Droplet Size Analysis Research Articles

Pickering stabilization of thymol through green emulsification using soluble fraction of almond gum – Whey protein isolate nano-complexes

In this study, the soluble fraction of almond gum (SFAG) as a sustainable biopolymer source and whey protein isolate (WPI) were used for self-assembly preparation of SFAG-WPI nano-complexes through electrostatic interaction. The SFAG was characterized using 1H and 13C NMR. The influence of total biopolymer concentration (0.2–0.4 %w/v) and ratios (1:3–3:1) as well as of the pH (2–6) on the formation of complexes was established by visual, light scattering, surface charge, and spectrometric observations. The outcomes proved the formation of negatively charged soluble complexes in the range of pH 4–5 and insoluble complexes at pH values 3 to 4. The soluble coacervate particles at pH 4.5 and total concentration of 0.4 %w/v were selected to induce Pickering stabilization of thymol. The static light scattering with microscopy studies (CLSM and Cryo-SEM) showed the formation of thymol oil-in-water emulsions by adsorption of nano-complexes on the surface of the droplets. Thymol emulsions stabilized using complexes had no size variation under storage (40 days) with an opaque and homogenous appearance. On the other hand, the emulsions containing solely WPI at pH 4.5 showed a substantial droplet size increase with severe creaming. Droplet size analysis together with coalescence and flocculation indices presented that coalescence was mainly responsible for droplet size coarsening of the emulsions stabilized by native WPI at pH 4.5. Overall, our outcomes indicated the improvement of WPI in the stabilization of emulsions through complexation.

Third-Generation Transdermal Delivery Systems Containing Zidovudine: Effect of the Combination of Different Chemical Enhancers and a Microemulsion System.

This study aimed to examine the influence of the combination of chemical enhancers and a microemulsion on the transdermal permeation of zidovudine (AZT). Ethanol, 1,8-cineole, and geraniol were incorporated in a microemulsion. The droplet size, zeta potential, rheology, and SAXS analysis were performed. The permeation enhancer effect was evaluated using pig ear skin. Snake skin (Boa constrictor) treated with the formulations was also used as a stratum corneum model and studied by attenuated total reflectance-infrared spectroscopy. As a result, it was observed that the incorporation of the chemical enhancers promoted a decrease of the droplet size and some rheological modifications. The 1,8-cineole associated with the microemulsion significantly increased the permeated amount of AZT. Conversely, ethanol significantly increased the quantity of the drug retained in the skin. The probable mechanism for the cineole and ethanol effects was respectively: fluidization and increasing of the diffusion coefficient, and increasing of the partition coefficient. Surprising, geraniol + microemulsion drastically decreased both the permeated and the retained amount of AZT into the skin. Thus, the adequate association of microemulsion and chemical enhancers showed to be a crucial step to enable the topical or transdermal use of drugs.

Fabrication and evaluation of self-nanoemulsifying oil formulations (SNEOFs) of Efavirenz

The current work designed to fabricate and evaluate self-nanoemulsfying oil formulations (SNEOFs) of Efavirenz (Efz) a BCS class II drug with the objective of increasing its solubility as well as in vitro dissolution rate for improvisation of bioavailability. Preliminary screening of drug which includes solubility, emulsifying ability and ternary phase diagrams was carried out to fabricate SNEOFs. Various thermodynamic stability studies were exercised to find out the stable SNEOFs. Robustness to dilution, % transmittance and turbidity, droplet size analysis, TEM study, cloud point measurement, viscosity and refractive index were executed on the stable SNEOFs to characterize the delivery system. FTIR study was adopted for the compatibility of the additives with the drug. In vitro release profiles of SNEOFs compared with Efz, percent dissolution efficiency (DE) and dissolution half-life (t50) were evaluated. A low percent DE (30.12%) and high t50 was obtained for Efz whereas all SNEOFs showed a DE of greater than 78.48% and less than 9 min t50. The optimized SNEOFs (F8) demonstrated a significant (p < 0.05) increase in bioavailability over Efz. Thus the designed optimized delivery system could be instrumental in increasing aqueous solubility of Efz, improving its release performance and enhancement of oral absorption.

Synthesis and evaluation of Jatropha oil-based emulsified acids for matrix acidizing of carbonate rocks

Matrix-acidizing operations have been accounted to be the most hazardous and environmentally harmful among all the well-stimulation techniques. For instance, diesel oil-based emulsified acids have been prohibited from usage due to their high level of toxicity. There is, therefore, a dire need for emulsified acids that are environmentally viable and technically competent to replace the diesel-based emulsified acids. In this study, a novel oil-based environmental friendly emulsified acid has been synthesized from Jatropha curcas oil and, then, compared against diesel and palm oil-based emulsified acids. The technical evaluation of the three acids has been done based on experimental results obtained from thermal stability, droplet size analysis, rheological study, acid solubility, and toxicity screening. In addition, core flooding experiments have been conducted to evaluate the performance of the three emulsified acids as well stimulants. The results revealed that Jatropha oil-based emulsified acid has the potential to replace diesel-based emulsified acid. Jatropha oil-based emulsified acid was found to perform better than the diesel-based emulsified acid as indicated by having greater thermal stability and more popular rheological properties at varying temperatures of ambient, 50 and 70 °C. Furthermore, it possessed a lower toxicity load and a higher retardation effect on acid solubility than that of the diesel oil-based emulsified acid. The core flooding results have also indicated better well-stimulation performance of Jatropha-based emulsified acid as compared with diesel-based emulsified acids.

High-Throughput Optofluidic Acquisition of Microdroplets in Microfluidic Systems.

Droplet optofluidics technology aims at manipulating the tiny volume of fluids confined in micro-droplets with light, while exploiting their interaction to create “digital” micro-systems with highly significant scientific and technological interests. Manipulating droplets with light is particularly attractive since the latter provides wavelength and intensity tunability, as well as high temporal and spatial resolution. In this review study, we focus mainly on recent methods developed in order to monitor real-time analysis of droplet size and size distribution, active merging of microdroplets using light, or to use microdroplets as optical probes.

In vivo evaluation of an oral self-emulsifying drug delivery system (SEDDS) for exenatide

BackgroundThe aim of the study was to develop an oral self-emulsifying drug delivery system (SEDDS) for exenatide and to evaluate its in vivo efficacy. MethodsExenatide was lipidised via hydrophobic ion pairing with sodium docusate (DOC) and incorporated in SEDDS consisting of 35% Cremophor EL, 25% Labrafil 1944, 30% Capmul-PG 8 and 10% propylene glycol. Exenatide/DOC was characterized in terms of lipophilicity evaluating the octanol/water phase distribution (logP). Exenatide/DOC SEDDS were characterized via droplet size analysis, drug release characteristics (log DSEDDS/release medium determination) and mucus permeation studies. Furthermore, the impact of orally administered exenatide/DOC SEDDS on blood glucose level was investigated in vivo on healthy male Sprague-Dawley rats. ResultsHydrophobic ion pairing in a molar ratio of 1:4 (exenatide:DOC) increased the effective logP of exenatide from −1.1 to 2.1. SEDDS with a payload of 1% exenatide/DOC had a mean droplet size of 45.87 ± 2.9 nm and a Log DSEDDS/release medium of 1.9 ± 0.05. Permeation experiments revealed 2.7-fold improved mucus diffusion for exenatide/DOC SEDDS compared to exenatide in solution. Orally administered exenatide/DOC SEDDS showed a relative bioavailability (versus s.c.) of 14.62% ± 3.07% and caused a significant (p < .05) 20.6% decrease in AUC values of blood glucose levels. ConclusionAccording to these results, hydrophobic ion pairing in combination with SEDDS represents a promising tool for oral peptide delivery.

Influence of non-ionic emulsifier type on the stability of cinnamaldehyde nanoemulsions: A comparison of polysorbate 80 and hydrophobically modified inulin

Cinnamaldehyde nanoemulsions were formulated to enable its application in an aqueous environment. The pure cinnamaldehyde nanoemulsions, stabilized by polysorbate 80 (at concentrations >0.5%), had both a higher stability and smaller droplet size, whereas the emulsions containing hydrophobically modified inulin (HMI) formed a colloidal dispersion with larger particle size. Incorporation of sunflower oil (SO) allowed postponement of Ostwald ripening for a sufficiently long period of time (at least 60 days). Cryo-SEM and droplet size analyses of the nanoemulsions emulsified by HMI revealed no significant changes during storage. Under these conditions, HMI as an emulsifier exhibited a powerful resistance to high salt contents (up to 2 M) and high thermal processing temperatures (90 °C). The surfactant type and SO content had no marked influence on the antimicrobial activity of the nanoemulsions. This study provides precious information for a commercial formulation of nanoemulsions with durable physical stability under severe stress conditions.

Microspray flow/thermal characteristics via a micro-piezoelectric atomizer with single and multiple arrays of micronozzles

An experimental study on the flow characteristics (only for a single microhole) and cooling performance (multiple array of microholes) of water spray impingement on a polished copper plate using a commercial piezoelectric (PZT) atomizer with multiple arrays of micronozzles (∼900 holes) was conducted. Microholes of dj = 35 µm were used and tested with a total volumetric flow rate of 0.361–22.5 cm3/min and a corresponding mass flow rate of 6 × 10−6 kg/s–3.7 × 10−4 kg/s using seven spray heights of 30 mm, 40 mm, 50 mm, 60 mm, 70 mm, 80 mm and 90 mm. µPIV and IPI optical velocimetry, as well as temperature distribution and a droplet size analyzer, were used to measure the downstream local velocity and temperature profile during the spray flight and its associated droplet size distribution for single and multiple arrays of micronozzles. Results of the flow characteristics show that a well-mixed atomization can be found at a spray height of 50 mm, and the spray pattern keeps its symmetry as the flow proceeds downstream. A very rapid cooling rate of −15 °C/s can be reached at the critical heat flux (CHF) for dj = 35 µm with a spray height of H = 50 mm. The effect of the spray height was examined, and it was found that the best cooling performance for a spray height of 50 mm with a CHF can be up to 259 W/cm2 (steady) and 209 W/cm2, respectively.

Increasing water solubility with decreasing droplet size limits the use of water NMR diffusometry in submicron W/O-emulsion droplet size analysis

HypothesisWater droplet size analysis of water-in-oil emulsions using water NMR diffusometry yielded values that were, from a certain shear intensity onwards, independent from the shear which was used during production. It was assumed that the constant water droplet size, obtained for samples prepared at higher shear, were only apparent droplet diameters. Considering the well-known increased solubility of the dispersed phase in the continuous phase at smaller droplet sizes, it is hypothesized that water diffusion in the oil phase was responsible for the fact that apparent rather than real sizes were obtained. ExperimentsW/O-emulsions, prepared with a varying shear intensity, were characterized using dynamic light scattering, light microscopy, T2-relaxometry and PFG-NMR diffusometry. The latter measurements were conducted on both a low- and a high-resolution device and was based on either water (LR- and HR-NMR) or a water-soluble marker (HR-NMR). FindingsLow-resolution PFG-NMR is incapable of accurately determining the droplet size of W/O-emulsions containing (sub)micron sized droplets. On the other hand, using high-resolution PFG-NMR diffusometry and the addition of an oil insoluble marker to the water phase, the application window could be extended towards smaller droplet sizes. Finally, it was shown that T2-relaxometry was capable of detecting differences in droplet size between (sub)micron sized W/O-emulsions.

Extraction of Ethylparaben by emulsion liquid membrane: Statistical analysis of operating parameters

Ethylparaben, alkyl esters of p-hydroxybenzoic acid, is an endocrine disruptor that interfere glandular activity and hormone production and even with considerable elimination of them using conventional treatment methods, it is still recognized in river water samples at high concentrations. In this study, Emulsion Liquid Membrane (ELM) consisted of trioctylamine (TOA) as carrier, n-heptane as diluent, Span 80 as surfactant and Na2CO3 as the stripping solution was used for the removal of ethylparaben (EP) from aqueous solution. Studies were conducted to analyse the effect of various operating parameters. Effect of factors like carrier concentration (C), stripping phase concentration (N), speed of homogenizer (H), surfactant concentration (S) on the extraction of EP were evaluated with Taguchi's method. Statistical analysis of variance (ANOVA) was applied to analyze the effect of each parameter and stripping phase concentration (0.5 N Na2CO3) followed by speed of homogenizer (13500 rpm) were found to be the most influencing parameters. Photomicrographs of emulsions and droplet size analyzer were used to study the impact of speed of homogenizer on emulsion droplet size and size distribution. Dispersion destabilization of the emulsion was detected by Turbiscan. Atomic force microscopy and Fourier transform infrared spectroscopy were used to analyse dimensions, shape of emulsion droplet and also to confirm bonding and the presence of different functional groups. Experimental design for multivariable optimization by Taguchi had also been implemented. Using a stable emulsion at optimum condition ∼90% extraction of EP was achieved.

ANTIFUNGAL ACTIVITY OF SOME ESSENTIAL OIL EMULSIONS AND NANOEMULSIONS AGAINST FUSARIUM OXYSPORUM PATHOGEN AFFECTING CUMIN AND GERANIUM PLANTS

In the present investigation, the antifungal activity of essential oil emulsions and nanoemulsions of sweet basil (Ocimum basilicum L.), marjoram (Majorana hortensis Moench), peppermint (Mentha piperita L.), spearmint (Mentha spicata L.) and thyme (Thymus vulgaris L.) were evaluated against Fusarium oxysporum isolated from infested cumin and geranium plants. Essential oils were obtained by hydrodistillation and analyzed by gas chromatography. The nanoemulsion was formulated using the essential oils, non-ionic surfactant (Tween 80) and water by ultrasonication method for 30 min and characterized by particle size analyzer and transmission electron microscope. Essential oil emulsions were prepared as mentioned above without sonication. The transmission electron micrograph showed that the essential oil nanoemulsions were spherical in shape and moderately mono or di-dispersed. The droplet size was correlated well with the results obtained from droplet size analysis showing that droplets are present in the nanometer range, with particle size of less than 100 nm and were stable after 3 months of storage under room temperature (27 °C). Four concentrations of the emulsions and nanoemulsions were used to evaluate the anti-fusarium activity in vitro. The results showed that maximum inhibition against Fusarium oxysporum. f.sp. cumini was resulted by thyme essential oil nanoemulsion and emulsion at 2000 ppm and sweet basil essential oil nanoemulsion at 4000 ppm. Also, maximum inhibition against Fusarium oxysporum isolated from geranium plant resulted by thyme essential oil nanoemulsion and emulsion at 2000 ppm. All essential oil nanoemulsions exhibited higher activities compared to emulsions against fungal growth at all concentrations. Treating cumin seeds with each of the concentrations of essential oil emulsions did not affect germination, while seed germination percentage sharply decreased at high concentrations of nanoemulsions treatments. The results suggest the potential effects of thyme and sweet basil essential oil nanoemulsions as novel fungicide agents against Fusarium spp.

The Assessment of Oil Sand Conditioning Using Droplet Size Analysis

The transportation of oil sand via slurry pipeline reduces downstream processing costs because some separation of bitumen from the sand/clay matrix occurs during transit (conditioning). However, there is currently no real-time method for assessing the extent of conditioning inside a pipeline. We investigated bitumen droplet size analysis as a technique for determining the extent of conditioning in a slurry line by conducting field tests at Syncrude Canada Ltd.'s oil sand operation in Fort McMurray, Alberta. Slurry was withdrawn from two different pipelines at five specially designed sampling stations and the liberated bitumen droplets were allowed to float through a water-filled viewing chamber. The droplets were videotaped and analyzed using particle sizing software to determine the average droplet size and shape. This data was correlated to feed grade, slurry temperature and transport distance to determine if a relationship existed between the physical slurry properties and the droplet data. Results suggest that droplet size analysis can be used to assess the extent of conditioning inside an oil sand slurry pipeline in real time. This technology could be incorporated into the control scheme of an oil sand processing circuit to improve separation efficiency and reduce costs.

Formulation and characterization of O/W emulsions stabilized using octenyl succinic anhydride modified kudzu starch

Kudzu starch esterified with octenyl succinic anhydride (OSA) was used as a food-grade emulsifier to formulate O/W emulsions. In addition, the difference between the physicochemical properties and emulsifying ability of native kudzu starch and those of OSA-modified kudzu starch was investigated. Granules of the OSA-modified kudzu starches increased in size after gelatinization. The interfacial tension between soybean oil and gelatinized OSA-modified kudzu starch was lower than that of kudzu starch. The droplet size of O/W emulsions decreased to 186nm at 100MPa after three passes. The emulsions stabilized using gelatinized OSA-modified kudzu starch were less stable when exposed to different ionic strengths (100mM to 500mM NaCl), than when exposed to different pH levels (2–8). The results of oil droplet size and confocal laser scanning microscopy analysis indicated that emulsions containing 2–5% OSA-modified kudzu starch remained stable at room temperature for 30 days.

The influence of ultrasound on the stability of dairy-based, emulsifier-free emulsions: rheological and morphological aspect

This study has been designed to examine incorporation of 7, 10 and 15% olive oil in milk-based media by using ultrasound (US) at 24 kHz, for 3 min in order to form new dairy-based, emulsifier-free emulsions. The prepared emulsions were characterized in terms of the emulsion capacity and stability, creaming index, zeta potential, droplet size, color and rheological analysis. The morphology of the emulsions was examined under the fluorescence microscope to evaluate the changes caused by US. The peroxide value and fatty acid composition were determined. After the treatment, application of the US increased the stability of emulsions. A decrease in the creaming index and droplet size and an increase in the zeta potential were observed. All the emulsions exhibited a weak gel structure. The fluorescence microscope images showed that the US decreased the size of oil droplet.

Enhanced Anti Arthritic Potential of Tacrolimus by Transdermal Nanocarrier System

Current work entails the development and assessment of a well-tolerated colloidal carrier system containing immunosuppressant drug tacrolimus (TL) for transdermal delivery to study its efficacy against arthritis. TL-NEs of different composition from phase diagram were prepared by high sheer homogenization and a comprehensive physico-chemical characterization of the novel NEs were performed using different techniques in order to get most optimum NE. Optimized NE was incorporated in to carbopol-934 gel and subjected to ex vivo skin permeation studies, droplet size analysis, zeta potential measurement, TEM examination, Rheology, and stability study. Moreover, we have evaluated the in vivo anti arthritic potential of same formulation and compared it with a marketed ointment (Protopic®, 0.03%) for the first time. Optimized TL-NG formulation composed of Capryol 90 (5.0% w/w), tween-20 (15.0% w/w), Transcutol HP (7.5% w/w), water (72.5%) w/w, carbopol-934 (1.0%) and found to have permeation flux (68.88 μg/cm2/h), release (1621.46 μg/24 h), small droplet size (12.72 nm), and viscosity of 1.07 Pa-s. The results of ZP indicated that formulation was stable and shelf life at room temperature was calculated as 1.59 years. The in vivo investigation demonstrated direct evidence on significant reduction (41.80%) in inflammation over a period of 24 h. On the basis of these preliminary finding, we conclude that developed TL-NG has good anti-inflammatory action and may provide promising perspective for treatment of Arthritis.

A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol

To develop a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for a water-insoluble oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) with improved stability and oral bioavailability, numerous S-SNEDDS were prepared with surfactant, hydrophilic polymer, antioxidant, and calcium silicate (porous carrier) using the spray-drying method. Their physicochemical properties were evaluated using emulsion droplet size analysis, SEM and PXRD. Moreover, the solubility, dissolution, stability, and pharmacokinetics of the selected S-SNEDDS were assessed compared with the drug and a commercial soft capsule. Sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) with the highest drug solubility were selected as surfactant and hydrophilic polymer, respectively. Among the antioxidants tested, only butylated hydroxyanisole (BHA) could completely protect the drug from oxidative degradation. The S-SNEDDS composed of PLAG/SLS/HPMC/BHA/calcium silicate at a weight ratio of 1: 0.25: 0.1: 0.0002: 0.5 provided an emulsion droplet size of less than 300 nm. In this S-SNEDDS, the drug and other ingredients might exist in the pores of carrier and attach onto its surface. It considerably improved the drug stability (about 100 vs. 70%, 60 °C for 5 d) and dissolution (about 80 vs. 20% in 60 min) compared to the commercial soft capsule. Moreover, the S-SNEDDS gave higher AUC, Cmax, and Tmax values than the commercial soft capsule; in particular, the former improved the oral bioavailability of PLAG by about 3-fold. Our results suggested that this S-SNEDDS provided excellent stability and oral bioavailability of PLAG. Thus, this S-SNEDDS would be recommended as a powerful oral drug delivery system for an oily drug, PLAG.

Fragmentation behavior of Y2O3 suspension in axially fed suspension plasma spray

The fragmentation behavior of Y2O3 suspension has been investigated using an Axial III system with axial feeding as a function of primary droplet size of atomized suspension, solid content in the suspension, and size distributions of raw powders. The results showed that very severe fragmentation of the suspension occurred due to the interaction of axially fed suspension with the thermal plasma jet. The volume of deposited splats was almost the same as that of the individual Y2O3 particles of the raw materials regardless of the above experimental parameters used in this study. In addition, in this axial feeding in the Axial III system, based on a few assumptions, the diameters of the fragmented liquid droplets were estimated to be around 1.9μm, which was below the usual detection limit of the droplet size analyzer. In this regard, the size distributions of raw powders appear to have a direct interrelationship with splat size distribution and thus have an important implication in the microstructure development of the deposited coatings.

Physicochemical analysis in the evaluation of reconstituted dry emulsion tablets

The aim of this study was to characterize the formation of emulsions by droplet size analysis and turbidimetry during reconstitution from a solid dosage form, namely from dry emulsion systems, which carry an oil phase for poorly soluble active ingredients. For the dry emulsion systems tablets were prepared either from oil-in-water systems using a freeze-drying process or through direct compression containing the same oil and excipients. The ratios of oil to emulgents and oil to xanthan gum were equal in both methods. In the preparation methods applied, mannitol, erythritol and lactose were used as excipients and mannitol was found to be the most effective excipient based on droplet size reconstitution, turbidimetry and physical properties. Quality control involved testing the physical properties of tablets and characterizing the reconstituted emulsions.

Effect of ionization of drug on drug solubilization in SMEDDS prepared using Capmul MCM and caprylic acid

The purpose of this study was to investigate the effect of ionization of drug on drug solubilization in SMEDDS (self-microemulsifying drug delivery system) prepared using Capmul MCM and caprylic acid. Solubilization capacity of blank SMEDDS dispersions for danazol, indomethacin and haloperidol as model drugs was determined. Based on the outcomes of solubilization capacity study, drug-loaded SMEDDS formulations were prepared and subjected to dispersion/precipitation study and droplet size analysis. Blank SMEDDS dispersions exhibited the highest solubilization capacity for haloperidol followed by indomethacin and danazol. Furthermore, the solubilization of the three drugs in blank SMEDDS dispersions was explained by a modified mathematical model. Dispersion/precipitation studies indicate that drug-loaded SMEDDS formulations exhibited superiority in solubilizing the drugs in comparison to their respective drug powder. In addition, indomethacin and haloperidol were found to reduce the droplet size of the microemulsions while danazol did not affect droplet size formation for drug-loaded SMEDDS formulations. These findings suggest that ionization of drug affects drug solubilization, droplet size formation, drug loading and drug dispersion/precipitation profiles for the SMEDDS formulations.

Influence of DC electric field upon the production of oil-in-water-in-oil double emulsions in upwards mm-scale channels at low electric field strength

A novel approach to create O/W/O is developed and described to achieve uniform oil drop size coated with thin layers of water. Drops were created using a test cell where the DC field is applied between different internal diameter (ID) needles (from which the O/W emulsion emits upwards into a continuous oil phase) and a grounded metal ring which was located at selected distances from the needle top. The advantages compared to the previous techniques consist of possibility of control on drop size and coating layer of the water using low electric field. A high speed imaging technique has been applied to determine drop size under different flow and electric field conditions. Without the electric field, several flow regimes were observed; stable formation of both the O/W/O emulsion and the O/W emulsion upstream of the cell was possible over a range of Reynolds numbers from 80 to 100. The effect of the electric field was found to be reverse below electric field strength of 60kVm−1, beyond this critical value there was significant impact upon the flow regime, drop size and emulsion structure. The impact of the electric field strength upon flow pattern and emulsion structure and a quantitative analysis of droplet size are presented. The work shows the results for the controlled creation of complex emulsion droplets combining electric field and mm scale channels. The differences with the other physical processes reported in the literature are discussed.