European Paediatric Formulation Initiative workshop report: Improving the administration of oral liquid medicines in paediatrics using dosing syringes and enteral accessories.

Accurate dosing of the right medicine to the right patient is a key element of safe and efficacious pharmacotherapy, yet prone to technical challenges and human error when dosing involves the administration of small volumes of liquid medicines. For this reason, the topic has gained increased attention over the last decade from multiple stakeholder parties e.g. academia, hospital pharmacy, the medical device and pharmaceutical industry, and regulatory agencies. It is now well acknowledged that spoons and cups are not suitable for the measurement of small volumes of oral liquid medicines and that syringes are a better alternative, but syringes for parenteral use should not be used for oral dosing in order to avoid accidental parenteral delivery of oral products. However, dosing accuracy of very small volumes of liquid medicines to young children, and especially pre-term neonates, is still not sufficiently ensured. A workshop was organised in 2018 by the European Paediatric Formulation Initiative to reflect on current status and challenges (first part) and possible strategies to improve the present situation (second part). A voting system (n = 24) was used to consider the most favourable solutions. The harmonisation and/or standardisation of the technical design of oral syringes (including e.g. female/male connection) was considered a key priority.

Spatial trends on an ungrazed West Cumbrian saltmarsh of surface contamination by selected radionuclides over a 25 year period.

Long term spatial and temporal variations in radionuclide activity have been measured in a contaminated ungrazed saltmarsh near Ravenglass, Cumbria. Over a twenty-five year period there has been a decrease in activity concentration with (106)Ru and (137)Cs showing the highest rate of change followed by Pu alpha and (241)Am. A number of factors contribute to the reduction with time; including radiological half lives, discharge and remobilisation. For (241)Am the lower reduction rate is partially due to ingrowth from (241)Pu and partially as a result of transport of sediment from the offshore Irish Sea mud patch. Considerable spatial variation for the different radionuclides was observed, which with time became less defined. The highest activity concentrations of long-lived radionuclides were in low energy areas, typically where higher rates of sedimentation and vegetation occurred. The trend was reversed for the shorter lived radionuclide, (106)Ru, with higher activity concentrations observed in high energy areas where there was frequent tidal inundation. Surface scrape samples provide a pragmatic, practical method of measuring sediment contamination over large areas and is a sampling approach adopted by most routine environmental monitoring programs, but it does not allow for interpretation of the effect of variation in sedimentation rates. This paper proposes a method for calculating indicative sedimentation rates across the saltmarsh using surface scrape data, which produces results consistent with values experimentally obtained.

Greenhouse gas emissions for refrigerant choices in room air conditioner units.

In this work, potential replacement refrigerants for window-mounted room air conditioners (RACs) in the U.S. have been evaluated using a greenhouse gas (GHG) emissions analysis. CO(2)-equivalent emissions for several hydrofluoroethers (HFEs) and other potential replacements were compared to the most widely used refrigerants today. Included in this comparison are pure refrigerants that make up a number of hydrofluorocarbon (HFC) mixtures, pure hydrocarbons, and historically used refrigerants such as propane and ammonia. GHG emissions from direct and indirect sources were considered in this thermodynamic analysis. Propylene, dimethyl ether, ammonia, R-152a, propane, and HFE-152a all performed effectively in a 1 ton window unit and produced slightly lower emissions than the currently used R-22 and R-134a. The results suggest that regulation of HFCs in this application would have some effect on reducing emissions since end-of-life emissions remain at 55% of total refrigerant charge despite EPA regulations that mandate 80% recovery. Even so, offsite emissions due to energy generation dominate over direct GHG emissions and all the refrigerants perform similarly in totals of indirect GHG emissions.

Determination of carbon-14 in environmental level, solid reference materials.

An intercomparison exercise to determine the (14)C activity concentrations in a range of solid, environmental level materials was conducted between laboratories in the UK. IAEA reference materials, C2, C6 and C7, and an in-house laboratory QA material were dispatched in 2006 to ten laboratories comprising of members of the Analyst Informal Working Group (AIWG) and one other invited party. The laboratories performed the determinations using a number of techniques, and using the results each one was evaluated in terms of levels of precision, sensitivity and limits of detection. The results of the study show that all techniques are capable of successfully analysing (14)C in environmental level materials, however, a shortage of certified environmental reference materials exists. The suitability of the IAEA reference materials and other material for use as reference materials was also assessed.

The adsorption of mercury-species on relaxed and rumpled CaO (0 0 1) surfaces investigated by density functional theory.

This research examines the importance of several computational choices in modeling mercury species adsorption on calcium oxide surfaces and is the second in a series of papers. The importance of surface relaxation was tested and it was found that adsorption energies changed for HgCl(2), moving adsorption from being at the borderline of physisorption and chemisorption to being strongly chemisorbed. Results for Hg and HgCl were unaffected. A second computational choice, that of the cluster or periodic model size was tested in both the plane of the model (4 × 4 or 5 × 5 model sizes) and for the depth (two or three layers). It was found that the minimum cluster size for handling mercury adsorption was 5 × 5 and that only two layers of depth were needed. The energetic results show that rumpled CaO surfaces will only weakly physisorb elemental mercury, but could be used to capture HgCl(2) from coal combustion flue gases, which is in agreement with limited experimental data.

Quantum mechanical modeling for the GeX(2)/GeHX + GeH(4) reactions (X = H, F, Cl, and Br).

A systematic theoretical investigation was carried out to study the reactions of various germylenes with germane. Molecular structures of the reactants (GeX(2) and GeHX, where X = H, F, Cl and Br) plus GeH(4), transition states, and products have been optimized to understand the effects of halo-substituted germylenes. The basis set used is of double-zeta plus polarization quality with additional s- and p-type diffuse functions. Consistent with experiment, the theoretical gas-phase reaction GeH(2) + GeH(4) --> Ge(2)H(6) possesses a negative activation energy. The predicted activation energies reveal interesting trends for both mono- and di- halo-substituted germylenes, -1.5 [GeH(2)], +20.5 [GeHF], +59.9 [GeF(2)], +18.0 [GeHCl], +46.8 [GeCl(2)], +17.3 [GeHBr], and +42.9 kcal mol(-1) [GeBr(2)]. There is a noteworthy relationship between the activation energies and the singlet-triplet splittings of the divalent germylenes. We report for the first time rate constants for the transfer of hydrogen, evaluated using standard transition-state theory with tunneling corrections. These results are analyzed and compared to the available experimental and previous theoretical findings for the gas-phase reactions involving germylene derivatives and germanium analogues.

Carbon dioxide emission implications if hydrofluorocarbons are regulated: a refrigeration case study.

The U.S. is strongly considering regulating hydrofluorocarbons (HFCs) due to their global climate change forcing effects. A drop-in replacement hydrofluoroether has been evaluated using a gate-to-grave life cycle assessment of greenhouse gas emissions for the trade-offs between direct and indirect carbon dioxide equivalent emissions compared to a current HFC and a historically used refrigerant. The results indicate current regulations being considered may increase global climate change.

Estimations of global warming potentials from computational chemistry calculations for CH(2)F(2) and other fluorinated methyl species verified by comparison to experiment.

In this work, the global warming potential (GWP) of methylene fluoride (CH(2)F(2)), or HFC-32, is estimated through computational chemistry methods. We find our computational chemistry approach reproduces well all phenomena important for predicting global warming potentials. Geometries predicted using the B3LYP/6-311g** method were in good agreement with experiment, although some other computational methods performed slightly better. Frequencies needed for both partition function calculations in transition-state theory and infrared intensities needed for radiative forcing estimates agreed well with experiment compared to other computational methods. A modified CBS-RAD method used to obtain energies led to superior results to all other previous heat of reaction estimates and most barrier height calculations when the B3LYP/6-311g** optimized geometry was used as the base structure. Use of the small-curvature tunneling correction and a hindered rotor treatment where appropriate led to accurate reaction rate constants and radiative forcing estimates without requiring any experimental data. Atmospheric lifetimes from theory at 277 K were indistinguishable from experimental results, as were the final global warming potentials compared to experiment. This is the first time entirely computational methods have been applied to estimate a global warming potential for a chemical, and we have found the approach to be robust, inexpensive, and accurate compared to prior experimental results. This methodology was subsequently used to estimate GWPs for three additional species [methane (CH(4)); fluoromethane (CH(3)F), or HFC-41; and fluoroform (CHF(3)), or HFC-23], where estimations also compare favorably to experimental values.

Adsorption energies of mercury-containing species on CaO and temperature effects on equilibrium constants predicted by density functional theory calculations.

The adsorption of Hg, HgCl, and HgCl2 on the CaO surface was investigated theoretically so the fundamental interactions between Hg species and this potential sorbent can be explored. Surface models of a 4 x 4 x 2 cluster, a 5 x 5 x 2 cluster, and a periodic structure using density functional theory calculations with LDA/PWC and GGA/BLYP functionals, as employed in the present work, offer a useful description for the thermodynamic properties of adsorption on metal oxides. The effect of temperature on the equilibrium constant for the adsorption of mercury-containing species on the CaO (0 0 1) surface was investigated with GGA/BLYP calculations in the temperature range of 250-600 K. Results show that, at low coverage of elemental mercury, adsorption on the surface is physisorption while the two forms of oxidized mercury adsorption undergo stronger adsorption. The adsorption energies decrease with increasing coverage for elemental mercury on the surfaces. The chlorine atom enhances the adsorption capacity and adsorbs mercury to the CaO surface more strongly. The adsorption energy is changed as the oxidation state varies, and the equilibrium constant decreases as the temperature increases, in good agreement with data for exothermic adsorption systems.

Understanding trichloroethylene chemisorption to iron surfaces using density functional theory.

This research investigated the thermodynamic favorability and resulting structures for chemical adsorption of trichloroethylene (TCE) to metallic iron using periodic density functional theory (DFT). Three initial TCE positions having the plane defined by HCC atoms parallel to the iron surface resulted in formation of three different chemisorption complexes between carbon atoms in TCE and the iron surface. The Cl-bridge initial configuration with the HCC plane of TCE perpendicular to the iron surface did not result in C-Fe bond formation. The most energetically favorable complex formed at the C-bridge site where the initial configuration had the C=C bond in TCE at a bridge site between adjacent iron atoms. In the C-bridge complex, one C atom formed two a bonds to different Fe atoms, while the second C atom formed a sigma bond with a second Fe atom. Surface complexation atthe C-bridge site resulted in scission of all three C-Cl bonds and also resulted in a shortening of the C==C bond to a distance intermediate between a double and a triple bond. Initial configurations with the C==C bond adsorbed at top or hollow sites on the iron surface resulted in formation of C-Fe a bonds between a single C and two adjacent Fe atoms, and the scission of only two C==Cl bonds. Bond angles and bond lengths indicated that there were no changes in bond order of the C==C bond for top and hollow adsorption. Chemisorption at the C-bridge site had an activation energy of 49 kJ/mol and an early transition state where all three C-CI bonds were activated. The early transition state and the loss of all three Cl atoms upon chemisorption are consistent with most experimental observations that TCE undergoes complete dechlorination in one interaction with the iron surface. The absence of chemisorption and scission of only two C--Cl bonds at the Cl-bridge site is consistent with experimental observations that trace amounts of chloroacetylene may also be produced from reactions of TCE with iron.

Global warming potentials of Hydrofluoroethers.

Global warming potentials are estimated for hydrofluoroethers, which are an emerging class of compounds for industrial use. Comparisons are made to the limited data previously available before observations about molecular design are discussed. We quantify how molecular structure can be manipulated to reduce environmental impacts due to global warming. We further highlight the need for additional research on this class of compounds so environmental performance can be assessed for green design.

Reactivity of isobutane on zeolites: a first principles study.

In this work, ab initio and density functional theory methods are used to study isobutane protolytic cracking, primary hydrogen exchange, tertiary hydrogen exchange, and dehydrogenation reactions catalyzed by zeolites. The reactants, products, and transition-state structures are optimized at the B3LYP/6-31G* level, and the final energies are calculated using the CBS-QB3 composite energy method. The computed activation barriers are 52.3 kcal/mol for cracking, 29.4 kcal/mol for primary hydrogen exchange, 29.9 kcal/mol for tertiary hydrogen exchange, and 59.4 kcal/mol for dehydrogenation. The zeolite acidity effects on the reaction barriers are also investigated by changing the cluster terminal Si-H bond lengths. The analytical expressions between activation barriers and zeolite deprotonation energies for each reaction are proposed so that accurate activation barriers can be obtained when using different zeolites as catalysts.

Evaluation of density functional theory methods for studying chemisorption of arsenite on ferric hydroxides.

Understanding adsorption of arsenic on ferric hydroxide surfaces is important for predicting the fate of arsenic in the environment and in designing treatment systems for removing arsenic from potable water. This research investigated the binding of arsenite to ferric hydroxide clusters using several density functional theory methods. Comparison of calculated and experimentally measured As-O and As-Fe bond distances indicated that As(III) forms both bidentate and monodentante corner-sharing complexes with Fe(III) octahedra. Edge-sharing As(III) complexes were less energetically favorable and had As-O and As-Fe distances that deviated more from experimentally measured values than corner-sharing complexes. The hydrated bidentate complex was the most energetically favorable in the vacuum phase, while the monodentate complex was most favored in the aqueous phase. Structures optimized using the Harris and Perdew-Wang local functionals were close to both experimental data and structures optimized using the nonlocal Becke-Lee-Yang-Parr (BLYP) functional. Binding energies calculated with the gradient-corrected BLYP functional were only weakly dependent on the method used for geometry optimization. The approach of using low-level structures coupled with higher level single-point energies was found to reduce computational time by 75% with no loss in accuracy of the computed binding energies.

Ab initio study of carbon-chlorine bond cleavage in carbon tetrachloride.

Chlorinated solvents in groundwater are known to undergo reductive dechlorination reactions with Fe(ll)-containing minerals and with corroding metals in permeable-barrier treatment systems. This research investigated the effect of the reaction energy on the reaction pathway for C-Cl bond cleavage in carbon tetrachloride (CCl4). Hartree-Fock, density functional theory, and modified complete basis set ab initio methods were used to study adiabatic electron transfer to aqueous-phase CCl4. The potential energies associated with fragmentation of the carbon tetrachloride anion radical (CCl4-) into a trichloromethyl radical (CCl3) and a chloride ion (Cl-) were explored as a function of the carbon-chlorine bond distance during cleavage. The effect of aqueous solvation was investigated using a continuum conductor-like screening model. Solvation significantly lowered the energies of the reaction products, suggesting that dissociative electron transfer was enhanced by solvation. The potential energy curves in an aqueous medium indicate that reductive cleavage undergoes a change from an inner-sphere to an outer-sphere mechanism as the overall energy change for the reaction is increased. The activation energy for the reaction was found to be a linear function of the overall energy change, and the Marcus-Hush model was used to relate experimentally measured activation energies for CCl4 reduction to overall reaction energies. Experimentally measured activation energies for CCl4 reduction by corroding iron correspond to reaction energies that are insufficiently exergonic for promoting the outer-sphere mechanism. This suggests that the different reaction pathways that have been observed for CCl4 reduction by corroding iron arise from different catalytic interactions with the surface, and not from differences in energy of the transferred electrons.

Reactivity of alkanes on zeolites: a computational study of propane conversion reactions.

In this work, quantum chemical methods were used to study propane conversion reactions on zeolites; these reactions included protolytic cracking, primary hydrogen exchange, secondary hydrogen exchange, and dehydrogenation reactions. The reactants, products, and transition-state structures were optimized at the B3LYP/6-31G level and the energies were calculated with CBS-QB3, a complete basis set composite energy method. The computed activation barriers were 62.1 and 62.6 kcal/mol for protolytic cracking through two different transition states, 30.4 kcal/mol for primary hydrogen exchange, 29.8 kcal/mol for secondary hydrogen exchange, and 76.7 kcal/mol for dehydrogenation reactions. The effects of basis set for the geometry optimization and zeolite acidity on the reaction barriers were also investigated. Adding extra polarization and diffuse functions for the geometry optimization did not affect the activation barriers obtained with the composite energy method. The largest difference in calculated activation barriers is within 1 kcal/mol. Reaction activation barriers do change as zeolite acidity changes, however. Linear relationships were found between activation barriers and zeolite deprotonation energies. Analytical expressions for each reaction were proposed so that accurate activation barriers can be obtained when using different zeolites as catalysts, as long as the deprotonation energies are first acquired.

Understanding reduction of carbon tetrachloride at nickel surfaces.

Nickel has been found to be an effective cathode material and catalyst for reductive destruction of chlorinated solvents in contaminated water. This study investigated reductive dechlorination of carbon tetrachloride (CT) at a nickel rotating disk electrode using chronoamperometry and electrochemical impedance spectroscopy. Chronoamperometry experiments were performed to determine rates of CT reduction as a function of the electrode potential, pH, CT concentration, and temperature. The reaction products of CT dechlorination were 95 +/- 4% methane and 4.1 +/- 2.5% chloroform. Only trace levels of methylene chloride and chloromethane were produced, indicating that sequential hydrogenolysis was not the predominant pathway for methane production. Electrochemical impedance spectroscopy showed that the rate-limiting step for methane production was the transfer of the first electron to a physically adsorbed CT molecule. The temperature independence of the electron transfer coefficient and the decreasing activation energy with decreasing electrode potential indicated that the rate-limiting step involved an outer-sphere electron transfer. At neutral pH values, oxides inactivated much of the electrode surface for both CT reduction and hydrogen evolution. At lower pH values, oxide dissolution served to increase the electroactive surface area of the disk electrode. Anson analysis and kinetic modeling showed that CT adsorption to electroactive sites was a nonlinear function of the CT concentration and was in equilibrium with the bulk solution. CT dechlorination rates on nickel electrodes were 16 times slower than those on iron electrodes under similar conditions. However, CT reactions at nickel surfaces produced predominantly methane as the first detectable product, while reduction at iron surfaces produced chloroform. These results suggest that, although nickel is not a catalyst for the rate-limiting step for CT dechlorination, it may serve a catalytic role in subsequent reaction steps.

Theoretically predicted rate constants for mercury oxidation by hydrogen chloride in coal combustion flue gases.

In this work, theoretical rate constants are estimated for mercury oxidation reactions by hydrogen chloride that may occur in the flue gases of coal combustion. Rate constants are calculated using transition state theory at the quadratic configuration interaction (QCI) level of theory with single and double excitations, and are compared to results obtained from density functional theory, both including high level pseudopotentials for mercury. Thermodynamic and kinetic data from the literature are used to assess the accuracy of the theoretical calculations when possible. Validation of the chosen methods and basis sets is based upon previous and current research on mercury reactions involving chlorine. The present research shows that the QCISD method with the 1992 Stevens et al. basis set leads to the most accurate kinetic and thermodynamic results for the oxidation of mercury via chlorine containing molecules. Also, a comparison of the heats of reaction data for a series of mercury oxidation reactions reveals that the density functional method, B3LYP, with the 1997 Stuttgart basis set provides reasonably accurate results for these large systems.

Experimental and molecular mechanics and ab initio investigation of activated adsorption and desorption of trichloroethylene in mineral micropores.

This research investigated activated adsorption of a hydrophobic organic contaminant(HOC) in mineral micropores using experimental and molecular modeling techniques. Adsorption of trichloroethylene (TCE) on a silica gel adsorbent was measured using a frontal analysis chromatography technique at atmospheric and elevated fluid pressures. Increasing the fluid pressure yielded increased TCE uptake that was not released upon lowering the pressure back to atmospheric conditions. This showed that the increase in pressure was able to rapidly induce the formation of a desorption-resistant fraction that previous investigations have shown requires months to develop at atmospheric pressure. Grand Canonical Monte Carlo (GCMC) modeling was then used to elucidate the nature of water and TCE behavior within silica micropores. The GCMC modeling showed that molecular scale packing restrictions resulted in pore fluid densities that ranged from 0.28 to 0.78 of those in the bulk solution. The modeling also showed that TCE was able to displace water from hydrophilic mineral pores due to molecular scale packing restrictions. Exothermic isosteric heats for TCE adsorption up to -27 kJ/mol were observed and were greatest in pores of 7 and 8 A. This indicated that TCE adsorption was energetically most favorable in pores that were minimally large enough to accommodate a TCE molecule. The pressure-induced uptake appeared to result primarily from an increase in the packing density in the smallest pores. Ab initio calculations showed that small distortions of a TCE molecule from its low energy conformation require high activation energies. Results from this study indicate that activated adsorption requiring bond angle distortions in the adsorbate may be responsible forthe slow attainment of adsorptive equilibrium of HOCs on microporous solids. Likewise, activated desorption from molecular-sized adsorption sites may contribute to the slow release of HOCs from aquifer sediments.