Electrostatic characterisation of inhaled powders: Effect of contact surface and relative humidity

Electrostatic charge accumulation on drug and excipient powders arising from interparticulate collisions or contacts between particles and other solid surfaces often leads to agglomeration and adhesion problems during the manufacture and use of dry powder inhaler (DPI) formulations. The aim of this work was to investigate the role of triboelectrification in particle interactions between micronised drug (salbutamol sulphate or ipratropium bromide monohydrate) and excipient (alpha-lactose monohydrate, 63-90 microm) during mixing in cylindrical vessels constructed from stainless steel, polypropylene and acetal under selected relative humidity (rh) conditions (0-86%). The charge was found to depend on both the nature of the powders and the mixing vessel surface. In addition, coating the vessels with drug or excipient removed the influence of the vessel material on charge generation, thus providing a technique to investigate interactions between the drug and excipient substances. A triboelectric series of all materials used, placed ipratropium at the positive end and polypropylene at the negative end. Micronised drug profoundly altered the charging properties of lactose in drug (1.46%, w/w)/lactose DPI formulations. An increase in rh in the range 0-86% produced a corresponding decrease in charge and adhesion values for each drug, lactose and DPI formulation during triboelectrification with each mixing vessel surface. The results provide increased knowledge of the role of electrostatics in DPI technology.     

Lactose characteristics and the generation of the aerosol

The delivery efficiency of dry-powder products for inhalation is dependent upon the drug formulation, the inhaler device, and the inhalation technique. Dry powder formulations are generally produced by mixing the micronised drug particles with larger carrier particles. These carrier particles are commonly lactose. The aerosol performance of a powder is highly dependent on the lactose characteristics, such as particle size distribution and shape and surface properties. Because lactose is the main component in these formulations, its selection is a crucial determinant of drug deposition into the lung, as interparticle forces may be affected by the carrier-particle properties. Therefore, the purpose of this article is to review the various grades of lactose, their production, and the methods of their characterisation. The origin of their adhesive and cohesive forces and their influence on aerosol generation are described, and the impact of the physicochemical properties of lactose on carrier-drug dispersion is discussed in detail.     

Influence of mechanical activation on the physical stability of salbutamol sulphate.

In order to obtain the optimal particle size distribution for pharmaceutical powders in dry powder inhalers the particles have to be micronised. In most cases the process of micronisation is connected with a high input of energy which induces disorder and defects on the surface of the drug particles and as a result changes in the crystallinity. Consequently, changes in the physical stability of the powders may occur. To investigate changes on the physical stability of the powder, different analytical methods are used in the present investigation: laser diffraction, Differential Scanning Calorimetry (DSC), isothermal microcalorimetry and DVS-method.Air-jet-milling is one of the most frequently used techniques in the pharmaceutical industry, in order to obtain particles of respirable size. In the treatise described here the influence of the critical parameters of the process, i.e. feed pressure, grind pressure and feed rate is assessed for salbutamol sulphate. The grind pressure is of utmost importance with respect to particle size distribution and the physical powder stability. For salbutamol sulphate, ground with a MC Jetmill 50, a grind pressure of 6 bar has been found optimal. Pressures below 6 bar are not sufficient to produce the required reduction in particle size. The feed pressure and rate have negligible influence on the powder quality. Furthermore, the micronisation process is optimised to achieve respirable particles while minimising the amorphous content. A correlation between mechanical activation and the amount of the amorphous regions is showed clearly.Air-jet-milling has been compared to ball milling in this investigation. In pilot tests ball milling was not suitable to achieve the needed particle size distribution, however, it generates a specific quantity of amorphous material. With the help of specific amorphous regions in the powder, the sensitivity of the used methods for salbutamol sulphate can be examined.     

Functionality testing of inhalation grade lactose.

Lactose monohydrate for inhalation is commonly produced by sieving out customer-specific size fractions of a crystallized bulk material of lactose. It was the aim of this study to investigate the influence of the raw material on the physico-chemical properties of the inhalation grade lactose and on the efficacy of powders for inhalation produced from these batches. The selected raw material lactose batches differed in the size distribution characteristics, the fines and the agglomerate content. These differences in the raw material could also be found to a smaller extent in the intermediate products and could not be completely levelled out in the final inhalation grade lactose. Efficiency testing was done using salbutamol sulphate in two different concentrations (drug-to-carrier ratio of 1:36 and 1:400) as a model drug; the powder blends were delivered using the Aerolizer and the Easyhaler device. With the high drug load, nearly no differences could be observed between both the delivery systems and the different produced lactose batches. The fine particle fraction (FPF) (%<5 microm) was on a high level of >39% in all cases. With the low drug load significant differences between the devices and the lactose batches were found. The FPF was distinctly reduced to 15-30%, with the Easyhaler generating a higher fraction of fine particles than the Aerolizer device. Although the observed differences between the lactose batches could not be linked to one specific physico-chemical parameter determined for the carrier, they led to the conclusion that the differences between the test batches of inhalation grade lactose especially manufactured for this study can affect the functionality of an inhalation powder. The effects are significantly smaller with high drug load formulations than using a low drug concentration.     

Understanding the effect of lactose particle size on the properties of DPI formulations using experimental design

Medicines for delivering therapeutic agents to the lung as dry powders primarily consist of a carrier and a micronised active pharmaceutical ingredient (API). The performance of an inhaled formulation will depend on a number of factors amongst which the particle size distribution (PSD) plays a key role. It is suggested that increasing the number of fine particles in the carrier can improve the aerosolisation of the API. In addition the effect of PSD upon a bulk powder is also broadly understood in terms of powder flow. Other aspects of functionality that different size fractions of the carrier affect are not clearly understood; for example, it is not yet clearly known how different size fractions contribute to the different functionalities of the carrier. It is the purpose of this investigation to examine the effects of different lactose size fractions on fine particle dose, formulation stability and the ability to process and fill the material in the preferred device. In order to understand the true impact of the size fractions of lactose on the performance of dry powder inhaled (DPI) products, a statistically designed study has been conducted. The study comprised various DPI blend formulations prepared using lactose monohydrate carrier systems consisting of mixtures of four size fractions. Interactive mixtures were prepared containing 1% (w/w) salbutamol sulphate. The experimental design enabled the evaluation of the effect of lactose size fractions on processing and performance attributes of the formulation. Furthermore, the results of the study demonstrate that an experimental design approach can be used successfully to support dry powder formulation development.     

Optimisation of powders for pulmonary delivery using supercritical fluid technology.

Supercritical fluid technology exploited in this work afforded single-step production of respirable particles of terbutaline sulphate (TBS). Different crystal forms of TBS were produced consistently, including two polymorphs, a stoichiometric monohydrate and amorphous material as well as particles with different degrees of crystallinity, size, and morphology. Different solid-state and surface characterisation techniques were applied in conjunction with measurements of powder flow properties using AeroFlow device and aerosol performance by Andersen Cascade Impactor tests. Improved fine particle fraction (FPF) was demonstrated for some powders produced by the SCF process when compared to the micronised material. Such enhanced flow properties and dispersion correlated well with the reduced surface energy parameters demonstrated by these powders. It is shown that semi-crystalline particles exhibited lower specific surface energy leading to a better performance in the powder flow and aerosol tests than crystalline materials. This difference of the surface and bulk crystal structure for selected powder batches is explained by the mechanism of precipitation in SCF which can lead to surface conditioning of particles produced.     

Physicochemical and in vitro deposition properties of salbutamol sulphate/ipratropium bromide and salbutamol sulphate/excipient spray dried mixtures for use in dry powder inhalers

The physicochemical and aerodynamic properties of spray dried powders of the drug/drug mixture salbutamol sulphate/ipratropium bromide were investigated. The in vitro deposition properties of spray dried salbutamol sulphate and the spray dried drug/excipient mixtures salbutamol sulphate/lactose and salbutamol sulphate/PEG were also determined. Spray drying ipratropium bromide monohydrate resulted in a crystalline material from both aqueous and ethanolic solution. The product spray dried from aqueous solution consisted mainly of ipratropium bromide anhydrous. There was evidence of the presence of another polymorphic form of ipratropium bromide. When spray dried from ethanolic solution the physicochemical characterisation suggested the presence of an ipratropium bromide solvate with some anhydrous ipratropium bromide. Co-spray drying salbutamol sulphate with ipratropium bromide resulted in amorphous composites, regardless of solvent used. Particles were spherical and of a size suitable for inhalation. Twin impinger studies showed an increase in the fine particle fraction (FPF) of spray dried salbutamol sulphate compared to micronised salbutamol sulphate. Co-spray dried salbutamol sulphate:ipratropium bromide 10:1 and 5:1 systems also showed an increase in FPF compared to micronised salbutamol sulphate. Most co-spray dried salbutamol sulphate/excipient systems investigated demonstrated FPFs greater than that of micronised drug alone. The exceptions to this were systems containing PEG 4000 20% or PEG 20,000 40% both of which had FPFs not significantly different from micronised salbutamol sulphate. These two systems were crystalline unlike most of the other spray dried composites examined which were amorphous in nature.     

Influence of crystal form of ipratropium bromide on micronisation and aerosolisation behaviour in dry powder inhaler formulations

Objectives This study aimed to investigate the relationship between the mechanical properties of anhydrous and monohydrate ipratropium bromide (IB) crystals, their processing behaviour upon air‐jet micronisation and aerosolisation performance in dry powder inhaler (DPI) formulations. Methods IB monohydrate and anhydrous crystals were produced from seed crystals and supercritical carbon dioxide crystallisation, respectively. Young's modulus of anhydrous and monohydrate IB crystals was determined using nanoindentation. For air‐jet micronised crystals, the physicochemical and surface interfacial properties via the cohesive–adhesive balance (CAB) approach were investigated. These data were correlated to in‐vitro aerosolisation performance of carrier‐based DPI formulations containing either anhydrous or monohydrate IB. Key findings Particle size and Young's modulus of both crystals were similar and this was reflected in their similar processing upon micronisation. Particle size of micronised anhydrous and monohydrate crystals were similar. CAB measurements of the micronised particles of monohydrate or anhydrous forms of IB with respect to lactose were 0.70 (R² = 0.998) and 0.77 (R² = 0.999), respectively. These data suggested that both samples had similar adhesion to lactose, which correlated with their similar in‐vitro aerosolisation performance in DPI formulations. Conclusions Monohydrate and anhydrous crystals of IB exhibited similar mechanical properties and interfacial properties upon secondary processing. As a result, the performance of the DPI formulations were similar.     

Comparative study of erythritol and lactose monohydrate as carriers for inhalation: atomic force microscopy and in vitro correlation.

The adhesion of micronised salbutamol sulphate to two carrier excipients, lactose monohydrate and erythritol, was investigated using the atomic force microscope (AFM) colloid probe technique and correlated with their respective physico-mechanical properties and aerosolisation performance. The particle size, morphology and moisture sorption properties of the carriers were similar thereby allowing direct comparison of functionality. AFM force measurements (n = 1024 force curves) were obtained between salbutamol sulphate drug probes (n = 4) and the excipients, as 63-90 microm sieve fractions and atomically smooth crystals. In general, significant differences in drug adhesion to lactose monohydrate and erythritol were observed (ANOVA, p<0.05), with erythritol exhibiting relatively greater adhesiveness. A linear relationship between drug probe adhesion to lactose monohydrate and drug probe adhesion to erythritol was established with salbutamol sulphate-lactose monohydrate adhesion being 60-70% of that of the erythritol system. In vitro analysis suggested good correlation with the adhesion measurements. The aerosolisation of salbutamol sulphate from erythritol carrier particles was significantly less (ANOVA, p<0.05) than from lactose monohydrate, with a fine particle dose (<6.4 microm) of 41.9 +/- 7.4 microg and 24.9 +/- 3.1 microg for the lactose monohydrate and erythritol carriers, respectively (n = 3).     

The relationship between physical properties of lactose monohydrate and the aerodynamic behaviour of adhered drug particles

The influence of particle size, shape, particle surface roughness and water loss on drying of lactose monohydrate carrier particles on the aerodynamic properties of dry powder inhalations based on interactive mixtures with a micronized drug has been investigated. Two sets of mixtures were prepared to relate the physical properties of the lactose monohydrate particles to the aerodynamic properties of the formulations: (A) constant mixing time and speed (25 min, 42 rev./min), and (B) optimal mixing time (speed 42 rev./min) to obtain a given adhesion force between drug and carrier particles. All ten lactose monohydrate batches provided different aerodynamic properties under test conditions (A) and (B). The relationship between the physical properties of the lactose monohydrate carrier particles and the aerodynamic properties of the drug is complex, and a simple interchange of the carrier material in terms of brand or grade appears impossible. Particle size, shape, water loss on drying, and to a lesser extent surface roughness influence the loss of drug for example in the device, preseparator and loss due to adhesion. The relationships can be quantified mathematically, if mixing has been undertaken under similar conditions, i.e. identical mixing time and speed (test condition (A)). However, for interactive mixtures, which have been manufactured under test condition (B), the connection between the physical properties of the carrier materials and the aerodynamic behaviour are less quantifiable. A similar adhesion force does not guarantee a similar aerodynamic behaviour of the drug in the cascade impactor. The findings indicate that it is mainly the site of adhesion, i.e. adhesion to fine or larger carrier particles which determines the drug lost in the device and preseparator, and is responsible for deviations in the MMAD.     

Characterisation and functionality of inhalation anhydrous lactose

The relationships between the physicochemical properties and functionality in dry powder inhaler (DPI) performance was investigated for inhalation grade anhydrous lactose and compared to monohydrate grades. The excipients were characterised using a range of techniques including particle size analysis, moisture sorption and powder rheometry. The inhalation anhydrous lactose grades were readily characterisable. The aerosolisation performance of capsule based DPI formulations containing budesonide (200 μg) and different grades of lactose evaluated using inertial impaction measurements produced fine particle doses of budesonide ranging from 24 to 49 μg. There were no apparent relationships between aerosolisation performance and excipient characteristics, such as particle size and powder density. However, formulations containing lactose grades which exhibit higher powder fluidisation energy values resulted in higher fine particle doses of budesonide.     

Influence of solvent on the morphology and subsequent comminution of ibuprofen crystals by air jet milling

Crystal morphology plays an important role in drug processing and delivery, which may be controlled during crystallisation. In this study, ibuprofen particles with different size and morphology were produced by controlled crystallisation in order to evaluate their impact on particle size reduction. Results suggest that the micronisation behaviour of ibuprofen was markedly influenced by the morphology and size of starting materials. It was possible to reduce the size of ibuprofen particles to sizes less than 5 μm during dry milling, which is markedly below the reported brittle-ductile transition size. Results also indicate that the particle size reduction mechanism is influenced by the size and morphology of the starting ibuprofen crystals. Dissolution behaviour of ibuprofen was shown to be influenced by the solid surface chemistry of micronised drug particles. The molecular modelling study provided deeper understanding of the experimental findings observed in this study.     

Improved aerosolization performance of salbutamol sulfate formulated with lactose crystallized from binary mixtures of ethanol-acetone

It has been shown that dry powder inhaler (DPI) formulations typically achieve low fine particle fractions (poor performance). A commonly held theory is that this is due, at least in part, to low levels of detachment of drug from lactose during aerosolization as a result of strong adhesion of drug particles to the carrier surfaces. Therefore, the purpose of the present study is to overcome poor aerosolization performance of DPI formulation by modification of lactose particles. Lactose particles were crystallized by adding solution in water to different ratios of binary mixtures of ethanol-acetone. The results showed that modified lactose particles had exceptional aerosolization performance that makes them superior to commercial lactose particles. Morphology assessment showed that crystallized lactose particles were less elongated, more irregular in shape, and composed of smaller primary lactose particles compared with commercial lactose. Solid-state characterization showed that commercial lactose particles were α-lactose monohydrate, whereas crystallized lactose particles were a mixture of α-lactose monohydrate and β-lactose according to the ratio of ethanol-acetone used during crystallization process. The enhanced performance could be mainly due to rougher surface and/or higher amounts of fines compared with the lactose crystallized from pure ethanol or commercial lactose.     

Quantifying electrostatic interactions in pharmaceutical solid systems

Triboelectrification of pharmaceutical powders with stainless steel and polymer contact surfaces was investigated. alpha-Lactose monohydrate, from 90 to 125 up to 355-500 microm, was used to quantify electrostatic interactions with negligible powder adhesion to the contact surface. Size fractions down to 53-75 microm alone and in binary mixtures with <10 microm lactose or micronized salbutamol were used to investigate triboelectrification with powder adhered to the contact surface. Triboelectrification was performed in a cyclone charger fitted with interchangeable contact surfaces of steel and polymers, representing the surfaces of pharmaceutical processing and manufacturing equipment, packaging materials and components of dry powder inhaler devices. The results for single component powders showed charge acquisition was inversely related to particle size, where contact surface contamination was negligible. However, with particulate contamination, triboelectrification was more complex due to particle collisions with clean and contaminated contact surfaces. Analysis of adhered and non-adhered powder provided information about changes in composition of two component powders during triboelectrification. Particle size and chemical analyses showed that composition changes of mixtures may be related to powder/contact surface affinity and interparticulate forces for separation of components in a cohesive mix during triboelectrification.     

Effect of crystallisation conditions and feedstock morphology on the aerosolization performance of micronised salbutamol sulphate

Salbutamol sulphate (SS) used in dry powder inhalers requires drug particles in the respirable size range of 1-5 μm to achieve a suitable therapeutic effect. The aim of this study was therefore to determine strategies for controlling drug substance characteristics pre and post-crystallisation to facilitate the production of micronised SS with desirable particle attributes for optimal delivery as an inhaled aerosol. SS batches were crystallised using an antisolvent method to produce a range of crystal morphologies. Air jet milling was then used to reduce the size of crystallised SS particles. Starting materials and micronised batches of SS were characterised in the solid state using a range of techniques with subsequent assessment of aerosol properties. Assessment of the aerodynamic characteristics of micronised SS delivered by DPI (without any carrier) indicated that fine particle fraction and emitted dose as a percentage of the total recovered dose were dependent on the quality attributes of the micronised SS, which were directly linked to the degree of imperfections and the morphology of the crystalline feedstock used in micronisation. Aerosolization performance of micronised SS can be optimised by manipulation of feedstock characteristics through crystal engineering and through definition of optimal processing conditions for micronisation.     

Evaluation of supercritical fluid engineered budesonide powder for respiratory delivery using nebulisers

Objectives Currently, suspensions prepared from micronised drug substances are the only delivery system marketed for nebulisation of steroids, and reported inconsistent or low bioavailability arising from their use provides a rationale for researching alternative formulations. Supercritical fluid processing of drug substances to obtain respirable‐sized particles has been used over the last decade to formulate dry powder inhalers. We aimed thus to process budesonide powder to improve its deposition characteristics. Methods In an attempt to overcome the limitations of nebuliser suspensions when prepared from micronised drug particles, budesonide powder was processed using a supercritical fluid based process and suspended using Tween 80 as a surfactant to provide an aqueous nebuliser formulation. The in‐vitro characteristics of the emitted dose on nebulisation for the prepared suspension were then compared to a commercially available suspension formulation of budesonide using a jet and a vibrating mesh nebuliser. Key findings The results showed a significant improvement of the in‐vitro deposition properties of the suspension containing supercritical fluid engineered budesonide particles. Conclusions The results indicated the benefit of such materials compared with traditionally micronised drug powders.     

Single-step granulation/tabletting of different grades of lactose: a comparison with high shear granulation and compression.

The influence of the particle size, particle morphology and crystallinity of lactose on the extrusion properties and on the quality of tablets were investigated using single-step granulation/tabletting as a tabletting technique. Results showed that particle size and type of lactose (alpha-lactose monohydrate, anhydrous beta-lactose and spray dried lactose) affected the powder feeding, the process performance as well as the process capacity. Different grades of lactose yielded tablets with similar tensile strength, but significantly different disintegration time. Single-step granulation/tabletting always yielded tablets with a significantly higher tensile strength and similar or significantly lower disintegration time compared to high shear granulation and compression. The tensile strength of alpha-lactose monohydrate tablets (without and with PVP) did not change during one year of storage at 60% RH-25 degrees C and at 75% RH-40 degrees C, whereas a significant increase in disintegration time was observed. It can be concluded that although the lactose grade affected the performance and the optimal parameters of single-step granulation/tabletting, all lactose grades can be efficiently processed using this technique.     

Protein Deposition from Dry Powder Inhalers: Fine Particle Multiplets as Performance Modifiers

Purpose. To evaluate the use of carrier-based dry powder aerosols for inhalation delivery of proteins and examine the effect of fine particle excipients as potential formulation performance modifiers. Methods. Bovine serum albumin (BSA) was co-processed with malto-dextrin by spray-drying to produce model protein particles. Aerosol formulations were prepared by tumble mixing protein powders with -lactose monohydrate (63–90 m) or modified lactoses containing between 2.5 and 10% w/w fine particle lactose (FPL) or micronised polyethylene glycol 6000. Powder blends were characterised in terms of particle size distribution, morphology and powder flow. Formulation performance in Diskhaler^® and Rotahaler^® devices was investigated using a twin stage impinger operating at 60 1 min^–1. Results. Inhalation performance of binary ordered mixes prepared using BSA-maltodextrin and lactose (63–90 m) was improved by addition of FPL and micronised PEG 6000. For the addition of 5% w/w FPL the protein fine particle fraction (0.5–6.4 m) using the Diskhaler^® was increased from 31.7 ± 2.4% to 47.4 ± 2.2%. Inclusion of FPL and micronised PEG 6000 changed the bulk properties of inhalation powders and reduced powder flow but did not affect device emptying. Unexpectedly, improvements in performance were found to be independent of the order of addition of FPL to the ternary powder formulations. SEM studies revealed that this was probably the result of a redistribution of protein particles between the coarse carrier lactose component and added FPL during mixing. Conclusions. Fine particle excipients can be used to improve the performance of carrier-based protein dry powder aerosols. Mechanistically, enhancement of performance is proposed to result from a redistribution of protein particles from coarse carrier particles to the fine particle component in the ternary mix.     

The influence of humidity on the aerosolisation of micronised and SEDS produced salbutamol sulphate.

The influence of storage humidity on the aerosolisation efficiency of micronised and supercritical fluid salbutamol sulphate formulations (containing a lactose carrier) were investigated using the twin stage impinger (TSI). Storage humidity had a significant effect on the aerosolisation efficiency of both micronised and solution enhanced dispersion by supercritical fluids (SEDS) salbutamol sulphate (ANOVA P <0.05), suggesting capillary interactions to be an important factor when considering formulation performance. Furthermore, significant differences between the aerosolisation performance of micronised and SEDS salbutamol sulphate were observed at elevated humidities (>63% RH) (Fishers pairwise P <0.05). It is suggested that such variations may be due to differences in physical stability of the micronised and SEDS produced material. Dynamic vapor sorption, and atomic force microscopy (AFM) phase imaging suggested the micronised material to contain amorphous content that was most likely present on the micronised particulate surfaces. Thus, at high humidity, surface amorphous regions may have the ability to re-crystallize and effectively 'fuse' to the lactose carrier surface. This would potentially reduce the ability for the micronised material to be aerosolized and thus result in a greater decrease in FPF when compared to SEDS produced material at equivalent RH.     

Stability and aerodynamic behaviour of glucocorticoid particles prepared by a supercritical fluids process.

Particle processing techniques using supercritical fluids (SF) are potential alternative technologies to design particles for inhalation. Powders of budesonide and flunisolide were prepared using solution enhanced dispersion by supercritical fluids (SEDS) process. The aim was to determine thermodynamic stability of different polymorphs of flunisolide including new forms from SEDS technology and to characterise micronised and SEDS produced powders of budesonide and flunisolide for their suitability as inhalation powders. Acetone and methanol solutions of budesonide and flunisolide, with a concentration of 2.5 mg/ml, were used for the particle preparation. The pressure was 100 bar and temperatures were 60 degrees C or 80 degrees C. The flow rates of CO(2) and drug solution were 9 ml/min and 0.3 ml/min, respectively. Chemical purity of different polymorphs of flunisolide was estimated using high performance liquid chromatography (HPLC) and thermal behaviour was determined using differential scanning calorimetry (DSC). Particle morphology and surface examination were performed using scanning electron microscopy (SEM) and atomic force microscopy (AFM), respectively. The particle size distribution and density of the powders were determined with the help of Coulter Counter and helium pycnometer respectively. The in vitro deposition of the powders was studied using multistage liquid impinger (MLI). From the stability study, it was found that the two forms of flunisolide, polymorphs II and hemihydrate, were the most stable. Flunisolide form III was transformed to hemihydrate during the stability study. The chemical purity of the material was increased after SEDS processing. SEDS produced powders of budesonide and flunisolide form III from acetone showed narrow volumetric particle size distributions with 90% of the particles below 4 microm and geometric mean size around 3 microm. However, in the MLI study, budesonide powder obtained from SEDS with acetone showed favorable deposition in the lower stages with a mass median aerodynamic diameter (MMAD) of around 3 microm whilst the flunisolide form III was preferentially deposited in the higher stages of the MLI with MMAD of over 5 microm, due to aggregation of the particles. Particles of budesonide and flunisolide, in the size range, suitable for inhalation, were reproducibly produced using SEDS.