Thiophilicity is a determinant of bioaccumulation in benthic fauna.

Aquatic contamination can settle into sediments, where it complexes with organic matter and becomes bioavailable. The resulting bioaccumulation of these contaminants by benthic fauna poses a serious threat due to the potential for trophic transfer. This paper offers an insight into the heterogenous accumulation behavior of different elements, and the consequences for ecological risk. In this study, we present field quantification of sediment-associated bioaccumulation factors (BAFS) in freshwater benthic macroinvertebrates. 17 elements were quantified using ICP-MS in sediment and Asellus aquaticus and Gammarus sp. samples. Previously published reports of contaminant concentrations in freshwater and marine sediments and benthic fauna were likewise analyzed to provide a complementary picture of bioaccumulation across contaminants and taxa. We demonstrate that the BAFS correlates strongly with the thiophilicity of the elemental contaminants, as defined by (Kepp, 2016), for all strata examined. These findings support the hypothesis that thiol-mediated processes, such as that of metallothionein, play a larger role in bioaccumulation than typically afforded. In conclusion, we demonstrate the potential for the thiophilic scale to act as a predictor of accumulation potential.

Sounding out falsified medicines from genuine medicines using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

The trade in falsified medicine has increased significantly and it is estimated that global falsified sales have reached $100 billion in 2020. The EU Falsified Medicines Directive states that falsified medicines do not only reach patients through illegal routes but also via the legal supply chain. Falsified medicines can contain harmful ingredients. They can also contain too little or too much active ingredient or no active ingredient at all. BARDS (Broadband Acoustic Resonance Dissolution Spectroscopy) harnesses an acoustic phenomenon associated with the dissolution of a sample (tablet or powder). The resulting acoustic spectrum is unique and intrinsic to the sample and can be used as an identifier or signature profile. BARDS was evaluated in this study to determine whether a product is falsified or genuine in a rapid manner and at lower cost than many existing technologies. A range of genuine and falsified medicines, including falsified antimalarial tablets from south-east Asia, were tested, and compared to their counterpart genuine products. Significant differences between genuine and falsified doses were found in their acoustic signatures as they disintegrate and dissolve. Principal component analysis was employed to differentiate between the genuine and falsified medicines. This demonstrates that the tablets and capsules included here have intrinsic acoustic signatures which could be used to screen the quality of medicines.

Sounding out stability of enteric coated dosage forms using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

Stability testing is essential in the pharmaceutical industry to determine product shelf- life and the conditions under which drug products should be stored. Stability testing involves a complex set of procedures, considerable cost, time, and scientific expertise to build quality, efficacy and safety in a drug formulation. This paper highlights a new complementary approach to stability testing called Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS measurements are based on reproducible changes in the compressibility of a solvent during dissolution. It is monitored acoustically via associated changes in the frequency of induced acoustic resonances. This study presents a novel approach to track the change of various drug formulations to determine the formulation's stability. Pellets, tablet and multiple-unit pellet system (MUPS) formulations were investigated to examine the effect of polymer coating and formulation core degradation over time. In combination with minimal usage of Ultra Violet - Visible Spectroscopy, BARDS can effectively track these changes. The technique offers a rapid approach to characterizing pharmaceutical formulations. BARDS can enable rapid development of solid drug formulation dissolution and disintegration testing as an In-Process Control test and drug stability analysis. The data show that a solid oral dose formulation has an intrinsic acoustic signature specific to the method of manufacture, excipient composition and elapsed time since the production of a product. BARDS data are also indicative of which aspect of a formulation may be unstable, whether a coating, sub-coating or core. It is potentially a time-efficient, cost-effective and greener approach to testing coating stability, disintegration and overall formulation stability.

The sound of tablets during coating erosion, disintegration, deaggregation and dissolution.

This research aims to address a gap in our understanding of the mechanisms by which pharmaceutical tablets achieve highly reproducible and predictable drug release. The present industrial and regulatory practice is centred around tablet dissolution, i.e. what follows disintegration, yet the vast majority of problems that are found in formulation dissolution testing can be traced back to the erratic disintegration behaviour of the medicinal product. It is only due to the distinct lack of quantitative measurement techniques for disintegration analysis that this situation arises. Current methods involve costly, and time-consuming test equipment, resulting in a need for more simple, green and efficient methods which have the potential to enable rapid development and to accelerate routine solid drug formulation dissolution and disintegration testing. In this study, we present a novel approach to track several sequential tablet dissolution processes, including coating erosion, disintegration, deaggregation and dissolution using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS, in combination with minimal usage of UV spectroscopy, can effectively track these processes. The data also show that a solid oral dose formulation has an intrinsic acoustic signature which is specific to the method of manufacture and excipient composition.

Tracking Yeast Metabolism and the Crabtree Effect in Real Time via CO2 Production using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

In this study, a new approach to measure metabolic activity of yeast via the Crabtree effect is described. BARDS is an analytical technique developed to aid powder and tablet characterisation by monitoring changes in the compressibility of a solvent during solute dissolution. It is a rapid and simple method which utilises a magnetic stir bar to mix added solute and induce the acoustic resonance of a vessel containing a fixed volume of solvent. In this study it is shown that initiation of fermentation in a yeast suspension, in aqueous buffer, is accompanied by reproducible changes in the frequency of induced acoustic resonance. These changes signify increased compressibility of the suspension due to CO2 release by the yeast. A simple standardised BARDS protocol reveals yeast carbon source preferences and can generate quantitative kinetic data on carbon source metabolism which are characteristic of each yeast strain. The Crawford-Woods equation can be used to quantify total gaseous CO2 produced by a given number of viable yeast when supplied with a fixed amount of carbon source. This allows for a value to be calculated for the amount of gaseous CO2 produced by each yeast cell. The approach has the potential to transform the way in which yeast metabolism is tracked and potentially provide an orthogonal or surrogate method to determining viability, vitality and attenuation measurements in the future.

A rapid in-process control (IPC) test to monitor the functionality of taste masking polymer coatings using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

Monitoring of the coating end-point of functional coatings during the coating application process is desirable. Since currently available PAT methods require expensive test equipment, there is a need for a rapid test that can easily be applied without major investment. BARDS is a novel technique that has the potential to economise the production process of these kinds of pellet and tablet formulations. The thickness of a controlled release coating is a key factor that determines the release rate of the drug in the gastro-intestinal tract or other targeted functionalities such as taste masking or moisture protection. Correspondingly, the amount of drug per unit mass of pellets decreases with increasing thickness of the functional coating. In this study, the functional polymer loading of the coating process is investigated by testing pellets via BARDS technology (Broadband Acoustic Resonance Dissolution Spectroscopy). The technique offers a rapid approach (<200 s) to characterising functional coatings at-line during their manufacture. Measurements are based on reproducible changes in the compressibility of a solvent during dissolution which is monitored acoustically via associated changes in the frequency of induced acoustic resonances. In case of enteric coatings a steady state acoustic lag time is associated with the erosion of the enteric coatings in acidic dissolution test media. This lag time is indicative of the coating layer thickness, assuming that the quality of the film coating is high. BARDS represents a possible future surrogate test for IPC testing, as a PAT method and possibly also for conventional USP dissolution testing. BARDS data correlate directly with the thickness of the functional coating, its integrity and also with the drug loading as validated by UV-Vis spectroscopy.

The freshwater isopod Asellus aquaticus as a model biomonitor of environmental pollution: A review.

Anthropogenic substances pollute freshwater systems worldwide, with serious, long-lasting effects to aquatic biota. Present methods of detecting elevated levels of trace metal pollutants are typically accurate but expensive, and therefore not suitable for applications requiring high spatial resolution. Additionally, these methods are not efficient solutions for the determination of long-term averages of pollution concentration. This is the rationale for the implementation of a biomonitoring programme as an alternative means of pollutant detection. This review summarises recent literature concerning the past and potential uses of the benthic isopod Asellus aquaticus as a biomonitor for pollution in freshwater systems. Recent studies indicate that A. aquaticus is well suited for this purpose. However, the mechanisms by which it bioaccumulates toxins have yet to be fully understood. In particular, the interactions between coexisting trace metal pollutants in the aquatic environment have only recently been considered, and it remains unclear how a biomonitoring programme should adapt to the effects of these interactions. It is evident that failing to account for these additional stressors will result in an ineffective biomonitoring programme; for this reason, a comprehensive understanding of the bioaccumulation mechanisms is required in order to reliably anticipate the effects of any interferences on the outcome.

The sound of salts by Broadband Acoustic Resonance Dissolution Spectroscopy.

Salts are available in different grades and in a wide price range. Some contain more impurities than others, while some have special culinary traits that determine their identity. Acoustic profiling, which is based on the 'hot chocolate effect', may provide an interesting strategy to characterise salts of various origins to underpin their identity. In this study, the link between the identity of 60 food grade and technical salts and their acoustic properties was examined by Broad Acoustic Resonance Dissolution Spectroscopy. In particular, the influence of the composition of the salts and the impact of the salts' particle size distributions on their acoustic profiles were examined. Sodium and potassium contents were measured by flame photometry and the salts' particle size distributions by laser light diffraction. Reference salts (NaCl, KCl, MgCl2) and mixtures thereof were analysed for comparison, as well as intact and ground versions of the salt samples. The results show that both the composition and morphology of the salt crystals determine the down-slope of the resonance frequency, which is caused by the rate of release of entrained and dissolved gas. Coarse salts with high levels of non-NaCl constituents showed a rapid decline in sound frequency, which corresponds to a high gas release rate. On the other hand fine salts composed of pure NaCl revealed a slower change in sound frequency and thus lower gas release rates. The frequency minimums were however not affected by the salts' compositions nor particle size distributions. It is primarily the particle size distribution that affects the rate at which gas is released, and thus the change in sound frequency. Only when the particles are more similar in size, the composition also starts playing a role. Since both particle size distribution and composition is unique for each salt, the various salts show distinct acoustic profiles. Evidently, the current study shows that 'listening' to the sound of salts reveals interesting information about their identity and origin.

Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A rapid test for enteric coating thickness and integrity of controlled release pellet formulations.

There are no rapid dissolution based tests for determining coating thickness, integrity and drug concentration in controlled release pellets either during production or post-production. The manufacture of pellets requires several coating steps depending on the formulation. The sub-coating and enteric coating steps typically take up to six hours each followed by additional drying steps. Post production regulatory dissolution testing also takes up to six hours to determine if the batch can be released for commercial sale. The thickness of the enteric coating is a key factor that determines the release rate of the drug in the gastro-intestinal tract. Also, the amount of drug per unit mass decreases with increasing thickness of the enteric coating. In this study, the coating process is tracked from start to finish on an hourly basis by taking samples of pellets during production and testing those using BARDS (Broadband Acoustic Resonance Dissolution Spectroscopy). BARDS offers a rapid approach to characterising enteric coatings with measurements based on reproducible changes in the compressibility of a solvent due to the evolution of air during dissolution. This is monitored acoustically via associated changes in the frequency of induced acoustic resonances. A steady state acoustic lag time is associated with the disintegration of the enteric coatings in basic solution. This lag time is pH dependent and is indicative of the rate at which the coating layer dissolves. BARDS represents a possible future surrogate test for conventional USP dissolution testing as its data correlates directly with the thickness of the enteric coating, its integrity and also with the drug loading as validated by HPLC.

Contactless, probeless and non-titrimetric determination of acid-base reactions using broadband acoustic resonance dissolution spectroscopy (BARDS).

pH determination is a routine measurement in scientific laboratories worldwide. Most major advances in pH measurement were made in the 19th and early 20th century. pH measurements are critical for the determination of acid base reactions. This study demonstrates how an acid-base reaction can be monitored without the use of a pH probe, indicator and titres of reagent. The stoichiometric reaction between carbonate and HCl acid yields specific quantities of CO2, which causes reproducible changes to the compressibility of the solvent. This in turn slows down the speed of sound in solution which is induced by a magnetic follower gently tapping the inner wall of the vessel. As a consequence the frequencies of the acoustic resonances in the vessel are reduced. This approach is called Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) which harnesses this phenomenon for many applications. The acid-carbonate experiments have also been validated using H2SO4 acid and using both potassium and sodium counterions for the carbonate. This method can be used to interrogate strong acid-base reactions in a rapid and non-invasive manner using carbonate as the base. The data demonstrate the first example of a reactant also acting as an indicator. The applicability of the method to weak acids has yet to be determined. A novel conclusion from the study is that a person with a well-trained ear is capable of determining the concentration and pH of a strong acid just by listening. This brings pH measurement into the realm of human perception.

Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A Novel Approach To Investigate the Wettability of Pharmaceutical Powder Blends.

The ability of broadband acoustic resonance dissolution spectroscopy (BARDS) to assess the wettability of powder blends is investigated. BARDS is a novel analytical technology developed on the basis of the change in acoustic phenomena observed when material is added into a solvent under resonance. Addition of solid material to the solvent results in the introduction of gas (air) into the solvent, changing the compressibility of the solvent system, and reducing the velocity of sound in the solvent. As a material is wetted and dissolved, the gas is released from the solvent and resonance frequency is altered. The main purpose of this work is to demonstrate the ability of BARDS to assess differences in the wetting behavior of tablet excipients (microcrystalline cellulose (MCC) and magnesium stearate (MgSt)) and a model drug (metoclopramide hydrochloride) as single component powders and multicomponent powder blends. BARDS acoustic responses showed a prolonged release of gas for the powdered blends with lubricant compared to unlubricated blends. As the elimination of gas from the solvent was assumed to follow first order elimination kinetics, a compressible gas elimination rate constant was calculated from the log plots of the gas volume profiles. The gas elimination rate constant was used as a parameter to compare the release of gas from the powder introduced to the solvent and hence the powder wetting behavior. A lower gas elimination rate constant was measured for lubricated blends compared to nonlubricated blends, suggesting the prolonged hydration of lubricated blends. Standard wetting techniques such as contact angle measurements and wetting time analysis were also used to analyze the blends and confirmed differences in wetting behavior determined by BARDS. The study results demonstrate the capability of BARDS as a rapid, analytical tool to determine the wetting behavior of the pharmaceutical powder blends and the potential of BARDS as a process analytical technology (PAT) tool.

Sustained-release multiparticulates for oral delivery of a novel peptidic ghrelin agonist: Formulation design and in vitro characterization.

There is an impetus to provide appropriate sustained release oral delivery vehicles to protect biofunctional peptide loads from gastric degradation in vivo. This study describes the generation of a high load capacity pellet formulation for sustained release of a freely water-soluble dairy-derived hydrolysate, FHI-2571. The activity of this novel peptidic ghrelin receptor agonist is reported using in vitro calcium mobilization assays. Conventional extrusion spheronization was then used to prepare peptide-loaded pellets which were subsequently coated with ethylcellulose (EC) film coats using a fluid bed coating system in bottom spray (Wurster) mode. Aqueous-based EC coating dispersions produced mechanically brittle coats which fractured due to osmotic pressure build-up within pellets in simulated media. In contrast, an ethanolic-based EC coating solution provided robust, near zero-order release in both USP Type 1 and Type 4 dissolution studies. Interestingly, the functionality of aqueous-based EC film coats was restored by first layering pellets with a methacrylic acid copolymer (MA) subcoat, thereby hindering pellet core swelling in acidic media. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) was utilised as a complementary technique to confirm the results seen in USP dissolution studies. Retention of activity of the ghrelinergic peptide hydrolysate in the final encapsulated product was confirmed as being greater than 80%. The described pellet formulation is amenable to oral dosing in small animal studies in order to assess in vivo efficacy of the whey-derived ghrelinergic hydrolysate. In more general terms, it is also suitable as a delivery vehicle for peptide-based bioactives to special population groups e.g paediatric and geriatric.

The relationship between dissolution, gas oversaturation and outgassing of solutions determined by Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

The addition of a solute to a solvent is known to reduce the solubility of dissolved gases in solution which leads to gas oversaturation and outgassing of the solvent. The importance of the processes involved have received relatively little attention due to a limited capacity to elucidate their effects in real time. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) is a recently introduced acoustic approach which can monitor changes in the compressibility of a solvent due to outgassing. BARDS spectra show that a time dependent and quantitative reduction in gas oversaturation, following the dissolution of a simple salt, takes place over several hours. It is shown how vigorous agitation quickly equilibrates a solution, post dissolution, by removing gas oversaturation consistently. The level of oversaturation can be elucidated by further dissolving a marker compound into a solution consecutively. BARDS spectra indicate that the dissolution of a compound produces a consistent and quantifiable oversaturation of a solvent and a consistent and quantifiable outgassing. Low frequency sonication in an immersion bath is also shown to play no significant role in removing gas oversaturation post dissolution.

Blend uniformity analysis of pharmaceutical products by Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS).

Blend uniformity analysis (BUA) is a routine and highly regulated aspect of pharmaceutical production. In most instances, it involves quantitative determination of individual components of a blend in order to ascertain the mixture ratio. This approach often entails the use of costly and sophisticated instrumentation and complex statistical methods. In this study, a new and simple qualitative blend confirmatory test is introduced based on a well known acoustic phenomenon. Several over the counter (OTC) product powder blends are analysed and it is shown that each product has a unique and highly reproducible acoustic signature. The acoustic frequency responses generated during the dissolution of the product are measured and recorded in real time. It is shown that intra-batch and inter-batch variation for each product is either insignificant or non-existent when measured in triplicate. This study demonstrates that Broadband Acoustic Resonance Dissolution Spectroscopy or BARDS can be used successfully to determine inter-batch variability, stability and uniformity of powder blends. This is just one application of a wide range of BARDS applications which are more cost effective and time efficient than current methods.

Principles and applications of broadband acoustic resonance dissolution spectroscopy (BARDS): a sound approach for the analysis of compounds.

The dissolution of a compound results in the introduction and generation of gas bubbles in the solvent. This formation is due to entrained gases adhered to or trapped within the particles. Furthermore, a reduction in gas solubility due to the solute results in additional bubble generation. Their presence increases the compressibility of the solvent with the added effect of reducing the velocity of sound in the solvent. This effect is monitored via the frequency change of acoustic resonances that are mechanically provoked in the solvent and are now used as an insightful analytical technique. An experimental set up was designed to study a large number of compounds as a function of time, concentration, and solvent system. This revealed the role of the various physical and chemical mechanisms in determining the observed response. It is also shown that this response is strongly dependent on the physical and chemical characteristics of the solute compound used, therefore resulting in a method for the characterization of compounds and mixtures. Additional factors such as morphology (polymorphism), particle size, and dissolution rate are shown to be key in the variation of the resulting response. A mathematical model has also been developed in parallel, which inter-relates the various processes involved in the observed response. It is anticipated that BARDS will open up a new window into transient dissolution processes and compound characterization.

2,4,6-Trichlorophenol mediated increases in extracellular peroxidase activity in three species of Lemnaceae.

Chlorinated phenols, or chlorophenols, are persistent priority pollutants that are widespread in the environment. Class III peroxidases are well-characterised plant enzymes that can catalyse the oxidative dechlorination of chlorophenols. Expression of these enzymes by plants is commonly associated with plant stress, therefore limiting scope for phytoremediation. In this study, we have quantitatively compared peroxidase activity and phytotoxicity as a function of 2,4,6-trichlorophenol (TCP) concentration in three species of Lemnaceae; Lemna minor, Lemna gibba and Landoltia punctata. Effects of TCP on the growth rates of the three species differed considerably with L. punctata being the most tolerant species. TCP also affected photosynthetic parameters, causing a decrease in open photosystem II reaction centres (qP) and, in L. punctata only, a decrease in non-photochemical quenching (qN). In parallel, TCP exposure resulted in increased peroxidase activity in all three species. Peroxidase activity in L. minor and L. gibba displayed an inverse relationship with biomass accumulation, i.e. the more growth reduction the more peroxidase activity. In contrast, induction of peroxidase activity in L. punctata was bi-phasic, with a TCP-induced activity peak at concentrations that had no major effect on growth, and further induction under phytotoxic concentrations. The mechanism by which L. punctata recognises and responds to low concentrations of an anthropogenic compound, in the absence of wide-ranging stress, remains enigmatic. However, we conclude that this "window" of peroxidase production in the absence of major growth inhibition offers potential for the development of sustainable, peroxidise-mediated phytoremediation systems.

Micellar electrokinetic chromatography with amperometric detection and off-line solid-phase extraction for analysis of carbamate insecticides.

Six selected primary carbamate insecticides, methomyl, carbaryl, carbofuran, propoxur, isoprocarb, and promecarb, were hydrolyzed in alkaline solution, resulting in electroactive derivatives detectable at a platinum (Pt) electrode poised at +0.8 V vs Ag/AgCl (3 M NaCl). The Pt electrode was inserted into a small electrochemical cell and positioned close to the capillary outlet as an end-column detector to detect the carbamate derivatives after electrophoretic separation. Based on their predicted pK(a) values and aqueous solubilities, micellar electrokinetic chromatography (MEKC) was optimized for baseline separation of the derivatives using 20 mM borate, pH 10.2 containing 20 mM sodium dodecyl sulfate as a running buffer. When combined with solid-phase extraction (SPE) on octadecyl silica, a preconcentration factor of 100-fold achieved detection to 0.5 microM methomyl and to 0.01 microM for the remaining five pesticides, significantly below the level regulated by government agencies of most countries. The SPE-MEKC method when applied to the separation and analysis of spiked river water and soil samples, yielded results with excellent reproducibility, recovery and selectivity.

Release characteristics of anionic drug compounds from liquid crystalline gels III. Chemical and iontophoretic enhancement of delivery across non-rate-limiting membranes.

This paper investigates the release and transport of a range of anionic drugs from liquid crystalline gels using chemical and physical enhancement techniques. Previous papers [Fitzpatrick, D., Corish, J., 2005. Release characteristics of anionic drug compounds from liquid crystalline gels. I. Passive release across non-rate limiting membranes. Int. J. Pharm. 301, 226-236; Fitzpatrick, D., Corish, J., 2006. Release characteristics of anionic drug compounds from liquid crystalline gels. II. The effects of ion pairing and buffering on the passive delivery of anionic drugs across non rate-limiting membranes. Int. J. Pharm.] have reported on the passive release profiles and those resulting from the incorporation of a chemical enhancer in the vehicle. This paper investigates the behaviour of the system under iontophoretic conditions and also under those of combined physical and chemical enhancement. The data presented here are directly comparable to previous work by Nolan et al. [; Nolan, L.M.A., Corish, J., Corrigan, O.I., Fitzpatrick, D., 2006. Combined effects of iontophoretic and chemical enhancement on drug delivery. II. Transport across human and hairless murine skin. Int. J. Pharm., submitted for publication] which investigated the behaviour of cationic compounds under analogous conditions. The iontophoretic release of diclofenac in the presence of model enhancers is thoroughly investigated. It is also shown that a range of anionic drug molecules undergo an electrochemical change during the course of the experiments which leads to their poor detection. This may be a factor in the under reporting of iontophoretic delivery of anionic drugs in the literature. However, it has been shown that the transport of the drugs is greatly enhanced by the application of an iontophoretic current. Results of combined enhancement studies provide a positive basis on which to proceed with in vitro studies of the system across human skin.

Release characteristics of anionic drug compounds from liquid crystalline gels. Part II. The effects of ion pairing and buffering on the passive delivery of anionic drugs across non-rate-limiting membranes.

This is the second in a series of papers that report on the release and transport of a range of anionic drugs (diclofenac, salicylic acid) from liquid crystalline gels and ultimately on their use in transdermal delivery. The previous paper [Fitzpatrick, D., Corish, J., 2005. Release characteristics of anionic drug compounds from liquid crystalline gels for transdermal delivery. Part I. Passive release across non-rate limiting membranes. Int. J. Pharm. 301, 226-236] investigated passive release profiles across a non-rate-limiting membrane: here we report on the search for a suitable model enhancer (benzyl dimethyldodecyl ammonium bromide) for the transdermal delivery of anionic compounds. The results presented reveal a significant role for ion pairing and for buffering, analogous to those found in the investigations of cationic species (salbutamol) by Nolan, L.M.A., Corish, J., Corrigan, O.I., Fitzpatrick, D., 2003. Iontophoretic and chemical enhancement of drug delivery. Part I. Across artificial membranes. Int. J. Pharm. 12, 41-55. The method of vehicle preparation is also investigated. It is shown that ion pairing of the drug with the enhancer decreases the amount of drug available for transport from the liquid crystalline gels into aqueous receptor media. This decrease is directly related to the ratio of the concentration of drug to that of the enhancer. Buffering the vehicle inhibits the ion-pair formation to some extent. Vehicle preparation was also found to influence the degree of ion-pair association. The inclusion of a similarly charged enhancer (oleic acid) to the drug was found not to impede the diffusion of the drug from the gels.

Release characteristics of anionic drug compounds from liquid crystalline gels I: Passive release across non-rate-limiting membranes.

Liquid crystalline gels (LCG) offer the formulator dynamic and flexible vehicles, into which actives, enhancers and other adjuvants with a wide range of physicochemical properties can be incorporated. This is achievable because of the biphasic oil/water composition of the gel. In this paper, the suitability of an isotropic liquid crystalline gel is investigated for a range of anionic drug molecules, with particular emphasis on sodium diclofenac. Parameters, which have been investigated, include the mode of vehicle preparation, the effect of the concentration of the drug and how buffering the gel and/or the receptor medium affect the release profiles. Such profiles have been measured for the sodium salts of benzoate, salicylate and indomethacin. The passive release from the standard system was found to adhere to matrix-controlled diffusion. An increase in concentration leads to a non-linear increase in the cumulative release of sodium diclofenac from the gels. In direct contrast to the result reported for cationic salbutamol base, optimum release from the gel was achieved when neither the receptor medium nor the aqueous phase of the gel was buffered. The percentages released of the sodium salts of benzoate, salicylate and indomethacin, after 24 h, were determined to be 25, 26 and 19%, respectively, and these are significantly greater than the release of sodium diclofenac. This suggests that diclofenac undergoes ion-pairing or complexation within the gel, which inhibits its diffusion from the vehicle. Future papers will report on the incorporation of enhancers and the effects of iontophoresis on the release profiles of drugs from these gels, and ultimately on the transdermal transport of drugs from these vehicles across human and porcine skin.