[1] Silvia Rizzato, Jacqueline Bergès, Sax A. Mason, Alberto Albinati and Jiří Kozelka, Angew. Chem. Int. Ed., in press.
[2] M. Grellier, L. Vendier, B. Chaudret, A. Albinati, S. Rizzato, S. A. Mason and S. Sabo-Etienne J. Am. Chem. Soc., 2005,127 (50), 17593
Morphological and structural effects of gels on coordination polymers crystallization
No full textThe use of gels or viscous materials as growth media for a wide range of compounds, including proteins and inorganic and organic compounds has been reported in the literature. In the presence of gel, sedimentation and convection currents are greatly suppressed and the mass transport of the molecules mainly occurs by diffusion, resulting, usually, in a lower nucleation density and a better crystal quality.[1a]
Here we report some new interesting phenomena observed in crystallization experiments of coordination compounds, such as, “coordination polymers”, by using gels as diffusion media.[1b]
By using a semi-liquid silica-gel system as a dispersion matrix, we were able to increase the quality of the crystals but also slow down the solvent loss, stabilizing the partially dehydrated structure of a very flexible porous framework. This has enabled an accurate determination of the dynamic behavior of the system during the desolvation process by using single crystal X-ray diffraction. Unit cells and structure solution has been obtained at any point during the process.
The improved stability of the crystals and the large flexibility of the network have also made possible to carry out in-situ high-pressure diffraction measurements.
Other important results concern the effects of gels on the macroscopic crystal shape and on the micromorphology of the crystal surfaces (Figure), and the capacity of gel media to promote the concomitant crystallization of topological isomers with a monotropic relationship.[2]
Funding from the Cariplo Foundation under the grant ‘‘2012‐0921” is gratefully acknowledged.
[1] a) K.H. Henisch, Crystals in Gels and Liesegang Rings, Cambridge University Press, Cambridge, 1998; b) L. Carlucci, G. Ciani, J. M. Garcìa-Ruiz, M. Moret, D. M. Proserpio and S. Rizzato Cryst. Growth Des., 2009, 9(12), 5024-5034.
[2] S.Rizzato et al., unpublished results
Assembling Metal Clusters with Covalent Linkers. Synthesis and Structure of a Roughly Planar Pt18 Derivative Containing Five Clusters Connected by sigma-Alkynyl Spacers
No full textSterically protected tri- and hexanuclear platinum clusters were used as building blocks for the high-yield synthesis of a first-generation dendrimer (see picture; tBu groups are omitted for clarity), which is chemically and thermally stable, and in which the cluster units are separated by conjugated 1,3,5-triethynylphenyl groups
Structural Characterization of 7-Chloro-4-(4-methyl-1-piperazinyl)quinoline Monohydrate
No full textThe crystal structure of the hydrated form of 7-chloro-4-(4-methyl-1-piperazinyl)
quinoline (BPIP) was determined by single-crystal X-ray diffraction analysis. This study
revealed a one-dimensional supramolecular network stabilized by hydrogen bonding
interactions between BPIP and water molecules. This compound represents one-half of a
piperaquine molecule, a member of the 4-aminoquinoline class of antimalarial treatments,
currently employed as a partner agent in modern combination therapies. As a simplified
structural analog, BPIP can serve as a critical model system for probing the intermolecular
interactions, physicochemical properties, and structural behavior of the parent compound.
As a result, conducting a thorough solid-state characterization of BPIP is critical for gaining
insight into its physical properties and verifying the material’s identity and purit
Alexander Hume's Of the Orthographie and Congruitie of the Britan Tongue: An Introduction
No full textPhase Stability and Morphology of Gel Grown Crystals: The Case of CdCl2-bpp Polymeric System
No full textA phenomenological study is carried out on a complex two-component di ff usion-reacting system in gel, that is, the Cd-1,3-bis(4-pyridyl) propane (Cd-bpp) coordination polymer. The latter can exist in three solid forms, which exploit a 1: 1 correspondence among the Cd /bpp ratio, the crystal structure and the crystal morphology (1 /2: bipyramids; 2 /3: needles; 1 /3: plates). The aim was to clarify the role of key physicochemical variables (reactant concentrations, composition of the solvent and density of the transport medium) in determining the chemical nature and the morphology of the final crystallization products. The gel method was tested in a variety of di ff erent crystallization configurations, including single and double di ff usion techniques. The density of the gel primarily a ff ects the morphology of the synthesized crystals, with denser media favouring the needle-like 2 /3 Cd-bpp species and diluted ones the 1 /2 Cd-bpp bipyramidal one. However, higher densities of the gel are generally associated to strained crystals. The solvent composition is also important, as for example the 1 /2 Cd-bpp bipyramids require at least a minimum amount of ethanol to appear. We demonstrated that in gel the strict " equality" stoichiometric criteria for metal-to-ligand ratios can be sometimes eluded, as non-equilibrium concentrations can be locally attained. In this respect, the crystallization geometry was proven to act as a key tool to influence the crystallization output, as it determines the direction and magnitude of the concentration gradients. Finally, the use of U tubes to perform one-pot screenings of a large part of the crystallization space is discussed
Mining the Cambridge Database for theoretical chemistry. Mi-{LJC}: A new set of Lennard-Jones-Coulomb atom-atom potentials for the computer simulation of organic condensed matter
No full textA set of 377 crystal structures extracted from the Cambridge Structural Database and matched to the experimental sublimation enthalpies of the corresponding materials is used to calibrate a new intermolecular potential field for organic compounds. The scheme includes usual R−6–R−12 Lennard-Jones dispersion–repulsion terms, with parameters for C, H, N, O, S and the halogens, fully transferable and unique for each atomic species without distinction among the hybridization states of carbon, or among valence states like carbonyl or ether oxygen or aza, nitro or nitrile nitrogen. This great economy in the number of parameters is countered by the need for using accurate coulombic terms over atomic point charges derived for each molecule from the fitting of the electrostatic potential (ESP method) of an ab initio MP2/6-31G** wavefunction. The potential scheme so derived, called Mi-LJC (Milano Lennard-Jones Coulomb), is able to reproduce the 377 sublimation enthalpies by the calculated lattice energies with an average percent deviation of 5% and a rmsd of 6.7 kJ mol−1. The potential scheme is also tested and proved applicable for the Monte Carlo simulation of some organic liquids, as well as for the molecular dynamic simulation of liquids and crystals
Molecular Dynamics Simulation of Molecular Crystals under Anisotropic Compression: Bulk and Directional Effects in Anthracene and Paracetamol
No full textParrinello−Rahman pressure-control algebra with an anisotropic external stress field, coupled with recently developed, accurate atom−atom potentials, has been incorporated into new modules of the Milano Chemistry Molecular Simulation (MiCMoS) computer program package for application in molecular dynamics (MD) simulations for organic crystals. Simulations were carried out for two widely different intermolecular environments, anthracene and paracetamol. The results reproduce quantitatively the anisotropic evolution obtained by pressure-dependent X-ray diffraction experiments in hydrostatic conditions. A less usual application concerns the probing of differently oriented uniaxial stresses, which for anthracene reveal a phase transition triggered by mechanical excitation along a direction parallel to the main molecular axis. For paracetamol, differences in compressibility along different crystal directions are borne out and are explained in molecular terms with reference to the hydrogen bonding scheme. Simulations of tensile stress, that is, negative pressure along different crystal directions, provide an estimate of yield points in a range of 0.2−0.5 GPa (2000−5000 atm) and indicate the weakest directions. On the basis of these results, we strongly suggest that classical MD in the atom−atom formulation, even in the absence of thorough treatment of quantum effects, but endowed with flexible algebra and coupled with carefully calibrated intermolecular potentials, can give reliable results of quantitative and semiquantitative character on the structural dynamics of organic crystals, providing an essential support to downstream studies of mechanical, optical, and electronic properties. Widespread use for further experience and validation is encouraged by the availability of the Fortran source codes
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