Effect Of Ion Pair Formation Research Articles

Ion Pairing with Bile Salts Modulates Intestinal Permeability and Contributes to Food–Drug Interaction of BCS Class III Compound Trospium Chloride

In the current study the involvement of ion pair formation between bile salts and trospium chloride (TC), a positively charged Biopharmaceutical Classification System (BCS) class III substance, showing a decrease in bioavailability upon coadministration with food (negative food effect) was investigated. Isothermal titration calorimetry provided evidence of a reaction between TC and bile acids. An effect of ion pair formation on the apparent partition coefficient (APC) was examined using (3)H-trospium. The addition of bovine bile and bile extract porcine led to a significant increase of the APC. In vitro permeability studies of trospium were performed across Caco-2-monolayers and excised segments of rat jejunum in a modified Ussing chamber. The addition of bile acids led to an increase of trospium permeation across Caco-2-monolayers and rat excised segments by approximately a factor of 1.5. The addition of glycochenodeoxycholate (GCDC) was less effective than taurodeoxycholate (TDOC). In the presence of an olive oil emulsion, a complete extinction of the permeation increasing effects of bile salts was observed. Thus, although there are more bile acids in the intestine in the fed state compared to the fasted state, these are not able to form ion pairs with trospium in fed state, because they are involved in the emulsification of dietary fats. In conclusion, the formation of ion pairs between trospium and bile acids can partially explain its negative food effect. Our results are presumably transferable to other organic cations showing a negative food effect.

Effect of ion pair formation on the structure of polymer micelles with ionic amphiphilic coronae

We report a theoretical study of micelles from diblock copolymers with an insoluble core-forming block and an amphiphilic ionic corona-forming block. We calculate the micelle structural parameters depending on the composition of the coronal block (ratio between the non-polar and ion-containing groups) as well as solvent quality and polarity for the coronal block. We focus on the effect of ion pair formation in a low polar corona medium and predict the existence of novel micelles with ionomer-type coronae. In these micelles most part of counterions is bound with ions in polymer chains. Two consecutive jump-like first-order phase transitions between different-type micelles can take place in the solution upon change of hydrophobic/polyelectrolyte balance within the micelle corona: large micelles with polyelectrolyte collapsed coronae → large micelles with ionomer-type coronae → small micelles with polyelectrolyte swollen coronae. These transitions are accompanied by non-monotonous change in the micelle aggregation number. New insight into the role of counterions is important for design of stimuli responsive systems.

Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments

This study shows the effect of ion pair formation on intestinal absorption and oral bioavailability of amifostine. Amifostine is a prodrug used as a highly potent and selective radiotherapy and chemotherapy protectant but due to its low lipophilicity and charge at physiological pH range, its trans epithelial transport and its potential for oral drug delivery is very low. Ion pair formation with negatively charged counter ions was evaluated by in situ rat perfusion studies as a possible strategy to enhance intestinal absorption of amifostine. Succinic acid, phthalic acid and benzoic acid were used as counter ions. Rat intestinal perfusion studies confirmed a statistically significant increase in amifostine permeability in the presence of the counter ions in the order of succinic>phthalic>benzoic. Rat pharmacokinetic studies in vivo were performed to calculate oral absolute bioavailability of amifostine alone and with ion pairs in order to confirm the in situ perfusion results and the applicability of the ion pair approach. Intravenous and intraduodenal administrations were done in rats using a permanent jugular vein cannulation technique and a duodenal cannulation method to avoid drug degradation in stomach. In vivo oral bioavailability studies demonstrated a 20–30-fold increase in amifostine bioavailability with succinic acid depending on counter ion ratio and 10-fold increase with phthalic acid as ion pair. In summary ion pair strategy with succinic acid could enable amifostine oral administration on enteric coated formulations.

Effect of ion-pair formation with bile salts on the in vitro cellular transport of berberine

The objective of this study was to examine the effect of ion-pair complexation with endogenous bile salts on the transport of a quarternary ammonium organic cationic (OC) drug, berberine, across the Caco-2 and LLC-PK1 cell monolayers. The basolateral-to-apical (BL-AP) transport of berberine in Caco-2 cells was temperature dependent and 10-fold higher than that of the apical-to-basolateral (AP-BL) transport. Similar results were observed for the transport of berberine across the LLC-PK1 cells. Moreover, the BL-AP transport in the Caco-2 cells was significantly reduced by the cis-presence of P-glycoprotein (P-gp) inhibitors such as cyclosporine A, verapamil, and digoxin. These results suggest that an efflux transporter, probably P-gp, is involved in the Caco-2 cell transport. The Km and Vmax values for the carrier-mediated transport were estimated to be 83.4 mM and 7640 pmole/h/cm2, respectively. The apparent partition coefficient (APC) of berberine between n-octanol and a phosphate buffer (pH 7.4) was increased by the presence of an organic anion (OA), taurodeoxycholate (TDC, a bile salt), suggesting the formation of a lipophilic ion-pair complex between an OC (berberine) and an OA (TDC). Despite the ion-pair complexation, however, the BL-AP transport of berberine across the Caco-2 and LLC-PK1 cells was not altered by the cis-presence of bile salts or the rat bile juice. This is consistent with the reportedly unaltered secretory transport of a quarternary ammonium compound, tributylmethylammonium (TBuMA), across the Caco-2 cell monolayers in the cis-presence of bile salts or the rat bile juice, but not with our previous report in which the secretory transport of TBuMA across the LLC-PK1 cell was increased in the cis-presence of TDC. Therefore, the effect of ion-pair formation with the bile components or bile salts on the secretory transport of OCs appears to depend on the molecular properties of OCs (e.g., molecular weight, lipophilicity and affinity to relevant transporters) and the characteristics of cell strains (e.g., expression and contribution of responsible transporters to the transport).

Complexation of Oppositely Charged Polyelectrolytes: Effect of Ion Pair Formation

Complexation in symmetric solutions of oppositely charged polyelectrolytes is studied theoretically. We include polyion crosslinking due to formation of thermoreversible ionic pairs. The electrostatic free energy is calculated within the Random Phase Approximation taking into account the structure of thermoreversible polyion clusters. The degree of ion association is obtained self-consistently from a modified law of mass action, which includes long-range electrostatic contributions. We analyze the relative importance of the three complexation driving forces: long-range electrostatics, ion association and van der Waals attraction. The conditions on the parameters of the system that ensure stability of the complex with addition of salt are determined.

Ion-transfer voltammetry at 1,6-dichlorohexane|water and 1,4-dichlorobutane|water interfaces

The usefulness of 1,6-dichlorohexane (1,6-DCH) and 1,4-dichlorobutane (1,4-DCB) as organic solvent (O) for ion-transfer voltammetry at O|water (W) interface has been examined, and the results are compared with those with 1,2-dichloroethane (1,2-DCE). The width of potential window of the 0.1 M tetraoctylammonium tetrakis(4-chlorophenyl)borate (O)|0.05 M Li 2SO 4 (W) interface increased in the sequence: O = 1,6-DCH > 1,4-DCB > 1,2-DCE. The voltammetric behavior of the transfer of various cations and anions at the 1,6-DCH|W and 1,4-DCB|W interfaces has been shown to be of reversible nature, and the midpoint potentials or the reversible half-wave potentials have been determined. The midpoint potentials of hydrophilic ions have also been determined by the analysis of anodic final rise or cathodic final decent of the voltammograms with the O|W interfaces, where the W contains a salt of the hydrophilic ion. Also, the effect of ion-pair formation in O on the midpoint potentials has also been discussed.

Low-voltage paper electrophoretic study of ion-pair formation and electrochromatography of inorganic anions on papers impregnated with titanium (IV) tungstate.

The ion-pair formation and electrochromatographic behavior of 22 anions are studied on plain and titanium (IV) tungstate impregnated papers using 0.1 N and 1 N solutions of NaNO3, Mg(NO3)2, Al(NO3)3, Cr(NO3)3, and Co(NO3)2 as background electrolytes. The effect of ion-pair formation on the migration of anions is studied. In general, the mechanism of migration is explained in terms of adsorption, precipitation, and complex formation. A number of binary and ternary separations are achieved. In Mg(NO3)2 media, the migration is correlated with the solubility of their magnesium salts for SO3(2-), C2O4(2-), SeO3(2-), AsO4(3-), and Fe(CN)6(4-).

Swelling of strong polyelectrolyte hydrogels in polymer solutions: effect of ion pair formation on the polymer collapse

A series of strong polyelectrolyte hydrogels based on acrylamide and 2-acrylamido-2-methylpropane sulfonic acid sodium salt or [(Methacrylamido)propyl]trimethyl ammonium chloride were prepared by free-radical crosslinking copolymerization. Their swelling behavior was investigated in a good solvent (water), in polymer melt and in aqueous polymer solutions. Poly(ethylene glycol) of various molecular weights was used as the linear polymer in the swelling experiments. The equilibrium volume swelling ratio q v of the hydrogels in water scales with the network charge density f by the relation q v∝ f 0.66. The volume of the hydrogels in the polymer melt decreases as the number of segments, y, on the polymer increases. It was shown, for the non-ionic hydrogels, that this deswelling occurs due to the mixing entropy of the linear polymer in the external solution, whereas, for the ionic gels, due to trapping of counterions caused by the decreased polarity of the medium. The network–polymer interaction parameter χ 23 was found to vary with y by the relation χ 23=constant/ y. The hydrogels also deswell in aqueous polymer solutions as the polymer concentration increases. This deswelling occurs smoothly or jumpwise, as a first-order phase transition, depending on the ionic group content of the hydrogels. The Flory–Huggins theory correctly predicts the swelling and collapsing behavior of the hydrogels in polymer solutions if the variation of the effective charge density depending on the medium polarity is taken into account.

Crystal Structures and Acetonitrile Exchange of Palladium(II) Complexes with Bis(3-aminopropyl)amine and Diethylenetriamine. Effects of Ion-Pair Formation

Abstract The crystal structures of palladium(II) complexes with tridentate amine and acetonitrile, [Pd(CH3CN)(dptn)](CF3SO3)2 (1) and [Pd(CH3CN)(dien)](CF3SO3)2 (2) (dptn = bis(3-aminopropyl)amine and dien = diethylenetriamine), have been determined by X-ray crystal structure analysis. The central palladium(II) ion has a distorted square-planar geometry. The five-membered chelate rings of the dien ligand in 2 are more strained than the six-membered chelate rings of the dptn ligand in 1, as indicated from the difference in the angles of terminal N–Pd–terminal N and the averaged Pd–N–C angles around the terminal nitrogens. The kinetics of acetonitrile exchange of 1, 2, and [Pd(CH3CN)(dien)](BF4)2 (3) have been investigated by the 1H NMR line-broadening technique. The observed rate constants can be expressed by kobs = k1 + k2 [CH3CN] from the dependence of kobs on the acetonitrile concentration. It has been indicated that the k1 and k2 paths proceed via the dissociative and associative modes of activation, respectively. The dissociative k1 path is promoted by the ion-pair formation where the bound ligand effect is enhanced by the electrostatic interaction between the counter anions and amine protons. The reaction mechanisms are discussed in terms of the steric and electronic factors of the bound ligands (dptn and dien) and the effect of the ion-pair formation with the counter anions (CF3SO3− and BF4−).

In vitro iontophoresis of isopropamide through rat skin and effect of ion-pair formation with organic anions

The iontophoretic delivery across rat skin of a quartemary ammonium salt (isopropamide: ISP), which is positively charged over a wide pH range, was measured in vitro. The study showed that: (a) iontophoresis significantly enhanced ISP delivery compared to passive transport; (b) ISP delivery was directly proportional to the applied continuous direct current density over the range of 0–0.69 mA/ cm 2; (c) ISP delivery was also proportional to the ISP concentration in the donor compartment over the range of 0–2 × 10 −2 M; (d) sodium ion in the donor compartment inhibited the ISP transport possibly due to decreasing the electric transference number of ISP; (e) ISP delivery increased as the pH of the donor solution increased over the pH range 2–7, suggesting permselective nature of the epidermis, and inhibition of the transference number of ISP by hydronium ion; (f) some organic anions such as taurodeoxycholate, salicylate and benzoate which form lipophilic ion-pair complexes with ISP inhibited the delivery of ISP. The degree of inhibition by the organic anions was linearly proportional to the extraction coefficient ( K e) of ISP from the partition system with each counteranion between phosphate buffer (pH 7.4 ) and n-octanol. It suggests that not only sodium ion and hydronium ion but also the counteranions which form lipophilic ion-pairs with ISP are not favorable components in formulating the donor solution of ISP, a cationic drug, to achieve an effective iontophoretic delivery.

Photochemistry of benzimidazolocyanine dyes in solvents of different polarity

The effect of ion pair formation on the kinetics of the decay of the photoisomers and triplet states of cationic benzimidazolocyanine dyes is studied by flash photolysis. An increase in the rate constant of the reversecis-trans isomerization of the photoisomers is observed when ion pairs are formed (in nonpolar solvents). In the case of benzimidazolocyanine dyes with the I− anion, ion-pair formation causes an increase in the rate constant of decay of the triplet state. Acceleration of S1 ⇝ S0 internal conversion is discovered for the dyes with I−1

Extraction mechanism of monovalent ion-pairs by polyurethane foams

The extractability sequence of K + ≈ Rb + > Cs + > Na + > Li + for the extraction with polyether foam suggests that the cation chelation mechanism might be operative. However, the same order was obtained for the extraction with 100% polypropylene oxide polyether foam which does not normally adopt a helical structure to form oxygen-rich cavities as easily or as effectively as polyethylene oxide to accommodate alkali metal ions. This result indicates that a hole-size/cation-diameter relationship may not be required for the high extraction of K +. The extraction of alkali metal DPAs and hydroxides from methanol demonstrates the importance of the solvent effect. It indicates that the water-structure enforced ion-pairing (WSEIP) is the driving force for extraction of the ion-pairs. The extraction mechanism for ionic species can be described as an ion-pair extraction process. The overall effect of ion-pair formation in water and interaction of the extracted ions with foam appears to determine the extractability of the ions of the extractable ion-pair.

Effect of Ion-Pair Formation on Boron Adsorption by Kaolinite

AbstractBoron adsorption on 2-0.2-μm size fractions of kaolinite at 25° ± 2°C at pH values between 6.0 and 10.5 was studied. The kaolinite sample was pretreated to remove any surface oxide and hydroxide coatings. The initial concentrations of boron in solution ranged between 2 and 10 mg/liter with either KClO4 or Ca(ClO4)2 as background electrolyte at constant ionic strength of 0.09 ± 0.01 mole/liter. Boron speciation in equilibrium solutions was calculated by using the chemical equilibrium computer program GEOCHEM. The adsorption of boron on kaolinite in either medium showed similar dependence on pH and initial boron concentrations. Boron adsorption at higher pHs was noticeably higher in Ca(ClO4)2 medium as compared to KClO4 medium. These differences were attributed to the formation and adsorption of CaB(OH4)+ ion-pair species.

Hepatic uptake and biliary excretion of organic cations—II: The influence of ion pair formation

The influence of an anorganic anion iodide (I −) and an organic anion tetraphenylborate (TPB −) on the hepatic uptake and biliary excretion of three organic cations, triethylmethyl ammonium (TEMA), tripropylmethyl ammonium (TPMA) and tri- n-butylmethyl ammonium (TBuMA) was studied. The compounds were injected as a bolus (D = 1 μmole) and studied in isolated perfused livers. In the perfusion medium 25% of the amount of NaCl (3 mmole) was replaced by NaI, whereas in two other experiments TPB − was added to the medium in two concentrations (2 μM and 200, μM). NaI did not affect the biliary output of the three quaternary ammonium compounds (QACs) although an increased net rate of hepatic uptake was found for all compounds, most likely due to a decreased liver to plasma transport. Liver to plasma concentration ratios were increased, while the ratios between bile to liver and bile to plasma were not affected. TP − in catalytic amounts added to the medium (2 μM) decreased the biliary output of TEMA and TBuMA, whereas the kinetic profile of TPMA was unchanged. The decreased biliary excretion rate of TEMA was explained by a decreased plasma level (due to the increased liver uptake) assuming that the small molecular weight compounds can enter the bile directly from plasma via the junctional complexes between the cells. The bile to plasma (B/P) ratio was not affected. In contrast, the bile to plasma (B/P) ratio and the bile to liver (B/L) ratio of TBuMA were decreased, compared with the control, probably due to an increased reabsorption from the bile, whereas the back transport from the liver into the plasma was also decreased. A large amount of TPB − (200 μM), added to the perfusion medium, dramatically changed the kinetic profile of the three QACs. Ion pair formation between the QACs and TPB − was supposed to be responsible for this effect. Plasma levels dropped more rapidly as a result of an increased rate of liver uptake. The biliary excretion of all compounds was greatly reduced (the excretion rates were 0.022, 0.19 and 0.18 nmole/min, compared with 0.047, 0.71 and 7.5 nmole/min for the controls). It is concluded that ion pair formation may play a role in the hepatobiliary transport. The rate of liver uptake of the QACs is enhanced in the presence of an anion, which is due to an increase in plasma to liver transport ( k 12) and a reduced liver to plasma transport ( k 21). The increased net uptake into the hepatocytes however does not result in an increased biliary output. In fact the effects of ion pair formation on the biliary output can be strongly negative. The intra membrane potential hill, which is supposed to be influenced by TPB −, may be a barrier for liver uptake of QACs with low lipophilicity and also for reabsorption from the biliary tree of QACs with a high lipophilicity. The remarkable decrease in biliary transport of the QACs caused by TPB − may therefore be explained by reduction of the effective concentration for the canalicular transport of onium compounds within the cells, due to ion pair formation and/or an increased intracellular binding or alternatively to an increased bile to liver transport (increased biliary reabsorption).

Ion-pair effects on the electroreduction of carbonyl compounds in N,-Dimethylformamide

Ion-pair formation effects on the electroreduction of 21 carbonyl compounds were studied systematically in N,N-dimethylformamide (DMF). The degree of the shift of half-wave potentials due to ion-pair formation was observed in the order of p-quinones ρ α -diketones<aromatic ketones<σ-quinones. The thermodunamic properties of several ion associates were evaluated and their structures were discussed, together with the results of the column electrolysis ESR method.

Study of weak Mn2+ and Cu2+ complexes by a nuclear magnetic resonance method

An NMR method is described and applied, which allows the investigation of the first coordination sphere of certain transition metal ions. It is based on the measurement of the solvent proton nuclear magnetic relaxation times both as a function of magnetic field and of concentration of an admixed diamagnetic salt. This procedure enables an unambiguous separation of dynamic effects from ion-pair formation effects, which both can influence the relaxation times. As an application of this method, the complex formation of Mn2+ and Cu2+ with Br−, I−, ClO 4 − , and SO 4 2− in aqueous solution is studied. Thus the hydration numbersn H2O of these cations as a function of anion concentration are obtained, allowing the detection of weak inner-sphere or outersphere complexes. Also several complex stability constants are derived and are compared with literature data.

The effect of ion pair formation on the antimuscarinic activity of methantheline.

The quaternary ammonium compound, methantheline, was found to antagonize acetylcholine induced contractions in isolated guinea pig ileum by a mechanism which did not conform to the criteria for either competitive or non-competitive inhibition. Enhancement of the lipid solubility of methantheline by formation of an ion pair with trichloracetate failed to influence its cholinergic inhibitory activity. The results suggest that in the guinea pig ileum a) an intracellular site of action does not exist for methantheline and b) the membrane receptors for methantheline most likely are located in an aqueous environment.

The effects of ion pairing on the EPR spectra of alkyl aromatic hydrocarbon radical anions

It is shown that the calculation of spin density changes in radical anions caused by a counterion can be usefully extended to radicals involving hyperconjugation. Such calculations are done for the acenaphthene and pyracene anions and show that the alternating linewidth effects in their EPR spectra are consistent with proposed double potential minima above the aromatic parts of these radicals. New experiments on acenaphthene are reported which support the calculations. The calculation is shown to account successfully for the effects of ion pair formation in 9,10-dihydroanthracene and in benzocyclobutane. Experiments with partially deuterated dihydroanthracene resolve some uncertainty about the assignment of the coupling constants.

ChemInform Abstract: POTENTIOMETRIC STUDIES OF CADMIUM‐ AND ZINC‐HALIDE COMPLEXES IN ACETONITRILE

AbstractDie Bildungskonstanten für Cd‐ und Zn‐halogenokomplexe in Acetonitril werden durch potentiometrische Titration mit einer gesättigten Amalgam‐Indikatorelektrode bestimmt.

Potentiometric Studies of Cadmium- and Zinc-Halide Complexes in Acetonitrile

Abstract The overall formation constants of cadmium- and zinc-halide complexes in acetonitrile were determined by potentiometric titration using a saturated metal amalgam indicator electrode. The effect of ion-pair formation was taken into consideration to elucidate the free halide ion concentration in the experiments. The values of logβ3 and logβ4 for cadmium-halide complex were found to be: I−, 22.4 and 26.5; Br−, 25.3 and 29.8; Cl−, 29.2 and 34.0. The values for zinc-chloride complex were 20.1 and 23.4.