Preclinical Evaluation of Zn(II) Self-Assemblies with Selective Cytotoxic Activity Against Cancer Cells In Vitro and In Ovo.

Dipodal pyridylthiazole amine ligands L1 and L2 both form different metallo-supramolecular self-assemblies with Zn2+ and Cu2+ and these are shown to be toxic and selective towards cancer cell lines in vitro. Furthermore, potency and selectivity are highly dependent upon the metal ions, ligand system and bound anion, with significant changes in chemosensitivity and selectivity dependent upon which species are employed. Importantly, significant anti-tumor activity was observed in ovo at doses that are non-toxic.

Self-Assembled Anion-Binding Cryptand for the Selective Liquid-Liquid Extraction of Phosphate Anions.

The ligands L1 and L2 form trinuclear self-assembled complexes with Cu2+ (i.e. [(L1 )2 Cu3 ]6+ or [(L2 )2 Cu3 ]6+ ) both of which act as a host to a variety of anions. Inclusion of long aliphatic chains on these ligands allows the assemblies to extract anions from aqueous media into organic solvents. Phosphate can be removed from water efficiently and highly selectively, even in the presence of other anions.

Application of hot-stage microscopy direct analysis in real time mass spectrometry (HDM) to the analysis of polymers.

RATIONALE: Polymers are ubiquitous, and characterisation of their chemical, thermal and mechanical properties is important in many applications. Hot-stage microscopy Direct Analysis in Real Time mass spectrometry (HDM) is a new technique which combines optical measurements with the benefits of ambient ionisation mass spectrometry. Physical and chemical information can be obtained as a function of sample temperature, in real time. METHODS: Samples were placed on a miniaturised hot-stage between a custom-made Direct Analysis in Real Time (DART) source and the inlet of an ion trap mass spectrometer, and subjected to both linear and cycled temperature programmes. Optical images were collected using a digital microscope and mass spectra (positive and negative ion) were recorded simultaneously. RESULTS: Mass spectra and optical images were used to monitor the thermal expansion and release of volatile oligomers from both medical and domestic grades of silicone. Series of ions separated by 74 m/z units were observed, consistent with the SiOMe2 monomer; the median mass of these increased with increasing temperature up to the decomposition point (340-400°C). The abundance of volatile material produced decreased with repeated thermal cycling. The coefficients of thermal expansion were calculated from optical data and were in agreement with conventional measurements (2.7-3.6 × 10-4 °C-1 ). Two samples of beach sand analysed for the presence of microplastics were found to contain polyethylene and polystyrene, respectively. CONCLUSIONS: Results indicate that the novel technique of HDM can be successfully applied to the characterisation of a wide range of polymers including those in complex matrices.

Prediction of human intestinal absorption using micellar liquid chromatography with an aminopropyl stationary phase.

The extent of human intestinal absorption (HIA) for a drug is considered to be an important pharmacokinetic parameter which must be determined for orally administered drugs. Traditional experimental methods relied upon animal testing and are renowned for being time consuming and expensive as well as being ethically unfavourable. As a result, the development of alternative methods to evaluate a drug's pharmacokinetics is crucial. Micellar liquid chromatography is considered to be one of these methods that can replace the use of animals in the prediction of HIA. In this study, the combination of an aminopropyl column with the biosurfactant sodium deoxycholate bile salt was used in the experimental determination of micelle-water partition coefficients (log Pmw ) for a group of compounds. Multiple linear regression was then used for the prediction of HIA using the experimentally determined log Pmw along with other molecular descriptors, leading to the construction of a model equation of R2 = 85% and a prediction power represented by R2 Pred. = 72%. The use of micellar liquid chromatography with an aminopropyl column in combination with sodium deoxycholate was found to be a good method for the prediction of human intestinal absorption, providing data for a far wider range of compounds compared with previous studies.

Incorporating physiologically relevant mobile phases in micellar liquid chromatography for the prediction of human intestinal absorption.

Micellar liquid chromatography is a popular method used in the determination of a compound's lipophilicity. This study describes the use of the obtained micelle-water partition coefficient (log Pmw ) by such a method in the prediction of human intestinal absorption (HIA). As a result of the close resemblance of the novel composition of the micellar mobile phase to that of physiological intestinal fluid, prediction was deemed to be highly successful. The unique micellar mobile phase consisted of a mixed micellar mixture of lecithin and six bile salts, i.e. a composition matching that found in the human intestinal environment, prepared in ratios resembling those in the intestine. This is considered to be the first method to use a physiological mixture of biosurfactants in the prediction of HIA. As a result, a mathematical model with high predictive ability (R2 PRED = 81%) was obtained using multiple linear regression. The micelle-water partition coefficient (log Pmw ) obtained from micellar liquid chromatography was found to be a successful tool for prediction where the final optimum model included log Pmw and polar surface area as key descriptors with high statistical significance for the prediction of HIA. This can be attributed to the nature of the mobile phase used in this study which contains the lecithin-bile salt complex, thus forming a bilayer system and therefore mimicking absorption across the intestinal membrane.

An Integrated Hot-Stage Microscope-Direct Analysis in Real Time-Mass Spectrometry System for Studying the Thermal Behavior of Materials.

This paper describes a new analytical instrument that combines a precisely temperature-controlled hot-stage with digital microscopy and Direct Analysis in Real Time-mass spectrometry (DART-MS) detection. The novelty of the instrument lies in its ability to monitor processes as a function of temperature through the simultaneous recording of images, quantitative color changes, and mass spectra. The capability of the instrument was demonstrated through successful application to four very varied systems including profiling an organic reaction, decomposition of silicone polymers, and the desorption of rhodamine B from an alumina surface. The multidimensional, real-time analytical data provided by this instrument allow for a much greater insight into thermal processes than could be achieved previously.

Predicting human intestinal absorption in the presence of bile salt with micellar liquid chromatography.

Understanding intestinal absorption for pharmaceutical compounds is vital to estimate the bioavailability and therefore the in vivo potential of a drug. This study considers the application of micellar liquid chromatography (MLC) to predict passive intestinal absorption with a selection of model compounds. MLC is already known to aid prediction of absorption using simple surfactant systems; however, with this study the focus was on the presence of a more complex, bile salt surfactant, as would be encountered in the in vivo environment. As a result, MLC using a specific bile salt has been confirmed as an ideal in vitro system to predict the intestinal permeability for a wide range of drugs, through the development of a quantitative partition-absorption relationship. MLC offers many benefits including environmental, economic, time-saving and ethical advantages compared with the traditional techniques employed to obtain passive intestinal absorption values. Copyright © 2016 John Wiley & Sons, Ltd.

Parameters affecting ion intensities in transmission-mode direct analysis in real-time mass spectrometry.

A survey of the effect of temperature, transmission module material and analysis time on ion intensities in transmission mode direct analysis in real time mass spectrometry is presented. Ion intensity profiles obtained for two related compounds are similar when analysed separately but are very different when analysed as a mixture.

A simple approach to analysing trace metals in aerosols produced by e-cigarettes.

Electronic cigarettes are a relatively new alternative to cigarettes, which have been marketed as being safer for users than conventional cigarettes. However, they may still result in inhalation of potentially toxic or carcinogenic substances, including metals produced by the heating element. This study looked at the levels of trace metals being produced by different atomizers used in e-cigarettes using a sample introduction technique based on the collection of aerosols produced by e-cigarettes in nitric acid, using glass midget impingers. Collected metals were then identified using an inductively coupled plasma-mass spectrometer (ICP-MS), which allowed detection in the low ppb range. Results obtained showed considerable variation in the levels of metals between both manufacturers of atomizers and also between different batches of coils. This variation is likely to be even greater if the ability of users to customise some types of e-cigarettes is considered. Although there are limitations in terms of possible interferences from other metallic components in the e-cigarettes, the findings suggest the proposed method could be of use in investigating the risk of inhalation of toxic metals from e-cigarette use.

Profiling flavourings in strawberry-flavoured e-liquid using headspace-gas chromatography-mass spectrometry.

E-liquids typically contain nicotine and flavourings in a matrix of propylene glycol (PG) and vegetable glycerine (VG). Some nicotine-free e-liquids are flavouring only in the aerosol carrier with the option for users to add their own nicotine. It is only the nicotine that is monitored in terms of level, as specified by the manufacturers. Little is known of the toxicological effect for some of the flavourings in the context of vaping as these are only regulated for ingestion and not inhalation. A method was developed to analyse volatile organic compounds (VOCs) evolved when e-liquids are vaporised based on headspace-gas chromatography-mass spectrometry (HS-GC-MS) for e-liquids. An in-house standard was prepared with sample matrix and purchased strawberry flavouring to simulate a simple e-liquid but with known levels. This standard was then used to optimise the analysis for use with e-liquid samples but not for full quantification purposes. These were purchased from a range of retailers and with different batches but mainly focussed on strawberry flavour. The results identified three key components indicative of strawberry flavour (ethyl-3-methyl butanoate, ethyl 2-methyl butanoate and ethyl butanoate) and showed considerable variation between both manufacturers and batches. Flavouring VOCs are regulated for ingestion but are not regulated for e-liquid inhalation, so these could have toxicological implications. In addition, the inconsistency between samples suggests further issues when users add their own nicotine to the e-liquids as the viscous sample matrix makes homogeneous mixing difficult.

Controlled microwave processing applied to the pharmaceutical formulation of ibuprofen.

The first successful development of controlled microwave processing for pharmaceutical formulations is presented and illustrated with a model drug (ibuprofen) and two excipients (stearic acid and polyvinylpyrrolidone). The necessary fine temperature control for formulation with microwave energy has been achieved using a uniquely modified microwave oven with direct temperature measurement and pulse-width modulation power control. In addition to comparing microwave and conventional heating, the effect of the presence of liquid (water) in aiding the mixing of the drug and excipient during formulation was also investigated. Analysis of the prepared formulations using differential scanning calorimetry and dissolution studies suggest that microwave and conventional heating produce similar products when applied to mixtures of ibuprofen and stearic acid. However, the differences were observed for the ibuprofen and polyvinylpyrrolidone formulation in terms of the dissolution kinetics. In all cases, the presence of water did not appear to influence the formulation to any appreciable degree. The application of controllable microwave heating is noteworthy as fine temperature control opens up opportunities for thermally sensitive materials for which microwave methods have not been feasible prior to this work.

Hot-stage microscopy - Direct Analysis in Real-time mass spectrometry (HDM) as a novel tool for monitoring thermally-driven reactions on a small scale.

There is a requirement for reliable real-time analytical tools for reaction monitoring to optimise chemical syntheses. We have developed a new technique which combines thermal analysis, digital microscopy and chemical identification using ambient ionisation mass spectrometry. We term this hot-stage microscopy-Direct Analysis in Real-Time mass spectrometry (HDM). The technique provides optical data as a function of temperature coupled with chemical characterisation of evolved species, including reactants, intermediates and products throughout the course of a reaction. In addition, only a few milligrams of sample are required with analyte detection down to the nanogram range. We demonstrate the benefits of HDM using a series of solvent-free reactions. Our results confirm the suitability of the technique as the reactions studied follow the same pathways as published previously. The accurate temperature control achieved with HDM could also be used to assess the optimum temperature at which thermally-driven reactions can proceed efficiently.

Formation of a Bile Salt-Drug Hydrogel to Predict Human Intestinal Absorption.

The unique character of bile salts to self-assemble into hydrogels in the presence of halide salts was exploited in this work to facilitate the prediction of human intestinal absorption (%HIA) for a set of 25 compounds. This was achieved by firstly incorporating each compound separately within the process of gel formation to create a series of gel-drug membranes. Scanning electron microscopy analysis of the freeze-dried samples of the blank bile salt hydrogels and drug-loaded bile salt hydrogels indicated a unique microstructure made of a network of intertwined fibrils. Drug-loaded sodium deoxycholate hydrogels were then utilized as the donor phase to study permeability using flow-through and static diffusion cells. The resulting values of the release-permeability coefficient (Kp) were then analyzed, along with other molecular descriptors, for the %HIA using multiple linear regression. Overall, when comparing predicted values (using the systems presented in this study) with known literature values, it can be seen that both methods (i.e., using static and flow-through cells) had good predictability with R2PRED values of 79.8% and 79.7%, respectively. This study therefore proposes a novel, accurate, and precise way to predict HIA for compounds of pharmaceutical interest using a simple in vitro permeation system. It is important to develop alternatives to the current methods used in prediction of HIA, which are expensive and time-consuming or include the use of animals. Therefore, the proposed method in this study being economic and time-saving provides superiority over these current methods and suggests the possibility of its use as an alternate to such methods for prediction of HIA.

Enhancing the dissolution of phenylbutazone using Syloid® based mesoporous silicas for oral equine applications.

Three mesoporous silica excipients (Syloid® silicas AL-1 FP, XDP 3050 and XDP 3150) were formulated with a model drug known for its poor aqueous solubility, namely phenylbutazone, in an attempt to enhance the extent and rate of drug dissolution. Although other forms of mesoporous silica have been investigated in previous studies, the effect of inclusion with these specific Syloid® silica based excipients and more interestingly, with phenylbutazone, is unknown. This work reports a significant enhancement for both the extent and rate of drug release for all three forms of Syloid® silica at a 1:1 drug:silica ratio over a period of 30 min. An explanation for this increase was determined to be conversion to the amorphous form and an enhanced drug loading ability within the pores. Differences between the release profiles of the three silicas were concluded to be a consequence of the physicochemical differences between the three forms. Overall, this study confirms that Syloid® silica based excipients can be used to enhance dissolution, and potentially therefore bioavailability, for compounds with poor aqueous solubility such as phenylbutazone. In addition, it has been confirmed that drug release can be carefully tailored based on the choice of Syloid® silica and desired release profile.

The Use of Bile Salt Micelles for the Prediction of Human Intestinal Absorption.

Human intestinal absorption (HIA) will dictate biopharmaceutical performance through its influence on absorption, distribution, metabolism, and elimination and can vary significantly depending upon the nature of the compound under consideration. In this study, an in vitro assay method is proposed for the prediction of HIA through the measurement of drug solubility in an aqueous phase containing micellar bile salt, namely sodium deoxycholate. A series of twenty compounds, displaying a range of physicochemical properties and known HIA values, were analyzed using UV spectroscopy to determine a solubilization ratio for each compound. A micelle/water partition coefficient (Kxm/a) was calculated and then used to develop an equation through simple linear regression; logit HIA = -0.919 + 0.4618 logKxm/a (R2 = 0.85). From this equation, a value for % HIA was determined which compared well with literature. Furthermore, 4 additional drugs were then analyzed using the developed equation and found to match well with literature, confirming the suitability of the method. Using a simple, economic, and robust UV bile salt assay allows prediction of HIA and avoids many of the disadvantages of other techniques, such as animal-based methods.

A system to investigate the remediation of organic vapors using microwave-induced plasma with fluidized carbon granules.

This article describes a system to investigate the parameters for the remediation of organic vapors using microwave-induced plasma on fluidized carbon granules. The system is based on a single mode microwave apparatus with a variable power (2.45 GHz) generator. Carbon granules are fluidized in a silica tube situated in the sample section of a waveguide incorporating two additional ports to allow plasma intensity monitoring using a light sensor and imaging with a digital camera. A fluoroptic probe is used for in situ measurement of the carbon granule temperature, while the effluent gas temperature is measured with a thermocouple situated in the silica tube outside the cavity. Data acquisition and control software allow experiments using a variety of microwave power regimes while simultaneously recording the light intensity of any plasma generated within the carbon bed, together with its temperature. Evaluation using two different granular activated carbons and ethyl acetate, introduced as a vapor into the fluidizing air stream at a concentration of 1 ppm, yielded results which indicated that significant destruction of ethyl acetate, as monitored using a mass spectrometer, was achieved only with the carbon granules showing high plasma activity under pulsed microwave conditions. The system is therefore suitable for comparison of the relative microwave activities of various activated carbon granules and their performance in microwave remediation and regeneration.