Molecular cocrystals of carboxylic acids. XXVII - An investigation into the use of triphenylphosphine oxide cocrystals for non-linear optics: the crystal structure of the adduct of triphenylphosphine oxide with N-methylpyrrole-2-carboxylic acid

Four adducts of triphenylphosphine oxide with aromatic carboxylic acids have been synthesized and tested for second-order non-linear optical properties. These were with N-methylpyrrole-2-carboxylic acid (I), indole-2-carboxylic acid (2), 3-dimethylaminobenzoic acid (3), and thiophen-2-carboxylic acid (4). Compound (1) produced clear, colourless crystals (space group P2(1)2(1)2(1) With a 9.892(1), b 14.033(1), c 15.305(1) Angstrom, Z 4) which allowed the structure to be determined by X-ray diffraction.

3-Nitrophenol-4,4 '-bipyridyl N,N '-dioxide (2/1): a DFT study and CSD analysis of DPNO molecular complexes

The title 2:1 complex of 3-nitrophenol (MNP) and 4,4'-bipyridyl N, N'-dioxide (DPNO), 2C(6)H(5)NO(3)center dot C(10)H(8)N(2)O(2) or 2MNP center dot DPNO, crystallizes as a centrosymmetric three-component adduct with a dihedral angle of 59.40 (8)degrees between the planes of the benzene rings of MNP and DPNO (the DPNO moiety lies across a crystallographic inversion centre located at the mid-point of the C-C bond linking its aromatic rings). The complex owes its formation to O-H center dot center dot center dot O hydrogen bonds [O center dot center dot center dot O = 2.605 (3) angstrom]. Molecules are linked by intermolecular C-H center dot center dot center dot O and C-H center dot center dot center dot N interactions forming R(2)(1) (6) and R(2)(2) (10) rings, and R(6)(6) (34) and R(4)(4) (26) macro-rings, all of which are aligned along the [(1) over bar 01] direction, and R(2)(2) (10) and R(2)(1) (7) rings aligned along the [010] direction. The combination of chains of rings along the [(1) over bar 01] and [010] directions generates the three-dimensional structure. A total of 27 systems containing the DNPO molecule and forming molecular complexes of an organic nature were analysed and compared with the structural characteristics of the dioxide reported here. The N-O distance [1.325 (2) angstrom] depends not only on the interactions involving the O atom at the N-O group, but also on the structural ordering and additional three-dimensional interactions in the crystal structure. A density functional theory (DFT) optimized structure at the B3LYP/6-311G(d,p) level is compared with the molecular structure in the solid state.

An insight into dapsone co-crystals: sulfones as participants in supramolecular interactions

Agência Financiadora: Fundação para a Ciência e a Tecnologia - Pest-OE/QUI/UI0100/2013; PTDC/CTM-BPC/122447/2010; RECI/QEQ-QIN/0189/2012; SFRH/BPD/78854/2011

Association supramoléculaire à l'état solide des fullerènes C60 et C70 avec le centrohexaindane

Le fullerène C60, une molécule sphérique, et le C70, un analogue ellisoïde, sont des composés aromatiques convexes constitués exclusivement d'atomes de carbone. La nature aromatique de la surface de ces cages de carbone rend possible leur association à l'état solide avec d'autres molécules aromatiques de topologie complémentaire. En particulier, l'association des fullerènes avec des composés présentant des motifs concaves aromatiques, via une association de type concave-convexe, est favorable. En effet, les interactions π•••π de type concave-convexe sont amplifiées grâce à la complémentarité topologique des partenaires impliqués. Le centrohexaindane est un hydrocarbure non planaire rigide qui a été synthétisé pour la première fois en 1988 par Kuck et collaborateurs. Cette molécule possède quatre surfaces aromatiques concaves orientées dans une géométrie tétraédrique qui sont susceptibles d'interagir favorablement avec les fullerènes. Nous avons ainsi avec succès cocristallisé le centrohexaindane avec les fullerènes C60 et C70. Puis, nous avons étudié les assemblages à l'état solide entre le centrohexaindane et les fullerènes par l'analyse des structures résolues via diffraction des rayons X. Les surfaces concaves aromatiques du centrohexaindane se sont révélées être propices à une association avec les fullerènes C60 et C70 via des interactions π•••π de type concave-convexe, tel que prévu. En outre, nous avons découvert que les liaisons C-H situées à la périphérie du centrohexaindane prennent part à une multitude de contacts C-H•••π avec les molécules de fullerène. Les échantillons de cocristaux composés de centrohexaindane et de fullerène ont aussi été caractérisés par diffraction de poudre des rayons X et par analyse thermogravimétrique dans le but d'en évaluer l'homogénéité.

Pyrene-Modified quartz crystal microbalance for the detection of polynitroaromatic compounds

The synthesis of a dithiol-functionalized pyrene derivative is reported, together with studies of interactions between this receptor (and other related pyrenes) and nitroaromatic compounds (NACs), in both solution and in the solid state. Spectroscopic analysis in solution and X-ray crystallographic analysis of cocrystals of pyrene and NACs in the solid state indicate that supramolecular interactions lead to the formation of defined pi-pi stacked complexes. The dithiolfunctionalized pyrene derivative can be used to modify the surface of a gold quartz crystal microbalance (QCM) to create a unique π-electron rich surface, which is able to interact with electron poor aromatic compounds. For example, exposure of the modified QCM surface to the nitroaromatic compound 2,4-dinitrotoluene (DNT) in solution results in a reduction in the resonant frequency of the QCM as a result of supramolecular interactions between the electron-rich pyrenyl surface layer and the electron-poor DNT molecules. These results suggest the potential use of such modified QCM surfaces for the detection of explosive NACs.

Crystal Engineering of an Anti-HIV Drug Based on the Recognition of Assembling Molecular Frameworks

A rational strategy was employed for design of an orthorhombic structure of lamivudine with maleic acid. On the basis of the lamivudine saccharinate structure reported in the literature, maleic acid was chosen to synthesize a salt with the anti-HIV drug because of the structural similarities between the salt formers. Maleic acid has an acid-ionization constant of the anti first proton and an arrangement of their hydrogen bonding functionalities similar to those of saccharin. Likewise, there is a saccharin-like conformational rigidity in maleic acid because of the hydrogen-bonded ring formation and the Z-configuration around the C=C double bond. As was conceivably predicted, lamivudine maleate assembles into a structure whose intermolecular architecture is related to that of saccharinate salt of the drug. Therefore, a molecular framework responsible for crystal assembly into a lamivudine saccharinate-like structure could be recognized in the salt formers. Furthermore, structural correlations and structure-solubility relationships were established for lamivudine maleate and saccharinate. Although there is a same molecular framework in maleic acid and saccharin, these salt formers are Structurally different in some aspects. When compared to saccharin, neither out-of-plane SO(2) oxygens nor a benzene group occur in maleic acid. Both features could be related to higher solubility of lamivudine maleate. Here, we also anticipate that multicomponent molecular crystals of lamivudine with other salt formers possessing the molecular framework responsible for crystal assembly can be engineered successfully.

Lamivudine salts with improved solubilities

To optimize solubility of drugs, current strategies mainly focus on engineering and screening of smart crystal phases. Two salts of the anti-human immunodeficiency virus (HIV) drug lamivudinenamely, lamivudine hydrochloride and lamivudine hydrochloride monohydrate, were prepared in the course of screening the crystallization conditions of lamivudine duplex, an uncommon DNA-mimic, double-stranded helical structure made up of partially protonated drug pairs. Here, water solubilities of lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex are reported. The aqueous solubility of this anti-HIV drug was significantly increased in both salts and also in lamivudine duplex in relation to the water solubility of lamivudine form II. In comparison with the lamivudine form II incorporated into therapeutic formulations, the drug solubility was increased at a temperature of 299 +/- 2 K by factors of 1.2, 3.3, and 4.5 in lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex, respectively, demonstrating that this solid-state property of lamivudine can be improved by crystal engineering strategies. Solubility profiles were understood on the basis of structural and solventsolute interaction approaches. At last, correlations between solubility and crystal structures allowed for a rational approach to understand how this physicochemical feature could be enhanced by engineering new salts of the drug. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:21432154, 2012

Salts of the anti-HIV drug lamivudine with phthalic and salicylic acids

Salts of the anti-HIV drug lamivudine, with phthalic acid and salicylic acid as counterions, were investigated in this study. Neither the packing of the (lamivudine)(+)(phthalic acid)(-) ion pairs nor the conformation of the lamivudine moiety itself were similar to those found in other multicomponent molecular salts of the drug, such as hydrogen maleate and saccharinate ones, even though all three salts crystallize in the same P2(1)2(1)2(1) orthorhombic space group with similar unit cell metrics. Lamivudine salicylate assumes a different crystal structure to those of the hydrogen maleate and saccharinate salts, crystallizing in the P2(1) monoclinic space group as a monohydrate whose (lamivudine)(+)(salicylic acid)(-) ion pair is assembled through two hydrogen bonds with cytosine as a dual donor to both oxygens of the carboxylate, such as in the pairing of lamivudine with a phthalic acid counterion. In lamivudine salicylate monohydrate, the drug conformation is related to the hydrogen maleate and saccharinate salts. However, such a conformational similarity is not related to the intermolecular interaction patterns. Lamivudine and water molecules alternate into helical chains in the salicylate salt monohydrate.

Cocristalli di acidi dicarbossilici: sintesi, caratterizzazione e stabilità allo stato solido

It is well-known that crystalline materials obtain their fundamental physical properties from the molecular arrangement within the solid, and altering the placement and or interactions between these molecules can impact the properties of the particular solid. Solid state chemistry looks at an attempt to alter the chemical and physical solid-state properties of APIs through many different strategies as the formation of salts, polymorphs, hydrates, solvates, and cocrystals. The final aim of this work is to study the chemical and physical propriety of new crystal structures. The work consists of three parts. The first is the cocrystallization of α,ω-alkanedicarboxylics acids with pirimidine. Single-crystal X-ray diffraction analysis of this adduct have been carried out at RT, 150 and 200 K. The cocrystals show an alteration of their melting point similar to pure acids. The two significant deviations are for the cocrystals with succinico and glutarico acids. The second object of work is the structure determination of β polymorph undecandioic acids. In literature is known the other polymorph α. We observed that the thermodynamic relation for this dimorphics system is monotropic. In the third part we synthesized and analyzed the stability of four new salts of serine and oxalic acid. This project highlights the advantage of the solid state synthesis.

Stabilization of APIs and nutraceuticals through cocrystallization and molecular confinement

Cocrystallization of the molecule of interest could be a smart and dainty way to tune solubility properties of solid phases leaving the molecule chemically unchanged, hence it is widely investigated by companies and by solid state scientists. Despite of this extremely high interest towards cocrystallization no particular emphasis has been paid to using it as a means to stabilize liquid molecules. In this work we define a benchmark of relevant molecules for human health that have been combined with suitable partners according to crystal engineering methods in order to obtain cocrystals. Solubility properties in different solvents of cocrystals new solid phases have been tested and compared to the properties of the drugs. A further approach to deal with volatile compounds is molecular confinement inside molecular scaffold. Nowadays metal organic frameworks (MOFs) are studied in many fields ranging from catalysis to trapping or storage of gases, such as hydrogen, methane, CO2 thanks to their extremely high porosity. Our goal is to confine liquid guests of biological relevance inside MOF pores, monitoring via X-ray diffraction, spectroscopy and thermal analysis the stabilization of the molecule of interest inside the cavities.

Cocrystallisation involving the thioamide, amide and imide functional groups

The work presented in this dissertation focused on the development and characterisation of novel cocrystals that incorporated the thioamide, amide and imide functional groups. A particular emphasis was placed on the characterisation of these cocrystals by single crystal X-ray diffraction methods. In Chapter One a summary of the intermolecular interactions utilised in this work and a short review of the solid state and multicomponent systems is provided. A brief introduction to the ways in which different multicomponent systems can be distinguished, crystal engineering strategies and a number of cocrystal applications highlights the importance the understanding of intermolecular interactions can have on the physical and chemical properties of crystalline materials. Chapter Two is the first Results and Discussion chapter and includes an introduction that is specific to the chapter. The main body of this work focuses on the primary aromatic thioamide functional group and its propensity to cocrystallise with a number of sulfoxides. Unlike the amide functional group, thioamides are not commonly employed in cocrystallisation studies. This chapter presents the first direct comparison between the cocrystallisation abilities of these two functional groups and the intermolecular hydrogen bonding interactions present in the cocrystal structures are examined. Chapter Three describes the crystal landscape of a short series of secondary aromatic amides and their analogous thioamides. Building on the results obtained in Chapter Two, a cocrystal screen of the secondary thioamides with the sulfoxide functional group was carried out in order to determine the effect removing a hydrogen bond had on the supramolecular synthons observed in the cocrystals. These secondary thioamides are also utilised in Chapter Four, which examines their halogen bonding capabilities with two organoiodine coformers: 1,2- and 1,4-diiodotetrafluorobenzene. Chapter Five explores the cocrystallisation abilities of three related cyclic imides as coformers for cocrystallisation with a range of commonly used coformers. Chapter Six is an overall conclusions chapter that highlights the findings of the results presented in Chapters Two to Five. Chapter Seven details the instrument and experimental data for the compounds and cocrystals discussed in the Results and Discussion Chapters. The accompanying CD contains all of the crystallographic data in .cif format for the novel single crystal structures characterised in this work.

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterisation

Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder. In this approach, we examine excipients that are amenable to hot melt extrusion, forming a suspension of cocrystal particulates embedded in a pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model cocrystal reagent pair, formulations extruded with a small molecular matrix carrier (xylitol) were examined to be intimate mixtures wherein the newly formed cocrystal particulates were physically suspended in a matrix. With respect to formulations extruded using polymeric carriers (Soluplus and Eudragit EPO, respectively), however, there was no evidence within PXRD patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was established in this study that an appropriate carrier for a cocrystal reagent pair during HME processing should satisfy certain criteria including limited interaction with parent reagents and cocrystal product, processing temperature sufficiently lower than the onset of cocrystal Tm, low melt viscosity, and rapid solidification upon cooling.