Dry Powder Aerosol Formulations Research Articles

Advancement of the Infant Air-Jet Dry Powder Inhaler (DPI): Evaluation of Different Positive-Pressure Air Sources and Flow Rates.

In order to improve the delivery of dry powder aerosol formulations to the lungs of infants, this study implemented an infant air-jet platform and explored the effects of different air sources, flow rates, and pulmonary mechanics on aerosolization performance and aerosol delivery through a preterm nose-throat (NT) in vitro model. The infant air-jet platform was actuated with a positive-pressure air source that delivered the aerosol and provided a full inhalation breath. Three different air sources were developed to provide highly controllable positive-pressure air actuations (using actuation volumes of ~10mL for the preterm model). While providing different flow waveform shapes, the three air sources were calibrated to produce the same flow rate magnitude (Q90: 90th percentile of flow rate). Multiple air-jet DPI designs were coupled with the air sources and evaluated with a model spray-dried excipient enhanced growth formulation. Compared to other designs, the D1-Single air-jet DPI provided improved performance with low variability across all three air sources. With the tested D1-Single air-jet and Timer air source, reducing the flow rate from 4 to 1.7L/min marginally decreased the aerosol size and significantly increased the lung delivery efficiency above 50% of the loaded dose. These results were not impacted by the presence of downstream pulmonary mechanics (resistance and compliance model). The selected design was capable of providing an estimated >50% lung delivery efficiency of a model spray-dried formulation and was not influenced by the air source, thereby enabling greater flexibility for platform deployment in different environments.

The safety and efficacy of BCG encapsulated alginate particle (BEAP) against M.tb H37Rv infection in Macaca mulatta : A pilot study

Due to the limited utility of Bacillus Calmette–Guérin (BCG), the only approved vaccine available for tuberculosis, there is a need to develop a more effective and safe vaccine. We evaluated the safety and efficacy of a dry powder aerosol (DPA) formulation of BCG encapsulated alginate particle (BEAP) and the conventional intradermal BCG immunization in infant rhesus macaques (Macaca mulatta). The infant macaques were immunized intratracheally with DPA of BEAP into the lungs. Animals were monitored for their growth, behaviour, any adverse and allergic response. The protective efficacy of BEAP was estimated by the ex-vivo H37Rv infection method. Post-immunization with BEAP, granulocytes count, weight gain, chest radiography, levels of liver secreted enzymes, cytokines associated with inflammation like TNF and IL-6 established that BEAP is non-toxic and it does not elicit an allergic response. The T cells isolated from BEAP immunized animals’ blood, upon stimulation with M.tb antigen, secreted high levels of IFN-γ, TNF, IL-6 and IL-2. The activated T cells from BEAP group, when co-cultured with M.tb infected macrophages, eliminated largest number of infected macrophages compared to the BCG and control group. This study suggests the safety and efficacy of BEAP in Non-human primate model.

Characterization of excipient enhanced growth (EEG) tobramycin dry powder aerosol formulations.

Spray drying can be utilized to produce highly dispersible powder aerosol formulations. However, these formulations are known to be hygroscopic, leading to potential solid-state stability and aerosol performance issues. This study aims to investigate if control of the spray drying particle formation conditions could be employed to improve the solid-state stability and alter the aerosol performance of tobramycin EEG formulations. Eight formulations were prepared, each had the same drug:excipient ratio of 60%w/w tobramycin, 20% w/w l-leucine, 18% w/w mannitol, and 2% w/w poloxamer 188. An experimental design matrix was performed with drying air water content of 1 or 10g/m3 and spray drying solution l-leucine concentrations of 4.6, 7.6, 15.2 or 23.0mmol/L. The particle size, morphology and crystallinity of spray dried formulations were characterized together with their dynamic moisture vapor sorption and aerosol performance. Higher crystallization and glass transition %RH were observed for the formulations spray dried using drying air with higher water content indicating more stable characteristics. Initial screening using a handheld dry powder inhaler of the realistic aerosol performance revealed that neither changing l-leucine concentration nor the drying gas water content affect the in-vitro expected lung dose. However, using a novel positive pressure inhaler, formulations produced using spray drying solutions with lower l-leucine concentrations showed better aerosol performance with MMAD around 2µm and FPF<5µm around 80%.

Development and physicochemical characterization of acetalated dextran aerosol particle systems for deep lung delivery

Biocompatible, biodegradable polymers are commonly used as excipients to improve the drug delivery properties of aerosol formulations, in which acetalated dextran (Ac-Dex) exhibits promising potential as a polymer in various therapeutic applications. Despite this promise, there is no comprehensive study on the use of Ac-Dex as an excipient for dry powder aerosol formulations. In this study, we developed and characterized pulmonary drug delivery aerosol microparticle systems based on spray-dried Ac-Dex with capabilities of (1) delivering therapeutics to the deep lung, (2) targeting the particles to a desired location within the lungs, and (3) releasing the therapeutics in a controlled fashion. Two types of Ac-Dex, with either rapid or slow degradation rates, were synthesized. Nanocomposite microparticle (nCmP) and microparticle (MP) systems were successfully formulated using both kinds of Ac-Dex as excipients and curcumin as a model drug. The resulting MP were collapsed spheres approximately 1μm in diameter, while the nCmP were similar in size with wrinkled surfaces, and these systems dissociated into 200nm nanoparticles upon reconstitution in water. The drug release rates of the Ac-Dex particles were tuned by modifying the particle size and ratio of fast to slow degrading Ac-Dex. The pH of the environment was also a significant factor that influenced the drug release rate. All nCmP and MP systems exhibited desirable aerodynamic diameters that are suitable for deep lung delivery (e.g. below 5μm). Overall, the engineered Ac-Dex aerosol particle systems have the potential to provide targeted and effective delivery of therapeutics into the deep lung.

Dry powder aerosols of curcumin-chitosan nanoparticle complex prepared by spray freeze drying and their antimicrobial efficacy against common respiratory bacterial pathogens

While the therapeutic benefits of curcumin delivery to the lung to treat various pulmonary disorders have been established, development of inhaled curcumin formulation that can address its inherently low aqueous solubility remains lacking. Although curcumin nanocapsules prepared by conventional encapsulation methods can improve the dissolution rate, their intricate preparation makes them less attractive for widespread implementation. Recently, our group developed a new class of curcumin nanoparticles in the form of curcumin-chitosan nanoparticle complex (or curcumin nanoplex in short) by a simple, cost-effective, and highly efficient method based on self-assembly drug-polysaccharide complexation. Owing to its nanosize and amorphous state, the curcumin nanoplex possessed high supersaturation generation capability upon dissolution that in turn produced high apparent solubility of curcumin.In the present work, we developed dry powder aerosol formulation of the curcumin nanoplex by spray freeze drying (SFD) using l-leucine and d-mannitol as adjuvants. The curcumin nanoplex aerosols were found to exhibit excellent aerosolization efficiency attributed to their large and low-density morphology, and the presence of l-leucine – a well-established aerosol dispersion enhancer – in their matrix. The aerosols, however, exhibited weaker supersaturation generation capability compared to the aqueous nanoplex suspension due to their slower dissolution rates caused by irreversible aggregations of the nanoplex during SFD. Nevertheless, the curcumin nanoplex aerosols still produced apparent solubility that was approximately 50% higher than the native curcumin’s solubility, thus signifying their dissolution enhancement capability. Despite their slower dissolution rate, the curcumin nanoplex aerosols maintained the same antimicrobial activity as the nanoplex suspension against four clinically-derived respiratory bacterial pathogens (i.e. Pseudomonas aeruginosa, Burkholderia cepacia, Klebsiella pneumoniae, and Stenotrophomonas maltophilia). Lastly, the aerosols exhibited minimal cytotoxicity towards the lung epithelium cells just like the native curcumin.

Manufacturing and Device Options for the Delivery of Biotherapeutics

Biotherapeutic aerosol formulations are an intense area of interest for systemic and local drug delivery. This article provides a short overview of typical factors required specifically for biotherapeutic aerosol formulation design, the processing options open for consideration, and the issue of inhalation device selection. Focusing on spray drying, four case studies are used to highlight the relevant issues, describing investigations into: (1) the mechanical stresses occurring in bacteriophage formulations during spray-dryer atomization; (2) modeling of the spray-dryer process and droplet drying kinetics, to assist process design and predictions of formulation stability; (3) a predictive approach to the design and processing of a five-component dry powder aerosol formulation; and (4) the survival of bacteriophages after pressurized metered dose inhaler atomization.

Development of Budesonide Nanocluster Dry Powder Aerosols: Preformulation

Wet milling was previously demonstrated as a simple process for producing agglomerates of budesonide nanoparticles (also known as NanoClusters) for use in dry powder aerosol formulation. The resulting budesonide NanoCluster powders exhibited a large emitted fraction and a high fine particle fraction (FPF) from a Monodose® dry powder inhaler. In this work, excipients were added premilling or postmilling and the performance of budesonide NanoCluster dry powders was investigated. Sodium chloride, Pluronic®, or ethanol was added prior to milling due to their ability to modify surface tension or ionic strength and thereby affect the attrition/agglomeration process. Lactose or l-leucine was added after milling because these are known to modify powder flow and dispersion. The chemical stability of budesonide was maintained in all cases, but the physical aerosol properties changed substantially with the addition of excipients. In all cases, the addition of excipients led to an increase in the size of the budesonide NanoClusters and tended to reduce the emitted fraction and FPF. Titrating excipients may provide a means to discretely modify the aerosol properties of budesonide NanoClusters but did not match the performance of excipient-free NanoCluster powder.

Development of Budesonide Nanocluster Dry Powder Aerosols: Formulation and Stability

The physical and chemical stability of dry powder aerosol formulations is an essential component in the development of an inhaled therapeutic. The pharmaceutical processing methods and storage conditions are primary determinants of the stability of a dry powder inhaler (DPI) formulation. Wet milling was used to produce budesonide NanoClusters (NCs), which are agglomerates of drug nanoparticles (≈ 300 nm) with a mean aerodynamic diameter between 1 and 3 µm, capable of deep lung penetration. In this study, the reproducibility of NC processing and performance was established. The physical stability of a selected budesonide NC formulation was investigated using industry standard dose content uniformity and cascade impaction techniques. The chemical stability of the lead formulation was also determined as a function of processing parameters and storage conditions. This study confirms the reproducibility and robust stability of NC powders as a novel means to turn drug particles into high-performance aerosols.

The role of fine particle lactose in agglomerated dry powder aerosol formulations

The role of fine particle lactose in agglomerated dry powder aerosol formulations

A new Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) to evaluate pulmonary drug absorption for metered dose dry powder formulations

Absorption studies with aerosol formulation delivered by metered dose inhalers across cell- and tissue-based in vitro models of the pulmonary epithelia are not trivial due to the complexity of the processes involved: (i) aerosol generation and deposition, (ii) drug release from the carrier, and (iii) absorption across the epithelial air–blood barrier. In contrast to the intestinal mucosa, pulmonary epithelia are only covered by a thin film of lining fluid. Submersed cell culture systems would not allow to studying the deposition of aerosol particles and their effects on this delicate epithelial tissue. We developed a new Pharmaceutical Aerosol Deposition Device on Cell Cultures (PADDOCC) to mimic the inhalation of a single metered aerosol dose and its subsequent deposition on filter-grown pulmonary epithelial cell monolayers exposed to an air–liquid interface. The reproducibility of deposition of these dry powder aerosols and subsequent drug transport across Calu-3 monolayers with commercially available dry powder inhalers containing salbutamol sulphate or budesonide could be demonstrated. In the context of developing new dry powder aerosol formulations, PADDOCC appears as a useful tool, allowing reducing animal testing and faster translation into clinical trials.

Nifedipine nanoparticle agglomeration as a dry powder aerosol formulation strategy

Efficient administration of drugs represents a leading challenge in pulmonary medicine. Dry powder aerosols are of great interest compared to traditional aerosolized liquid formulations in that they may offer improved stability, ease of administration, and simple device design. Particles 1–5 μm in size typically facilitate lung deposition. Nanoparticles may be exhaled as a result of their small size; however, they are desired to enhance the dissolution rate of poorly soluble drugs. Nanoparticles of the hypertension drug nifedipine were co-precipitated with stearic acid to form a colloid exhibiting negative surface charge. Nifedipine nanoparticle colloids were destabilized by using sodium chloride to disrupt the electrostatic repulsion between particles as a means to achieve the agglomerated nanoparticles of a controlled size. The aerodynamic performance of agglomerated nanoparticles was determined by cascade impaction. The powders were found to be well suited for pulmonary delivery. In addition, nanoparticle agglomerates revealed enhanced dissolution of the drug species suggesting the value of this formulation approach for poorly water-soluble pulmonary medicines. Ultimately, nifedipine powders are envisioned as an approach to treat pulmonary hypertension.

A novel cell compatible impingement system to study in vitro drug absorption from dry powder aerosol formulations

A modified Astra type multistage liquid impinger (MSLI) with integrated bronchial cell monolayers was used to study deposition and subsequent drug absorption on in vitro models of the human airway epithelial barrier. Inverted cell culture of Calu-3 cells on the bottom side of cell culture filter inserts was integrated into a compendial MSLI. Upside down cultivation did not impair the barrier function, morphology and viability of Calu-3 cells. Size selective deposition with subsequent absorption was studied for three different commercially available dry powder formulations of salbutamol sulphate and budesonide. After deposition without size separation the absorption rates from the aerosol formulations differed but correlated with the size of the carrier lactose particles. However, after deposition in the MSLI, simulating relevant impaction and causing the separation of small drug crystals from the carrier lactose, the absorption rates of the three formulations were identical, confirming the bioequivalence of the three formulations.

Poly(d,l-lactide-co-glycolide) Nanoparticle Agglomerates as Carriers in Dry Powder Aerosol Formulation of Proteins

A dry powder aerosol drug delivery system was designed with both nano- and microstructure to maximize the protein loading via surface adsorption and to facilitate delivery to the deep lung, respectively. Ovalbumin was employed as a model protein to adsorb to and controllably flocculate DOTAP-coated PLG nanoparticles into "nanoclusters" possessing low density microstructure. The mechanism of nanoparticle flocculation was probed by evaluating the effects of ionic strength, shear force, and protein concentration on the geometric and aerodynamic diameters of the nanoclusters as well as the protein adsorption efficiency. Salt ions were found to compete with ovalbumin adsorption to nanoparticles and facilitate flocculation; therefore, formulation of nanoclusters for inhaled drug delivery may require the lowest possible ionic strength to maximize protein adsorption. Additional factors, such as shear force and total protein-particle concentration can be altered to optimize nanocluster size, suggesting the possibility of regional lung delivery. Immediate release of ovalbumin was observed, and native protein structure upon release was confirmed by circular dichroism and fluorescence spectroscopy studies. Controlled flocculation of nanoparticles may provide a useful alternative to spray drying when formulating dry powders for pulmonary or nasal administration of protein therapeutics or antigens.

Correlations between cascade impactor analysis and laser diffraction techniques for the determination of the particle size of aerosolised powder formulations

The purpose of the study was to examine the suitability of the Spraytec ® laser diffraction technique for measuring the size distribution of aerosol particles generated from dry powder inhalators. A range of formulations with different dispersion properties were produced by spray-drying. The percentage of particles below 5.0 μm of these formulations was measured by laser diffraction (Mastersizer ® 2000 and Spraytec ®) and inertial impaction (MsLI and NGI) using various inhaler devices and at different flow rates between 30 and 100 l/min. Linear relationships and correlations ( R 2 > 0.9) existed between the results obtained from, on one hand, the Mastersizer ® 2000 and the Spraytec ®, and, on the other hand, the MsLI and the Spraytec ® regardless of flow rates and inhaler devices. The Spraytec ® could be a reliable technique for the development, evaluation and quality control of dry powder aerosol formulations.

Influence of Realistic Inspiratory Flow Profiles on Fine Particle Fractions of Dry Powder Aerosol Formulations

The purpose of the study was to determine how air flow profiles affect fine particle fractions (FPF) (<5 microm) from dry powder aerosol formulations and whether laser diffraction (LD) could be used to measure FPF of aerosols generated by variable flows. Carrier-based formulations containing 1.5% w/w micronized salbutamol base blended with the 63-90 microm fraction of alpha-lactose monohydrate or sorbitol or maltose were aerosolised from a model glass device using either a constant flow rate or a predetermined flow profile. The FPFs of the same aerosolised particles were first measured by LD and then by a liquid impinger. Volunteer inhalation airflow profiles and 3-phase (acceleration, constant flow rate and deceleration) square wave airflow profiles were generated using the Electronic Lung and an Inhalation Profile Recorder. Similar experiments were conducted for a carrier-free formulation from the Bricanyl Turbohaler. Salbutamol FPFs of all carrier-based formulations were found to increase by increasing the initial flow increase rate (FIR) from 200 to 600 l min(-1) s(-1) although they could be placed in an increasing order of maltose blend < sorbitol blend < lactose blend. A significant linear correlation was found between FPFs measured by LD and by inertial impaction (R (2) = 0.95, p < 0.01, ANOVA). For the Bricanyl Turbohaler, increasing FIR from 120 to 600 l min(-1) s(-1) for a constant peak flow rate (PFR) of 60 l min(-1) increased the mean Terbutaline FPF from 18.2% to 45.5%. For the volunteer inhalation profiles, a higher FIR tended to be associated with higher PFR, leading to a marked increase in drug FPF due to the combined effect of FIR and PFR. Drug FPF from either carrier-free or carrier-based formulations is determined by both FIR and PFR. LD is a viable technique to measure the performance of dry powder aerosol formulations at realistic inspiratory flow profiles.

Humidity-induced changes of the aerodynamic properties of dry powder aerosol formulations containing different carriers

This paper presents the findings of two related studies. The aim of the first was to study any changes in the aerodynamic properties of salbutamol base powder formulations when different sugars were used as the carriers, after storage at an elevated humidity (75% RH), and whether any such changes (if any) were related to the physical properties of the carriers. The aim of the second was to investigate whether "ageing", i.e. storage of the carrier, drug and blends under desiccation for more than 2 years, affected the aerodynamic properties of salbutamol sulphate powder formulations. Different formulations were prepared, each containing 1.5% (w/w) micronised salbutamol base or sulphate blended with the sieved fraction (63-90 microm) of one of the following sugars: alpha lactose monohydrate, sorbitol, maltose and dextrose. The salbutamol base blends were then stored unprotected at 75% RH (ambient temperature) and salbutamol fine particle fractions (FPFs) were measured by laser diffraction (LD) (% < 5.2 microm) and a multistage liquid impinger (MSLI) (% < 5.3 microm), following aerosolisation at 100 l min(-1) from a model glass inhaler, after storage of each formulation at the elevated conditions for 0, 1 and 6 days. Particle morphology and equilibrium moisture content (EMC) of each formulation prior to and after storage were also evaluated. However, the salbutamol sulphate blends containing either "fresh" or "aged" components were only characterized using LD at 60 l min(-1). Prior to exposure to 75% RH, the lactose blend was found to give the highest FPF of salbutamol (30% by LD and 37% by MSLI), followed by the sorbitol blend (17% by LD and 29% by MSLI), then by the dextrose blend (15% by LD and 25% by MSLI) and finally by the maltose blend (13% by LD and 13% by MSLI). Exposure to 75% RH for 6 days resulted in a small reduction of salbutamol FPF from the lactose blend but drastic diminution of salbutamol FPFs from other blends. After exposure to the high RH, the lactose blend adsorbed ca. 0.4% whilst each of the other sugars took up larger quantities of water (15-40%) and underwent a marked change in the surface texture of the particles. "Ageing" of the carriers and/or formulations did not seem to alter the aerodynamic properties of the drug. "Ageing" of micronised salbutamol sulphate prior to blending, however, was found to improve the FPF of drug. LD was capable of detecting subtle differences between the various formulations and generated FPF results that correlated with those measured by MSLI.

Characterisation of a Carrier-Free Dry Powder Aerosol Formulation Using Inertial Impaction and Laser Diffraction

The purpose of the study was to examine the suitability of using laser diffraction to measure the fine particle fraction (FPF) of drugs emitted from carrier-free dry powder aerosol formulations. Particle size distribution of terbutaline sulphate from Bricanyl Turbohaler, which contained loose agglomerates of drug particles only, was measured separately by laser diffraction apparatus equipped with a metal throat and a twin-stage, multi-stage liquid impingers, or Andersen cascade impactor at flow rates ranging from 28.3 to 100 l min(-1). In-line measurements were then conducted which allowed the same aerosolised particles to be measured first by laser diffraction then captured by an impactor or impinger for subsequent chemical analysis. A significant linear correlation (p < 0.001, R2 = 0.96, ANOVA) existed between the results obtained from two techniques when measurements were conducted independently. There was little difference in FPFs measured by inertial impaction and laser diffraction at the same flow rate. When in-line measurements were conducted, the FPFs measured by inertial impaction were approximately 0.7-0.9 times the aerosol FPFs measured by laser diffraction. This linear relationship was statistically significant and had a statistically insignificant y-intercept, regardless of inhaler batches, impinger types and measuring position of the laser beam. Laser diffraction could prove to be a reliable technique for development, evaluation and quality control of carrier-free, dry powder aerosol formulations.

Correlation between Inertial Impaction and Laser Diffraction Sizing Data for Aerosolized Carrier-based Dry Powder Formulations

The purpose of the study was to determine whether the drug fine particle fraction (FPF) from different dry powder aerosol formulations measured by laser diffraction at a range of flow rates correlated with that measured by inertial impaction. Ten binary formulations were prepared containing 1.5% w/w salbutamol base or sulphate, blended with the sieved (63-90 microm) fraction of different sugars (regular lactose, spray-dried lactose, sorbitol, dextrose or maltose). A further six ternary formulations were prepared containing 1.5% w/w salbutamol sulphate, 97% coarse lactose (63-90 microm) and 1.5% micronised or intermediate-sized lactose (1-50 microm). The FPF particles (< 5 microm) of these formulations were measured by laser diffraction and inertial impaction at flow rates between 28.3 and 100 l min(-1). When only the particles with diameter < 60 microm obtained by laser diffraction were considered the FPF (< 5 microm) could be determined and this enabled the aerosolisation of all 16 blends to be feasibly compared at flow rates ranging from 28.3 to 100 l min(-1). A significant linear correlation was found between the fine fractions measured by laser diffraction and the salbutamol fine fractions determined by inertial impaction (r2 = 0.934). Such correlation was also confirmed for formulations containing added fine lactose. Particle size measured by laser diffraction under the employed conditions reflected the aerodynamic properties of the drug. Laser diffraction can be used as on-, in- and/or at-line measurements and controls for dry powder aerosol formulations.

Development of a laser diffraction method for the determination of the particle size of aerosolised powder formulations

Impactor data are an essential component of marketing authorisation for new dry powder aerosol formulations. However such data are time-consuming to obtain and therefore impede the rapid screening of pilot formulations. In this phase of development it would be of considerable benefit to employ a technique where data acquisition was more rapid, such as laser diffraction, to predict the fine particle fraction. It was the aim of this study to investigate whether this is a feasible premise. Five different formulations were prepared, each containing 1.5% (w/w) micronised salbutamol base (volume median diameter: 2.42 μm) blended with the sieved fraction (63–90 μm) of one of the following sugars: regular crystalline lactose, spray dried lactose “Zeparox™”, sorbitol, maltose and dextrose monohydrate. A Perspex™ box was constructed to contain particles released from a glass inhaler and allow the particles to be measured by laser diffraction at different flow rates. After being validated using monodisperse aerosols, this assembly was then employed to measure the particle size distributions of each powder formulation and its respective sugar carrier at flow rates ranging from 28.3 to 100 l min −1. Aerodynamic particle size distribution of salbutamol base from each formulation was also measured after aerosolisation at 28.3 l min −1 from the glass inhaler into an Andersen cascade impactor. The flight of monodisperse particles with diameters (2–6 μm) in the desired size range of dry powders for inhalation could be contained and the size distribution determined by laser diffraction using the assembly at all flow rates investigated. Treatment of the particle size distributions measured by laser diffraction, i.e. examining only the aerosol particles with diameter <60 μm, highlighted the fine fraction (<5 μm) and enabled the aerosolisation of different blends to be feasibly compared at a range of different flow rates. The blends containing the following excipients could be placed in the following order of increasing fine fraction: spray-dried lactose < dextrose ≪ maltose < lactose < sorbitol. At 28.3 l min −1 a significant linear correlation was found between the fine fractions measured by laser diffraction and the salbutamol fine fractions determined by inertial impaction ( R 2 = 87.4%, p = 0.02, ANOVA). Therefore, the laser diffraction technique could prove to be an important tool for particle size characterisation of dry powder aerosol formulations.

The use of different sugars as fine and coarse carriers for aerosolised salbutamol sulphate

The aim of this study was to investigate the dispersion and deaggregation of a model drug, salbutamol sulphate (SS), using lactose, mannitol or sorbitol as coarse and fine carriers. Binary and tertiary formulations containing micronised salbutamol sulphate (SS) and sieved (63–90 μm) coarse sugar crystals or salbutamol sulphate (SS) with a mixture of coarse and fine sugar particles were prepared. Factorial design was employed to investigate the effects of three variables, i.e. the chemical entity of the coarse sugar carrier, the chemical entity of the fine sugar and the concentration of fine sugar, on the dispersion and deaggregation of salbutamol sulphate after aerosolisation at 60 l/min via a Rotahaler® into a twin stage liquid impinger (TSI). The binary formulations containing the different sugar entities produced differences in the fine (<6.4 μm) particle fraction (FPF) of SS in a decreasing order of mannitol>sorbitol>lactose, but failed to produce efficient dispersion of SS since the FPF was <10%. Adding fine sugar particles and increasing their concentration to the binary mixtures generally resulted in an increase in the FPF of salbutamol sulphate. The chemical nature of the fine carriers was found to play a less important role in determining respirable fraction of the drug than the coarse carriers. In conclusion, other sugars such as mannitol or sorbitol, besides lactose, may be employed as coarse and/or fine carriers for incorporation into dry powder aerosol formulations to increase FPF.