Effect of surface coating with magnesium stearate via mechanical dry powder coating approach on the aerosol performance of micronized drug powders from dry powder inhalers.

The objective of this study was to investigate the effect of particle surface coating with magnesium stearate on the aerosolization of dry powder inhaler formulations. Micronized salbutamol sulphate as a model drug was dry coated with magnesium stearate using a mechanofusion technique. The coating quality was characterized by X-ray photoelectron spectroscopy. Powder bulk and flow properties were assessed by bulk densities and shear cell measurements. The aerosol performance was studied by laser diffraction and supported by a twin-stage impinger. High degrees of coating coverage were achieved after mechanofusion, as measured by X-ray photoelectron spectroscopy. Concomitant significant increases occurred in powder bulk densities and in aerosol performance after coating. The apparent optimum performance corresponded with using 2% w/w magnesium stearate. In contrast, traditional blending resulted in no significant changes in either bulk or aerosolization behaviour compared to the untreated sample. It is believed that conventional low-shear blending provides insufficient energy levels to expose host micronized particle surfaces from agglomerates and to distribute guest coating material effectively for coating. A simple ultra-high-shear mechanical dry powder coating step was shown as highly effective in producing ultra-thin coatings on micronized powders and to substantially improve the powder aerosolization efficiency.

Understanding the interfacial properties of nanostructured liquid crystalline materials for surface-specific delivery applications.

Nonlamellar liquid crystalline dispersions such as cubosomes and hexosomes have great potential as novel surface-targeted active delivery systems. In this study, the influence of internal nanostructure, chemical composition, and the presence of Pluronic F127 as a stabilizer, on the surface and interfacial properties of different liquid crystalline particles and surfaces, was investigated. The interfacial properties of the bulk liquid crystalline systems with coexisting excess water were dependent on the internal liquid crystalline nanostructure. In particular, the surfaces of the inverse cubic systems were more hydrophilic than that of the inverse hexagonal phase. The interaction between F127 and the bulk liquid crystalline systems depended on the internal liquid crystalline structure and chemical composition. For example, F127 adsorbed to the surface of the bulk phytantriol cubic phase, while for monoolein cubic phase, F127 was integrated into the liquid crystalline structure. Last, the interfacial adsorption behavior of the dispersed liquid crystalline particles also depended on both the internal nanostructure and the chemical composition, despite the dispersions all being stabilized using F127. The findings highlight the need to understand the specific surface characteristics and the nature of the interaction with colloidal stabilizer for understanding and optimizing the behavior of nonlamellar liquid crystalline systems in surface delivery applications.

Powder strength distributions for understanding de-agglomeration of lactose powders.

PURPOSE: The purpose was to calculate distributions of powder strength of a cohesive bed to explain the de-agglomeration of lactose. METHODS: De-agglomeration profiles of Lactohale 300(®) (L300) and micronized lactose (ML) were constructed by particle sizing aerosolised plumes dispersed at air flow rates of 30-180 l/min. The work of cohesion distribution was determined by inverse gas chromatography. The primary particle size and tapped density distributions were determined. Powder strength distributions were calculated by Monte Carlo simulations from distributions of particle size, work of cohesion and tapped density measurements. RESULTS: The powder strength distribution of L300 was broader than that of ML. Up to 85th percentile, powder strength of L300 was lower than ML which was consistent with the better de-agglomeration of L300 at low flow rates. However, ~15% of L300 particles had higher powder strength than ML which likely to cause lower de-agglomeration for L300 at high air flow rates. CONCLUSION: Cohesive lactose powders formed matrices of non-homogenous powder strength. De-agglomeration of cohesive powders has been shown to be related to powder strength. This study provided new insights into powder de-agglomeration by a new approach for calculating powder strength distributions to better understand complex de-agglomeration behaviour.

Different surface charge of colistin-susceptible and -resistant Acinetobacter baumannii cells measured with zeta potential as a function of growth phase and colistin treatment.

OBJECTIVES: electrostatic forces mediate the initial interaction between cationic colistin and Gram-negative bacterial cells. Lipopolysaccharide (LPS) loss mediates colistin resistance in some A. baumannii strains. Our aim was to determine the surface charge of colistin-susceptible and -resistant A. baumannii as a function of growth phase and in response to polymyxin treatment. METHODS: the zeta potential of A. baumannii ATCC 19606 and 10 clinical multidrug-resistant strains (MICs 0.5-2 mg/L) was assessed. Colistin-resistant derivatives (MIC >128 mg/L) of wild-type strains were selected in the presence of 10 mg/L colistin, including the LPS-deficient lpxA mutant, ATCC 19606R. To determine the contribution of LPS to surface charge, two complemented ATCC 19606R derivatives were examined, namely ATCC 19606R + lpxA (containing an intact lpxA gene) and ATCC 19606R + V (containing empty vector). Investigations were conducted as a function of growth phase and polymyxin treatment (1, 4 and 8 mg/L). RESULTS: wild-type cells exhibited a greater negative charge (-60.5  ±â€Š 2.36 to -26.2  ±â€Š 2.56 mV) thancolistin-resistant cells (-49.2  ±â€Š 3.09 to -19.1  ±  2.80 mV) at mid-log phase (ANOVA, P  <  0.05). Opposing growth-phase trends were observed for both phenotypes: wild-type cells displayed reduced negative charge and colistin-resistant cells displayed increased negative charge at stationary compared with mid-logarithmic phase. Polymyxin exposure resulted in a concentration-dependent increase in zeta potential. Examination of ATCC 19606R and complemented strains supported the importance of LPS in determining surface charge, suggesting a potential mechanism of colistin resistance. CONCLUSIONS: zeta potential differences between A. baumannii phenotypes probably reflect compositional outer-membrane variations that impact the electrostatic component of colistin activity.

Design, synthesis, and evaluation of a new fluorescent probe for measuring polymyxin-lipopolysaccharide binding interactions.

Fluorescence assays employing semisynthetic or commercial dansyl-polymyxin B have been widely employed to assess the affinity of polycations, including polymyxins, for bacterial cells and lipopolysaccharide (LPS). The five primary γ-amines on diaminobutyric acid residues of polymyxin B are potentially derivatized with dansyl-chloride. Mass spectrometric analysis of the commercial product revealed a complex mixture of di- or tetra-dansyl-substituted polymyxin B. We synthesized a mono-substituted fluorescent derivative, dansyl[Lys]¹polymyxin B3. The affinity of polymyxin for purified gram-negative LPS and whole bacterial cells was investigated. The affinity of dansyl[Lys]¹polymyxin B3 for LPS was comparable to polymyxin B and colistin, and considerably greater (K(d)<1 µM) than for whole cells (K(d)∼6-12µM). Isothermal titration calorimetric studies demonstrated exothermic enthalpically driven binding between both polymyxin B and dansyl[Lys]¹polymyxin B3 to LPS, attributed to electrostatic interactions. The hydrophobic dansyl moiety imparted a greater entropic contribution to the dansyl[Lys]¹polymyxin B3-LPS reaction. Molecular modeling revealed a loss of electrostatic contact within the dansyl[Lys]¹polymyxin B3-LPS complex due to steric hindrance from the dansyl[Lys]¹ fluorophore; this corresponded with diminished antibacterial activity (MIC≥16µg/mL). Dansyl[Lys]¹polymyxin B3 may prove useful as a screening tool for drug development.

Determination of the polar and total surface energy distributions of particulates by inverse gas chromatography.

This Letter reports a technique of measuring polar surface energy distributions of lactose using inverse gas chromatography (IGC). The significance of this study is that the total surface energy distributions can now be characterized by combining the already known dispersive surface energy distribution with polar surface energy distribution determined in this study. The polar surface energy was calculated from the specific free energies for surface interactions with a monopolar basic probe, ethyl acetate, and a monopolar acidic probe, dichloromethane.

Assessment of plasma concentrations of (-)-epigallocatechin gallate in mice following administration of a dose reflecting consumption of a standard green tea beverage.

The plasma exposure of (-)-epigallocatechin gallate (EGCg) is typically assessed following administration of EGCg at doses equivalent to the consumption of at least 10 cups of green tea in one sitting. This study determines the plasma concentrations of EGCg in mice following administration of a dose reflecting typical consumption of one standard green tea beverage. Swiss Outbred mice were orally administered 0.76mg/kg EGCg, and using a validated HPLC method, the Cmax of un-conjugated and total EGCg was determined to be 31.5±3.3 and 34.3±2.0nM, respectively (mean±s.d., n=3-5). The area under the plasma concentration versus time curve for un-conjugated and total EGCg was 114.3±4.1 and 116.4±4.1nM·h, respectively (mean±s.d., n=3-5). To minimise potential ex vivo plasma degradation, a novel stabilizing solution of 20mM ascorbic acid (AA) and 13mM tris[2-carboxyethyl]phosphine hydrochloride (TCEP) was employed. Comparative evaluation of the efficacy of the 20mM AA and 13mM TCEP stabilizing solution to the commonly used stabilizing solution of 114mM AA and 0.13mM Na2EDTA, indicated that the AA/TCEP solution provided significantly greater (p<0.05) protection to EGCg than the AA/Na2EDTA stabilizing solution. Overall, this study demonstrates that plasma concentrations of EGCg are in the low nM range following oral administration to mice at a dose reflecting the consumption of a standard green tea beverage. In addition, a novel stabilizing solution has been identified which may be useful in stabilizing plasma samples obtained from pharmacokinetic studies.

Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization.

Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and potentially circumvent the associated toxicity. Roflumilast was cospray-dried with trehalose and L-leucine with varied feed concentrations and spray-gas flow rates to produce the desired dry powder. A Next-Generation Impactor (NGI) was used to assess the aerosolization efficiency. In addition, different devices (Aerolizer, Rotahaler, and Handihaler) and flow rates were used to investigate their effects on the aerosolization efficiency. A cytotoxicity assay was also performed. The powders produced under optimized conditions were partially amorphous and had low moisture content. The powders showed good dispersibility, as evident by the high emitted dose (>88%) and fine particle fraction (>52%). At all flow rates (≥30 L/min), the Aerolizer offered the best aerosolization. The formulation exhibited stable aerosolization after storage at 25 °C/15% Relative Humidity (RH) for one month. Moreover, the formulation was non-toxic to alveolar basal epithelial cells. A potential inhalable roflumilast formulation including L-leucine and trehalose has been developed for the treatment of COPD. This study also suggests that the choice of device is crucial to achieve the desired aerosol performance.

Development of a Vertically Integrated Pharmacy Degree.

Whilst curriculum revision is commonplace, whole degree transformation is less so. In this paper we discuss the rationale, design and implementation of a unique pharmacy program by a research-intensive faculty. The new Monash pharmacy curriculum, which had its first intake in 2017, was built using a range of key innovations that aimed to produce graduates that demonstrate key conceptual understanding and all the skills required to deliver world-best patient outcomes. The key elements of the re-design are outlined and include the process and principles developed, as well as key features such as a student-centred individualised program of development arranged around specific, authentic tasks for each skill and earlier enhanced experiential placements where students become proficient in entrustable professional activities. It is hoped the dissemination of this process, as well as the lessons learnt in the process, will be useful to others looking to transform a health curriculum.

Nonequilibrium effects in self-assembled mesophase materials: unexpected supercooling effects for cubosomes and hexosomes.

Polar lipids often exhibit equilibrium liquid crystalline structures in excess water, such as the bicontinuous cubic phases (Q(II)) at low temperatures and inverse hexagonal phase (H(II)) at higher temperatures. In this study, the equilibrium and nonequilibrium phase behavior of glyceryl monooleate (GMO) and phytantriol (PHYT) systems in excess water were investigated using both continuous heating and cooling cycles, and rapid temperature changes. Evolution of the phase structure was followed using small-angle X-ray scattering (SAXS). During cooling, not only was supercooling of the liquid crystalline systems by up to 25 degrees C observed, but evidence for nonequilibrium phase structures (not present on heating; such as the gyroid cubic phase only present at low water content in equilibrium) was also apparent. The nonequilibrium phases were surprisingly stable, with return to equilibrium structure for dispersed submicrometer sized particle systems taking more than 13 h in some cases. Inhibition of phase nucleation was the key to greater supercooling effects observed for the dispersed particles compared to the bulk systems. These findings highlight the need for continued study into the nonequilibrium phase structures for these types of systems, as this may influence performance in applications such as drug delivery.

Atomic force microscopy investigation of the morphology and topography of colistin-heteroresistant Acinetobacter baumannii strains as a function of growth phase and in response to colistin treatment.

The prevalence of infections caused by multidrug-resistant gram-negative Acinetobacter baumannii strains and the lack of novel antibiotics under development are posing a global dilemma, forcing a resurgence of the last-line antibiotic colistin. Our aim was to use atomic force microscopy (AFM) to investigate the morphology and topography of paired colistin-susceptible and -resistant cells from colistin-heteroresistant A. baumannii strains as a function of bacterial growth phase and colistin exposure. An optimal AFM bacterial sample preparation protocol was established and applied to examine three paired strains. Images revealed rod-shaped colistin-susceptible cells (1.65 +/- 0.27 microm by 0.98 +/- 0.07 microm) at mid-logarithmic phase, in contrast to spherical colistin-resistant cells (1.03 +/- 0.09 microm); the latter were also more diverse in appearance and exhibited a rougher surface topography (7.05 +/- 1.3 nm versus 11.4 +/- 2.5 nm for susceptible versus resistant, respectively). Cellular elongation up to approximately 18 microm at stationary phase was more commonly observed in susceptible strains, although these "worm-like" cells were also observed occasionally in the resistant population. The effects of colistin exposure on the cell surface of colistin-susceptible and -resistant cells were found to be similar; topographical changes were minor in response to 0.5 microg/ml colistin; however, at 4 microg/ml colistin, a significant degree of surface disruption was detected. At 32 microg/ml colistin, cellular clumping and surface smoothening were evident. Our study has demonstrated for the first time substantial morphological and topographical differences between colistin-susceptible and -resistant cells from heteroresistant A. baumannii strains. These results contribute to an understanding of colistin action and resistance in regard to this problematic pathogen.

Structured Multi-Stakeholder Workshops to Advance a Global Transformative Roadmap for Pharmaceutical Workforce.

In November 2016, the International Pharmaceutical Federation (FIP) endeavored to create an environment to foster a shared vision to lead a transformative pharmaceutical workforce roadmap. Three milestone documents were developed and presented at the Global Conference on Pharmacy and Pharmaceutical Education. Workshops with the key themes and connecting Pharmaceutical Workforce Development Goals (PWDG) were conducted and analyzed. This Note serves to summarize the key aspects of these workshops, reporting on the innovative approaches used to generate guidance for stakeholders regarding implementation. INNOVATION: Seven workshops with a uniform structure were developed. These were designed to improve communication, harmonise outcome-generation, and allow for aggregate analysis. A team of seven conducted each workshop, each team consisted of: a Chair, a facilitator, one rapporteur, and four speakers purposively selected from FIP member organisations and other key stakeholders with expertise for sharing a variety of perspectives. Guidelines and templates were developed for all roles and each team was briefed in advance. KEY FINDINGS: Approximately 200 personnel participated in the seven workshops, with around 20 country representatives per workshop, covering all six World Health Organisation regions. Three key aspects of workforce transformation, using the PWDGs, were explored in each workshop: drivers for implementation; challenges to implementation; and ways of encouraging implementation. Drivers for implementation mentioned were enhancing collaboration and engagement. Challenges to implementation were identified as variance in terminology. Several ways of encouraging implementation were acknowledged, such as communication strategies, advocating for workforce development and sharing best practices to foster partnerships. NEXT STEPS: The unique format of the workshops, the innovative approach to include stakeholders across an array of settings and the parallel structure in all the seven workshops, aided in creating reliable findings. The achievability of the PWDGs depends on several factors. Engagement with stakeholders and engagement from and between professional associations are important factors to achieving workforce development goals.

Impact of a Virtual Dementia Experience on Medical and Pharmacy Students' Knowledge and Attitudes Toward People with Dementia: A Controlled Study.

BACKGROUND: Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals' attitudes and knowledge toward people with dementia. OBJECTIVE: Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students' knowledge and attitudes toward people with dementia. METHODS: A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention. RESULTS: A total of 278 students (n = 64 medical, n = 214 pharmacy) were analyzed (n = 80 intervention, n = 198 control). The majority of students were female (n = 184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p < 0.001). CONCLUSION: The intervention had a positive impact on medical and pharmacy students' knowledge and attitudes toward people with dementia.

Adhesion and redistribution of salmeterol xinafoate particles in sugar-based mixtures for inhalation.

The aim of this study was to evaluate coarse and fine sugars as potential alternative excipients in dry powder inhalation formulations and to develop a greater understanding of the key interactions between the particulate species in these mixtures. Interactive mixtures composed of salmeterol xinafoate (SX) and different type of sugars (lactose, glucose, mannitol and sorbitol) were prepared using validated laboratory scale mixing. The sugars and SX were characterised by laser diffraction, scanning electron microscopy, atomic force microscopy and loss on drying method. Deposition of SX was measured using a twin-stage impinger and analysed using validated HPLC method (r(2)=1.0, CV=0.4-1.0%). Good correlation existed between the fine particle fraction (FPF) of SX and both the adhesion force and the moisture content. The addition of 10% fine sugars to produce ternary mixtures (i.e. SX, coarse and fine sugars) generally increased dispersion, with the addition of fine glucose>fine mannitol>fine lactose>fine sorbitol. The dispersion of SX showed a reciprocal relationship with the moisture content of the sugars with glucose showing the greatest and sorbitol showing the lowest extent of SX dispersion. The study clearly demonstrated that strong SX adhesion to coarse sugars reduced the extent of dispersion and that surface detachment of the SX and fine sugar from the coarse sugar carrier was important in the dispersion process.

Strategies to analyse data obtained from liquid intrusion experiments of loose porous materials.

Liquid intrusion remains one of the most common methods to measure the contact angle of liquids to powders. However, as there are two unknown variables in the Washburn equation: the material constant (that is, the pore structure of the powder bed) and the contact angle of the liquid to the powder, this method requires the use of two liquids-a liquid of interest (the probe liquid) and a reference liquid. The reference liquid should, ideally, make a contact angle of 0° to the sample. However, in practice a low surface tension liquid is normally selected. This paper proposes a more standardised approach for the selection of the reference liquid based on experimental data. Additionally, a major assumption of the liquid intrusion method is that the pore structure, as measured by the material constant, C, is identical for all powder beds (provided that the same packing procedure is used for the same samples). In real systems, however, this is an approximation, and not likely to hold strictly true. Therefore, difficulties may arise with data analysis as there is a potential uncertainty in the most appropriate order to divide the gradient of the probe liquid by the gradient of the reference liquid. This paper proposes three specific methods of analysing such data, each with their own advantages and limitations. Hence, the selection of which method should be used is criteria-based, assessed on the basis of the obtained data.

Student Engagement with a Flipped Classroom Teaching Design Affects Pharmacology Examination Performance in a Manner Dependent on Question Type.

Objective: To investigate the relationship between student engagement with the key elements of a flipped classroom approach (preparation and attendance), their attitudes to learning, including strategy development, and their performance on two types of examination questions (knowledge recall and providing rational predictions when faced with novel scenarios). Methods. This study correlated student engagement with the flipped classroom and student disposition to learning with student ability to solve novel scenarios in examinations. Results. Students who both prepared for and attended classes performed significantly better on examination questions that required analysis of novel scenarios compared to students who did not prepare and missed classes. However, there was no difference for both groups of students on examination questions that required knowledge and comprehension. Student motivation and use of strategies correlated with higher examination scores on questions requiring novel scenario analysis. Conclusion. There is a synergistic relationship between class preparation and attendance. The combination of preparation and attendance was positively correlated to assessment type; the relationship was apparent for questions requiring students to solve novel problems but not for questions requiring knowledge or comprehension.

Effect of the deformability of guest particles on the tensile strength of tablets from interactive mixtures.

In this study, we investigated the influence of deformability of specifically-engineered guest particles on the tensile strength of tablets of interactive mixtures. The binder polyvinylpyrrolidone (PVP) of different molecular weights were spray dried with l-leucine to create guest particle formulations. The guest particle formulations were characterized by their particle size, surface l-leucine concentration and glass transition temperature (Tg). These spray-dried particles were then blended with paracetamol to form interactive mixtures, which were compacted into tablets and tablet tensile strength and elastic recovery were determined. The guest particles had particle diameters in the range of 1-10µm, and surfaces that were l-leucine enriched. The Tg of guest particle formulations increased with increasing molecular weight of the PVP. All the guest particle formulations formed an observed homogeneous interactive mixture with paracetamol. The tensile strength of the tablets of interactive mixtures increased with decreasing Tg of the guest particles. In these interactive mixtures, higher tensile strength was also associated with lower tablet elastic recovery. The elastic recovery of the tablets showed a correlation with the elastic recovery of the tablets of guest particles. Thus, our results indicated that the deformability of guest particles dictates the tensile strength of the tablets of these interactive mixtures.

Enabling Noninvasive Systemic Delivery of the Kv1.3-Blocking Peptide HsTX1[R14A] via the Buccal Mucosa.

The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, a well-recognized therapeutic target for autoimmune diseases. To overcome the poor oral absorption and consequent need for regular injections, the potential of the buccal mucosa for systemic delivery of HsTX1[R14A] was investigated. For in vitro studies, FITC-HsTX1[R14A] and HsTX1[R14A], in solution or formulated in a mucoadhesive chitosan-based gel (3%, w/v) with or without cetrimide (5%, w/w), were applied to porcine buccal epithelium mounted between Ussing chambers and buccal mucosal permeation assessed. HsTX1[R14A] was also administered to Swiss outbred mice at a dose of 10 mg/kg in the same formulations. In vitro, administration of FITC-HsTX1[R14A] and HsTX1[R14A] in the chitosan gel containing cetrimide resulted in detectable buccal permeation with 0.75% and 0.58%, respectively, of the applied dose appearing in the receptor chamber over 5 h. After buccal administration to mice, HsTX1[R14A] was detected in plasma, with the presence of cetrimide in the gel further enhancing plasma exposure, with area under the plasma concentration-time curve values of 77.9 ± 9.7 and 31.0 ± 2.3 nM·h, respectively. The buccal mucosa is a promising alternative administration route for the systemic delivery of HsTX1[R14A] for the treatment of autoimmune diseases.

Relationship between the cohesion of guest particles on the flow behaviour of interactive mixtures.

In this study, we aimed to investigate the effects cohesion of small surface-engineered guest binder particles on the flow behaviour of interactive mixtures. Polyvinylpyrrolidone (PVP) - a model pharmaceutical binder - was spray-dried with varying l-leucine feed concentrations to create small surface-engineered binder particles with varying cohesion. These spray-dried formulations were characterised by their particle size distribution, morphology and cohesion. Interactive mixtures were produced by blending these spray-dried formulations with paracetamol. The resultant blends were visualised under scanning electron microscope to confirm formation of interactive mixtures. Surface coverage of paracetamol by guest particles as well as the flow behaviour of these mixtures were examined. The flow performance of interactive mixtures was evaluated using measurements of conditioned bulk density, basic flowability energy, aeration energy and compressibility. With higher feed l-leucine concentrations, the surface roughness of small binder particles increased, while their cohesion decreased. Visual inspection of the SEM images of the blends indicated that the guest particles adhered to the surface of paracetamol resulting in effective formation of interactive mixtures. These images also showed that the low-cohesion guest particles were better de-agglomerated that consequently formed a more homogeneous interactive mixture with paracetamol compared with high-cohesion formulations. The flow performance of interactive mixtures changed as a function of the cohesion of the guest particles. Interactive mixtures with low-cohesion guest binder particles showed notably improved bulk flow performance compared with those containing high-cohesion guest binder particles. Thus, our study suggests that the cohesion of guest particles dictates the flow performance of interactive mixtures.