Ion-pairing HPLC methods to determine EDTA and DTPA in small molecule and biological pharmaceutical formulations

Ion-pairing high-performance liquid chromatography-ultraviolet （HPLC-UV） methods were developed to determine two commonly used chelating agents, ethylenediaminetetraacetic acid （EDTA） in Abilify （a small molecule drug with aripiprazole as the active pharmaceutical ingredient） oral solution and die- thylenetriaminepentaacetic acid （DTPA） in Yervoy （a monoclonal antibody drug with ipilimumab as the active pharmaceutical ingredient） intravenous formulation. Since the analytes, EDTA and DTPA, do not contain chromophores, transition metal ions （Cu2＋, Fe3＋） which generate highly stable metallocom- plexes with the chelating agents were added into the sample preparation to enhance UV detection. The use of metallocomplexes with ion-pairing chromatography provides the ability to achieve the desired sensitivity and selectivity in the development of the method. Specifically, the sample preparation in- volving metallocomplex formation allowed sensitive UV detection. Copper was utilized for the de- termination of EDTA and iron was utilized for the determination of DTPA. In the case of EDTA, a gradient mobile phase separated the components of the formulation from the analyte. In the method for DTPA, the active drug substance, ipilimumab, was eluted in the void. In addition, the optimization of the concentration of the ion-pairing reagent was discussed as a means of enhancing the retention of the aminopolycarboxylic acids （APCAs） including EDTA and DTPA and the specificity of the method. The analytical method development was designed based on the chromatographic properties of the analytes, the nature of the sample matrix and the intended purpose of the method. Validation data were presented for the two methods. Finally, both methods were successfully utilized in determining the fate of the chelates.

Contacted Ion Pairs in Aqueous CuCl2 by the Combination of Ratio Spectra, Difference Spectra, Second Order Difference Spectra in the UV-Visible Spectra

The microstructure of aqueous CuCl2 has been studied through lots of technologies for many years; however, it remains a controversial subject. In this study, a new spectroscopic method has been proposed to analyze the UV-visible spectra of thin fihn of CuCl2/H2O solutions at different concentrations. This method is the combination of ratio spectra, difference spectra and second order difference spectra. By using this method, two new bands at -230 and -380 nm are obviously observed. The bands are assigned as the contacted ion pairs [CuCl3（H2O）n]- or [CuCl4（H2O）n]2-, which demonstrates that ion pairs exist in the CuCl2/H2O solution. Such finding agrees with the recent theoretical spectra obtained by time-dependent density functional theory. Furthermore, the populations of the contacted ion pairs are discussed. This study not only offers the direct spectroscopic evidence of [CuCl3（H2O）n]- or [CuCl4（H2O）n]2- in aqueous CuCl2, but also suggests that the spec- troscopic analysis method is powerful to extract the weak bands in a strong overlapping spectrum.

Ion Pairing Kinetics Does not Necessarily Follow the Eigen-Tamm Mechanism

The most recognized and employed model of the solvation equilibration in the ionic solutions was proposed by Eigen and Tamm, in which there are four major states for an ion pair in the solution： the completely solvated state, 2SIP （double solvent separate ion pair）, SIP （single solvent separate ion pair）, and CIP （contact ion pair）. Eigen and Tamm suggested that the transition from SIP to CIP is always the slowest step during the whole pairing process, due to a high free energy barrier between these two states. We carried out a series of potential of mean force calculations to study the pairing free energy profiles of two sets of model mono- atomic 1：1 ion pairs 2.0：x and x：2.0. For 2.0：x pairs the free energy barrier between the SIP and CIP states is largely reduced due to the salvation shell water structure. For these pairs the SIP to CIP transition is thus not the slowest step in the ion pair formation course. This is a deviation from the Eigen-Tamm model.

An intravenous clarithromycin lipid emulsion with a high drug loading, H-bonding and a hydrogen-bonded ion pair complex exhibiting excellent antibacterial activity

The aim of this study was to develop an intravenous clarithromycin lipid emulsion(CLE)with good stability and excellent antibacterial activity. The CLE was prepared by the thinfilm dispersed homogenization method. The interaction between clarithromycin(CLA) and cholesteryl hemisuccinate(CHEMS) was confirmed by DSC, FT-IR and^1H NMR analysis. The interfacial drug loading, thermal sterilization, freeze–thaw stability, and in vitro and in vivo antibacterial activity were investigated systematically. DSC, FT-IR and^1H NMR spectra showed that CHEMS(CLA: CHEMS, M ratio 1:2) could interact with CLA through H-bonding and a hydrogen-bonded ion pair. The CHEMS was found necessary to maintain the stability of CLE.Ultracentrifugation showed that almost 88% CLA could be loaded into the interfacial layer.The optimized CLE formulation could withstand autoclaving at 121 °C for 10 min and remain stable after three freeze–thaw cycles. The in vitro susceptibility test revealed that the CLA–CHEMS ion-pair and CLE have similar activity to the parent drug against many different bacterial strains. The in vivo antibacterial activity showed that the ED50 of intravenous CLE was markedly lower than that of CLA solution administrated orally. CLE exhibited pronounced antibacterial activity and might be a candidate for a new nanocarrier for CLA with potential advantages over the current commercial formulation.

Double Z-Scheme g-C_(3)N_(4)/BiOI/CdS heterojunction with I_(3)^(-)/I^(-) pairs for enhanced visible light photocatalytic performance

The g-C_(3)N_(4)/BiOI/CdS double Z-scheme heterojunction photocatalyst with I_(3)^(-)/I^(-) redox pairs is prepared using simple calcination,solvothermal,and solution chemical deposition methods.The photocatalyst comprised mesoporous,thin g-C_(3)N_(4) nanosheets loaded on flower-like microspheres of BiOI with CdS quantum dots.The g-C_(3)N_(4)/BiOI/CdS double Z-scheme heterojunction has abundant active sites and in situ redox I_(3)^(-)/I^(-) mediators and shows quantum size effects,which are all conducive to enhancing the separation of photoinduced charges and increasing the photocatalytic degradation efficiency for bisphenol A,a model pollutant.Specifically,the heterojunction photocatalyst achieves a photocatalytic degradation efficiency for bisphenol A of 98.62%in 120 min and photocatalytic hydrogen production of 863.44 mmol h^(-1) g^(-1) on exposure to visible light.The excellent visible-light photocatalytic performance is as a result of the Z-scheme heterojunction,which extends absorption to the visible light region,as well as the I_(3)^(-)/I^(-) pairs,which accelerate photoinduced charge carrier transfer and separation,thus dramatically boosting the photocatalytic performance.In addition,the key role of the charge transfer across the indirect Z-scheme heterojunction has been elucidated and the transfer mechanism is confirmed based on the detection of intermediate I_(3)^(-)ions.Thus,this study provides guidelines for the design of indirect Z-scheme heterojunction photocatalysts.

Novel Properties of Supramolecular Complexes Formed by Pairing Cationic Porphyrin and Anionic Metal-Oxo Cluster

MTBPyP (meso-tetrakis(4-N-benzylpyridyl)porphyrin, M=H-2, Zn) bearing positive charge has been shown to associate with SiW12O404- in water solution. The spectral evolution and Job's plots analyses reveal that the relatively stable aggregates contain equal numbers of MTBPyP4(+) and SiW12O404-.

Novel additives for the separation of organic acids by ion-pair chromatography

This paper proposes the use of novel surfactant additives for the separation of organic acids by ion-pair chromatography and studies the influences of surfactants on the chromatographic separation behaviors.Researches have been carried out on both silica gel matrix and polymer supporters in order to compare the two ordinary kinds of stationary phases,and the phenomenon is similar. Separation is based on differences in the stabilities of analyte-additive complexes in solution.Retention times of analytes can ...

Enantiomeric Separation of Amino Alcohols by Ion-pair Chromatography

Enantiomers of four amino alcohols were resolved by ion-pair chromatography with (+)-10-camphorsulphonic acid as chiral counter ion. Studies of the influence of the mobile phase composition, the solute structure and the mobile phase flow-rate on separation are presented. Under the optimized conditions enantiomeric propanolol, norephedrine, metropolol and salbutamol were separated using dichloromethane-1-pentanol (97:3 v/v) as mobile phase on Lichrospher-100-DIOL column.

The Quantum Scattering Study for Ion-pair Formation Reaction Na+I_2→Na^+I_2^- with the LCAC-SW method

The selected-state probabilities of collinear ion-pair formation process Na+I2→Na++I2-on Aten-Laming-Los two-State potential energy surface have been calculated by using LCAC-SW method. The results show that reaction probabilities are oscillatory with collision energy; the threshold energy of this ioniZation reaction is 2.8 ev, which is in modest agreement with experimental result.

Synthesis and Crystal Structure of a Novel Ion-pair Compound Consisting of 1-(4-Bromobenzyl)pyridinium Cation and 7,7,8,8-Tetracyanoquinodimethanide Anion

The title compound [BrBzPy][TCNQ] （BrBzPy^＋=1-（4-bromobenzyl）pyridinium cation, TCNQ = 7,7,8,8-tetracyanoquinodimethanide anion） was synthesized by the reaction of [BrBzPy]Br and LiTCNQ in ethanol solution and its structure was determined by single-crystal X-ray diffraction. The crystal belongs to monoclinic, space group P21/c with a = 14.067（3）, b = 7.3089（14）, c = 23.796（4）A, β = 122.011（9）°, V= 2074.6（7）A^3, Z = 4, C24H15BrN5, Mr = 453.32, Dc = 1.451 g/cm^3,μ = 2.002 mm^-1, S = 1.047, F（000） = 916, R = 0.0398 and wR = 0.0921. The most prominent structural features are the completely segregated stacking columns of the TCNQ- anions and [BrBzPy]^＋ cations. In a TCNQ column, the centroid-to-centroid distances of the neighboring anions of TCNQ are 3.2693 and 4.9464 A, respectively.

Synthesis and Crystal Structure of an Ion-pair Compound: [H_2(teta)]^(2+)·[Ni(CN)_4]^(2-)·2H_2O (teta = Meso-5,7,7,12,14,14-hexamethyl- 1,4,8,11-tetraazacyclotetradecane)

The ion-pair compound [H2（teta）]^2＋·[Ni（CN）4]^2-·2H2O （C20H42N8NiO2, teta = meso- 5,7,7,12,14,14-hexamethyl- 1,4,8,11-tetraazacyclotetradecane） was synthesized and characterized by single-crystal X-ray diffraction. The crystal belongs to monoclinic, space group P211n with a = 10.0784（10）, b = 9.5411（7）, c = 14.1010（14）А, β= 106.752（2）°, V= 1298.4（2）A^3, Mr = 485.33, Z= 2, De= 1.241 g/cm^3,μ（MoKα） = 0.778 mm^-1 and F（000） = 524. The structure was refined to R = 0.0391 and wR = 0.0870 for 2614 observed reflections with I 〉 2σ（I）. The title compound contains one [Ni（CN）4]^2- anion, one protonated macrocyclic tetraamine cation [H2（teta）]^2＋ and two water molecules. There are multiform hydrogen bonds in the compound to link the different components and stabilize the crystal structure.

Preparation,Crystal Structure and Density Functional Theory Calculations of the Ion-pair Compound [Cl2Bz(3-MeQl)](TCNQ)

A novel compound [Cl2Bz（3-MeQl） ]（TCNQ） （[Cl2Bz（3-MeQl） ]^＋ = 1-（3,4-dichlo-robenzyl） 3-methlquinoline cation,TCNQ-= 7,7,8,8-tetracyanoquinodimethanide anion） has been synthesized by the reaction of [Cl2Bz（3-MeQl） ]Br and LiTCNQ,and its structure was determined by single-crystal X-ray diffraction. The crystal belongs to monoclinic,space group P21/c. The structure analysis shows that the anions are stacked into a column with isolated π-dimers,and there is one type of TCNQ entries（TCNQ^-） ,in agreement with the IR spectra analysis and density functional theory calculations of the compound. The most prominent structural features are the completely segregated stacking columns of the TCNQ- anions and [Cl2Bz（3-MeQl）]＋ cations.

Synthesis and Crystal Structure of a Novel Ion-pair Compound Consisting of 1,3-Bis(4-cynobenzyl) Imidazole Cation and 7,7,8,8-Tetracyanoquinodimethanide Anion

A novel compound [（CNBz）2Im]2（TCNQ）3（CH3CN）（（CNBz）2Im = 1,3-bis（4-cyano-benzyl） imidazole cation,TCNQ-1 = 7,7,8,8-tetracyanoquinodimethanide anion） was synthesized by the reaction of [（CNBz）2Im]Br and LiTCNQ in water and its structure was determined by single-crystal X-ray diffraction.The crystal belongs to monoclinic,space group P21/c with a = 10.1823（17）,b = 20.292（3）,c = 16.952（3） ,β = 104.73（0）°,V = 3387.6（10）3,Z = 4,C39H24N11,Mr = 646.69,Dc = 1.268 g/cm3,μ = 0.080 mm-1 and F（000） = 1340.The structure was solved by direct methods and refined to R = 0.0596 and wR = 0.0911 for 2690 observed reflections（Ⅰ 〉 2σ（Ⅰ））.The most prominent structural feature is that there are two types of TCNQ entries（TCNQ-1 and TCNQ0） in agreement with the IR spectra analysis of the compound.

Synthesis and Structure of a Novel Ion-pair Palladium(Ⅱ) Compound Containing 2-Thioxo-1,3-dithiole-4,5-bis(thiolate)

A novel ion-pair palladium（Ⅱ） compound, （NOzBzPy）2[Pd（dmit）2] （NO2BzPy^＋ = 1-（4-nitrobenzyl）pyridinium, dmit^2- = 2-thioxo-1,3-dithiole-4,5-bis（thiolate））, was synthesized and characterized by single-crystal X-ray structure determination. This compound crystallizes in the monoclinic system, space group P21/n with a = 10.4463（11）, b = 8.5627（9）, e = 20.017（2）A, β = 97.7730（10）°, V = 1774.1（3）A^3, Z = 2, C30H22N4O4S10Pd, Mr = 929.52, Dc = 1.740 g/cm^3,μ = 1.155 mm^-1, S = 1.006, F（000） = 936, R = 0.0354 and wR = 0.0675. The most intriguing general structural feature of the compound is the completely segregated columnar stacks of anions and cations. There exist hydrogen-bonding interactions within the cation column.

Theoretical Study on the Ion-pair Formation Mechanism for the Li+I_2 →Li^+ + I_2^- System

For the Li + I2 →Li+ + I2- system, theoretical study has been performed on the QCISD(T) level by using the ab initio method. The collision complex in ion-pair formation process was found and optimized. These results show that the crossed molecule beam (CMB) experimental phenomenon is verified and the detailed geometry is given for the first time. A mechanism for ion-pair formation was proposed in detail. The position where the collision complex occurs affects the reaction path. Specifically, the process has threshold when the collision complex appeared before the crossing point between the covalent and ionic state potential energy surfaces. On the contrary, the process has no threshold after the crossing point. Theoretically, the title system belongs to the former case.

Ca and Sr co-doping induced oxygen vacancies in 3DOM La_(2-x)Sr_(x)Ce_(2-y)CayO_(7-δ)catalysts for boosting low-temperature oxidative coupling of methane

It is urgent to develop catalysts with application potential for oxidative coupling of methane(OCM)at relatively lower temperature.Herein,three-dimensional ordered macro porous(3 DOM)La_(2-x)Sr_(x)Ce_(2-y)CayO_(7-δ)(A_(2)B_(2)O_(7)-type)catalysts with disordered defective cubic fluorite phased structure were successfully prepared by a colloidal crystal template method.3DOM structure promotes the accessibility of the gaseous reactants(O2and CH4)to the active sites.The co-doping of Ca and Sr ions in La_(2-x)Sr_(x)Ce_(2-y)CayO_(7-δ)catalysts improved the formation of oxygen vacancies,thereby leading to increased density of surface-active oxygen species(O_(2)^(-))for the activation of CH4and the formation of C2products(C2H6and C2H4).3DOM La_(2-x)Sr_(x)Ce_(2-y)CayO_(7-δ)catalysts exhibit high catalytic activity for OCM at low temperature.3DOM La1.7Sr0.3Ce1.7Ca0.3O7-δcatalyst with the highest density of O_(2)^(-)species exhibited the highest catalytic activity for low-temperature OCM,i.e.,its CH4conversion,selectivity and yield of C2products at 650℃are 32.2%,66.1%and 21.3%,respectively.The mechanism was proposed that the increase in surface oxygen vacancies induced by the co-doping of Ca and Sr ions boosts the key step of C-H bond breaking and C-C bond coupling in catalyzing low-temperature OCM.It is meaningful for the development of the low-temperature and high-efficient catalysts for OCM reaction in practical application.

The Kadomtsev-Petviashvili equation for dust ion-acoustic solitons in pair-ion plasmas

Using the reductive perturbation method,we have derived the Kadomtsev-Petviashvili（KP） equation to study the nonlinear properties of electrostatic collisionless dust ion-acoustic solitons in pair-ion（p-i） plasmas.We have chosen the fluid model for the positive ions,the negative ions,and a fraction of static charged（both positively and negatively） dust particles.Numerical solutions of these dust ion-acoustic solitons are plotted and their characteristics are discussed.It is found that only the amplitudes of the electrostatic dust ion-acoustic solitons vary when the dust is introduced in the pair-ion plasma.It is also noticed that the amplitude and the width of these solitons both vary when the thermal energy of the positive or negative ions is varied.It is shown that potential hump structures are formed when the temperature of the negative ions is higher than that of the positive ions,and potential dip structures are observed when the temperature of the positive ions supersedes that of the negative ions.As the pair-ion plasma mimics the electron-positron plasma,thus our results might be helpful in understanding the nonlinear dust ion acoustic solitary waves in super dense astronomical bodies.

An Ion-Pair HPLC Method for Simultaneous Determination of Exogenous Phosphocreatine and Its Metabolite Creatine and Related ATP in Rabbit Plasma and RBC: Application to a Pharmacokinetic Study

A specific, precise and accurate ion-pair HPLC-UV method has been developed and validated for simultaneous determination of phosphocreatine (PCr), and its metabolite creatine (Cr) as well as related ATP in plasma and red blood cell (RBC) of rabbits. After addition of TMP as IS, the samples were deproteinized with 6% PCA. The analytes were separated on a Kromasil C18 column using a tertiary gradient mobile phase composed of buffer A (0.2% KH2PO4 + 0.08% tetrabutyl ammonium hydrogen sulphate, pH 3.0), buffer B (buffer A adjusted to pH 7.5 with 1 mol/L NaOH) and MeOH. Detection wavelengths were set at 210 nm for PCr and Cr and 260 nm for ATP and TMP. Some blank samples were initially run for baseline subtraction. The linear detection responses were obtained for PCr concentration over a range of 10 - 7500 mg/ml (plasma) and 5 - 2500 mg/ml (RBC) and for both Cr and ATP concentrations of 10 - 1500 mg/ml (plasma) and 5 - 750 mg/ml (RBC) (r > 0.99). The QC samples of 3 analytes showed intra-day and inter-day precisions (RSD) of - 107%. The method was successfully used to simultaneously determine plasma and RBC concentrations of the 3 analytes and to study pharmacokinetics after iv administration of PCr to rabbits.

EPR STUDY OF THE FORMATION OF[Li^+O^-]ION PAIR ON Li-DOPED ZnO

In this letter the study of Li-doped zinc oxide by electron paramagnetic resonance method is described.A signal observed at g_=2.013,g_=1.955 on the degassed sample at 923K was designated to F_s^+ centers(surface oxygen ion vacancies with a single trapped electron).When the sample was quenched from 1003K into liquid oxygen at 77K under 24 KPa O_2,[Li^+O^-] ion pairs valued at g_=2.026 and g=2.003 with superhyperfine constant a=2.0G,which resulted from ~7Li nucleus,formed at Li^+-substitutional site in ZnO lattice.A probable mechanism of [Li^+O^-]ion pair formation was proposed.

INTRA-ION PAIR ELECTRON TRANSFER OF PHOTOEXCITED METHYLENE BLUE BORATE

The photochemical reaction of methylene blue (n-butyltriphenyl) borate, MBRBPh3 was examined. The ultrafast quenching rate and large negative value of Delta G indicated that the intra-ion pair ET plays an important role in photoreaction of MBRBPh3. The sequent boron- carbon bond cleavage of butyltriphenylboranyl radical intermediate was found by GC-MS and photo-CIDNP studies.