Laura J. Waters

Inclusion of fenofibrate in a series of mesoporous silicas using microwave irradiation

A selection of porous silicas were combined with a model drug using a recently developed, controlled microwave heating process to determine if the application of microwave irradiation could enhance subsequent drug release. Five mesoporous silica types were investigated (core shell, core shell rehydrox, SBA-15, silica gel, SYLOID®) and, for comparison, one non-porous silica (stober). These were formulated using a tailored microwave heating method at drug/excipient ratios of 1:1, 1:3 and 1:5. In addition, all experiments were performed both in the presence and absence of water, used as a fluidising media to aid interaction between drug and support, and compared with results obtained using more traditional heating methods. All formulations were then characterised using differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transformation infrared spectroscopy (FT-IR). Pharmaceutical performance was investigated using in vitro drug release studies. A significant enhancement in the release profile of fenofibrate was observed for formulations prepared using microwave heating in the absence of water for five of the six silica based formulations. Of all the formulations analysed, the greatest extent of drug release within the experimental 30 min was the 1:5 core shell rehydrox achieving a total of 86.6 ± 2.8%. The non-porous (stober) particles did not exhibit an increased release of the drug under any experimental conditions studied. This anomaly is thought to be a result of the comparatively small surface area of the silica particles, thus preventing the adsorption of drug molecules.

The emergence of new psychoactive substance (NPS) benzodiazepines: a review

The market for new psychoactive substances has increased markedly in recent years and there is now a steady stream of compounds appearing every year. Benzodiazepines consist of only a fraction of the total number of these compounds but their use and misuse has rapidly increased. Some of these benzodiazepines have only been patented, some of them have not been previously synthesised, and the majority have never undergone clinical trials or tests. Despite their structural and chemical similarity, large differences exist between the benzodiazepines in their pharmacokinetic parameters and metabolic pathways and so they are not easily comparable. As benzodiazepines have been clinically used since the 1960s, many analytical methods exist to quantify them in a variety of biological matrices and it is expected that these methods would also be suitable for the detection of benzodiazepines that are novel psychoactive substances. Illicitly obtained benzodiazepines have been found to contain a wide range of compounds such as opiates which presents a problem since the use of them in conjunction with each other can lead to respiratory depression and death. This review collates the available information on these benzodiazepines and provides a starting point for the further investigation of their pharmacokinetics which is clearly required.

In vitro controlled drug release from loaded microspheres - dose regulation through formulation

PURPOSE Drug release profiles were established for ibuprofen encapsulated within several types of microspheres and a range of dissolution buffer media to study the effect these variables have in controlling the rate and extent of drug release. METHODS Fatty acid microspheres containing ibuprofen were prepared by a process previously developed and refined to produce microspheres of a known size and composition, namely 80-125 mum diameter and an excipient to ibuprofen ratio of 3:1. Drug release profiles from these encapsulated formulations were compared with those obtained for the dissolution of ibuprofen alone under the same conditions. RESULTS Stearic acid microspheres were found to only partially retard the release of ibuprofen over a twenty minute period compared with the dissolution of ibuprofen alone. However, a significant retardation of ibuprofen release was observed with cetostearyl alcohol microspheres over the same period of time. Secondly, drug release profiles for encapsulated ibuprofen were determined using five distinct dissolution buffer media; sodium phosphate, potassium phosphate, citric acid and phosphate mix, MOPS and tris. Significant differences in the extent and rate of drug release were recorded between the different dissolution buffer solutions. These differences were also shown to be independent of variations in pH, temperature, buffer concentrations and the type of cations present. CONCLUSIONS The presence and choice of microsphere formulation, and the choice of buffer present in the dissolution solution, can influence drug release in vitro, i.e. it is possible to achieve controlled drug release from microspheres. To explain the control achieved through the choice of buffer in solution it is proposed that the buffer anion exerts a stabilising influence on the ibuprofen-microsphere matrix.

Modelling skin permeability with micellar liquid chromatography.

This study evaluates the potential application of micellar liquid chromatography (MLC) to predict skin permeation with a series of model compounds. MLC has previously been found to be useful in the prediction of partition coefficient values (logP) for pharmaceutical compounds, yet has not been incorporated in skin permeability models prior to this work. This article provides statistically supported data that this technique enhances the ability to predict the permeability of similar drugs through the skin (K(p)). The replacement of a traditional physicochemical parameter, namely the octanol-water partition coefficient (logP(ow)) with a chromatographically determined value (logP(mw)), results in a quantitative partition-permeability relationship that is robust to variation. MLC offers many benefits compared with the traditional techniques employed to obtain logP values.

Surfactant and temperature effects on paraben transport through silicone membranes

This study investigates the effects of two surfactants (one anionic and one non-ionic) and controlled modifications in temperature (298-323K) on the permeation of two structurally similar compounds through a silicone membrane using a Franz diffusion cell system. In all cases the presence of an anionic surfactant, namely sodium dodecyl sulphate (SDS), reduced the permeation of both compounds (methylparaben and ethylparaben) over a period of 24h. The degree of permeation reduction was proportional to the concentration of surfactant with a maximum effect observed, with an average reduction of approximately 50%, at the highest surfactant concentration of 20mM. Differences were seen around the critical micelle concentration (CMC) of SDS implying the effect was partially connected with the favoured formation of micelles. In contrast, the presence of non-ionic surfactant (Brij 35) had no effect on the permeation of methylparaben or ethylparaben at any of the concentrations investigated, both above and below the CMC of the surfactant. From these findings the authors conclude that the specific effects of SDS are a consequence of ionic surfactant-silicone interactions retarding the movement of paraben through the membrane through indirect modifications to the surface of the membrane. As expected, an increase in experimental temperature appeared to enhance the permeation of both model compounds, a finding that is in agreement with previously reported data. Interestingly, in the majority of cases this effect was optimum at the second highest temperature studied (45°C) which suggests that permeation is a temperature-dependent phenomenon.

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.

Saturation determination of micellar systems using isothermal titration calorimetry

SummaryA novel method for the determination of the point of micellar saturation has been developed. To exemplify the theory a model system was considered, this being the saturation of two aqueous micellar solvents with dimethyl phthalate ester (DMP). Upon addition of a hydrophobic compound to an aqueous micellar system partitioning will occur. On further addition, the inner hydrophobic regions will eventually be unable to accommodate any more DMP and, at this specific concentration, the micelle is saturated. With a comparatively large enthalpy change upon partitioning the point of saturation can be determined by a corresponding significant reduction in enthalpy change.

pH effects in micellar liquid chromatographic analysis for determining partition coefficients for a series of pharmaceutically related compounds

Five drugs were studied using micellar liquid chromatography (MLC) to determine micelle-water partition coefficients (Pmw) over a range of mobile phase pH values and column temperatures. In all cases the sodium dodecyl sulphate mobile phase utilised a CN reversed-phase column with UV detection, optimised for the λmax of each drug. The pH of the mobile phase was systematically varied over the range 3 to 7 pH units, incorporating values above and below the pKa‘s of the drugs studied. From this it was possible to determine MLC based values of Pmw and establish their relationships with pKa values, software predicted partition coefficients (clogP), dissociation constants (logD) and published partitioning data (logPow). This study also considered the relationship between column temperature, from 294K to 317K, and Pmw. For all five drugs it was found that Pmw decreased with increasing pH implying a systematic increased preference for the drug to remain in the aqueous phase rather than partition into the micellar phase. In addition, the partition coefficient displayed a linear relationship with log D over the pH range for each drug with a ‘break-point’ observed at the pKa for each drug. With respect to increasing temperature, the results were non-linear indicating that there is no general relationship for these drugs with temperature. Overall, it was found that MLC is suited to the measurement of partition coefficients for pharmaceutical compounds yet it should be noted that both pH and temperature play a significant role in the values obtained.

A calorimetric investigation of doxorubicin-polymer bead interactions.

Isothermal titration calorimetry (ITC) was utilised to investigate suitability of the technique to determine the stoichiometry and thermodynamics of the interactions that occur between a commonly used chemotherapeutic drug, namely doxorubicin, and a polymer bead-based drug delivery embolisation system (DC Bead™). Six temperatures were selected for drug-polymer titrations (293-313 K) and in all cases an initially exothermic signal reverted to an endothermic response upon the saturation of the beads with drug. From these experiments, and subsequent calculations, the molar ratio of drug to SO3(-) (polymer) was found to be 0.4:1 at all temperatures studied. Enthalpic data was calculated from the raw ITC data with an average enthalpy of drug-polymer binding of - 14.8 kJ mol(-1) at 293 K through to - 19.4 kJ mol(-1) at 313 K implying the process is enthalpically-driven yet only affected by an increase in experimental temperature to a limited extent whereby an increase in experimental temperature results in a small increase in the negativity in change in enthalpy recorded. The application of ITC in this study (with its unique ability to monitor real-time interactions and facilitate stoichiometric calculations) resolves the lack of knowledge regarding the thermodynamics of this specific drug-polymer interaction. This study confirms that ITC is not only useful for this specific system, but also highlights the potential use of ITC for more general studies in this area.

Selective complexation of divalent cations by a cyclic α,β-peptoid hexamer: a spectroscopic and computational study

We describe the qualitative and quantitative analysis of the complexation properties towards cations of a cyclic peptoid hexamer composed of alternating α- and β-peptoid monomers, which bear exclusively chiral (S)-phenylethyl side chains (spe) that have no noticeable chelating properties. The binding of a series of monovalent and divalent cations was assessed by 1H NMR, circular dichroism, fluorescence and molecular modelling. In contrast to previous studies on cations binding by 18-membered α-cyclopeptoid hexamers, the 21-membered cyclopeptoid cP1 did not complex monovalent cations (Na+, K+, Ag+) but showed selectivity for divalent cations (Ca2+, Ba2+, Sr2+ and Mg2+). Hexacoordinated C-3 symmetrical complexes were demonstrated for divalent cations with ionic radii around 1 Å (Ca2+ and Ba2+), while 5-coordination is preferred for divalent cations with larger (Ba2+) or smaller ionic radii (Mg2+).