Interaction of Naproxen with Crystalline and Amorphous Methylated β-Cyclodextrin in the Liquid and Solid State

Abstract

Interactions of naproxen (NAP) with amorphous, randomly methylated β-cyclodextrin at a degree of substitution per anhydroglucose unit of 1.8 (RAMEB) and with crystalline heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB) were studied in aqueous solution and in the solid state using, respectively, phase-solubility analysis (at 25 °C, 37 °C and 47 °C) and differential scanning calorimetry (DSC) supported by X-ray powder diffractometry. RAMEB and DIMEB displayed similar solubilizing and complexing abilities towards NAP, suggesting analogous inclusion modes of the drug in the host cavity in aqueous solution. Differences were instead observed in interactions in the solid state, where the amorphizing capacity of RAMEB toward NAP (evaluated by DSC) was about twice that of DIMEB at each drug-to-carrier ratio. Assuming that inclusion complexation is also involved in solid-state interactions, molecular modelling accounted for the experimental results in terms of structural features of DIMEB, i.e. the particular inwards orientation of O-6-C-8 groups of three alternate glucoses on the primary hydroxyl side which hampers a deep penetration of NAP in the DIMEB cavity in the solid state. On the contrary, no obstruction of the cavity apparently occurs with RAMEB due its noncrystalline state. The aqueous dissolution rate of NAP from NAP-RAMEB and NAP-DIMEB blends containing 0.59, 0.73, 0.85, and 0.92 mass fraction of carrier linearly increased at decreasing drug-to-carrier ratios. The improvement was 5 to 20 times (from powders) and 50 to 200 times (from discs) the dissolution rate of NAP alone for both carrier. Therefore the choice of the amorphous RAMEB in pharmaceutical formulations can be recommended mainly for economic reasons, though the anhydrous and non-hygroscopic nature of crystalline DIMEB might be of particular advantage in case of moisture sensitive formulations.     

Electrically insulated molecular wires

This paper is an up-to-date mini-review based on literature data and own results regarding synthesis and properties of conducting (pseudo)rotaxane supramolecular structures. Conjugated polymers, such as polyarylene, polyheteroarylene, polyaniline, polyarylenevinylene or polyaryleneimine, were used as axle, while the macrocyclic components were cyclodextrins, cucurbiturils, cyclophanes or crown ethers. Properties of the supramolecular structure such as solubility, thermal or chemical stability, conductivity, etc. can be drastically modified by the inclusion of hydrophobic conjugated polymers inside the macrocycle, without any chemical modification. For instance, the photophysical properties (i.e. quantum yield of fluorescence and electroluminescence) of the supramolecular structures were enhanced when compared with uninsulated conjugated polymers. The doping process is also affected, because the access of a dopant to the conjugated chain is limited only to the uncovered domains of the conjugated chain.     

Ethylene spacer-linked bis-acetamidopyridine for dicarboxylic acid recognition and polymeric new wave-like anti-perpendicular arrangement of a host–guest in the solid state

In this paper, 1,2-bis(2-acetamido-6-pyridyl)ethane, receptor 1, having an ethylene spacer is reported to recognise dicarboxylic acids. The binding study in the solution phase is carried out using ¹H NMR (1:1) and UV–vis experiments and in the solid phase by single-crystal X-ray analysis. In ¹H NMR, the downfield shifts of specific amide protons of receptor 1 in 1:1 complexes of receptor and guest diacids, and in the UV–vis experiment, the appearance of an isosbestic point as well as significant binding constants are observed, which thus unambiguously support the complexation of receptor 1 with dicarboxylic acids in solution. Receptor 2, simple 2-acetamido-6-methylpyridine, has lower binding constants than receptor 1 due to cooperative binding of two pyridine amide groups with two acid groups of diacids. In the solid phase, the ditopic receptor 1 shows a grid-like polymeric hydrogen-bonded network that changes to a polymeric wave-like 1:1 anti-perpendicular network instead of the syn–syn polymeric 1:1 (Goswami, S.; Dey, S.; Fun, H.-K.; Anjum, S.; Rahman, A.-U. Tetrahedron Lett. 2005 (a) Goswami, S., Ghosh, K. and Dasgupta, S. 2000. J. Org. Chem., 65: 1907–1914. (b) Goswami, S.; Ghosh, K.; Mukherjee, R. Tetrahedron2001, 57, 4987–4993. (c) Goswami, S.; Ghosh, K.; Halder, M. Tetrahedron Lett.1999, 40, 1735–1738. (d) Goswami, S.; Dey, S.; Fun, H.-K.; Anjum, S.; Rahman, A.-U. Tetrahedron Lett.2005, 46, 7187–7191. (e) Goswami, S.; Jana, S.; Dey, S.; Razak, I.A.; Fun, H.-K. Supramol. Chem.2006, 18, 571–574. (f) Goswami, S.; Jana, S.; Fun, H.-K. Cryst. Eng. Comm.2008, 10, 507–517. (g) Goswami, S.; Jana, S.; Dey, S.; Sen, D.; Fun, H.-K.; Chantrapromma, S. Tetrahedron2008,64, 6426–6433. (h) Goswami, S.; Dey, S.; Jana, S. Tetrahedron2008, 64, 6358–6363 [Google Scholar], 46, 7187–7191), anti–anti polymeric 1:1 (Goswami, S.; Jana, S.; Dey, S.; Razak, I.A.; Fun, H.-K. Supramol. Chem. 2006 (a) Goswami, S., Ghosh, K. and Dasgupta, S. 2000. J. Org. Chem., 65: 1907–1914. (b) Goswami, S.; Ghosh, K.; Mukherjee, R. Tetrahedron2001, 57, 4987–4993. (c) Goswami, S.; Ghosh, K.; Halder, M. Tetrahedron Lett.1999, 40, 1735–1738. (d) Goswami, S.; Dey, S.; Fun, H.-K.; Anjum, S.; Rahman, A.-U. Tetrahedron Lett.2005, 46, 7187–7191. (e) Goswami, S.; Jana, S.; Dey, S.; Razak, I.A.; Fun, H.-K. Supramol. Chem.2006, 18, 571–574. (f) Goswami, S.; Jana, S.; Fun, H.-K. Cryst. Eng. Comm.2008, 10, 507–517. (g) Goswami, S.; Jana, S.; Dey, S.; Sen, D.; Fun, H.-K.; Chantrapromma, S. Tetrahedron2008,64, 6426–6433. (h) Goswami, S.; Dey, S.; Jana, S. Tetrahedron2008, 64, 6358–6363 [Google Scholar], 18, 571–574; Goswami, S.; Jana, S.; Fun, H.-K. Cryst. Eng. Comm. 2008, 10, 507–517; Goswami, S.; Jana, S.; Dey, S.; Sen, D.; Fun, H.-K.; Chantrapromma, S. Tetrahedron 2008, 64, 6426–6433), syn–syn 2:2 (Karle, I.L.; Ranganathan, D.; Haridas, V. J. Am. Chem. Soc. 1997 (a) Garcia-Tellado, F., Goswami, S., Chang, S.K., Geib, S.J. and Hamilton, A.D. 1990. J. Am. Chem. Soc., 112: 7393–7394. (b) Geib, S.J.; Vicent, C.; Fan, E.; Hamilton, A.D. Angew. Chem. Int. Ed. Engl.1993, 32, 119–121. (c) Garcia-Tellado, F.; Geib, S.J.; Goswami, S.; Hamilton, A.D. J. Am. Chem. Soc.1991, 113, 9265–9269. (d) Karle, I.L.; Ranganathan, D.; Haridas, V. J. Am. Chem. Soc.1997, 119, 2777–2783. (e) Moore, G.; Papamicaël, C.; Levacher, V.; Bourguignon, J.; Dupas, G. Tetrahedron2004, 60, 4197–4204. (f) Korendovych, I.V.; Cho, M.; Makhlynets, O.V.; Butler, P.L.; Staples, R.J.; Rybak-Akimova, E.V. J. Org. Chem.2008, 73, 4771–4782. (g) Ghosh, K.; Masanta, G.; Fröhlich, R.; Petsalakis, I.D.; Theodorakopoulos, G. J. Phys. Chem. B2009, 113, 7800–7809 [Google Scholar], 119, 2777–2783) or top–bottom-bound 1:1 (Garcia-Tellado, F.; Goswami, S.; Chang, S.K.; Geib, S.J.; Hamilton, A.D. J. Am. Chem. Soc. 1990 (a) Goswami, S., Ghosh, K. and Dasgupta, S. 2000. J. Org. Chem., 65: 1907–1914. (b) Goswami, S.; Ghosh, K.; Mukherjee, R. Tetrahedron2001, 57, 4987–4993. (c) Goswami, S.; Ghosh, K.; Halder, M. Tetrahedron Lett.1999, 40, 1735–1738. (d) Goswami, S.; Dey, S.; Fun, H.-K.; Anjum, S.; Rahman, A.-U. Tetrahedron Lett.2005, 46, 7187–7191. (e) Goswami, S.; Jana, S.; Dey, S.; Razak, I.A.; Fun, H.-K. Supramol. Chem.2006, 18, 571–574. (f) Goswami, S.; Jana, S.; Fun, H.-K. Cryst. Eng. Comm.2008, 10, 507–517. (g) Goswami, S.; Jana, S.; Dey, S.; Sen, D.; Fun, H.-K.; Chantrapromma, S. Tetrahedron2008,64, 6426–6433. (h) Goswami, S.; Dey, S.; Jana, S. Tetrahedron2008, 64, 6358–6363 [Google Scholar], 112, 7393–7394) co-crystals.

     

Recognition of anions and monocarboxylic acids by a fluorescent guanidine-based receptor

A guanidine-based fluorescent receptor has been synthesised to study its binding behaviour towards anions (F^? , Cl^? , Br^? , I^?  and AcO^? ). The two donor N–H bonds of the receptor do not point in the same direction; rather, one N–H bond is intramolecularly hydrogen-bonded with the carbonyl oxygen atom. The nature of the donor–acceptor (DA) arrangement induces moderate binding properties. The binding behaviour towards monocarboxylic acids (benzoic acid and phenylacetic acid) is also compared. The binding behaviour of receptor 1 towards the F^?  anion is higher among the anions studied, whereas in the case of monocarboxylic acid, the binding constant with phenylacetic acid is higher than benzoic acid.     

Investigation of the complexation of essential oil components with cyclodextrins

The formation of inclusion complexes of six essential oil (EO) components (β-caryophyllene, cis-ocimene, trans-ocimene, sabinene hydrate (thujanol), γ-terpinene and α-terpineol) with six cyclodextrins (CDs) (α-CD, β-CD, γ-CD, HP-β-CD, RAMEB and CRYSMEB) was investigated by using static headspace-gas chromatography and UV–visible spectroscopy. Retention studies showed that CDs could efficiently reduce the volatility of EO components except for β-caryophyllene with α-CD. In this case, no inclusion complex was detected while for other compounds the formation of 1:1 inclusion complexes was observed. Results revealed that the inclusion stability mainly depends on geometric complementarity between encapsulated molecule and CD's cavity. Molecular modelling was used to investigate the complementarities between host and guest. Thus, CDs could efficiently be regarded as promising encapsulants for EO components leading to improve their application in cosmetic, pharmaceutical and agriculture fields.     

Complexation of M3+ Lanthanide Cations by Calix[4]arene-CMPO Ligands: A Molecular Dynamics Study in Methanol Solution and at a Water/Chloroform Interface

Abstract

We report a molecular dynamics study on the 1:1 M³⁺ lanthanide (La³⁺, Eu³⁺ and Yb³⁺) inclusion complexes of an important extractant molecule L: a calix[4]arene-tetraalkyl ether substituted at the wide rim by four NH-C(O)-CH₂-P(O)Ph₂ arms. The M(NO₃)₃ and MCl₃ complexes of L are compared in methanol solution and at a water / chloroform interface. In the different environments the coordination sphere of M³⁺ involves the four phosphoryl oxygens and three to four loosely bound carbonyl oxygens of the CMPO-like arms. Based on free energy simulations, we address the question of ion binding selectivity in pure liquid phases and at the liquid-liquid interface where L and the complexes are found to adsorb. According to the simulations, the enhancement of M³⁺ cation extraction in the presence of the calixarene platform, examined by comparing L to the (CMPO)₄ “ligand” at the interface, is related to the fact that (i) the (CMPO)₄Eu(NO₃)₃ complex is more hydrophilic than the LEu(NO₃) one and (ii) the free CMPO ligands spread at the interface, and are therefore less organized for cation capture than L.     

Supramolecular Self-organization of Potential Hydrogelators on Attracting Surfaces

This article highlights the aggregation behaviour of potential low molecular weight hydrogelators on attracting surfaces. Our goal was the development of a method, which enables the finding of new hydrogelators that are not easily recognizable as such because they only form instable or no hydrogels in aqueous solution. To this end, a series of negatively charges azo-dyes was synthesized and positive charged glass slides were immersed into their aqueous solutions. All dyes showed supramolecular organization and significant concentration on the attracting glass surface. Microscopic investigations mostly revealed the formation of crystals. However, one compound, (1-(2-n-octylphenylazo)-2-hydroxy-6-naphthalenesulphonate, selectively formed a hydrogel on the surface whereas it does not gel in aqueous solution. This reveals the hydrogel as the stable form of this compound under equilibrium conditions. This method of surface-induced hydrogelation might facilitate the identification of new hydrogelators. Further more, it might also allow the mimicking of surface gelation as a process of biological relevance.     

An in silico expert system for the identification of eye irritants

This report describes development of an in silico, expert rule-based method for the classification of chemicals into irritants or non-irritants to eye, as defined by the Draize test. This method was developed to screen data-poor cosmetic ingredient chemicals for eye irritancy potential, which is based upon exclusion rules of five physicochemical properties – molecular weight (MW), hydrophobicity (log P), number of hydrogen bond donors (HBD), number of hydrogen bond acceptors (HBA) and polarizability (Pol). These rules were developed using the ADMET Predictor software and a dataset of 917 eye irritant chemicals. The dataset was divided into 826 (90%) chemicals used for training set and 91 (10%) chemicals used for external validation set (every 10th chemical sorted by molecular weight). The sensitivity of these rules for the training and validation sets was 72.3% and 71.4%, respectively. These rules were also validated for their specificity using an external validation set of 2011 non-irritant chemicals to the eye. The specificity for this validation set was revealed as 77.3%. This method facilitates rapid screening and prioritization of data poor chemicals that are unlikely to be tested for eye irritancy in the Draize test.