Are pharmaceuticals potent environmental pollutants? Part I: environmental risk assessments of selected active pharmaceutical ingredients

As part of achieving national environmental goals, the Swedish Government commissioned an official report from the Swedish Medical Products Agency on environmental effects of pharmaceuticals. Considering half-lives/biodegradability, environmental occurrence, and Swedish sales statistics, 27 active pharmaceutical ingredients were selected for environmental hazard and risk assessments. Although there were large data gaps for many of the compounds, nine ingredients were identified as dangerous for the aquatic environment. Only the sex hormones oestradiol and ethinyloestradiol were considered to be associated with possible aquatic environmental risks. We conclude that risk for acute toxic effects in the environment with the current use of active pharmaceutical ingredients is unlikely. Chronic environmental toxic effects, however, cannot be excluded due to lack of chronic ecotoxicity data. Measures to reduce potential environmental impact posed by pharmaceutical products must be based on knowledge on chronic ecotoxic effects of both active pharmaceutical ingredients as well as excipients. We believe that the impact pharmaceuticals have on the environment should be further studied and be given greater attention such that informed assessments of hazards as well as risks can be done.     

Influence of module configuration on total economics during ultrafiltration at high concentration

The influence of module configuration on the ultrafiltration of highly concentrated fluids in tubular membrane plants was investigated. Previous work has shown that frictional pressure drop in the feed flow channel can have a significant influence on the performance when treating viscous fluids. In the present study, three module alternatives were compared: polymeric membranes connected either in series or parallel, and a ceramic membrane element with all flow channels in parallel. An economic evaluation was performed of an additional stage in the ultrafiltration plant at Stora Enso Nymölla pulp and paper mill treating bleach plant effluent. A parametric study in a laboratory equipment provided information on how the flux and frictional pressure drop vary with transmembrane pressure and cross-flow velocity along the membrane. A full-size stage was scaled-up from the experimental data obtained from the laboratory experiments. All three alternatives were shown to be economically viable. The cost of the polymeric membrane in parallel configuration (€70 200 per year) was lowest, making it the most attractive alternative. It was shown that the cross-flow velocity had a significant effect on the performance and hence on the economics of the plant. For all three alternatives, the lowest cross-flow velocity employed (2 m/s) gave the best performance.     

Volatiles from a Mite-Infested Spruce Clone and Their Effects on Pine Weevil Behavior

Induced responses by Norway spruce (Picea abies) seedlings to feeding damage by two mite species were studied by analyzing the volatiles emitted during infestation. Four specimens of a Norway spruce (Picea abies L.) clone were infested with mites of Nalepella sp., another four with Oligonychus ununguis, and four were kept mite-free as controls. After a year of infestation, spruce volatiles were collected, analyzed, and identified using SPME-GC-MS. In addition, enantiomers of chiral limonene and linalool were separated by two-dimensional GC. Methyl salicylate (MeSA), (-)-linalool, (E)-β-farnesene, and (E,E)-α-farnesene were the main volatiles induced by both species of mites, albeit in different proportions. The ability of the main compounds emitted by the mite-infested spruces to attract or repel the pine weevil, Hylobius abietis (L.), was tested. (E)-β-farnesene was found to be attractive in the absence of spruce odor, whereas methyl salicylate had a deterrent effect in combination with attractive spruce odor. The other tested compounds had no significant effects on the behavior of the weevils.     

A finite element based level-set method for multiphase flow applications

A numerical method for simulating incompressible two-dimensional multiphase flow is presented. The method is based on a level-set formulation discretized by a finite-element technique. The treatment of the specific features of this problem, such as surface tension forces acting at the interfaces separating two immiscible fluids, as well as the density and viscosity jumps that in general occur across such interfaces, have been integrated into the finite-element framework. Using a method based on the weak formulation of the Navier-Stokes equations has its advantages. In this formulation, the singular surface tension forces are included through line integrals along the interfaces, which are easily approximated quantities. In addition, differentiation of the discontinuous viscosity is avoided. The discontinuous density and viscosity are included in the finite element integrals. A strategy for the evaluation of integrals with discontinuous integrands has been developed based on a rigorous analysis of the errors associated with the evaluation of such integrals. Numerical tests have been performed. For the case of a rising buoyant bubble the results are in good agreement with results from a front-tracking method. The run presented here is a run including topology changes, where initially separated areas of one fluid merge in different stages due to buoyancy effects. Received: 1 March 1999 / Accepted: 17 June 1999     

Volatiles of Bracket Fungi Fomitopsis pinicola and Fomes fomentarius and Their Functions as Insect Attractants

Volatiles released from fruiting bodies of the polypores Fomitopsis pinicola and Fomes fomentarius (Polyporaceae) were collected by entrainment and SPME techniques and analyzed by GC-MS. The most significant difference between the two species was found in the terpene fraction. F. fomentarius emitted a more complex blend, with more than 10 sesquiterpenes. During the sporulating phase, the release of (R)- and (S)-oct-1-en-3-ol, octan-3-one, and some sesquiterpene hydrocarbons (mainly -barbatene) increased in F. pinicola, whereas in F. fomentarius the release of octan-3-one, cis-furanoid linalool oxide, -phellandrene, -myrcene, and several sesquiterpene hydrocarbons increased. -Barbatene was identified for the first time in fungi. Chopping of the fruiting bodies altered the odor composition more in F. fomentarius than in F. pinicola. Five volatiles giving a typical fungal odor (rac-oct-1-en-3-ol, nonan-1-ol, rac-octan-3-ol, octan-1-ol, and octan-3-one) were tested for insect attraction in the field. Females of the three wood-living generalist beetles Malthodes fuscus, Anaspis marginicollis, and A. rufilabris and both sexes of the moth Epinotia tedella were attracted to rac-oct-1-en-3-ol. The generalist predator on fungus-insects Lordithon lunulatus was attracted to rac-oct-1-en-3-ol and octan-3-one in combination. Previous results regarding the host-specific attraction of beetles to the odors emanating from chopped fruiting bodies of F. pinicola and F. fomentarius are discussed in the light of this investigation.     

A case study where pharmaceutical salts were used to address the issue of low in vivo exposure

The present active pharmaceutical ingredient (API) is a lipophilic compound with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The aim of the presented studies was to investigate whether three novel salts of a new selected candidate in the cardiovascular therapy area could be applied to improve intestinal absorption and the subsequent in vivo exposure. Three salts (chloride, hydrogen sulfate, and hemi-1.5-naphtalenedisulphonate) of the compound were manufactured and investigated regarding solubility, dissolution rate, and in vivo exposure in rats. The chemical and physical stability of the salt forms (and the crystalline parent compound) were followed in solid state, when dissolved and when formulated as microsuspensions. All salts showed improved solubility in investigated media, increased dissolution rate, and elevated in vivo exposures compared to a nanocrystal formulation (top-down) of the parent free base of the compound. The chloride- and the hydrogen sulfate salts of the API showed similar patterns regarding the chemical stability in solid state as the crystalline free base, while the salt formed of the hemi-1.5-naphtalenedisulphonic acid showed significantly improved stability. In conclusion, this study showed that three salts of a new selected candidate drug could be used to improve solubility, increase dissolution rate, and enhance oral absorption compared with a more commonly used nanocrystal formulation of the API. However, the identity of the counter ion appeared to be of less importance. On the other hand, only the salt of the hemi-1.5-naphtalenedisulphonic acid seemed to improve chemical stability compared with the API.     

Interaction of encapsulation glass and silicon nitride ceramic during HIPing

Interaction between ceramic compacts and the encapsulation glass during the HIP process has been studied in a model system of silicon nitride and borosilicate glass. Attention has been focused on what happens when the pressure is first applied in the HIP-cycle, i.e. between about 1200 and 1500°C. At this stage the pore system of the ceramic green body is still rather unaffected by sintering. The model system was characterised to evaluate a possible viscous flow of glass into the green body. Two glass compositions, one with high and one with low viscosity, were used, measurements being made of their viscosity and their contact angle on the nitride. Applying Darcy's law it was predicted that the encapsulation glass with the lowest viscosity should penetrate about 1200 microns into the still open pore structure at 1450°C, but this was not observed experimentally. In the calculations no chemical reactions were assumed to take place. However, increases in hardness of heat-treated mixture of glass and silicon nitride powder indicates that nitrogen dissolves in the glass. It is known that nitrogen increases the viscosity of the glass and this would result in a more limited glass intrusion. After HIP the surface region of the dense ceramic exhibited a phase composition gradient of silicon oxynitride, down to approximately 100–200 microns into the bulk. ©     

Carbamate Chemistry at Interfaces: Practical Considerations and Challenges of Studying Amine Surfactants

It is well known that CO₂ reacts with primary and secondary amines in aqueous solutions and forms carbamates. This reaction can have consequences when studying the self-assembly of amines. In this article, we discuss the practical challenges when working with an alkyl Y-shaped amine (Y12-amine) and demonstrate how the formation of carbamate species influences the physicochemistry of the amine-based surfactant. A drift in dynamic surface tension was observed for Y12-amine at pH above pKa due to the reaction with the naturally occurring CO₂ from the atmosphere. The drift in dynamic surface tension was more pronounced at pH above pKa, than at and below pKa. Furthermore, the drift in dynamic surface tension of Y12-amine at pH 12 also affected the surfactant's critical micelle concentration (CMC). CMC of Y12-amine determined by the pendant drop at the air/water interface was almost five times higher than at the N₂/water interface. The latter result was in agreement with the one determined by monitoring the change in chemical shift of ¹H NMR in a N₂ atmosphere. Moreover, it was also shown that the adsorption of the amine at different interfaces influences carbamate formation.     

Chemistry of post-annealing of epitaxial CoFe2O4 thin films

CoFe₂O₄ thin films of different thicknesses were grown on SrTiO₃ substrates. The X-ray diffraction analysis and atomic force microscopy indicated both epitaxy and a granular microstructure. We studied the magnetic properties of these films as a function of oxygen post-annealing and film thickness. All as-deposited films exhibited similar magnetic properties with saturated magnetization (M_s) of approximately 50% of the bulk M_s, (80 Am² kg^− 1). After the post-annealing the M_s changes as a consequence of crystallographic restructuring of the film. Cation ordering in 100 nm thick films reduces M_s, whereas re-oxidation increases M_s for thinner films. 13 nm films, annealed for 1 h, reach the bulk M_s. For even thinner films the quantum-size effect reduces M_s. For a synthesis of ≥ 30 nm films an annealing cycle after deposition of every 15 nm layer is recommended.