Developing Dry Powder Inhaler Formulations.

This section aims to provide a concise and contemporary technical perspective and reference resource covering dry powder inhaler (DPI) formulations. While DPI products are currently the leading inhaled products in terms of sales value, a number of confounding perspectives are presented to illustrate why they are considered surprisingly, and often frustratingly, poorly understood on a fundamental scientific level, and most challenging to design from first principles. At the core of this issue is the immense complexity of fine cohesive powder systems. This review emphasizes that the difficulty of successful DPI product development should not be underestimated and is best achieved with a well-coordinated team who respect the challenges and who work in parallel on device and formulation and with an appreciation of the handling environment faced by the patient. The general different DPI formulation types, which have evolved to address the challenges of aerosolizing fine cohesive drug-containing particles to create consistent and effective DPI products, are described. This section reviews the range of particle engineering processes that may produce micron-sized drug-containing particles and their subsequent assembly as either carrier-based or carrier-free compositions. The creation of such formulations is then discussed in the context of the material, bulk, interfacial and ultimately drug-delivery properties that are considered to affect formulation performance. A brief conclusion then considers the future DPI product choices, notably the issue of technology versus affordability in the evolving inhaler market.

Scale resolving simulations of the effect of glottis motion and the laryngeal jet on flow dynamics during respiration.

BACKGROUND AND OBJECTIVE: The movement of the respiratory walls has a significant impact on airflow through the respiratory tract. The majority of computational fluid dynamics (CFD) studies assume a static geometry which may not provide a realistic flow field. Furthermore, many studies use Reynolds Averaged Navier-Stokes (RANS) turbulence models that do not resolve turbulence structure. Combining the application of advanced scale-resolving turbulence models with moving respiratory walls using CFD will provide detailed insights into respiratory flow structures. METHODS: This study simulated a complete breathing cycle involving inhalation and exhalation in a nasal cavity to trachea geometry that incorporated moving glottis walls. A second breathing cycle was simulated with static glottis walls for comparison. A recently developed hybrid RANS-LES turbulence model, the Stress-Blended Eddy Simulation (SBES), was incorporated to resolve turbulent flow structures in fine detail for both transient simulations. Transient results were compared with steady-state RANS simulations for the same respiratory geometry. RESULTS: Glottis motion caused substantial effects on flow structure through the complete breathing cycle. Significant flow structure and velocity variations were observed due to glottal motion, primarily in the larynx and trachea. Resolved turbulence structures using SBES showed an intense mixing section in the glottis region during inhalation and in the nasopharynx during expiration, which was not present in the RANS simulations. CONCLUSION: Transient simulations of a realistic breathing cycle uncovered flow structures absent in simulations with a constant flow rate. Furthermore, the incorporation of glottis motion impacted airflow characteristics that suggest rigid respiratory walls do not accurately describe respiratory flow. Future research in respiratory airflow should be conducted using transient scale-resolving models in conjunction with moving respiratory walls to capture flow structures in detail.

The perfect storm: temporal analysis of air during the world's most deadly epidemic thunderstorm asthma (ETSA) event in Melbourne.

BACKGROUND: There have been 26 epidemic thunderstorm asthma (ETSA) events worldwide, with Melbourne at the epicentre of ETSA with 7 recorded events, and in 2016 experienced the deadliest ETSA event ever recorded. Health services and emergency departments were overwhelmed with thousands requiring medical care for acute asthma and 10 people died. OBJECTIVES: This multidisciplinary study was conducted across various health and science departments with the aim of improving our collective understanding of the mechanism behind ETSA. DESIGN: This study involved time-resolved analysis of atmospheric sampling of the air for pollen and fungal spores, and intact and ruptured pollen compared with different weather parameters, pollution levels and clinical asthma presentations. METHODS: Time-resolved pollen and fungal spore data collected by Deakin AirWATCH Burwood, underwent 3-h analysis, to better reflect the 'before', 'during' and 'after' ETSA time points, on the days leading up to and following the Melbourne 2016 event. Linear correlations were conducted with atmospheric pollution data provided by the Environment Protection Authority (EPA) of Victoria, weather data sourced from Bureau of Meteorology (BOM) and clinical asthma presentation data from the Victorian Agency for Health Information (VAHI) of Department of Health. RESULTS: Counts of ruptured grass pollen grains increased 250% when the thunderstorm outflow reached Burwood. Increased PM10, high relative humidity, decreased temperature and low ozone concentrations observed in the storm outflow were correlated with increased levels of ruptured grass pollen. In particular, high ozone levels observed 6 h prior to this ETSA event may be a critical early indicator of impending ETSA event, since high ozone levels have been linked to increasing pollen allergen content and reducing pollen integrity, which may in turn contribute to enhanced pollen rupture. CONCLUSION: The findings presented in this article highlight the importance of including ruptured pollen and time-resolved analysis to forecast ETSA events and thus save lives.

Bulk Flow Optimisation of Amorphous Solid Dispersion Excipient Powders through Surface Modification.

Particulate amorphous solid dispersions (ASDs) have been recognised for their potential to enhance the performance of various solid dose forms, especially oral bioavailability and macromolecule stability. However, the inherent nature of spray-dried ASDs leads to their surface cohesion/adhesion, including hygroscopicity, which hinders their bulk flow and affects their utility and viability in terms of powder production, processing, and function. This study explores the effectiveness of L-leucine (L-leu) coprocessing in modifying the particle surface of ASD-forming materials. Various contrasting prototype coprocessed ASD excipients from both the food and pharmaceutical industries were examined for their effective coformulation with L-leu. The model/prototype materials included maltodextrin, polyvinylpyrrolidone (PVP K10 and K90), trehalose, gum arabic, and hydroxypropyl methylcellulose (HPMC E5LV and K100M). The spray-drying conditions were set such that the particle size difference was minimised, so that it did not play a substantial role in influencing powder cohesion. Scanning electron microscopy was used to evaluate the morphology of each formulation. A combination of previously reported morphological progression typical of L-leu surface modification and previously unreported physical characteristics was observed. The bulk characteristics of these powders were assessed using a powder rheometer to evaluate their flowability under confined and unconfined stresses, flow rate sensitivities, and compactability. The data showed a general improvement in maltodextrin, PVP K10, trehalose and gum arabic flowability measures as L-leu concentrations increased. In contrast, PVP K90 and HPMC formulations experienced unique challenges that provided insight into the mechanistic behaviour of L-leu. Therefore, this study recommends further investigations into the interplay between L-leu and the physico-chemical properties of coformulated excipients in future amorphous powder design. This also revealed the need to enhance bulk characterisation tools to unpack the multifactorial impact of L-leu surface modification.

Highlighting DEM's Potential to Gauge Mechanistic Attributes of MUPS Tablet and Capsule Formulations.

Simulation of pharmaceutical unit operations by the discrete element method (DEM) has elevated our understanding of the impact of single-particle interactions on themselves, and on the entire tablets/powder. Studies in the past have shown how this knowledge helps to mitigate/solve multiple challenges during conventional formulation and process development/modernization/troubleshooting, with minimal use of active drug material. This communication adds to this- highlighting the tool's potential for a rapid preliminary assessment of the mechanistic attributes of multiple unit particle system (MUPS) based tablet and capsule drug products.

To Protect and to Preserve: Novel Preservation Strategies for Extracellular Vesicles.

Extracellular vesicles (EVs)-based therapeutics are based on the premise that EVs shed by stem cells exert similar therapeutic effects and these have been proposed as an alternative to cell therapies. EV-mediated delivery is an effective and efficient system of cell-to-cell communication which can confer therapeutic benefits to their target cells. EVs have been shown to promote tissue repair and regeneration in various animal models such as, wound healing, cardiac ischemia, diabetes, lung fibrosis, kidney injury, and many others. Given the unique attributes of EVs, considerable thought must be given to the preservation, formulation and cold chain strategies in order to effectively translate exciting preclinical observations to clinical and commercial success. This review summarizes current understanding around EV preservation, challenges in maintaining EV quality, and also bioengineering advances aimed at enhancing the long-term stability of EVs.

The effect of mechanical dry coating with magnesium stearate on flowability and compactibility of plastically deforming microcrystalline cellulose powders.

Mechanofusion is a dry coating method that can be used to improve the flowability of cohesive powder by coating host particles with a lubricant, for example magnesium stearate (MgSt). It has been shown previously that fragmenting material can under some circumstances be mechanofused with MgSt without impairing compactibility of the powder and without reducing the dissolution rate of the resulting tablets. However, the effects on material with viscoelastic behaviour, known to be sensitive for the negative effects of MgSt, is not known. Therefore, mechanofusion of microcrystalline cellulose (MCC) with MgSt was investigated in this study. Four MCC grades were mechanofused with different MgSt concentrations and process parameters, and the resulting flowability and compactibility were studied. Starting materials and low-shear blended binary mixtures were studied as a reference. Mechanofusion improved the flow properties of small particle size MCC powders (d50 < 78 µm) substantially, but increasing the MgSt content consequently resulted in weaker tablets. Larger particle size MCC grades, however, fractured under the shear forces during the mechanofusion process and hence their flow properties were decreased. Improvement of the flow properties but also the negative effects on compactibility of small particle size grades were observed even at relatively mild mechanofusion parameters and low lubricant concentrations.

Single-step Coprocessing of Cohesive Powder via Mechanical Dry Coating for Direct Tablet Compression.

This study aims at testing the feasibility of a single-step coating process to produce a powder formulation of active and inactive ingredients for direct compression. A cohesive ibuprofen powder was coprocessed with a coating material, a binder (polyvinylpyrrolidone K25), and a superdisintegrant (crospovidone). Magnesium stearate (MgSt), l-leucine, and silica were selected as coating materials (1% w/w). A coprocessed powder without any coating material was employed as a control. Coating with MgSt, l-leucine, or silica produced significantly improved powder flow in comparison to the control batch. Robust tablets were produced from the processed powders for each coating material. The tablets compacted using the coated powders with MgSt or l-leucine also exhibited significantly lower tablet ejection forces than the control batch, demonstrating their lubrication effect. Furthermore, the disintegration time and dissolution rates of these tablets made of the formulations coprocessed with lubricants were enhanced, even for those coated with the hydrophobic material such as MgSt that has been previously reported to inhibit dissolution. However, the tablets made with silica-coated powders would not disintegrate. This study indicated the feasibility of a single-step dry coating process to produce powders with both flow-aid and lubrication effects, which are suitable for direct compression.

Applying surface energy derived cohesive-adhesive balance model in predicting the mixing, flow and compaction behaviour of interactive mixtures.

OBJECTIVE: In this study, we investigated the applicability of cohesive-adhesive balance (CAB) model to predict the interactive mixing behaviour of small excipient particles. Further, we also investigated the application of this CAB model to predict the flow and compactibility of resultant blends. METHODS: Excipients created by co-spraying polyvinylpyrrolidone (PVP, a model pharmaceutical binder) with various l-leucine concentrations were used for this study. Paracetamol was used as model active pharmaceutical ingredient (API). The surface energy was used to derive the work of cohesion (wco) and work of adhesion (wad) to predict the interactive mixing behaviour of the excipients with paracetamol. The blends were visualised under a scanning electron microscopy microscope to assess the interactive mixing behaviour. In addition, the flow performance and tabletting behaviour of various blends were characterised. RESULTS: The surface-energy derived work of adhesion (wad) between excipient and paracetamol particles increased, while the corresponding work of cohesion (wco) between excipient particles decreased, with increasing l-leucine concentrations. In blends for which the work of cohesion was higher than the work of adhesion (wco>wad), small excipient particles were apparent as agglomerates. For excipients with 5% and higher l-leucine concentrations, the work of adhesion between excipient and paracetamol particles was higher than or equivalent to the work of cohesion between excipient particles (wad⩾wco) and agglomerates were less apparent. This is an indicator of formation of homogeneous interactive mixtures. At 5% (w/w) excipient proportions, blends for which wad⩾wco demonstrated higher compactibility than other blends. Furthermore, at 10% (w/w) and higher excipient proportions, these blends also demonstrated better flow performance than other blends. CONCLUSION: In conclusion, this is the first study to demonstrate that surface-energy derived CAB data effectively predict the interactive mixing behaviour of small excipient particles. Furthermore, at certain proportions of small excipient particles the CAB model also predicts the flow and compaction behaviour of the API/excipient blends.

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.

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.

Investigation of the Changes in Aerosolization Behavior Between the Jet-Milled and Spray-Dried Colistin Powders Through Surface Energy Characterization.

This study aimed to investigate the surface energy factors behind improved aerosolization performance of spray-dried colistin powder formulations compared with those produced by jet milling. Inhalable colistin powder formulations were produced by jet milling or spray drying (with or without l-leucine). Scanning electron micrographs showed the jet-milled particles had irregularly angular shapes, whereas the spray-dried particles were more spherical. Significantly higher fine particle fractions were measured for the spray-dried (43.8%-49.6%) versus the jet-milled formulation (28.4%) from a Rotahaler at 60 L/min; albeit the size distribution of the jet-milled powder was smaller. Surprisingly, addition of l-leucine in the spray drying feed solution gave no significant improvement in fine particle fraction. As measured by inverse gas chromatography, spray-dried formulations had significantly (p < 0.001) lower dispersive, specific, and total surface energy values and more uniform surface energy distributions than the jet-milled powder. Interestingly, no significant difference was measured in the specific and total surface energy values between the spray-dried formulation with or without l-leucine. Based on our previous findings in the self-assembling behavior of colistin in aqueous solution and the surface energy data obtained here, we propose the self-assembly of colistin molecules during spray drying contributed significantly to the reduction of surface free energy and the superior aerosolization performance.

Particle Engineering Via Mechanical Dry Coating in the Design of Pharmaceutical Solid Dosage Forms.

Cohesive powders are problematic in the manufacturing of pharmaceutical solid dosage forms because they exhibit poor flowability, fluidization and aerosolization. These undesirable bulk properties of cohesive powders represent a fundamental challenge in the design of efficient pharmaceutical manufacturing processes. Recently, mechanical dry coating has attracted increasing attention as it can improve the bulk properties of cohesive powders in a cheaper, simpler, safer and more environment-friendly way than the existing solvent-based counterparts. In this review, mechanical dry coating techniques are outlined and their potential applications in formulation and manufacturing of pharmaceutical solid dosage forms are discussed. Reported data from the literature have shown that mechanical dry coating holds promise for the design of superior pharmaceutical solid formulations or manufacturing processes by engineering the interfaces of cohesive powders in an efficient and economical way.

On the Methods to Measure Powder Flow.

The flow of powders can often play a critical role in the manufacturing of pharmaceutical products. Many of these processes require good, consistent and predictable flow of powders to ensure continuous production of pharmaceutical dosages and to ensure their quality. Therefore, the flow of powders is of paramount importance to the pharmaceutical industry and thus the measuring and evaluating of powder flow is of utmost importance. At present, there are numerous methods in which the flow of powders can be measured. However, due to the complex and environment-dependent nature of powders, no one method exists that is capable of providing a complete picture of the behaviour of powders under dynamic conditions. Some of the most commonly applied methods to measure the flow of powders include: density indices, such as the Carr index and Hausner ratio, powder avalanching, the angle of repose (AOR), flow through an orifice, powder rheometry and shear cell testing.

Influence of coating material on the flowability and dissolution of dry-coated fine ibuprofen powders.

This study investigates the effects of a variety of coating materials on the flowability and dissolution of dry-coated cohesive ibuprofen powders, with the ultimate aim to use these in oral dosage forms. A mechanofusion approach was employed to apply a 1% (w/w) dry coating onto ibuprofen powder with coating materials including magnesium stearate (MgSt), L-leucine, sodium stearyl fumarate (SSF) and silica-R972. No significant difference in particle size or shape was measured following mechanofusion with any material. Powder flow behaviours characterised by the Freeman FT4 system indicated coatings of MgSt, L-leucine and silica-R972 produced a notable surface modification and substantially improved flow compared to the unprocessed and SSF-mechanofused powders. ToF-SIMS provided a qualitative measure of coating extent, and indicated a near-complete layer on the drug particle surface after dry coating with MgSt or silica-R972. Of particular note, the dissolution rates of all mechanofused powders were enhanced even with a coating of a highly hydrophobic material such as magnesium stearate. This surprising increase in dissolution rate of the mechanofused powders was attributed to the lower cohesion and the reduced agglomeration after mechanical coating.

Relationship between surface concentration of L-leucine and bulk powder properties in spray dried formulations.

The amino acid L-leucine has been demonstrated to act as a lubricant and improve the dispersibility of otherwise cohesive fine particles. It was hypothesized that optimum surface L-leucine concentration is necessary to achieve optimal surface and bulk powder properties. Polyvinylpyrrolidone was spray dried with different concentration of L-leucine and the change in surface composition of the formulations was determined using X-ray photoelectron spectroscopy (XPS) and time of flight-secondary ion mass spectrometry (ToF-SIMS). The formulations were also subjected to powder X-ray diffraction analysis in order to understand the relationship between surface concentration and solid-state properties of L-leucine. In addition, the morphology, surface energy and bulk cohesion of spray dried formulations were also assessed to understand the relation between surface L-leucine concentration and surface and bulk properties. The surface concentration of L-leucine increased with higher feed concentrations and plateaued at about 10% L-leucine. Higher surface L-leucine concentration also resulted in the formation of larger L-leucine crystals and not much change in crystal size was noted above 10% L-leucine. A change in surface morphology of particles from spherical to increasingly corrugated was also observed with increasing surface l-leucine concentration. Specific collapsed/folded over particles were only seen in formulations with 10% or higher l-leucine feed concentration suggesting a change in particle surface formation process. In addition, bulk cohesion also reduced and approached a minimum with 10% L-leucine concentration. Thus, the surface concentration of L-leucine governs particle formation and optimum surface L-leucine concentration results in optimum surface and bulk powder properties.

Spray-Dried Influenza Antigen with Trehalose and Leucine Produces an Aerosolizable Powder Vaccine Formulation that Induces Strong Systemic and Mucosal Immunity after Pulmonary Administration.

BACKGROUND: Pulmonary immunization has recently gained increased interest as a means to induce both systemic and mucosal immunity while eliminating issues associated with the use of needles in parenteral vaccination. However, in contrast to the inhaled delivery of small molecule drugs, a dry powder carrier platform that is readily adaptable to the incorporation of biomacromolecules (e.g., vaccine antigens) as a common standard is lacking. Spray-dried trehalose with leucine has previously been characterized and demonstrated to produce highly aerosolizable powders containing an amorphous glassy matrix suitable for stabilization of biomacromolecules. This study aimed to further extend the understanding in the use of this formulation as a dry powder carrier platform in an in vivo setting, using influenza antigen as a model, for pulmonary delivery of biomacromolecules. METHODS: Spray-dried influenza vaccine was produced using previously established spray-drying conditions. The formulations were characterized to examine the impact of influenza antigen on the solid-state properties of the spray-dried powders. The optimal vaccine formulation was then selected for in vivo immunogenicity study in rats to evaluate the efficacy of the reconstituted spray-dried vaccine compared to liquid vaccine administered via pulmonary and subcutaneous routes. RESULTS: The formation of amorphous glassy matrix and morphology of the spray-dried particles, within the protein concentration range used in the study, was not affected by the incorporation of the influenza antigen. However, the amount of proteins incorporated increased water content and reduced the glass transition temperature (Tg) of the formulation. Nevertheless, the spray-dried vaccine induced strong mucosal and systemic immunity comparable to liquid vaccine after pulmonary and subcutaneous immunization without causing any inflammation to the lung parenchyma. CONCLUSIONS: The study demonstrated the usability of the spray-dried carrier as a promising platform for pulmonary delivery of influenza vaccine. The potential utility of this delivery system for other biomacromolecules may also be further explored.

Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate.

Intensive dry powder coating (mechanofusion) with tablet lubricants has previously been shown to give substantial powder flow improvement. This study explores whether the mechanofusion of magnesium stearate (MgSt), on a fine drug powder can substantially improve flow, without preventing the powder from being directly compacted into tablets. A fine ibuprofen powder, which is both cohesive and possesses a low-melting point, was dry coated via mechanofusion with between 0.1% and 5% (w/w) MgSt. Traditional low-shear blending was also employed as a comparison. No significant difference in particle size or shape was measured following mechanofusion. For the low-shear blended powders, only marginal improvement in flowability was obtained. However, after mechanofusion, substantial improvements in the flow properties were demonstrated. Both XPS and ToF-SIMS demonstrated high degrees of a nano-scale coating coverage of MgSt on the particle surfaces from optimized mechanofusion. The study showed that robust tablets were produced from the selected mechanofused powders, at high-dose concentration and tablet tensile strength was further optimized via addition of a Polyvinylpyrrolidone (PVP) binder (10% w/w). The tablets with the mechanofused powder (with or without PVP) also exhibited significantly lower ejection stress than those made of the raw powder, demonstrating good lubrication. Surprisingly, the release rate of drug from the tablets made with the mechanofused powder was not retarded. This is the first study to demonstrate such a single-step dry coating of model drug with MgSt, with promising flow improvement, flow-aid and lubrication effects, tabletability and also non-inhibited dissolution rate.

An insight into powder entrainment and drug delivery mechanisms from a modified Rotahaler®.

This study aims to improve understanding of the powder fluidisation and aerosolisation processes unique to a split capsule dry powder inhaler. It uses a combination of dynamic real-time methods and a suite of powder material physicochemical characterisation methods. The study focused on examining the effect of different characteristics of lactose carrier employed, and considered specifically the powder fluidisation, entrainment and de-agglomeration mechanisms. A GSK Rotahaler(®) was selected as the inhaler device. Powder fluidisation and entrainment were investigated using the ensemble technique of laser diffraction and high-speed imaging. This ensemble technique afforded both the powder entrainment profile and simultaneous visual confirmation of the capsule movement and powder fluidisation within the Rotahaler. The results showed that powder fluidisation from a dynamic split capsule was substantially different to that from a static powder bed. Furthermore, the presence of the split capsule dominated powder emission mechanisms from the Rotahaler, regulated by its impaction on the grid/Rotahaler wall and the rotational movement in the entrained air. Of all the material characterisation metrics, the most significant linear correlation was revealed between powder permeability and the aerosolisation efficiency as measured by fine particle fraction (R(2)=0.98). This indicates that drug delivery from the Rotahaler was mainly governed by the influence of the cohesive fine particle size component. Powder permeability as a practical test may afford an effective and practical predictive link between the raw excipients and drug delivery performance from the capsule device.