Exploring the structure of type V deep eutectic solvents by xenon NMR spectroscopy.

Hydrophobic non-ionic (type V) deep eutectic solvents (DESs) have recently emerged as a new class of sustainable materials that have shown unique properties in several applications. In this study, type V DESs thymol : camphor, menthol : thymol and eutectic mixtures (EMs) based on menthol : carboxylic acids with variable chain length, are experimentally investigated using xenon NMR spectroscopy, with the aim to clarify the peculiar nanostructure of these materials. The results, obtained from the analysis of the 129Xe chemical shifts and of the longitudinal relaxation times, reveal a correlation between the deviation from ideality of the DESs and their structure free volume. Furthermore, the effect of varying the composition of DESs and EMs on the liquid structure is also studied.

Molecular Recognition of Aromatics in Spherical Nanocages.

In general, due to the lack of efficient specific molecular interactions, achieving host-guest molecular recognition inside large and neutral metal-organic cages (MOCs) is challenging. Preferential molecular recognition of aromatics using the internal binding sites of interlocked icosahedral (i. e., spherical) M12 L8 MOCs within poly-[n]-catenane (1) is reported. The guest absorption was monitored directly in the solid-state by consecutive single-crystal-to-single-crystal (SCSC) reactions in a gas-solid environment, in single-crystal X-ray diffraction (SC-XRD) experiments. The preferential guest uptake was corroborated by density functional theory (DFT) calculations by determining the host-guest interaction energy (Ehost-guest ) with a nitrobenzene (NB)≫p-xylene (p-xy)≫o-dichlorobenzene (o-DCB) trend (i. e., from 44 to 25 kcal mol-1 ), assessing the XRD outcomes. Combining SC-XRD, DFT and solid-state 13 C NMR, the exceptional stability of the M12 L8 cages, together with the guest exchange/release properties were rationalized by considering the presence of mechanical bonds (efficient π-π interactions) and by the pyridine's rotor-like behaviour (with 3 kcal mol-1 rotational energy barrier). The structure-function properties of M12 L8 makes 1 a potential candidate in the field of molecular sensors.

Xenon Diffusion in Ionic Liquids with Blurred Nanodomain Separation.

The dynamics of xenon gas, loaded in a series of 1-alkyl-3-methylimidazolium based ionic liquids, probes the formation of increasingly blurred polar/apolar nanodomains as a function of the anion type and the cation chain length. Exploiting 129 Xe NMR spectroscopy techniques, like Pulse Gradient Spin Echo (PGSE) and inversion recovery (IR), the diffusion motion and relaxation times are determined for 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [Cn C1 im][TFSI]. A correlation between the ILs nano-structure and both xenon diffusivity and relaxation times, as well as chemical shifts, is outlined. Interestingly, comparison with previous results of the same properties in the homologous imidazolium chlorides and hexafluorophospate shows an opposite trend with the alkyl chain length. Classical molecular dynamics (MD) simulations are used to calculate the xenon and cation and anion diffusion coefficients in the same systems, including imidazolium cations with longer chains (n=4, 6, 8 … 20). An almost quantitative agreement with the experiments validates the MD simulations and, at the same time, provides the necessary structural and dynamic microscopic insights on the nano-segregation and diffusion of xenon in bistriflimide, chloride and hexafluorphosphate salts allowing to observe and rationalize the shaping effect of the cation in the nanostructure.

Spectral deconvolution in electrophoretic NMR to investigate the migration of neutral molecules in electrolytes.

Electrophoretic nuclear magnetic resonance (eNMR) is a powerful tool in studies of nonaqueous electrolytes, such as ionic liquids. It delivers electrophoretic mobilities of the ionic constituents and thus sheds light on ion correlations. In applications of liquid electrolytes, uncharged additives are often employed, detectable via 1 H NMR. Characterizing their mobility and coordination to charged entities is desirable; however, it is often hampered by small intensities and 1 H signals overlapping with major constituents of the electrolyte. In this work, we evaluate methods of phase analysis of overlapping resonances to yield electrophoretic mobilities even for minor constituents. We use phase-sensitive spectral deconvolution via a set of Lorentz distributions for the investigation of the migration behavior of additives in two different ionic liquid-based lithium salt electrolytes. For vinylene carbonate as an additive, no field-induced drift is observed; thus, its coordination to the Li+ ion does not induce a correlated drift with Li+ . On the other hand, in a solvate ionic liquid with tetraglyme (G4) as an additive, a correlated migration of tetraglyme with lithium as a complex solvate cation is directly proven by eNMR. The phase evaluation procedure of superimposed resonances thus broadens the applicability of eNMR to application-relevant complex electrolyte mixtures containing neutral additives with superimposed resonances.

On the structural origin of free volume in 1-alkyl-3-methylimidazolium ionic liquid mixtures: a SAXS and 129Xe NMR study.

Ionic liquid (IL) mixtures enable the design of fluids with finely tuned structural and physicochemical properties for myriad applications. In order to rationally develop and design IL mixtures with the desired properties, a thorough understanding of the structural origins of their physicochemical properties and the thermodynamics of mixing needs to be developed. To elucidate the structural origins of the excess molar volume within IL mixtures containing ions with different alkyl chain lengths, 3 IL mixtures containing 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ILs have been explored in a joint small angle X-ray scattering (SAXS) and 129Xe NMR study. The apolar domains of the IL mixtures were shown to possess similar dimensions to the largest alkyl chain of the mixture with the size evolution determined by whether the shorter alkyl chain was able to interact with the apolar domain. 129Xe NMR results illustrated that the origin of excess molar volume in these mixtures was due to fluctuations within these apolar domains arising from alkyl chain mismatch, with the formation of a greater number of smaller voids within the IL structure. These results indicate that free volume effects for these types of mixtures can be predicted from simple considerations of IL structure and that the structural basis for the formation of excess molar volume in these mixtures is substantially different to IL mixtures formed of different types of ions.

On the parallelism between the mechanisms behind chromatography and drug delivery: the role of interactions with a stationary phase.

A huge number of studies and work in the drug delivery literature are focused on understanding and modeling transport phenomena, the pivotal point for a good device design. The rationalization of all phenomena involved is fundamental, but several concerns arise leaving many issues unsolved. In order to change the point of view we decided to focus our attention on the parallelisms between two fields that seem to be very far from each other: chromatography and drug release. Taking advantages of the studies conducted by many researchers using chromatographic columns we decided to explain all the phenomena involved in drug delivery considering sodium ibuprofen (IP) molecules as analytes and hydrogel as a stationary phase. In particular, we considered not only diffusion, but also drug-polymer interactions as adsorption on the stationary phase and drug-drug interactions as aggregation of analytes. The hydrogel investigated is a promising formulation made of agarose and carbomer 974p (AC) loaded with IP, a non-steroidal common anti-inflammatory drug. The self-diffusion coefficient of IP in AC formulations was measured by using an innovative method based on a magic angle spinning NMR spectroscopic technique to produce high resolution (liquid-like) spectra. This method (HR-MAS NMR) is used in combination with pulsed field gradient spin echo (PGSE) liquid-state techniques. The model predictions satisfactorily match with the experimental data obtained in water and the gel environment, indicating that the model presented here, despite its simplicity, is able to describe the key phenomena governing the device behavior and could be used to rationalize the experimental activity.

Inclusion complexes of ß-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study.

Tricyclic fused-ring cyclobenzaprine (1) and amitriptyline (2) form 1:1 inclusion complexes with ß-cyclodextrin (ß-CD) in the solid state and in water solution. Rotating frame NOE experiments (ROESY) showed the same geometry of inclusion for both 1/ß-CD and 2/ß-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features matched those found in the molecular dynamics (MD) simulations in solution and in the solid state from single-crystal X-ray diffraction of 1/ß-CD and 2/ß-CD complexes. The latter complex was found in a single conformation in the solid state, whilst the MD simulations in explicit water reproduced the conformational transitions observed experimentally for the free molecule.

Dynamics and interactions of ibuprofen in cyclodextrin nanosponges by solid-state NMR spectroscopy.

Two different formulations of cyclodextrin nanosponges (CDNS), obtained by polycondensation of ß-cyclodextrin with ethylenediaminetetraacetic acid dianhydride (EDTAn), were treated with aqueous solutions of ibuprofen sodium salt (IbuNa) affording hydrogels that, after lyophilisation, gave two solid CDNS-drug formulations. 1H fast MAS NMR and 13C CP-MAS NMR spectra showed that IbuNa was converted in situ into its acidic and dimeric form (IbuH) after freeze-drying. 13C CP-MAS NMR spectra also indicated that the structure of the nanosponge did not undergo changes upon drug loading compared to the unloaded system. However, the 13C NMR spectra collected under variable contact time cross-polarization (VCT-CP) conditions showed that the polymeric scaffold CDNS changed significantly its dynamic regime on passing from the empty CDNS to the drug-loaded CDNS, thus showing that the drug encapsulation can be seen as the formation of a real supramolecular aggregate rather than a conglomerate of two solid components. Finally, the structural features obtained from the different solid-state NMR approaches reported matched the information from powder X-ray diffraction profiles.

The Role of Drug-Drug Interactions in Hydrogel Delivery Systems: Experimental and Model Study.

To address the increasing need for improved tissue substitutes, tissue engineering seeks to create synthetic, three-dimensional scaffolds made from polymeric materials able to incorporate cells and drugs. The interpretation of transport phenomena is a key step, but comprehensive theoretical data is still missing and many issues related to these systems are still unsolved. In particular, the contribution of solute-solute interactions is not yet completely understood. Here, we investigate a promising agar-carbomer (AC) hydrogel loaded with sodium fluorescein (SF), a commonly used drug mimetic. The self-diffusion coefficient of SF in AC formulations was measured by using high resolution magic angle spinning NMR spectroscopy (HR-MAS NMR). Starting from experimental data, a complete overview on SF transport properties is provided, in particular a mathematical model that describes and rationalizes the differences between gel and water environments is developed and presented. The hydrogel molecular environment is able to prevent SF aggregation, owing to the adsorption mechanism that reduces the number of monomers available for oligomer formation at low solute concentration. Then, when all adsorption sites are saturated free SF molecules are able to aggregate and form oligomers. The model predictions satisfactorily match with experimental data obtained in water and the gel environment, thus indicating that the model presented here, despite its simplicity, is able to describe the key phenomena governing device behavior and could be used to rationalize experimental activity.

Competitive and Synergistic Interactions between Polymer Micelles, Drugs, and Cyclodextrins: The Importance of Drug Solubilization Locus.

Polymeric micelles, in particular PEO-PPO-based Pluronic, have emerged as promising drug carriers, while cyclodextrins (CD), cyclic oligosaccharides with an apolar cavity, have long been used for their capacity to form inclusion complexes with drugs. Dimethylated ß-cyclodextrin (DIMEB) has the capacity to fully breakup F127 Pluronic micelles, while this effect is substantially hindered if drugs are loaded within the micellar aggregates. Four drugs were studied at physiological temperature: lidocaine (LD), pentobarbital sodium salt (PB), sodium naproxen (NP), and sodium salicylate (SAL); higher temperatures shift the equilibrium toward higher drug partitioning and lower drug/CD binding compared to 25 °C ( Valero, M.; Dreiss, C. A. Growth, Shrinking, and Breaking of Pluronic Micelles in the Presence of Drugs and/or ß-Cyclodextrin, a Study by Small-Angle Neutron Scattering and Fluorescence Spectroscopy . Langmuir 2010 , 26 , 10561 - 10571 ). The impact of drugs on micellar structure was characterized by small-angle neutron scattering (SANS), while their solubilization locus was revealed by 2D NOESY NMR. UV and fluorescence spectroscopy, Dynamic and Static Light Scattering were employed to measure a range of micellar properties and drug:CD interactions: binding constant, drug partitioning within the micelles, critical micellar concentration of the loaded micelles, aggregation number (Nagg). Critically, time-resolved SANS (TR-SANS) reveal that micellar breakup in the presence of drugs is substantially slower (100s of seconds) than for the free micelles (<100 ms) ( Valero, M.; Grillo, I.; Dreiss, C. A. Rupture of Pluronic Micelles by Di-Methylated ß-Cyclodextrin Is Not Due to Polypseudorotaxane Formation . J. Phys. Chem. B 2012 , 116 , 1273 - 1281 ). These results combined together give new insights into the mechanisms of protection of the drugs against CD-induced micellar breakup. The outcomes are practical guidelines to improve the design of drug delivery systems as well as a better understanding of competitive assembly mechanisms leading to shape and function modulation.

Synthesis and Structural Properties of Aza[n]helicene Platinum Complexes: Control of Cis and Trans Stereochemistry.

The synthesis and structural characterization of azahelicene platinum complexes obtained from cis-PtCl2(NCEt)(PPh3) and from ligands that differ in terms of both the position of the nitrogen atom and the number of fused rings are reported. These square-planar complexes of the general formula PtCl2(nHm)(PPh3) (n = 4, 5; m = 5, 6) display mainly a cis configuration. However, by X-ray crystallographic analysis, we show that for both PtCl2(4H6)(PPh3) and PtCl2(5H6)(PPh3) there is chirality control of the cis/trans stereochemistry. Indeed, starting from a racemic mixture of aza[6]helicene, platinum complexes with a cis configuration are invariably obtained, and the more thermodynamically stable trans isomers are formed when using enantiopure ligands. We further corroborated these results by NMR analysis in solution.

Influence of oligo(ethylene oxide) substituents on pyrrolidinium-based ionic liquid properties, Li(+) solvation and transport.

The presence of oligoether functional groups in the cations of ionic liquids has a significant effect on Li(+) coordination. In this work, a series of N-alkoxylether-N-methyl pyrrolidinium bis(trifluoromethanesulfonyl)imide ionic liquids were synthesized to investigate the effect of the number of ether units on Li(+) coordination and transport. The nature of Li(+) coordination was elucidated through the combination of Raman spectroscopy and heteronuclear Overhauser effect NMR spectroscopy. The presence of a simple ether in the cation side chain results in improved physical properties as compared to N-alkyl-N-methyl pyrrolidinium-based ionic liquids, but does not significantly affect Li(+) coordination possibly due to steric effects of the pyrrolidinium ring. Increasing the number of ethylene oxide units in the side chain results in the progressive displacement of IL anions in the first Li(+) solvation shell by IL cations due to the preferential coordination of Li(+) by the ether oxygen atoms. The apparent transference number of the IL cation decreases and that of the IL anion increases with increasing side chain length. Unfortunately, this does not result in an increase in the Li transference. Nonetheless, the results of this study have important implications for electrolyte systems where the desolvation of the metal cation from the IL anions is the limiting factor in the charge transport mechanism.

Drug-Polymer Interactions in Hydrogel-based Drug-Delivery Systems: An Experimental and Theoretical Study.

In drug-delivery systems, drug transport is a key step, but the interpretation of the transport mechanism is still controversial. Here, we investigated a promising hydrogel library loaded with the anticonvulsant drug ethosuximide (ESM). The self-diffusion coefficient of ESM was measured using two methods: a direct and advanced measurement with a pulsed field gradient spin-echo (PFGSE) method, using an NMR spectrometer equipped with high-resolution magic angle spinning (HR-MAS) probe, and an indirect one based on fitting in vitro drug-delivery data. Starting from the experimental data a mathematical model without fitted parameters was developed and all the phenomena involved, that is, adsorption and diffusion, were considered. At low drug concentrations, adsorption prevails and consequently the diffusivity in the gels is lower than that in water. At high drug concentrations, where all adsorption sites are saturated, the diffusion in the gels is similar to that in a water solution. This study may pave the way for better device design.

Polymer hydrogel functionalized with biodegradable nanoparticles as composite system for controlled drug delivery.

The possibility to direct pharmacological treatments targeting specific cell lines using polymer nanoparticles is one of the main novelties and perspectives in nanomedicine. However, sometimes, the ability to maintain NPs localized at the site of the injection that work as a drug reservoir can represent a good and complementary option. In this direction we built a composite material made of polymeric hydrogel functionalized with polymer NPs. ϵ-caprolactone and polyethylene glycol have been copolymerized in a two-step synthesis of PEGylated NPs, while hydrogel was synthesized through polycondensation between NPs, agarose and branched polyacrylic acid. NP functionalization was verified with Fourier transform infrared spectroscopy (FTIR), high resolution magic angle spinning-nuclear magnetic resonance (HRMAS-NMR) spectroscopy and release kinetics from a hydrogel matrix and compared with NPs only physically entrapped into a hydrogel matrix. The characteristics of the resulting composite hydrogel-NPs system were studied both in terms of rheological properties and in its ability to sustain the release of To-Pro3, used as a drug mimetic compound to represent a promising drug delivery device.

Polydisperse methyl ß-cyclodextrin-epichlorohydrin polymers: variable contact time (13)C CP-MAS solid-state NMR characterization.

The polymerization of partially methylated ß-cyclodextrin (CRYSMEB) with epichlorohydrin was carried out in the presence of a known amount of toluene as imprinting agent. Three different preparations (D1, D2 and D3) of imprinted polymers were obtained and characterized by solid-state (13)C NMR spectroscopy under cross-polarization magic angle spinning (CP-MAS) conditions. The polymers were prepared by using the same synthetic conditions but with different molar ratios of imprinting agent/monomer, leading to morphologically equivalent materials but with different absorption properties. The main purpose of the work was to find a suitable spectroscopic descriptor accounting for the different imprinting process in three homogeneous polymeric networks. The polymers were characterized by studying the kinetics of the cross-polarization process. This approach is based on variable contact time CP-MAS spectra, referred to as VCP-MAS. The analysis of the VCP-MAS spectra provided two relaxation parameters: T CH (the CP time constant) and T 1ρ (the proton spin-lattice relaxation time in the rotating frame). The results and the analysis presented in the paper pointed out that T CH is sensitive to the imprinting process, showing variations related to the toluene/cyclodextrin molar ratio used for the preparation of the materials. Conversely, the observed values of T 1ρ did not show dramatic variations with the imprinting protocol, but rather confirmed that the three polymers are morphologically similar. Thus the combined use of T CH and T 1ρ can be helpful for the characterization and fine tuning of imprinted polymeric matrices.

Chiroptical phenomena in reverse micelles: the case of (1R,2S)-dodecyl (2-hydroxy-1-methyl-2-phenylethyl)dimethylammonium bromide (DMEB).

(1R,2S)-Dodecyl(2-hydroxy-1-methyl-2-phenylethyl)dimethylammonium bromide (DMEB) aggregates dispersed in carbon tetrachloride have been investigated by Fourier transform infrared (FT-IR), vibrational circular dichroism (VCD) and (1)H nuclear magnetic resonance (NMR) spectroscopy at various surfactant concentration and water-to-surfactant molar ratio. Experimental data indicate that, even at the lowest investigated concentration and in absence of added water, DMEB molecules associate in supramolecular assemblies. At higher DMEB concentration the aggregates can confine water molecules, making it plausible to think that DMEB form reverse micelles and that water molecules are quite uniformly distributed among them and mainly located in the proximity of surfactant head groups. Moreover, the water state in DMEB reverse micelles has been found to be different from that in pure water, due to system-specific water/surfactant head group interactions. (1)H NMR diffusion measurements of both water and DMEB emphasize their joined translational motion characterized by a diffusion rate one order of magnitude lower than that of free molecules. Finally, VCD allowed us to show some characteristics of the association of optically active DMEB molecules as reverse micelles and water confinement inside; namely, we monitored the vibrational optical activity of deuterated hydroxyl bonds of the self-assembled DMEB molecules and their interaction with D(2)O molecules.

Aza[6]helicene platinum complexes: chirality control of cis-trans isomerism.

It was serendipitously observed that cis-[PtCl2(NCEt)PPh3] reacted differently with either racemic or enantiopure 4-aza[6]helicene, giving respectively cis (racemic) and trans (enantiopure) [Pt(II)Cl2(4-aza[6]helicene)PPh3] complexes. This unexpected reactivity is explained through a dynamic process (crystallization-induced diastereoselective transformation) and enables a new aspect of reactivity in chiral transition-metal complexes to be addressed.

Anomalous diffusion of Ibuprofen in cyclodextrin nanosponge hydrogels: an HRMAS NMR study.

Ibuprofen sodium salt (IP) was encapsulated in cyclodextrin nanosponges (CDNS) obtained by cross-linking of ß-cyclodextrin with ethylenediaminetetraacetic acid dianhydride (EDTAn) in two different preparations: CDNSEDTA 1:4 and 1:8, where the 1:n notation indicates the CD to EDTAn molar ratio. The entrapment of IP was achieved by swelling the two polymers with a 0.27 M solution of IP in D2O, leading to colourless, homogeneous hydrogels loaded with IP. The molecular environment and the transport properties of IP in the hydrogels were studied by high resolution magic angle spinning (HRMAS) NMR spectroscopy. The mean square displacement (MSD) of IP in the gels was obtained by a pulsed field gradient spin echo (PGSE) NMR pulse sequence at different observation times t d. The MSD is proportional to the observation time elevated to a scaling factor α. The α values define the normal Gaussian random motion (α = 1), or the anomalous diffusion (α < 1, subdiffusion, α > 1 superdiffusion). The experimental data here reported point out that IP undergoes subdiffusive regime in CDNSEDTA 1:4, while a slightly superdiffusive behaviour is observed in CDNSEDTA 1:8. The transition between the two dynamic regimes is triggered by the polymer structure. CDNSEDTA 1:4 is characterized by a nanoporous structure able to induce confinement effects on IP, thus causing subdiffusive random motion. CDNSEDTA 1:8 is characterized not only by nanopores, but also by dangling EDTA groups ending with ionized COO(-) groups. The negative potential provided by such groups to the polymer backbone is responsible for the acceleration effects on the IP anion thus leading to the superdiffusive behaviour observed. These results point out that HRMAS NMR spectroscopy is a powerful direct method for the assessment of the transport properties of a drug encapsulated in polymeric scaffolds. The diffusion properties of IP in CDNS can be modulated by suitable polymer synthesis; this finding opens the possibility to design suitable systems for drug delivery with predictable and desired drug release properties.

Synthesis and characterization of a hyper-branched water-soluble ß-cyclodextrin polymer.

A new hyper-branched water-soluble polymer was synthesized by reacting ß-cyclodextrin with pyromellitic dianhydride beyond the critical conditions that allow the phenomenon of gelation to occur. The molar ratio between the monomers is a crucial parameter that rules the gelation process. Nevertheless, the concentration of monomers in the solvent phase plays a key role as well. Hyper-branched ß-cyclodextrin-based polymers were obtained performing the syntheses with excess of solvent and cross-linking agent, and the conditions for critical dilution were determined experimentally. A hyper-branched polymer with very high water solubility was obtained and fully characterized both as for its chemical structure and for its capability to encapsulate substances. Fluorescein was used as probe molecule to test the complexation properties of the new material.