The Interplay of Solvation and Polarization Effects on Ion Pairing in Nanoconfined Electrolytes.

The nature of ion-ion interactions in electrolytes confined to nanoscale pores has important implications for energy storage and separation technologies. However, the physical effects dictating the structure of nanoconfined electrolytes remain debated. Here we employ machine-learning-based molecular dynamics simulations to investigate ion-ion interactions with density functional theory level accuracy in a prototypical confined electrolyte, aqueous NaCl within graphene slit pores. We find that the free energy of ion pairing in highly confined electrolytes deviates substantially from that in bulk solutions, observing a decrease in contact ion pairing but an increase in solvent-separated ion pairing. These changes arise from an interplay of ion solvation effects and graphene's electronic structure. Notably, the behavior observed from our first-principles-level simulations is not reproduced even qualitatively with the classical force fields conventionally used to model these systems. The insight provided in this work opens new avenues for predicting and controlling the structure of nanoconfined electrolytes.

Comparative Analysis of PEG-Free and PEG-Based Self-Emulsifying Drug Delivery Systems for Enhanced Oral Bioavailability of Therapeutic (Poly) Peptides.

This study aims to compare the potential of Polyethylene glycol (PEG-free and PEG-based self-emulsifying drug delivery systems (SEDDS) for the oral administration of insulin glargine (IG). Hydrophobic ion pairs (HIPs) of IG are formed using various counterions. HIPs are assessed for log P octanol/water and dissociation behavior. They are incorporated into SEDDS based on polyglycerol (PG) and zwitterionic surfactant (ZW) using response surface methodology and compared to conventional PEG-SEDDS in size, stability, and log D SEDDS/release medium. Oral IG bioavailability in PG/ZW-SEDDS and PEG-SEDDS is evaluated in rats. Among the various counterions studied, IG-BIS (bis(isotridecyl)sulfosuccinate) HIPs demonstrated the highest log P and an improved dissociation profile. PG/ZW-SEDDS and PEG-SEDDS have similar ≈40 nm sizes and are stable over 24 h. Both formulations have log D > 4 in water and >2 in 50 mM phosphate buffer pH 6.8. PG/ZW-SEDDS yielded an oral bioavailability of 2.13 ± 0.66% for IG, while the employment of PEG-SEDDS resulted in an oral bioavailability of 1.15 ± 0.35%. This study highlights the prospective utilization of PEG-free SEDDS involving the concurrent application of PG and ZW surfactants, an alternative to conventional PEG surfactants, for improved oral therapeutic (poly) peptide delivery.

Ion Coupling, Bonding, and Transfer in Narrow Carbon Nanotubes.

Narrow carbon nanotubes (nCNT) are unique mimics of biological channels with water-ion selectivity attractive for applications such as water purification and osmotic energy harvesting, yet their understanding is still incomplete. Here, an ab initio computation is employed to develop the full picture of ion transfer in nCNT including specificity and coupling between ions. The thermodynamic costs of ion transfer are computed for single ions and ion pairs and used to evaluate different local coupling scenarios including strong (pairing) and weak (free-ion) coupling as well as "electroneutrality breakdown" (EB), possible for cations only due to their chemisorption-like interaction with nCNT. The results also indicate that nCNT behaves as a highly polarizable metal-like shell, which eliminates the dielectric energy when CNT accommodates coupled cation and anion. This allows facile computation and comparison of the full transfer costs, including translation entropy, for different ions in different coupling modes to identify the dominant regime. EB transfer appears most favorable for K+, while anions strongly favor transfer as pairs, except for chloride which favors weak coupling and, at neutral pH, transfers as a trace ion coupled to both cation and OH-. The results demonstrate that, in general, observed ion permeation and conduction in nCNT, especially for anions, reflect a complex ion-specific and composition-dependent interplay between different ions.

Ion-Pairing Assemblies of Anion-Responsive π-Electronic Systems That Have Noncovalently Assisted Expanded Planar Region.

Arylethynyl-substituted dipyrrolyldiketone BF2 complexes as anion-responsive π-electronic molecules exhibited characteristic electronic properties derived from conformation changes upon anion binding, which caused an increase in UV/vis absorption and associated two-photon absorption. The anion complexes showed expanded planar regions assisted by intramolecular interactions, resulting in charge-by-charge ion-pairing assemblies in the solid state.

Improvement of oligonucleotide separation using a repetto high-performance liquid chromatography recycling approach.

A new approach for the improvement of separation of oligonucleotides by recycling ion-pairing chromatography is described. In the so-called repetto process, segments of separated compounds are sequentially returned to the inlet for multiple passages through the column without a need to pass a pump and with the possibility of detecting the level of separation between individual passages. Unlike in the recently described twin-column recycle approach in which eluents are repeatedly transferred between two separation columns, with the repetto method a single column is sufficient, and the detector is not exposed to high back pressure. The repetto principle was used for the separation of synthetic oligonucleotides, resulting in a multi-fold improvement in single nt resolution of long (> 50 nt) synthetic oligonucleotide fragments with high gas chromatography (guanine-cytosine) content > 40% and their separation from impurities of the original synthesis.

Enhancement of Exfoliating Effects through the Novel Cosmetic Ingredient Mandelic acid_Carnitine Ion-Pairing Complex.

PURPOSE: This study aimed to develop a novel exfoliating material with high efficacy and low irritation by synthesizing the Mandelic acid_Carnitine ion pairing complex (M_C complex) and evaluating its exfoliating properties. Additionally, the study assessed the skin improvement effects of the M_C complex through clinical evaluations. METHODS: The M_C complex was synthesized in a 1:1 molar ratio of Mandelic acid and Carnitine. Structural characterization was performed using dynamic light scattering and Fourier-transform infrared spectroscopy. Exfoliating efficacy was evaluated on porcine skin, and clinical assessments were conducted on human subjects to measure various skin improvement parameters. RESULTS: The formation of the M_C complex was confirmed through particle size analysis, zeta-potential measurements, and FT-IR spectroscopy. The M_C complex demonstrated superior exfoliating efficacy compared to Mandelic acid alone, especially at pH 4.5. Clinical evaluations showed significant improvements in blackheads, whiteheads, pore volume, depth, density, count, and affected area, as well as skin texture. No adverse reactions were observed. CONCLUSION: The M_C complex exhibits high exfoliating efficacy and minimal irritation, making it a promising cosmetic ingredient for improving skin health. These findings support its potential as a low-irritation exfoliating material under mildly acidic conditions, contributing to overall skin health enhancement.

Ion-pairing assemblies of π-extended anion-responsive organoplatinum complexes.

PtII complexes of π-extended dipyrrolyldiketones were synthesized as anion-responsive π-electronic molecules. The dipyrrolyldiketone PtII complexes exhibited red-shifted absorption and photoluminescence properties. In the solid state, [1 + 1]-type anion complexes formed charge-by-charge ion-pairing assemblies when combined with countercations. Detailed theoretical studies of the packing structures revealed favorable interactions between the planar anion complexes and π-electronic cations.

Pt^II complexes of π-extended dipyrrolyldiketones, introducing arylethynyl substituents, in the form of anion complexes exhibited the formation of charge-by-charge assemblies with π-electronic cations via ⁱπ­ⁱπ interactions.

Diffusion Nuclear Magnetic Resonance Measurements on Cationic Gold (I) Complexes in Catalytic Conditions: Counterion and Solvent Effects.

The amount of free ions, ion pairs, and higher aggregate of the possible species present in a solution during the gold(I)-catalyzed alkoxylation of unsaturated hydrocarbon, i.e., ISIP (inner sphere ion pair) [(NHC)AuX] and OSIP (outer sphere ion pairs) [(NHC)Au(TME)X] [NHC 1,3-bis(2,6-di-isopropylphenyl)-imidazol-2-ylidene; TME = tetramethylethylene (2,3-bis methyl-butene); X- = Cl-, BF4-, OTf-; and OTs- BArF4- (ArF = 3,5-(CF3)2C6H3)], has been determined. The 1H and 19F DOSY NMR measurements conducted in catalytic conditions indicate that the dissociation degree (α) of the equilibrium ion pair/free ions {[(NHC)Au(TME)X] [(NHC)Au(TME)]+ + X-} depends on the nature of the counterion (X-) when chloroform is the catalytic solvent: while the compounds containing OTs- and OTf- as the counterion gave a low α (which means a high number of ion pairs) of 0.13 and 0.24, respectively, the compounds containing BF4- and BArF4- showed higher α values of 0.36 and 0.32, respectively. These results experimentally confirm previous deductions based on catalytic and theoretical data: the lower the α value, the greater the catalytic activity because the anion that can activate methanol during a nucleophilic attack, although the lower propensity to activate methanol of BF4- and BArF4-, as suggested by the DFT calculations, cannot be completely overlooked. As for the effect of the solvent, α increases as the dielectric constant increases, as expected, and in particular, green solvents with high dielectric constants show a very high α (0.90, 0.84, 0.80, and 0.70 for propylene carbonate, γ-valerolactone, acetone, and methanol, respectively), thus confirming that the moderately high activity of NHC-Au-OTf in these solvents is due to the specific effect of polar functionalities (O-H, C=O, O-R) in activating methanol. Finally, the DOSY measurements conducted in p-Cymene show the formation of quadrupole species: under these conditions, the anion can better exercise its 'template' and 'activating' roles, giving the highest TOF.

Counterion Effect in Cobaltate-Catalyzed Alkene Hydrogenation.

We show that countercations exert a remarkable influence on the ability of anionic cobaltate salts to catalyze challenging alkene hydrogenations. An evaluation of the catalytic properties of [Cat][Co(η4 -cod)2 ] (Cat=K (1), Na (2), Li (3), (Dep nacnac)Mg (4), and N(n Bu)4 (5); cod=1,5-cyclooctadiene, Dep nacnac={2,6-Et2 C6 H3 NC(CH3 )}2 CH)]) demonstrated that the lithium salt 3 and magnesium salt 4 drastically outperform the other catalysts. Complex 4 was the most active catalyst, which readily promotes the hydrogenation of highly congested alkenes under mild conditions. A plausible catalytic mechanism is proposed based on density functional theory (DFT) investigations. Furthermore, combined molecular dynamics (MD) simulation and DFT studies were used to examine the turnover-limiting migratory insertion step. The results of these studies suggest an active co-catalytic role of the counterion in the hydrogenation reaction through the coordination to cobalt hydride intermediates.

Delving into the Variability of Supramolecular Affinity: Self-Ion Pairing as a Central Player in Aqueous Host-Guest Chemistry.

The determination of binding constants is a key matter in evaluating the strength of host-guest interactions. However, the profound impact of self-ion pairing on this parameter is often underrated in aqueous solution, leading in some cases to a misinterpretation of the true potential of supramolecular assemblies. In the present study, we aim to shed further light on this critical factor by exploring the concentration-dependent behavior of a multicharged pillararene in water. Our observations reveal an extraordinary 1-million-fold variability in the affinity of this macrocycle toward a given anion, showcasing the highly dynamic character of electrostatic interactions. We argue that these findings bring to the forefront the inherent determinism that underlies the estimation of affinity constants, a factor profoundly shaped by both the sensitivity of the instrumental technique in use and the intricacies of the experimental design itself. In terms of applications, these results may provide the opportunity to optimize the operational concentrations of multicharged hosts in different scenarios, aiming to achieve their maximum efficiency based on the intended application. Unlocking the potential of this hidden variability may pave the way for the creation of novel molecular materials with advanced functionalities.

Selecting Counterions to Improve Ionized Hydrophilic Drug Encapsulation in Polymeric Nanoparticles.

Hydrophobic ion pairing (HIP) can successfully increase the drug loading and control the release kinetics of ionizable hydrophilic drugs, addressing challenges that prevent these molecules from reaching the clinic. Nevertheless, polymeric nanoparticle (PNP) formulation development requires trial-and-error experimentation to meet the target product profile, which is laborious and costly. Herein, we design a preformulation framework (solid-state screening, computational approach, and solubility in PNP-forming emulsion) to understand counterion-drug-polymer interactions and accelerate the PNP formulation development for HIP systems. The HIP interactions between a small hydrophilic molecule, AZD2811, and counterions with different molecular structures were investigated. Cyclic counterions formed amorphous ion pairs with AZD2811; the 0.7 pamoic acid/1.0 AZD2811 complex had the highest glass transition temperature (Tg; 162 °C) and the greatest drug loading (22%) and remained as phase-separated amorphous nanosized domains inside the polymer matrix. Palmitic acid (linear counterion) showed negligible interactions with AZD2811 (crystalline-free drug/counterion forms), leading to a significantly lower drug loading despite having similar log P and pKa with pamoic acid. Computational calculations illustrated that cyclic counterions interact more strongly with AZD2811 than linear counterions through dispersive interactions (offset π-π interactions). Solubility data indicated that the pamoic acid/AZD2811 complex has a lower organic phase solubility than AZD2811-free base; hence, it may be expected to precipitate more rapidly in the nanodroplets, thus increasing drug loading. Our work provides a generalizable preformulation framework, complementing traditional performance-indicating parameters, to identify optimal counterions rapidly and accelerate the development of hydrophilic drug PNP formulations while achieving high drug loading without laborious trial-and-error experimentation.

(Thio)urea Containing Chiral Ammonium Salt Catalysts.

(Thio)-urea-containing bifunctional quaternary ammonium salts emerged as powerful non-covalently interacting organocatalysts over the course of the last decade. The most commonly employed catalysts in this field are either based on Cinchona alkaloids, α-amino acids, or trans-cyclohexane-1,2-diamine. Our group has been heavily engaged in the design and use of such catalysts, i. e. trans-cyclohexane-1,2-diamine-based ones for around 10 years now, and it is therefore the intention of this short personal account to provide an overview of the, at least in our opinion, most significant and pioneering achievements in this field by looking on catalyst design and asymmetric method development, with a special focus on our own contributions.

Determination of polyamines in urine via electrospun nanofibers-based solid-phase extraction coupled with GC-MS and application to gastric cancer patients.

The simultaneous determination of polyamines and their metabolites in urine samples was achieved by gas chromatography-mass spectrometry in the selected ion monitoring mode. After conjugating with the ion-pair reagent bis-2-ethylhexylphosphate in the aqueous phase, the polyamines in the samples were extracted with polystyrene nanofiber-based packed-fiber solid-phase extraction followed by a derivatization step using pentafluoropropionyl anhydride. With optimal conditions, all analytes were separated well. For analytes of putrescine, cadaverine, N-acetylputrescine, and N-acetylcadaverine, the linearity was good in the range of 0.05-500 µmol/L (R2  ≥ 0.993). While for spermidine, spermine, acetylspermidine, N8 -acetylspermidine, and N-acetylspermine, the linearity was good in the range of 0.5-500 µmol/L (R2  ≥ 0.990). The recoveries of three spiked concentrations (0.5, 5, 300 µmol/L) were 85.6%-108.4%, and relative standard deviations for intra- and interday were in the range of 2.9%-13.4% and 4.5%-15.1%, respectively. The method was successfully applied to the analysis of urine samples of gastric cancer patients. The results showed that the levels of most polyamines and N-acetylated polyamines from the patient group were significantly higher than those from the control group. The altered concentrations of the above-mentioned metabolites suggest their role in the pathogenesis of gastric cancer, and they should be further evaluated as potential markers of gastric cancer.

Preparation and characterisation of self-emulsifying drug delivery system (SEDDS) for enhancing oral bioavailability of metformin hydrochloride using hydrophobic ion pairing complexation.

AIM: The aim of this study was preparation of a self-emulsifying drug delivery system (SEEDS) containing metformin hydrochloride. METHODS: Hydrophobic ion paired complexes were prepared by electrostatic interaction between metformin and sodium lauryl sulphate (SLS). The nanodroplets were optimised using two-level full factorial methodology and their morphology were examined. In vitro release of metformin from SEDDS was evaluated in simulated gastric and intestinal fluids. Finally, the ex-vivo efficacy of the optimised formulation in enhancing the intestinal permeability of metformin was evaluated using non-everted intestinal sac. RESULTS: The data revealed that in weight ratio 1:4(metformin: SLS), the highest recovery was achieved. The physico-chemical properties of the optimised nano-droplets including size, polydispersity index (PdI), zeta potential, and loading efficiency (%) were 192.33 ± 9.9 nm, 0.275 ± 0.051; -1.52 mV, and 93.75 ± 0.77% (w/w), respectively. CONCLUSIONS: The data obtained from the intestinal transport study demonstrated that SEDDS can significantly enhance the oral permeability of the compound.

Diagonal Interactions between Glutamate and Arginine Analogs with Varying Side-Chain Lengths in a ß-Hairpin.

Cross-strand interactions are important for the stability of ß-sheet structures. Accordingly, cross-strand diagonal interactions between glutamate and arginine analogs with varying side-chain lengths were studied in a series of ß-hairpin peptides. The peptides were analyzed by homonuclear two-dimensional nuclear magnetic resonance methods. The fraction folded population and folding free energy of the peptides were derived from the chemical shift data. The fraction folded population trends could be rationalized using the strand propensity of the constituting residues, which was not the case for the peptides with lysine analogs, highlighting the difference between the arginine analogs and lysine analogs. Double-mutant cycle analysis was used to derive the diagonal ion-pairing interaction energetics. The most stabilizing diagonal cross-strand interaction was between the shortest residues (i.e., Asp2-Agp9), most likely due to the least side-chain conformational penalty for ion-pair formation. The diagonal interaction energetics in this study involving the arginine analogs appears to be consistent with and extend beyond our understanding of diagonal ion-pairing interactions involving lysine analogs. The results should be useful for designing ß-strand-containing molecules to affect biological processes such as amyloid formation and protein-protein interactions.

Charge-Segregated Stacking Structure with Anisotropic Electric Conductivity in NIR-Absorbing and Emitting Positively Charged π-Electronic Systems.

Squarylium-based π-electronic cation with an augmented dipole was synthesized by methylation of zwitterionic squarylium. The cation formed various ion pairs in combination with anions, and the ion pairs exhibited distinct photophysical properties in the dispersed state, ascribed to the formation of J- and H-aggregates. The ion pairs provided solid-state assemblies based on cation stacking. It is noteworthy that complete segregation of cations and anions was observed in a pseudo-polymorph of the ion pair with pentacyanocyclopentadienide as a π-electronic anion. In the crystalline state, the ion pairs exhibited photophysical properties and electric conductivity derived from cation stacking. In particular, the charge-segregated ion-pairing assembly induces an electric conductive pathway along the stacking axis. The charge-segregated mode and fascinating properties were derived from the reduced electrostatic repulsion between adjacent π-electronic cations via dipole-dipole interactions.

Ion-Pairing Chromatography and Amine Derivatization Provide Complementary Approaches for the Targeted LC-MS Analysis of the Polar Metabolome.

Liquid chromatography coupled to mass spectrometry is a key metabolomics/metabonomics technology. Reversed-phase liquid chromatography (RPLC) is very widely used as a separation step, but typically has poor retention of highly polar metabolites. Here, we evaluated the combination of two alternative methods for improving retention of polar metabolites based on 6-aminoquinoloyl-N-hydroxysuccinidimyl carbamate derivatization for amine groups, and ion-pairing chromatography (IPC) using tributylamine as an ion-pairing agent to retain acids. We compared both of these methods to RPLC and also to each other, for targeted analysis using a triple-quadrupole mass spectrometer, applied to a library of ca. 500 polar metabolites. IPC and derivatization were complementary in terms of their coverage: combined, they improved the proportion of metabolites with good retention to 91%, compared to just 39% for RPLC alone. The combined method was assessed by analyzing a set of liver extracts from aged male and female mice that had been treated with the polyphenol compound ampelopsin. Not only were a number of significantly changed metabolites detected, but also it could be shown that there was a clear interaction between ampelopsin treatment and sex, in that the direction of metabolite change was opposite for males and females.

Physical insight into the entropy-driven ion association.

The ion association is widely believed to be dominated by the favorable entropy change arising from the release of water molecules from ion hydration shells. However, no direct thermodynamic evidence exists to validate the reliability and suitability of this view. Herein, we employ complicated free energy calculations to rigorously split the free energy including its entropic and enthalpic components into the water-induced contributions and ion-ion interaction terms for several ion pairs from monatomic to polyatomic ions, spanning the size range from small kosmotropes to large chaotropes (Na+ , Cs+ , Ca2+ , F- , I- , CO3 2- , and HPO4 2- ). Our results successfully reveal that though ion associations are indeed determined by a delicate balance between the favorable entropy variation and the repulsive enthalpy change, the entropy gain dominated by the solvent occurs only for the monatomic ion pairing. The water-induced entropic contribution significantly goes against the ion pairing between polyatomic anion and cation, which is, alternatively, dominated by the favorable entropy from the ion-ion interaction term, due to the configurational arrangement of polyatomic anions involved in ion association. The structural and dynamic analysis demonstrates that the entropy penalty from the water phase is primarily ascribed to the enhanced stability of water molecules around the cation imposed by the incoming anion. Our study successfully provides a fundamental understanding of water-mediated ion associations and highlights disparate lengthscale dependencies of the dehydration thermodynamics on the specific types of ions.

High-Temperature Quantum Tunneling and Hydrogen Bonding Rearrangements Characterize the Solid-Solid Phase Transitions in a Phosphonium-Based Protic Ionic Liquid.

We report the complex phase behavior of the glass forming protic ionic liquid (PIL) d3-octylphosphonium bis(trifluoromethylsulfonyl)imide [C8 H17 PD3 ][NTf2 ] by means of solid-state NMR spectroscopy. Combined line shape and spin relaxation studies of the deuterons in the PD3 group of the octylphosphonium cation allow to map and correlate the phase behavior for a broad temperature range from 71 K to 343 K. In the solid PIL at 71 K, we observed a static state, characterized by the first deuteron quadrupole coupling constant reported for PD3 deuterons. A transition enthalpy of about 12 kJ mol-1 from the static to the mobile state with increasing temperature suggests the breaking of a weak, charge-enhanced hydrogen bond between cation and anion. The highly mobile phase above 100 K exhibits an almost disappearing activation barrier, strongly indicating quantum tunneling. Thus, we provide first evidence of tunneling driven mobility of the hydrogen bonded P-D moieties in the glassy state of PILs, already at surprisingly high temperatures up to 200 K. Above 250 K, the mobile phase turns from anisotropic to isotropic motion, and indicates strong internal rotation of the PD3 group. The analyzed line shapes and spin relaxation times allow us to link the structural and dynamical behavior at molecular level with the phase behavior beyond the DSC traces.

Melittin and diclofenac synergistically promote wound healing in a pathway involving TGF-ß1.

A dysregulation of the wound healing process can lead to the development of various intractable ulcers or excessive scar formation. Therefore it is essential to identify novel pharmacological strategies to promote wound healing and restore the mechanical integrity of injured tissue. The goal of the present study was to formulate a nano-complex containing melittin (MEL) and diclofenac (DCL) with the aim to evaluate their synergism and preclinical efficacy in an in vivo model of acute wound. After its preparation and characterization, the therapeutic potential of the combined nano-complexes was evaluated. MEL-DCL nano-complexes exhibited better regenerated epithelium, keratinization, epidermal proliferation, and granulation tissue formation, which in turn showed better wound healing activity compared to MEL, DCL, or positive control. The nano-complexes also showed significantly enhanced antioxidant activity. Treatment of wounded skin with MEL-DCL nano-complexes showed significant reduction of interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) pro-inflammatory markers that was paralleled by a substantial increase in mRNA expression levels of collagen, type I, alpha 1 (Col1A1) and collagen, type IV, alpha 1 (Col4A1), and hydroxyproline content as compared to individual drugs. Additionally, MEL-DCL nano-complexes were able to significantly increase hypoxia-inducible factor 1-alpha (HIF-1α) and transforming growth factor beta 1 (TGF-ß1) proteins expression compared to single drugs or negative control group. SB431542, a selective inhibitor of type-1 TGF-ß receptor, significantly prevented in our in vitro assay the wound healing process induced by the MEL-DCL nano-complexes, suggesting a key role of TGF-ß1 in the wound closure. In conclusion, the nano-complex of MEL-DCL represents a novel pharmacological tool that can be topically applied to improve wound healing.