Solubilization of Sirolimus in Aqueous Solution Through Complexation with Metal Ions

Sirolimus is one of the most successful immunosuppressant drugs available but it has an extremely low solubility in water that dramatically limits its oral bioavailability to approximately 20%. This study is aimed to increase solubility of Sirolimus in aqueousolutions through complexation with a metal ion. Using computer modeling and UV absorbance spectroscopy, it was demonstrated that 1) Sirolimus interacts with AJ3+,Cu2+, Fe3+ , Mn2+, Zn2+ ; 2) this interaction decreases UV light absorbance of Sirolimus measured at ^=280 nm; 3) a previously reported value of solubility of Sirolimus in water is underestimated; 4) Sirolimus can exist in aqueous solutions in different soluble physical forms, including multimers; 5) complexation of Sirolimus with Al³+ increases its aqueous solubility that potentially can improve its oral bioavailability. Similar approach, i.e. complexation with a metal ion, can be used to increase aqueous solubility of other compounds containing ligands with unshared electron pairs, for example, cyclic macrolides like Tacrolimus, derivatives of Tacrolimus and Sirolimus, as well as peptide drugs such as Cyclosporin A

ADME prediction with KNIME: In silico aqueous solubility consensus model based on supervised recursive random forest approaches

In-silico prediction of aqueous solubility plays an important role during the drug discovery and development processes. For many years, the limited performance of in-silico solubility models has been attributed to the lack of high-quality solubility data for pharmaceutical molecules. However, some studies suggest that the poor accuracy of solubility prediction is not related to the quality of the experimental data and that more precise methodologies (algorithms and/or set of descriptors) are required for predicting aqueous solubility for pharmaceutical molecules. In this study a large and diverse database was generated with aqueous solubility values collected from two public sources; two new recursive machine-learning approaches were developed for data cleaning and variable selection, and a consensus model based on regression and classification algorithms was created. The modeling protocol, which includes the curation of chemical and experimental data, was implemented in KNIME, with the aim of obtaining an automated workflow for the prediction of new databases. Finally, we compared several methods or models available in the literature with our consensus model, showing results comparable or even outperforming previous published models.  </p

Flash Point Measurements and Modeling for Ternary Partially Miscible Aqueous­Organic Mixtures

Flash point is the most important variable used to characterize the fire and explosion hazard of liquids. This paper presents the first partially miscible aqueousorganic mixtures flash point measurements and modeling for the ternary type-I mixtures, water + ethanol + 1-butanol, water + ethanol + 2-butanol, and the type-II mixture, water + 1-butanol + 2-butanol. Results reveal that the flash points are constant in each tie line. Handling the non-ideality of the liquid phase through the use of activity coefficient models, the general flash-point model of Liaw et al. extended to partially miscible mixtures predicts the experimental data well when using literature LLE and the VLE activity coefficient model binary parameters to estimate sequentially the span and flash point in each tie line and the flash point in the mutual solubility region, respectively. The constant flash-point behavior in a tie line is also observed and predicted, in agreement with the VLLE tie line property that a single vapor is in equilibrium with all liquid composition on a tie line. For the aqueousorganic mixtures here studied, a deviation between prediction and measurements is observed, arising from the failure of the constant lower flammable limit assumption in the mutual solubility inert-rich region. Potential application for the model concerns the assessment of fire and explosion hazards and the development of inherently safer designs for chemical processes containing partially miscible aqueousorganic mixtures

Thermodynamic interpretation of neptunium coprecipitation in uranophane for application to the Yucca Mountain repository

Interpretation and modeling of recent experimental data [1] yield thermodynamic constants for the distribution of trace Np(V) between aqueous solutions and uranophane. These data indicate that neptunyl is relatively excluded from the uranyl mineral structure, but the interpretation depends on uncertain aqueous speciation and thermodynamic properties as a function of temperature. Despite Np exclusion, the low calculated solubility of uranophane at 25 °C under conditions relevant to the proposed nuclear waste repository at Yucca Mountain, Nevada, leads to Np concentrations at equilibrium with a Np-bearing uranophane solid solution that are low compared to concentrations invoked as solubility limits in Yucca Mountain performance assessments

Contributions to predicting contaminant leaching from secondary materials used in roads

Slags, coal ashes, and other secondary materials can be used in road construction. Both traditional and secondary materials used in roads may contain contaminants that may leach and pollute the groundwater. The goal of this research was to further the understanding of leaching and transport of contaminants from pavement materials. Towards this goal, a new probabilistic framework was introduced which provided a structured guidance for selecting the appropriate model, incorporating uncertainty, variability, and expert opinion, and interpreting results for decision making. In addition to the framework, specific contributions were made in pavement and embankment hydrology and reactive transport, Bayesian statistics, and aqueous geochemistry of leaching. Contributions on water movement and reactive transport in highways included probabilistic prediction of leaching in an embankment, and scenario analyses of leaching and transport in pavements using HYDRUS2D, a contaminant fate and transport model. Water flow in a Minnesota highway embankment was replicated by Bayesian calibration of hydrological parameters against water content data. Extent of leaching of Cd from a coal fly ash was estimated. Two dimensional simulations of various scenarios showed that salts in the base layer of pavements are depleted within the first year whereas the metals may never reach the groundwater if the pavement is built on adsorbing soils. Aqueous concentrations immediately above the groundwater estimated for intact and damaged pavements can be used for regulators to determine the acceptability of various recycled materials. Contributions in the aqueous geochemistry of leaching included a new modeling approach for leaching of anions and cations from complex matrices such as weathered steel slag. The novelty of the method was its simultaneous inclusion of sorption and solubility controls for multiple analytes. The developed model showed that leaching of SO4, Cr, As, Si, Ca, Mg, and V were controlled by corresponding soluble solids. Leaching of Pb was controlled by Pb(VO4)3 solubility at low pHs and by surface precipitation reactions at high pHs. Leaching of Cd and Zn were controlled by surface complexation and surface precipitation, respectively

Changes in dissolved iron deposition to the oceans driven by human activity: a 3-D global modelling study

The global atmospheric iron (Fe) cycle is parameterized in the global 3-D chemical transport model TM4-ECPL to simulate the proton- and the organic ligand-promoted mineral-Fe dissolution as well as the aqueous-phase photochemical reactions between the oxidative states of Fe (III/II). Primary emissions of total (TFe) and dissolved (DFe) Fe associated with dust and combustion processes are also taken into account, with TFe mineral emissions calculated to amount to ~ 35 Tg-Fe yr−1 and TFe emissions from combustion sources of ~ 2 Tg-Fe yr−1. The model reasonably simulates the available Fe observations, supporting the reliability of the results of this study. Proton- and organic ligand-promoted Fe dissolution in present-day TM4-ECPL simulations is calculated to be ~ 0.175 Tg-Fe yr−1, approximately half of the calculated total primary DFe emissions from mineral and combustion sources in the model (~ 0.322 Tg-Fe yr−1). The atmospheric burden of DFe is calculated to be ~ 0.024 Tg-Fe. DFe deposition presents strong spatial and temporal variability with an annual flux of ~ 0.496 Tg-Fe yr−1, from which about 40 % (~ 0.191 Tg-Fe yr−1) is deposited over the ocean. The impact of air quality on Fe deposition is studied by performing sensitivity simulations using preindustrial (year 1850), present (year 2008) and future (year 2100) emission scenarios. These simulations indicate that about a 3 times increase in Fe dissolution may have occurred in the past 150 years due to increasing anthropogenic emissions and thus atmospheric acidity. Air-quality regulations of anthropogenic emissions are projected to decrease atmospheric acidity in the near future, reducing to about half the dust-Fe dissolution relative to the present day. The organic ligand contribution to Fe dissolution shows an inverse relationship to the atmospheric acidity, thus its importance has decreased since the preindustrial period but is projected to increase in the future. The calculated changes also show that the atmospheric DFe supply to the globe has more than doubled since the preindustrial period due to 8-fold increases in the primary non-dust emissions and about a 3-fold increase in the dust-Fe dissolution flux. However, in the future the DFe deposition flux is expected to decrease (by about 25 %) due to reductions in the primary non-dust emissions (about 15 %) and in the dust-Fe dissolution flux (about 55 %). The present level of atmospheric deposition of DFe over the global ocean is calculated to be about 3 times higher than for 1850 emissions, and about a 30 % decrease is projected for 2100 emissions. These changes are expected to impact most on the high-nutrient–low-chlorophyll oceanic regions

Evaluation of CO2 and Carbonated Water EOR for Chalk Fields

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