Measured Distribution Coefficients Research Articles

Preformulation-Assisted Design of Ketorolac Tromethamine for Effective Ophthalmic Delivery.

Background: The eye is a highly protected organ from ocularly administered drugs; drug- and formulation-related factors contribute significantly to ocular bioavailability. There has been a growing interest in using nonsteroidal anti-inflammatory drugs in ophthalmology for treating postoperative pain, inflammation, and seasonal allergic conjunctivitis. A preformulation-assisted design boosts efficacy and reduces dose requirements. Methods: This work aims to study the preformulation characteristics of ketorolac tromethamine to improve ocular performance and future formulation development through developing an high-performance liquid chromatography (HPLC) stability-indicating assay, forced degradation under stress conditions, solubility, as well as partition and distribution coefficient measurements. An isocratic HPLC with diode array detector method was developed and validated. Accelerated degradation under different stressors (acid, alkali, heat, and oxidative) was studied. In addition, solubility, partition, and distribution were investigated at different pHs of 3.5-7.4. Results: The results indicated that the developed HPLC method was simple, rapid (retention time ≃3 min), sensitive, selective, robust, and stability indicating. The drug seems more chemically sensitive to acid degradation (∼30% and 40% of the drug was degraded under 0.1 M and 1 M HCl at 60°C for 24 h, respectively). Another significant degradation was recorded in the following order: Oxidative > alkali > heat (phosphate-buffered saline) > heat (distilled water). Being a weak ionizable drug, both water and lipid solubility, as measured through partition coefficients, it demonstrated pH-dependency. Conclusion: For the optimum balance of water and lipid solubility required for penetration through the lipophilic corneal epithelial barrier, ketorolac eye drops would be better formulated between pH 5.5 and 6.6 than being formulated at the physiological fluid pH 7.4, where the drug is extremely hydrophilic and less permeable.

Electrochemical Measurement of Interfacial Distribution and Diffusion Coefficients of Electroactive Species for Ion-Exchange Membranes: Application to Br2/Br- Redox Couple.

A novel method has been proposed for rapid determination of principal transmembrane transport parameters for solute electroactive co-ions/molecules, in relation to the crossover problem in power sources. It is based on direct measurements of current for the electrode, separated from solution by an ion-exchange membrane, under voltammetric and chronoamperometric regimes. An electroactive reagent is initially distributed within the membrane/solution space under equilibrium. Then, potential change induces its transformation into the product at the electrode under the diffusion-limited regime. For the chronoamperometric experiment, the electrode potential steps backward after the current stabilization, thus inducing an opposite redox transformation. Novel analytical solutions for nonstationary concentrations and current have been derived for such two-stage regime. The comparison of theoretical predictions with experimental data for the Br2/Br- redox couple (where only Br- is initially present) has provided the diffusion coefficients of the Br- and Br2 species inside the membrane, D(Br-) = (2.98 ± 0.27) 10-6 cm2/s and D(Br2) = (1.10 ± 0.07) 10-6 cm2/s, and the distribution coefficient of the Br- species at the membrane/solution boundary, K(Br-) = 0.190 ± 0.005, for various HBr additions (0.125-0.75 M) to aqueous 2 M H2SO4 solution. This possibility to determine transport characteristics of two electroactive species, the initial solute component and its redox product, within a single experiment, represents a unique feature of this study.

Automated high throughput pKa and distribution coefficient measurements of pharmaceutical compounds for the SAMPL8 blind prediction challenge.

The goal of the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) challenge is to improve the accuracy of current computational models to estimate free energy of binding, deprotonation, distribution and other associated physical properties that are useful for the design of new pharmaceutical products. New experimental datasets of physicochemical properties provide opportunities for prospective evaluation of computational prediction methods. Here, aqueous pKa and a range of bi-phasic logD values for a variety of pharmaceutical compounds were determined through a streamlined automated process to be utilized in the SAMPL8 physical property challenge. The goal of this paper is to provide an in-depth review of the experimental methods utilized to create a comprehensive data set for the blind prediction challenge. The significance of this work involves the use of high throughput experimentation equipment and instrumentation to produce acid dissociation constants for twenty-three drug molecules, as well as distribution coefficients for eleven of those molecules.

Solute Diffusion into Polymer Swollen by Supercritical CO2 by High-Pressure Electron Paramagnetic Resonance Spectroscopy and Chromatography.

High-pressure electron paramagnetic resonance (EPR) was used to measure translational diffusion coefficients (Dtr) of a TEMPONE spin probe in poly(D,L-lactide) (PDLLA) and swollen in supercritical CO2. Dtr was measured on two scales: macroscopic scale (>1 μm), by measuring spin probe uptake by the sample; and microscopic scale (<10 nm), by using concentration-dependent spectrum broadening. Both methods yield similar translational diffusion coefficients (in the range 5–10 × 10−12 m2/s at 40–60 °C and 8–10 MPa). Swollen PDLLA was found to be homogeneous on the nanometer scale, although the TEMPONE spin probe in the polymer exhibited higher rotational mobility (τcorr = 6 × 10−11 s) than expected, based on its Dtr. To measure distribution coefficients of the solute between the swollen polymer and the supercritical medium, supercritical chromatography with sampling directly from the high-pressure vessel was used. A distinct difference between powder and bulk polymer samples was only observed at the start of the impregnation process.

Actinide ion uptake from acidic radioactive feeds using an extraction chromatographic resin containing a branched dialkyl amide

A dialkyl amide with branched alkyl group, viz. N,N-di(2-ethylhexyl)-propionamide (D2EHPrA) was used as the organic extractant in an extraction chromatographic resin prepared for the first time and evaluated for the separation of uranium from acidic feeds. The distribution coefficient measurements, carried out at varying HNO3 concentrations, indicated an increase in the UO22+ ion sorption with increasing nitric acid concentration. The UO22+ ion sorption kinetics and sorption isotherms with this resin were investigated in details. The column studies indicated that 8.3 mg of uranium could be loaded on a 2.1 cm3 column bed volume containing 0.35 g resin. Batch distribution data for other actinides such as Np4+ and Pu4+ indicated that the resin can also be used for effective separation of these metal ions from acidic feeds. Though the resin showed effectiveness for Np and Pu, detailed investigations dealing with macro concentrations of metal ions (in gm quantities) were restricted to uranium only due to hazardous nature of plutonium and limited availability of neptunium. The encouraging results reported in this work is an indication of the possible application of this resin for the recovery or pre-concentration of UO22+, Np4+ and Pu4+ ions from large volumes of aqueous solutions of moderate acidity.

Measurement of distribution coefficients on TODGA resin and development of a group separation for mixed activation and fission product samples

Batch equilibrium experiments were performed to determine the distribution coefficients for Sc, Ir, and Ta on N,N,N′,N′ tetraoctyl-1,5-diglycolamide (TODGA) resin in various acid matrices. Distribution coefficients were determined in hydrochloric acid (Sc, Ir), nitric acid (Sc, Ta), and a mixture of nitric acid and 0.2 M hydrofluoric acid (Sc, Ir, Ta). The distribution coefficients determined through these experiments were then utilized to create a group separation method for activation products, fission products, and environmental constituents.

Recovery of Precious Metals (Au, Ag, Pt, and Pd) from Urban Mining Through Copper Smelting

With the aim of investigating deportments of precious metals in pyrometallurgical processing of waste electrical and electronic equipment, the distributions of selected precious metals (gold, silver, platinum, and palladium) between copper matte and three different silica-saturated slags (pure FeOx-SiO2, FeOx-SiO2-Al2O3, and FeOx-SiO2-Al2O3-CaO slag) were investigated at 1300 °C in controlled flowing CO-CO2-SO2-Ar gas atmosphere by a high-temperature isothermal equilibration technique. The phase compositions were analyzed by Electron Probe X-ray Microanalysis and Laser Ablation-High Resolution Inductively Coupled Plasma-Mass Spectrometry. It was shown that the distribution coefficients of gold, platinum, and palladium between matte and slag (Lm/s(Me) = [Me]in matte/(Me)in slag) were very high and increased with increasing matte grade. The distributions to the matte phase were increased by adding basic oxides alumina and lime into the acidic silicate slags. The experimentally measured distribution coefficients Lm/s(Me) followed the order of platinum > palladium > gold > silver. The present experimental results can be used for upgrading thermodynamic databases for the complex recycling processes through nonferrous smelting.

Miniaturized shake-flask HPLC method for determination of distribution coefficient of drugs used in inflammatory bowel diseases.

A new method for determination of distribution coefficient of drugs azathioprine, 6-mercaptopurine and 6-thioguanine and nutrient folic acid used in the treatment of inflammatory bowel disease based on a miniaturized shake-flask and HPLC/DAD was developed. Special attention was made to the most commonly reported problems in the measurement of distribution coefficients using a shake-flask method such as mixing technique, speed and time, the temperature of experiment, type of buffer and its pH as well as n-octanol/buffer phase ratio. The concentration of compounds in the buffer is determined by HPLC directly from shake flasks or conventional 2-mL vials. The developed method was fully validated according to ICH guidelines. Furthermore, experimental data were successfully compared with lipophilicity and human intestinal absorption calculated by the use of four different theoretical approaches. The method shows potential for high-throughput measurements of a large number of compounds.

Measurement and correlation of vapor-liquid distribution coefficients of flavonoids in high pressure carbon dioxide – ethanol – water systems

Vapor-liquid equilibria (VLE) and distribution coefficients (K-values) of carbon dioxide (CO2) - ethanol - water ternary systems and CO2 - ethanol - water - flavonoid (flavone, 6-methoxyflavone or 7-hydroxyflavone) quaternary systems were measured with a flow type apparatus at (313 to 353) K and (10 to 20) MPa. CO2 - ethanol - flavonoid ternary systems were measured at a nominal range of temperatures and pressures. The K-values of all flavonoids increased with increasing pressure. It was also indicated that the K-values of relatively lipophilic components such as flavone and 6-methoxyflavone increased with increasing water composition in feed while those of relatively hydrophilic components such as 7-hydroxyflavone increased with increasing ethanol composition in feed. A simple dimensionless relationship in terms of the K-values of the solvents (KCO2, KEtOH, KH2O) and the entropy-based solubility parameters of the vapor and liquid phases was developed to correlate the K-values of the three solutes in the CO2 - ethanol - water systems over the full range of conditions studied.

Magnesian calcite solid solution thermodynamics inferred from authigenic deep-sea carbonate

Abstract Magnesian calcite is perhaps the most well studied solid solution in the geosciences due to the widespread use of marine carbonates to reconstruct paleoenvironment. Despite decades of research, the low temperature thermodynamic properties of magnesian calcite in seawater are poorly constrained, largely because very slow reaction kinetics prevent the direct measurement of equilibrium distribution coefficients (KdMg) for anhydrous Mg-bearing minerals. In this study, we use the Mg content of authigenic calcite formed in deep-sea marine carbonate sediments to determine the dependence of KdMg on temperature and aqueous Mg/Ca between ∼2 and 25 °C. We find that the solid activity coefficient of magnesite in Mg-calcite is strongly temperature dependent in this range, leading to predicted exsolution of Mg at low temperatures. At the temperatures typical of ocean bottom water, equilibrium Mg distribution coefficients are at least an order of magnitude lower than values inferred from inorganic calcite growth experiments. Moreover, the equilibrium temperature dependence of KdMg agrees well with field-based paleotemperature calibrations determined for low-Mg benthic and planktonic foraminifera at temperatures

Measurement of uranium distribution coefficient and 235U/238U ratio in soils affected by Fukushima dai-ichi nuclear power plant accident

Fukushima Daiichi Nuclear Power Plant (FDNPP) accident resulted radioactive contamination in soil due to deposition of mainly radiocesium as well as many long-lived radionuclides surrounding a large area around FDNPP. Depending upon environmental conditions, radionuclides in soil can be mobilized in aquatic systems. Therefore, the fate and transfer of these radionuclides in the soil water system is very important for radiation protection and dose assessment. In the present study, soil and water samples were collected from contaminated areas around FDNPP. Inductively coupled plasma mass spectrometry (ICP-MS) is used for total uranium concentration. Emphasis has been given on isotope ratio measurement of 235U/238U ratio using thermal ionization mass spectrometry (TIMS) that gives us the idea about its contamination during accident. For the migration behavior, its distribution coefficient (Kd) has been determined using laboratory batch method. Chemical characterization of soil with respect to different parameters has been carried out. The effect of these soil parameters on distribution coefficient of uranium has been studied in order to explain the radionuclide mobility in this particular area. The distribution coefficient values for uranium are found to vary from 30 to 36000 L/kg. A large variation in the distribution coefficient values shows the retention or mobility of uranium is highly dependent on soil characteristics in the particular area. This variation is explained with respect to soil pH, Fe, Mn, CaCO3 and organic content. There is a very good correlation of uranium Kd obtained with Fe content. There is no enrichment of 235U has been noticed in the studied area.

Dioxin leaching risk assessment through selected soils by estimating distribution coefficient and breakthrough curves.

From health and environmental point of views, dioxins are important due to their toxicity and persistence. Dioxins have the potential to reside in the environment for longer time if sorbed onto the clay and organic content of the soil matrix. Their transport or leaching under certain environmental conditions such as preferential flow can increase the risk of groundwater contamination. In the current study, breakthrough curves (BTCs) against time were plotted for selected dioxin transport prediction; based on measured distribution coefficient (Kd), dispersion coefficient (D), and retardation factor (R). Three representative soil series named Burhan, Warsak, and Kunda were selected. For dibenzo-p-dioxin (DD), Kd values followed the order as: Burhan> Warsak > Kunda, while for 2-chloro dibenzo-p-dioxin (2 Cl-DD), Kd values followed an order as: Kunda > Burhan > Warsak. Dioxin transport was measured at two different linear velocities (20 and 50cmday-1). Attainment of equilibrium was verified to be dependent upon the Kd, R, D, and chlorination on dioxin. Kunda series with low OM (0.6%), clay (0.2%), and R (377) was found to have relatively high DD transport potential under normal velocity, due to high dispersion values for its sandy nature. Under the steady or preferential flow conditions, all the plots obtained were identical irrespective of soil type and dioxin nature.

Unique reversibility in extraction mechanism of U compared to solvent extraction for sorption of U(VI) and Pu(IV) by a novel solvent impregnated resin containing trialkyl phosphine oxide functionalized ionic liquid

Novel Solvent Impregnated Resin (SIR) material was prepared by impregnating a trialkyl phosphine oxide functionalized ionic liquid (IL) into an inert polymeric material XAD-7. A series of SIR materials were prepared by varying the IL quantity. Sorption of both U(VI) and Pu(IV) were found to increase with increasing IL concentration in SIR up to an optimum IL concentration of 435 mg g−1 of SIR beyond which no effect of IL concentration was observed. A change of mechanism of sorption for U(VI) by SIR was observed in comparison to solvent extraction. The dependency of U(VI) sorption with nitric acid concentration showed a reverse trend compared to solvent extraction studies while for Pu(IV) the trend remained same as observed with solvent extraction. Sorption of both the radionuclides was found to follow pseudo second order mechanism and Langmuir adsorption isotherm. Distribution co-efficient measurements on IL impregnated SIR showed highly selective sorption of U(VI) and Pu(IV) over other trivalent f-elements and fission products from nitric acid medium.

Experimental and computational evidence of halogen bonds involving astatine.

The importance of halogen bonds-highly directional interactions between an electron-deficient σ-hole moiety in a halogenated compound and an acceptor such as a Lewis base-is being increasingly recognized in a wide variety of fields from biomedicinal chemistry to materials science. The heaviest halogens are known to form stronger halogen bonds, implying that if this trend continues down the periodic table, astatine should exhibit the highest halogen-bond donating ability. This may be mitigated, however, by the relativistic effects undergone by heavy elements, as illustrated by the metallic character of astatine. Here, the occurrence of halogen-bonding interactions involving astatine is experimentally evidenced. The complexation constants of astatine monoiodide with a series of organic ligands in cyclohexane solution were derived from distribution coefficient measurements and supported by relativistic quantum mechanical calculations. Taken together, the results show that astatine indeed behaves as a halogen-bond donor-a stronger one than iodine-owing to its much more electrophilic σ-hole.

Ion exchange and structural properties of a new cyanoferrate mesoporous silica material for Cs removal from natural saline waters

The demand for effective and inexpensive treatment for decontamination of waters from radionuclides, such as 137Cs, is presently high. In this context a selective adsorbent material for Cs (SORBMATECH® 202) was designed, consisting of potassium/copper ferrocyanide nanoparticles deposited in the mesoporosity of silica grains. Several batch experiments were carried out in order to obtain kinetic and thermodynamic data concerning the ion exchange. Isotherms and measurements of distribution coefficients (Kd,Cs) in waters of increasing salinity (pure water, Ca-bicarbonate fresh water and seawater) were conducted in a radioactive environment. This study shows a fast ion-exchange kinetics (<5min), due to the open silica porosity combined to cyanoferrate nanoparticles, as well as high selectivity with Kd,Cs in fresh and sea waters (106 and 2.0×105mL/g, respectively). These experiments also demonstrated the competitive effects of the major cations present in natural waters (K+, Na+, Mg2+ and Ca2+) and led to the determination of the Vanselow’s selectivity coefficients. Integrating this dataset into the CHESS geochemical speciation code allowed the correct modeling of Kd,Cs values in these different water types over a wide range of Cs concentrations. The dataset can be extrapolated to the modeling of other K-ferrocyanides and effluent compositions.

Elucidation of complexation of tetra and hexavalent actinides towards an amide ligand in polar and non-polar diluents: Combined experimental and theoretical approach

A combined experimental and theoretical study has been put forward to investigate the complexation behaviour of tetravalent Pu4+ and hexavalent UO22+ ions with the N,N-dihexyloctanamide (DHOA) ligand in different diluents. Solvent extraction experiments were conducted with Pu4+ and UO22+ ions using DHOA in different diluents, namely dodecane, toluene, chloroform, octanol, nitrophenyl-octyl ether (NPOE) and nitrobenzene (NB). The experimentally measured distribution coefficients (D) of both the Pu4+ and UO22+ ions followed the order: nitrobenzene>NPOE>octanol>chloroform>toluene>dodecane. In order to complement the experimental distribution data, the structure, energetic and thermodynamic parameters of the Pu4+ and UO22+ complexes with DHOA have been calculated using density functional theory. The free energy of extraction, ΔGext, for the Pu4+ and UO22+ ions with DHOA was calculated using the Born–Haber thermodynamic cycle in the different experimentally studied diluents. The value of ΔGext for the Pu4+ ion in dodecane was found to be higher than that of the UO22+ ion, as measured in the experiments. The value of ΔGext was shown to increase with the increase in the dielectric constant of the diluent for both Pu4+ and UO22+ ions, similar to the experimental studies. Thus, the combined experimental and theoretical studies help to understand the underlying complexation mechanism of the UO22+ and Pu4+ ions with DHOA, which explains its selectivity towards the Pu4+ ion.

Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge.

Small molecule distribution coefficients between immiscible nonaqueuous and aqueous phases-such as cyclohexane and water-measure the degree to which small molecules prefer one phase over another at a given pH. As distribution coefficients capture both thermodynamic effects (the free energy of transfer between phases) and chemical effects (protonation state and tautomer effects in aqueous solution), they provide an exacting test of the thermodynamic and chemical accuracy of physical models without the long correlation times inherent to the prediction of more complex properties of relevance to drug discovery, such as protein-ligand binding affinities. For the SAMPL5 challenge, we carried out a blind prediction exercise in which participants were tasked with the prediction of distribution coefficients to assess its potential as a new route for the evaluation and systematic improvement of predictive physical models. These measurements are typically performed for octanol-water, but we opted to utilize cyclohexane for the nonpolar phase. Cyclohexane was suggested to avoid issues with the high water content and persistent heterogeneous structure of water-saturated octanol phases, since it has greatly reduced water content and a homogeneous liquid structure. Using a modified shake-flask LC-MS/MS protocol, we collected cyclohexane/water distribution coefficients for a set of 53 druglike compounds at pH 7.4. These measurements were used as the basis for the SAMPL5 Distribution Coefficient Challenge, where 18 research groups predicted these measurements before the experimental values reported here were released. In this work, we describe the experimental protocol we utilized for measurement of cyclohexane-water distribution coefficients, report the measured data, propose a new bootstrap-based data analysis procedure to incorporate multiple sources of experimental error, and provide insights to help guide future iterations of this valuable exercise in predictive modeling.

Multi-podant diglycolamides and room temperature ionic liquid impregnated resins: An excellent combination for extraction chromatography of actinides

Extraction chromatography resins, prepared by impregnating two multi-podant diglycolamide ligands, viz. diglycolamide-functionalized calix[4]arene (C4DGA) and tripodal diglycolamide (T-DGA) dissolved in the room temperature ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide (RTIL: C4mimTf2N) on Chromosorb-W (an inert solid support), gave excellent results for the removal of trivalent actinides from acidic waste solutions. Distribution coefficient measurements on several metal ions showed selective sorption of Am(III) over hexavalent uranyl ions and other fission product elements such as strontium and cesium. The sorbed metal ions could be efficiently desorbed with a complexing solution containing guanidine carbonate and EDTA buffer. The sorption of Am(III) on both resins followed pseudo-second order rate kinetics with rate constants of 1.37×10−6 and 6.88×10−7g/cpmmin for T-DGA and C4DGA resins, respectively. The metal sorption on both resins indicated the Langmuir monolayer chemisorption phenomenon with Eu(III) sorption capacities of 4.83±0.21 and 0.52±0.05mg per g of T-DGA and C4DGA resins, respectively. The results of column studies show that these resins are of interest for a possible application for the recovery of hazardous trivalent actinides from dilute aqueous solutions.

Use of a phenomenological chemical scale for the identification of high distribution coefficient impurities within the ITS-90

The International Temperature Scale of 1990 standardises practical temperature measurement based on the reproducibility of the solidification phase transition temperature of highly pure metals. The effect of impurities can be the biggest block to establishing international equivalence of temperature metrology and so it is important to have knowledge of the distribution coefficients for all potential impurities. In particular impurities with a high distribution coefficient cause problems with applying corrections, and so it is helpful to identify which impurities are likely to be an issue. By plotting the published measured distribution coefficients of impurities in the metals used as references in the International Temperature Scale of 1990, as a function of a quantum mechanical based scale intended to provide separation of binary alloy crystal structure, an apparent resonance peak is found. This could allow a simple fit equation to be applied to determine whether a given impurity is likely to cause an error to any correction strategy.

Demonstration of the Use of Formohydroxamic Acid in the UREX Process

The Uranium Extraction (UREX) process was developed to separate U and Tc from the transuranic elements and the remaining fission products. To prevent the extraction of Np and Pu, a dilute nitric acid scrub stream containing acetohydroxamic acid (AHA) is used in the process. When the AHA contacts nitric acid, the complexant begins to decompose producing acetic acid and hydroxylamine nitrate (HAN). The HAN decomposes to gaseous products and water; however, the acetic acid is relatively stable and will contaminate nitric acid recovered from waste streams. To address this issue, formohydroxamic acid (FHA) was evaluated as a replacement for AHA. Formohydroxamic acid prevents the extraction of Np and Pu and its decomposition products (formic acid and HAN) readily decompose. Neptunium and Pu distribution coefficient measurements demonstrated that FHA was an acceptable replacement for AHA. Additional extraction experiments performed with the addition of uranyl nitrate to the aqueous phase showed that its presence had little effect on the distribution coefficients. A steady increase in distribution coefficients with increasing nitrate concentrations was consistent with a salting-out effect. When the actinides were back-extracted into the aqueous phase, the Np and Pu distribution coefficients were larger than the distribution coefficients measured in an extraction mode potentially due to kinetic limitations. These data imply that a greater number of scrub stages would be required in the first bank of the UREX process contactors than would be calculated based on the Pu and Np distribution data generated in the extraction experiments.