Metastatic melanoma causing small intestinal perforation at the jejunojejunostomy after Roux-en-Y gastric bypass: a case report.

BACKGROUND: Metastatic melanoma of the small intestine is relatively common, and among affected patients, the proportion with involvement of the small intestine ranges from 35% to 70%. Small intestinal perforation as a primary manifestation of metastatic melanoma is rare. We present the exceptional case of a perforation at the jejunojejunostomy after Roux-en-Y gastric bypass caused by metastatic melanoma. CASE PRESENTATION: A 59-year-old woman with a history of a laparoscopic Roux-en-Y gastric bypass and toe amputation due to malignant melanoma (stadium IIIC) presented with an acute abdomen. The abdominal computed tomography scan showed a covered perforation at the jejunojejunostomy of the gastric bypass. The patient underwent an urgent surgical exploration revealing massive tumoral invasion of the anastomosis. The tumoral mass and anastomosis were resected and a new jejunojejunostomy was created. Histopathological examination identified the tumor as a malignant melanoma, so the current abdominal lesions were presumed to be metastases. The postoperative course was uneventful and adjuvant immunotherapy was started a week later. One year after surgery she was doing well with maintenance immunotherapy and there was no evidence of recurrent metastatic disease. CONCLUSION: We report the first case of a perforation at the jejunojejunostomy after Roux-en-Y gastric bypass caused by metastatic melanoma. This exceptional case illustrates that a history of malignant melanoma in case of an acute abdomen should raise suspicion of possible metastatic disease.

Is the flexion-abduction-supination magnetic resonance imaging view more accurate than standard magnetic resonance imaging in detecting distal biceps pathology?

BACKGROUND AND HYPOTHESIS: Partial biceps tendon pathology is difficult to diagnose. The flexion-abduction-supination (FABS) magnetic resonance imaging (MRI) view has been advocated to improve the accuracy of MRI investigation. The purpose of this study was to evaluate the accuracy of the FABS view MRI in the diagnosis of distal biceps tendon pathology. METHODS: The study included 50 patients with surgically confirmed distal biceps tendon pathology and 50 patients with other elbow disorders. In both groups, standard elbow MRI (retrospective review of previously obtained MRI data) was performed in half of the patients whereas FABS views MRI were obtained in the other half. These were evaluated by 2 independent musculoskeletal radiologists. The sensitivity and specificity of both MRI views were determined. Tendinosis and grade of rupture were reported from MRI and then compared with surgical findings. RESULTS: There were no significant differences in sensitivity and specificity in detecting partial distal biceps injuries when the FABS view MRI (sensitivity, 84%; specificity, 86%) and standard MRI (sensitivity, 76%; specificity, 98%) were compared. The interobserver reliability was 92% for the FABS view MRI with biceps pathology and 68% for standard MRI. In the control group, the interobserver reliability was 88% for the FABS view MRI and 96% for standard MRI. FABS MRI was significantly better regarding grade of injury. CONCLUSIONS: No significant differences in sensitivity and specificity were found between the FABS view and standard elbow MRI in the diagnosis of partial distal biceps tendon injuries, with high sensitivity and specificity for both views. Inter-rater reliability was better for FABS views, and FABS views were significantly more accurate than surgical findings in grading the extent of pathology.

Ease of disassembly of products to support circular economy strategies.

Circular economy strategies encourage, among others, concrete actions to extend the product lifetime. Product's repair and reuse, and component harvesting for reuse, all require the facilitated access to product components. Consequently, a reduction of the disassembly time and the related costs will increase the economic feasibility of product lifetime extension and therefore increase the viability of a circular economy in industrialised regions. Furthermore, disassembly has the potential to significantly increase the recycling yield and purity for precious metals, critical metals and plastics. For this reason, the European Commission and several ecolabels have considered to include design for disassembly requirements in legislation or voluntary environmental instruments. However, up to date, there is no standardised method to evaluate the ease of disassembly in an unambiguous manner with a good trade-off between the efforts required to apply the method and the accuracy of the determined disassembly time. The article proposes a robust method "eDiM" (ease of Disassembly Metric), to calculate the disassembly time based on the Maynard operation sequence technique (MOST). A straightforward calculation sheet is employed in eDiM to calculate the disassembly time given the sequence of actions and basic product information. This makes the results fully verifiable in an unambiguous manner, which makes eDiM suited to be used in policy measures in contrast to the results of prior developed methods One of the innovative aspects of eDiM is the categorization of disassembly tasks in six categories, which provides better insights on which disassembly tasks are the most time consuming and how the product design could be improved. The proposed method is illustrated by means of a case study of an LCD monitor. The presented case study demonstrates how the proposed method can be used in a policy context and how the calculated disassembly times per category can provide insights to manufacturers to improve the disassemblability of their products. The results also demonstrate how the proposed method can produce realistic results with only limited detail of input data.

Forecasting global aluminium flows to demonstrate the need for improved sorting and recycling methods.

The probable emergence of a global aluminium scrap surplus in the coming decade is one of the main incentives for the aluminium recycling industry to invest in new methods and technologies to collect, sort and recycle aluminium scrap. However, due to the considerable uncertainty in the evolution of the global scrap surplus, it is difficult for policymakers and the recycling industry to accurately estimate the economic and environmental advantages of implementing enhanced sorting and recycling methods. The International Aluminium Institute (IAI) has developed a model to track and forecast the global flows of aluminium, but this model is not extensive enough to estimate the scrap surplus evolution. Therefore, this paper introduces an alloy series resolution to the supply and demand of aluminium in the IAI's global flow model and estimates the composition of the recovered scrap flows to improve the estimate of the technical potential of secondary alloy production. The estimated scrap surplus evolution is subjected to a sensitivity analysis, considering the most critical parameters, including the speed of electrification in the automotive sector, the recovered scrap's composition and the lifetime of aluminium products. In addition, the estimated composition of the recovered aluminium scrap in the model is compared to composition measurements of alumimium scrap collected at a Belgian recycling facility as a means of validation. This study allows to estimate that the global aluminium scrap surplus will emerge soon and reach a size of 5.4 million tonnes by 2030 and 8.7 million tonnes by 2040, if currently adopted aluminium sorting and recycling methods are not improved.

On the influence of second use, future battery technologies, and battery lifetime on the maximum recycled content of future electric vehicle batteries in Europe.

The European Union is promoting the uptake of low emission vehicles to reduce greenhouse gas emissions from transportation. However, this transition will increase the demand for five important battery raw materials; i.e. lithium, nickel, cobalt, copper, and graphite. Therefore, a substance flow analysis and forecasting model are proposed to investigate the flow of these materials through the different lifecycle stages of electric vehicle batteries. The model forecasts that by 2040, the vehicle stock will be from 72 to 78 million vehicles, while the second use stock will be from 3 to 11 million batteries. In addition, the annual recycling waste stream in 2040 will grow to roughly 3 million batteries with a capacity of 125 GWh. Results indicate that this waste stream could cover between 10% and 300% of future raw materials demand for electric vehicles. The width of this range is dominated by uncertainties on the rapidly evolving material composition of automotive batteries and the possible commercialization of cobalt-free battery technologies. The remaining uncertainty is attributed to the battery lifetime in vehicle use and potential second use of retired batteries.

Quantifying the environmental impact of clustering strategies in waste management: A case study for plastic recycling from large household appliances.

The complex composition of waste electrical and electronic equipment (WEEE) plastics represents a challenge during post-consumption plastic recycling. A single WEEE category, e.g. large household appliances (LHA), can contain several different plastic types with overlapping material properties, making the sorting of individual plastics a challenge. Significant increases in plastic recovery rates can be expected by clustering product categories, as clustering can avoid mixing of non-compatible plastics with overlapping material properties. For this purpose, a life cycle assessment (LCA) is conducted to investigate the influence of different clustering strategies on the environmental performance of waste treatment and the production of recycled plastic from LHA waste stream. To assure comparability between waste treatment scenarios a system expansion approach is applied, and to allocate the burden of shared processes over the first and second use cycle of the material partitioning is applied. Results show that an increased separation of product clusters by plastic type can improve the plastic recovery rate from 5.8% to 47.1% and reduce the overall environmental impact, quantified with the ReCiPe (2016) method, by up to 23%. The environmental impacts of using recycled plastics from LHA waste can be reduced by 27 to 38% compared to single-use plastic. The holistic approach used in this study demonstrates (1) the potential benefits of implementing product clustering strategies for LHA plastic recycling, (2) the relevance of different allocation procedures when integrating recycling into an LCA, (3) the importance of using less virgin material and avoiding final waste treatment, and (4) the limitation of the recycling system to reduce the environmental burden associated with products.

Comparative interaction of 2-hydroxypropyl-beta-cyclodextrin and sulfobutylether-beta-cyclodextrin with itraconazole: phase-solubility behavior and stabilization of supersaturated drug solutions.

Cyclodextrins can increase the apparent solubility and dissolution rate of poorly water-soluble drug candidates improving their biopharmaceutical performance. The current data assess the ability of hydrophilic cyclodextrins to solubilize compounds via stabilization of supersaturated drug solutions presumably by inhibition of nucleation and arresting crystal growth. To these points, the effects of 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutylether-beta-cyclodextrin (SBEbetaCD) on equilibrium solubility was assessed via phase-solubility analysis as were the interactions of these excipients on drug solubility under conditions favoring supersaturation. Phase-solubility analysis indicated that different profiles were generated as a function of the cyclodextrin examined and the pH of the complexing medium. When kinetic solubility measurements were completed, the cyclodextrins were found to stabilize concentrations of itraconazole significantly in excess of their equilibrium solubility when supersaturated solutions were formed using the co-solvent/solvent quench approach. These solutions were stable over 240 min falling in concentration at the 24 h time point of the experiment unlike those formed using surfactants and other polymers which demonstrated a rapid decrease in concentration over time. These data suggest that hydrophilic cyclodextrins might be useful formulation adjuncts in supersaturating drug delivery systems.

Effect of the unstirred water layer on permeability enhancement by hydrophilic cyclodextrins.

Saturated solutions of three test compounds, carbamazepine, griseofulvin and hydrocortisone, were prepared in aqueous buffer (pH 7.4) containing 0, 1, 5 and 10% HPbetaCD. The permeability and flux of the drugs though a PAMPA membrane at different unstirred water layer (UWL) thicknesses was determined. In absence of HPbetaCD, permeability coefficients increased two- to three-fold with decreasing UWL thickness to a certain minimum values of about 40 microm. Addition of HPbetaCD to systems exhibiting larger UWL thicknesses significantly increased compound flux. The effect of HPbetaCD was linked to its association constant (K(1:1)) with the model drugs and decreased with decreasing UWL thickness to a certain minimum value. This suggests that hydrophilic cyclodextrins enhance flux when the UWL resistance significantly contributes to the overall barrier resistance.

Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design.

Assessing the effect of excipients on the ability to attain and maintain supersaturation of drug-based solution may provide useful information for the design of solid formulations. Judicious selection of materials that affect either the extent or stability of supersaturating drug delivery systems may be enabling for poorly soluble drug candidates or other difficult-to-formulate compounds. The technique suggested herein is aimed at providing a screening protocol to allow preliminary assessment of these factors based on small to moderate amounts of drug substance. A series of excipients were selected that may, by various mechanisms, affect supersaturation including pharmaceutical polymers such as HMPC and PVP, surfactants such as Polysorbate 20, Cremophor RH40 and TPGS and hydrophilic cyclodextrins such as HPbetaCD. Using a co-solvent based method and 25 drug candidates, the data suggested, on the whole, that the surfactants and the selected cyclodextrin seemed to best augment the extent of supersaturation but had variable benefits as stabilizers, while the pharmaceutical polymers had useful effect on supersaturation stability but were less helpful in increasing the extent of supersaturation. Using these data, a group of simple solid dosage forms were prepared and tested in the dog for one of the drug candidates. Excipients that gave the best extent and stability for the formed supersaturated solution in the screening assay also gave the highest oral bioavailability in the dog.

Hot stage extrusion of p-amino salicylic acid with EC using CO2 as a temporary plasticizer.

The aim of the current research project was to explore the possibilities of combining pressurized carbon dioxide with hot stage extrusion during manufacturing of solid dispersions of the thermally labile p-aminosalicylic acid (p-ASA) and ethylcellulose 20cps (EC 20cps) and to evaluate the ability of the pressurized gas to act as a temporary plasticizer. The thermal stability of the p-ASA was investigated using DSC, TGA and HPLC. The compound decomposes completely upon melting. Below 110 degrees C and under atmospheric conditions, the compound is thermally stabile for 10min. Pressurized carbon dioxide was injected into a Leistritz Micro 18 intermeshing co-rotating twin-screw melt extruder using an ISCO 260D syringe pump. Carbon dioxide acted as plasticizer for p-ASA/EC 20cps, reducing the processing temperature during the hot stage extrusion process. HPLC showed that without carbon dioxide injection, approximately 17% of p-ASA degraded, while less than 5% degraded with CO(2) injection. The experiments clearly showed that injecting pressurized carbon dioxide broadens the application of hot stage extrusion to thermally labile compounds in a one step process.

Preparation and physicochemical characterization of biodegradable nerve guides containing the nerve growth agent sabeluzole.

The objective of this study was to develop and characterize a biodegradable drug-loaded nerve guide for peripheral nerve regeneration. Sabeluzole, a nerve growth agent, was selected as model compound. Four biodegradable polymers were selected for this study: a copolymer of polylactic acid and polycaprolactone (PCL); a copolymer of polyglycolic acid and polycaprolactone PCL; a copolymer of PCL/polydioxanone (PDO) and PDO. Placebo and drug loaded nerve guides were obtained by melt compression and melt extrusion. It was observed that melt compression and melt extrusion are feasible techniques to prepare the nerve guides. Based on the physicochemical characterization, all samples show absence of crystalline sabeluzole, indicating the formation of an amorphous dispersion. The in vitro release measurements show that the release of sabeluzole is complete, reproducible and can be controlled by the proper selection of the polymer. The release mechanism for all samples follows Fickian release behaviour.

Study of the physicochemical properties and stability of solid dispersions of loperamide and PEG6000 prepared by spray drying.

Solid dispersions of PEG6000 and loperamide-a poorly water-soluble agent-were prepared by spray drying. Their physicochemical properties were evaluated immediately after preparation. The dissolution was higher than that of pure crystalline loperamide. DSC- and XRD-measurements revealed that in the dispersions, loperamide is partially present in the crystalline state. A eutectic state diagram was obtained. The samples containing 20% loperamide were stored under different conditions (40 degrees C and 0% RH, 25 degrees C and 52% RH, 4 degrees C and 0% RH) to investigate their stability as a function of time. The dissolution properties deteriorate upon storage at high temperature (40 degrees C and 0% RH) and in conditions of higher relative humidity (25 degrees C and 52% RH). The DSC-curves clearly indicate an increase in the amount of crystalline compound under these conditions. From these observations it could be concluded that loperamide, which is partially crystalline and partially amorphous in the freshly prepared samples, continues to crystallize under these conditions, resulting in progressively poorer dissolution properties.

Salt formation in solid dispersions consisting of polyacrylic acid as a carrier and three basic model compounds resulting in very high glass transition temperatures and constant dissolution properties upon storage.

The purpose of the study was to investigate the suitability of polyacrylic acid (PAA) as a carrier in solid dispersions, with the aim to delay crystallization of basic drugs and improve their dissolution behaviour. The physicochemical properties were investigated in order to link the physical state of some model compounds to their dissolution properties. Loperamide and two structurally related substances were selected as model compounds. Solid dispersions were prepared by spray drying. The amount of residual solvents and water was determined with gas chromatography (GCS: S: solvent) and thermogravimetric analysis (TGA). The drug loading of the dispersions was determined using high performance liquid chromatography (HPLC). ADSC (alternating or temperature modulated DSC), XRD and FT-IR-spectroscopy were used to evaluate the physical state and in vitro dissolution tests were performed to measure the dissolution properties. IR-measurements demonstrated the formation of a salt between the COOH-groups of the polymer and the amino-groups of the compounds. This phenomenon results in high T(g)-values of the dispersions, suppression of crystallization of the fragment molecules during preparation and an increase of the dissolution rate. Furthermore, the stability study conducted on the dispersions with loperamide showed that both, the amorphous state of the drug and the dissolution behaviour are stable under the applied storage conditions. Hence, from the experimental results it could be concluded that PAA is a suitable carrier in the formulation of stable solid dispersions for the basic compounds that were investigated.

Physical stability of the amorphous state of loperamide and two fragment molecules in solid dispersions with the polymers PVP-K30 and PVP-VA64.

The purpose of the present study was to investigate the impact of intermolecular forces on the stability of the amorphous state of loperamide and two of its fragment molecules (4-dimethylamino-N,N-dimethyl-2,2-diphenyl-butyramide (F1) and 4-(4-chlorophenyl)-4-piperidinol (F2)) in solid dispersions with PVP-K30 and PVP-VA64. The stability of originally homogeneous and amorphous dispersions was investigated under different storage conditions. The chemical stability of the compounds was evaluated with HPLC. TGA-analysis was used in order to assess the amount of water in the samples, whereas MT-DSC-measurements were performed to investigate changes in the physical state of the compounds caused by the storage procedure. TGA-analysis reveals a higher uptake of water in humid conditions of the dispersions with PVP-K30 in comparison to those with PVP-VA64, hereby reflecting the more hydrophilic nature of the former polymer. This water acts as a plasticizing agent resulting in an increased mobility and decreased glass transition temperature. Since the degree of supersaturation and the molecular mobility have an influence on the stability of the amourphous state, both parameters were assessed. With respect to the degree of supersaturation of the compounds in the dispersions, the materials seem to be very much alike. Therefore it was postulated that the induction of crystallization in the F1/polymer dispersions stored at high RH (52%) is due to higher molecular mobility of this compound in the dispersions in comparison to F2. The hydrogen bonds that are being formed between F2 and the polymers reduce its mobility and secure this compound from crystallization upon storage, thus indicating the importance of specific interactions with respect to stability issues of solid dispersions. No hydrogen bonds are formed between F1 and the polymers. As a result, the stability of the amorphous state of the compound is being compromised and crystallization takes place. Loperamide, that also does not form hydrogen bonds with the polymers, is less susceptible to crystallization due to its intrinsic good glass forming properties.

Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion.

The aim of this study was to investigate the performance of three new solid dispersion formulations of itraconazole in human volunteers in comparison with Sporanox, the marketed form. Solid dispersions made up of itraconazole (40%, w/w) and HPMC 2910, Eudragit E100 or a mixture of Eudragit E100-PVPVA64 were manufactured by hot-stage extrusion and filled in gelatin capsules. The formulations were tested in eight human volunteers in a double blind, single dose, and cross-over study. Concentrations of the drug and its metabolite hydroxyitraconazole in the plasma were determined using HPLC. The in vivo performance was evaluated by comparing the mean area under the plasma concentration-time curves (AUC), the mean maximum plasma concentration (C(max)), and the mean time to reach C(max) (T(max)). The mean bioavailability of itraconazole was comparable after administration of the HPMC solid dispersion, compared to Sporanox, while it was lower after administration of the Eudragit E100 or Eudragit E100-PVPVA64 dispersions. Due to high variability, a significant decrease in AUC and C(max) was only observed for the Eudragit E100-PVPVA formulation. Although the solid dispersions showed different in vitro dissolution behaviour, T(max) values were comparable. The same observations with respect to AUC, C(max) and T(max) could be made for hydroxyitraconazole. The present results indicate that hot-stage extrusion can be considered as a valuable alternative for manufacturing solid dispersions of itraconazole.

The effect of pressurized carbon dioxide as a temporary plasticizer and foaming agent on the hot stage extrusion process and extrudate properties of solid dispersions of itraconazole with PVP-VA 64.

The aim of the current research project was to explore the possibilities of combining pressurized carbon dioxide with hot stage extrusion during manufacturing of solid dispersions of itraconazole and polyvinylpyrrolidone-co-vinyl acetate 64 (PVP-VA 64) and to evaluate the ability of the pressurized gas to act as a temporary plasticizer as well as to produce a foamed extrudate. Pressurized carbon dioxide was injected into a Leistritz Micro 18 intermeshing co-rotating twin-screw melt extruder using an ISCO 260D syringe pump. The physicochemical characteristics of the extrudates with and without injection of carbon dioxide were evaluated with reference to the morphology of the solid dispersion and dissolution behaviour and particle properties. Carbon dioxide acted as plasticizer for itraconazole/PVP-VA 64, reducing the processing temperature during the hot stage extrusion process. Amorphous dispersions were obtained and the solid dispersion was not influenced by the carbon dioxide. Release of itraconazole from the solid dispersion could be controlled as a function of processing temperature and pressure. The macroscopic morphology changed to a foam-like structure due to expansion of the carbon dioxide at the extrusion die. This resulted in increased specific surface area, porosity, hygroscopicity and improved milling efficiency.

Forecasting waste compositions: A case study on plastic waste of electronic display housings.

Because of the rapid succession of technological developments, the architecture and material composition of many products used in daily life have drastically changed over the last decades. As a result, well-adjusted recycling technologies need to be developed and installed to cope with these evolutions. This is essential to guarantee continued access to materials and to reduce the ecological impact of our material consumption. However, limited information is currently available on the material composition of arising waste streams and even less on how these waste streams will evolve. Therefore, this paper presents a methodology to forecast trends in the material composition of waste streams. To demonstrate the applicability and value of the proposed methodology, it is applied to forecast the evolution of plastic housing waste from flat panel display (FPD) TVs, FPD monitors, cathode ray tube (CRT) TVs and CRT monitors. The results of the presented forecasts indicate that a wide variety of plastic types and additives, such as flame retardants, are found in housings of similar products. The presented case study demonstrates that the proposed methodology allows the identification of trends in the evolution of the material composition of waste streams. In addition, it is demonstrated that the recycling sector will need to adapt its processes to deal with the increasing complexity of plastics of end-of-life electronic displays while respecting relevant directives.

Incorporation of drugs in an amorphous state into electrospun nanofibers composed of a water-insoluble, nonbiodegradable polymer.

Electrostatic spinning was applied to the preparation of drug-laden nonbiodegradable nanofiber for potential use in topical drug administration and wound healing. The specific aim of these studies was to assess whether these systems might be of interest as delivery systems for poorly water-soluble drugs. Itraconazole and ketanserin were selected as model compounds while a segmented polyurethane (PU) was selected as the nonbiodegradable polymer. For both itraconazole and ketanserin, an amorphous nanodispersion with PU was obtained when the drug/polymer solutions were electrospun from dimethylformide (DMF) and dimethylacetamide (DMAc), respectively. The collected nonwoven fabrics were shown to release the drugs at various rates and profiles based on the nanofiber morphology and drug content. Data were generated using a specially designed release apparatus based around a rotating cylinder. At low drug loading, itraconazole was released from the nanofibers as a linear function of the square root of time suggesting Fickian kinetics. No initial drug burst was observed. A biphasic release pattern was observed for ketanserin in which two sequential linear components were noted. These release phases may be temporally correlated with (1) drug diffusion through the polymer and (2) drug diffusion through formed aqueous pores.

The use of three different solid dispersion formulations--melt extrusion, film-coated beads, and a glass thermoplastic system--to improve the bioavailability of a novel microsomal triglyceride transfer protein inhibitor.

A bioavailable formulation for a water-insoluble microsomal triglyceride transfer protein inhibitor, R103757, was developed using solid dispersion technology. The need for an advanced formulation was tested in the dog by assessing the oral bioavailability of three generic concepts: a tablet (crystalline drug), a capsule (film-coated beads), and an oral solution. These screening studies steered further development in the direction of a solid dispersion. Three solid dispersion platforms were assessed: melt extrusion, film-coated beads, and a glass thermoplastic system. Thermal and spectrophotometric analysis revealed that no crystalline drug was present in any of the formulations. The dissolution profiles of the three dispersion systems showed that release was improved compared with the unmanipulated drug. In addition, stability studies confirmed the physical and chemical integrity of the formulation. A human clinical trial was performed to assess the pharmacokinetics of the three amorphous dispersions. Plasma levels were obtained after single oral administration in both the fasting and fed state. The study indicated that all three approaches improved the bioavailability of R103757 with the glass thermoplastic system providing the best performance. These studies point to the potential usefulness of solid dispersion approaches and expand the possible number of ways to implement these methodologies.

Characterization of the interaction of 2-hydroxypropyl-beta-cyclodextrin with itraconazole at pH 2, 4, and 7.

Phase-solubility techniques were used to assess the effect of pH on itraconazole complexation with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). In addition, molecular modeling using beta-cyclodextrin as a surrogate for HPbetaCD was completed. Data suggested A(p)-type solubility relationships, indicating higher order complexation at higher HPbetaCD concentrations. Stability constants were derived from the solubility isotherms using a simplex optimization procedure. At pH 2 (2 units below the pK(a4)), a 1:2 complex formation was observed, whereas at pH 4 (i.e., the pK(a4) for itraconazole) and at pH 7, 1:3 complexation occurred. The lower order of complexation observed at lower pH may be related to substructure protonation which reduced HPbetaCD interaction. Molecular mechanics also suggest 1:3 complex formation for the neutral species, indicating that possible interaction sites may include (in order of binding) triazole > 1,4-diaminophenyl > 2-butyl approximate, equals piperazine.