Effect of separation characteristics between salbutamol sulfate (SS) particles and model carrier excipients on dry powder for inhalation]

Most often dry powder for inhalation are formulated as ordered mixtures of a carrier excipient and a micronized drug substance. In the present study, model powder blends were prepared from a mixture of lactose alpha-monohydrate, micro-crystalline cellulose pellets or synthesized sugar as carrier particles, and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO dry powder inhaler (DPI) and their in vitro deposition properties were evaluated by a twin impinger (TI). The separation force between SS particles and carrier particles was investigated by the centrifuge method. In addition, the use of the air jet sieve (AJS) method was investigated to assess the separation behavior of drug particles from carrier excipient. Powder blends were sieved through a 325 mesh wire screen of an air jet sieve at an air pressure of 1500 Pa. The amount of drug deposited at the carrier surface was analysed before and after the sieving to calculate the percentage of the drug retained. A relationship was found between in vitro deposition properties (fine particle fraction, FPF) and the separation characteristics obtained by the centrifuge method and by the AJS method. The AJS method might be a suitable alternative for evaluating separation of a drug particle from carrier particles and hence can be used for the formulation screening of the dry powder inhalation.     

The Influence of Fine Excipient Particles on the Performance of Carrier-Based Dry Powder Inhalation Formulations

The inclusion of a small amount of fine particle excipient in a carrier-based dry powder inhalation system is a well researched technique to improve formulation performance and is employed in the pharmaceutical industry. The removal of intrinsic fines from a lactose carrier has been found to decrease formulation performance, whereas adding fines of many different materials into formulations increased performance. Changing the particle size of these fines, the amount added and the technique by which they were prepared also affected formulation behaviour. Despite this body of research, there is disagreement as to the mechanism by which fines improved formulation performance, with two main hypotheses presented in the literature. The first hypothesis suggested that fines prevent the drug from adhering to the strongest binding sites on the carrier, whilst the second proposed that fine particles of drug and excipient form mixed agglomerates that are more easily dispersed and deaggregated during aerosolisation. The evidence in support of each hypothesis is limited and it is clear that future research should aim to produce stronger mechanistic evidence. The investigation of interparticulate interactions using techniques such as atomic force microscopy and inverse gas chromatography may prove useful in achieving this aim.     

Air permeability of powder: A potential tool for Dry Powder Inhaler formulation development

Dry Powder Inhalers have drawn great attention from pharmaceutical scientists in recent years in particular those consisting of low-dose micronized drug particles associated with larger carrier particles and called interactive mixtures. However, there is little understanding of the relation between bulk powder properties such as powder structure and its aerodynamic dispersion performance. The aim of this work was to develop a simple method to measure the air permeability of interactive mixtures used in Dry Powder Inhalers by using Blaine’s apparatus – a compendial permeameter and to relate it to the aerodynamic behaviour. The study was done with fluticasone propionate and terbutaline sulphate as drug models that were blended with several lactoses having different particle size distribution thus containing different percentages of fine particle lactose. The quality of the blends was examined by analysing the drug content uniformity. Aerodynamic evaluation of fine particle fraction was obtained using a Twin Stage Impinger. A linear correlation between a bulk property – air permeability of packed powder bed – and the fine particle fraction of drug was observed for the tested drugs. The air permeability reflects the quantity of the free particle fraction in the interparticulate spaces of powder bed that leads to fine particle fraction during fluidization in air flow. A theoretical approach was developed in order to link the air permeability of powder bed and drag force acting on powders during aerosolization process. The permeability technique developed in this study provides a potential tool for screening Dry Powder Inhaler formulations at the development stage.     

Effect of mixing of fine carrier particles on dry powder inhalation property of salbutamol sulfate (SS)

The most commonly used formulations for dry powder inhalations are binary ordered mixes composed of micronized drugs and coarse carriers. An optimal dry powder aerosol formulation should possess an optimal inhalation property and a good flow property. These characteristics are especially important for a multidose dry powder inheler (DPI). In the present study, model powder blend were prepared consisting of synthesized sugar (different particle sized isomalt; IM-PF, IM-FS, IM-F) as a carrier and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO DPI (SkyePharma AG) and in vitro deposition properties (fine particle fraction, FPF) were evaluated by a twin impinger (TI) at a flow rate of 60 l/min. The separation property between SS and carrier particles was investigated by the centrifuge method and air jet sieve (AJS) method. It was found that FPF decreased with increasing carrier particle size. However, a large carrier particle possesses a good flow property. Therefore, the effect of mixing of fine carrier particles (IM-PF) into the large carrier particles (IM-FS) on dry powder inhalation property was investigated. When the proportion of IM-PF (fine carrier) increase from 0% to 25% of the total carrier powder blend, the FPF also increases from 16.7% to 38.9%. It is concluded that the effect of mixing of fine carrier particles might be a suitable method for improving the dry powder inhalation properties.     

In vitro evaluation of powders for inhalation: the effect of drug concentration on particle detachment

Limited information on the effect of the drug concentration on the performance of powders for inhalation is currently published. The aim of this work was to study the influence of drug concentration on the adhesion between drug and carrier and on the drug detachment from the carrier. The study was done with formoterol fumarate and fluticasone propionate blended with lactose Lactohale 200. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. Adhesion characteristics were evaluated by submitting the mixtures to a sieving action by air depression with an Alpine air-jet sieve. Aerodynamic evaluation of fine particle dose and emitted dose was obtained using a Twin Stage Impinger (TSI). Drug concentration of powder blends used in dry powder inhalers influenced adhesion, content uniformity and in vitro deposition of the drug. For the higher concentration of formoterol, it seemed that a lower quantity of drug adhered to the lactose. This was confirmed by the aerosolization assays done in the TSI. The fine particle fraction increased linearly with the formoterol concentration. A correlation was observed between adhesion characteristics and inertial impaction. In the case of fluticasone, the influence of the concentration was different. First, the fine particle fraction increased with the concentration and then decreased with a further increase of the fluticasone concentration. This could be explained by the lack of homogeneity when the fluticasone concentration was high because of agglomerates of pure drug which can not be redispersed, or by the physico-chemical characteristics of this drug.     

The Role of Fines in the Modification of the Fluidization and Dispersion Mechanism Within Dry Powder Inhaler Formulations

PURPOSE: To investigate the role of in situ generated fine excipient particles on the fluidization and aerosolization properties of dry powder inhaler (DPI) formulations. MATERIALS AND METHODS: Carrier based DPI formulations were prepared under low and high shear blending. Powder rheometery was utilized to measure bulk powder properties in a consolidated and aerated state. Powder fluidization and aerosolization characteristics were related to bulk powder properties using high speed imaging and inertial impaction measurements. RESULTS: High shear blending of formulations resulted in the in situ generation of excipient fines, which corresponded to an increase in aerosolization efficiency. The generation of fines were shown to increase the tensile strength and free volume of the carrier, which resulted in a characteristic change in the fluidization properties, as observed by high speed imaging. The increase in minimum fluidization velocity and aerodynamic drag forces required to aerate the powder may provide the source of energy for the increase in fine particle re-suspension. CONCLUSIONS: The in situ generation of excipient fines affect bulk powder properties of DPI formulations, which directly affects fluidization and aerosolization behaviour of DPI formulations. The study suggests an alternative mode of action by which fines increase DPI formulation performance.     

The Cohesive-Adhesive Balances in Dry Powder Inhaler Formulations II: Influence on Fine Particle Delivery Characteristics

PURPOSE: To investigate the influence of the cohesive-adhesive balances on dry powder formulation aerosolization and delivery characteristics. METHODS: De-agglomeration properties of pharmaceutical powders were investigated using an Aerosizer at various shear forces. Aerosol drug deposition properties of drug-only formulations and carrier-based formulations were investigated using a low-resistance device (Rotahaler) and a high-resistance device (Turbuhaler) via a twin-stage impinger. RESULTS: A paradoxical relationship between particle cohesive strength and de-agglomeration efficiencies of drug-only formulations was observed, where an increase in cohesive strength led to a higher fine particle fraction. A possible explanation for the variation in the fluidization and aerosolization properties between low and high cohesive particles was modeled on the relationship between cohesion, metastable agglomerate size, and the resulting aerodynamic drag force acting on the fluidized agglomerates. The addition of a fine particle lactose carrier influenced the drug deposition patterns in different ways depending on the relative cohesive and adhesive force balances within the formulation. CONCLUSIONS: The use of the colloid Atomic Force Microscrope (AFM) technique in combination with the cohesive-adhesive balance (CAB) system provides a novel preformulation tool for investigating the likely behavior of a dry powder formulation and a possible means of interpreting the possible de-aggregation and dispersion mechanisms of carrier-based formulations.     

The effect of budesonide particle mass on drug particle detachment from carrier crystals in adhesive mixtures during inhalation.

The different fine particle fractions (FPFs) that are obtained, when different dry powder inhalers (DPIs) are used for the same powder formulation at the same flow rate, is the result of different powder de-agglomeration efficiencies for these DPIs. For adhesive mixtures, this is the efficiency with which the kinetic energy of the air flow through the DPI is converted into separation forces that detach drug particles from carrier crystals. We investigated the effect of drug particle diameter (mass) on drug-carrier separation during inhalation with three different inhalers (Sofotec Novolizer, Inhalator Ingelheim and a special test inhaler), at two different flow rates (30 and 60l/min). Two different size fractions were used as carrier material (45-63 and 100-150 microm). We measured decreasing amounts of residual drug on the carrier crystals after inhalation with increasing drug particle mass for all inhalers at both flow rates. The observed trends were the same for both carrier fractions. The decrease in residual drug on carrier is in agreement with increasing FPFs in an Erweka impactor. However, it has been calculated that the magnitude of the effect decreases with increasing de-agglomeration efficiency.     

Powder flow analysis: A simple method to indicate the ideal amount of lactose fines in dry powder inhaler formulations

Many efforts have been made in the past to understand the function of lactose fines which are given as a ternary component to carrier-based dry powder inhaler formulations. It is undisputed that fines can significantly improve the performance of such formulations, but choosing the right amount of fines is a crucial point, because too high concentrations can have negative effects on the dispersion performance. The aim of this study was to indicate the optimal concentration of fines with a simple test method. For this purpose, mixtures with salbutamol sulfate and two different lactose carriers were prepared with a high shear mixer, measured with a FT4 powder rheometer and tested for fine particle delivery with two different inhaler devices. A correlation between the fluidization energy, measured with the aeration test set up, and the fine particle fractions (FPF) could be proven. This also applied for the aeration ratio, as well as the permeability of the powder samples. In addition, drug-free mixtures hardly differed in their rheological properties from mixtures containing the active pharmaceutical ingredient (API), which indicates that the method could be suitable for cost-saving screening trials. Furthermore, important aspects that explain the function of fines, such as the saturation of active sites, the formation of agglomerates and an increase in fluidization energy, could be shown in this study.     

Carriers in drug powder delivery

The performance of dry powder inhaler (DPI) systems depends on the design of the powder formulation, the dose-metering system, and the device used to disperse the powder as an aerosol. Multiple factors associated with drug and carrier particles are known to influence dry powder performance. Elucidation of a mechanistic understanding of particulate system properties and how these relate to powder performance and the disruption of inter-particulate forces that cause aggregation has not yet been achieved. However, the complexity of interactions within dry powder formulations has not restricted research in this area. Various strategies of overcoming inter-particulate forces have been devised, ranging from active inhaler designs to powder engineering approaches. The influence of the interactive carrier system’s physicochemical properties (i.e. size, shape, chemical properties, surface roughness, electrostatics, humidity, and ternary excipients) on the performance of carrier-based systems has been examined extensively in the literature. In addition, matrix carriers, which contain drug and functional excipients for promotion of powder performance, control of pharmacokinetics, stability, controlled release of active drug and enhanced control of drug targeting, have also been investigated. Both the interactive carrier and matrix carrier approaches are attempts to develop DPI systems that perform as device-independent formulations and/or provide patient-independent delivery (controlled carrier systems). It seems likely that the future of DPI systems will combine both of these strategies with future developments in device design (formulation independency).     

An investigation into the relationship between carrier-based dry powder inhalation performance and formulation cohesive–adhesive force balances

The inclusion of different carrier materials in a dry powder inhaler (DPI) system can alter formulation performance, which might be attributable to variation in the adhesion between drug and carrier particles. The aim of this study was, therefore, to further examine the relationship between drug-carrier adhesion and performance, by comparing data relating to many different drug-carrier combinations. Four drugs and four carriers were employed, giving a total of 16 combinations. The relative magnitude of the drug-carrier adhesion for each combination was quantified using the cohesion-adhesion balance (CAB) approach to colloidal probe atomic force microscopy. The in vitro inhalation performance of the 16 formulations (1.5% w/w drug) was investigated and found to vary significantly. Plots of fine particle dose against drug-carrier CAB ratio revealed that performance was optimised when the drug-carrier CAB ratio was slightly cohesive. This trend was found to fit with those from similar previous studies, although due to the smaller number of formulations investigated previously, the full extent of this relationship had not been revealed. It was concluded, therefore, that when developing a carrier-based DPI, the selection of a drug-carrier combination with a slightly cohesive CAB ratio might result in optimal performance.     

Three-dimensional DEM–CFD analysis of air-flow-induced detachment of API particles from carrier particles in dry powder inhalers

Air flow and particle–particle/wall impacts are considered as two primary dispersion mechanisms for dry powder inhalers (DPIs). Hence, an understanding of these mechanisms is critical for the development of DPIs. In this study, a coupled DEM–CFD (discrete element method–computational fluid dynamics) is employed to investigate the influence of air flow on the dispersion performance of the carrier-based DPI formulations. A carrier-based agglomerate is initially formed and then dispersed in a uniformed air flow. It is found that air flow can drag API particles away from the carrier and those in the downstream air flow regions are prone to be dispersed. Furthermore, the influence of the air velocity and work of adhesion are also examined. It is shown that the dispersion number (i.e., the number of API particles detached from the carrier) increases with increasing air velocity, and decreases with increasing the work of adhesion, indicating that the DPI performance is controlled by the balance of the removal and adhesive forces. It is also shown that the cumulative Weibull distribution function can be used to describe the DPI performance, which is governed by the ratio of the fluid drag force to the pull-off force.KEY WORDS: Dry powder inhaler, Dispersion, Detachment, Air flow, DEM–CFD     

Engineered Mannitol Ternary Additives Improve Dispersion of Lactose–Salbutamol Sulphate Dry Powder Inhalations

The aim of this study was to evaluate the influence of novel engineered fine mannitol particles (4.7%, w/w) on the performance of lactose–salbutamol sulphate dry powder inhaler (DPI) formulations to obtain promising aerosolisation properties. The results showed that the more elongated the fine mannitol particles, the weaker the drug–carrier adhesion, the better the drug content homogeneity, the higher the amount of drug expected to be delivered to the lower airways and the higher the total DPI formulation desirability. Linear relationships were established showing that mannitol particles with a more elongated shape generated powders with broader size distributions and that were less uniform in shape. The weaker the drug–carrier adhesion, the higher the fine particle fraction of the drug is upon aerosolisation. It is believed that more elongated fine mannitol particles reduce the number of drug–carrier and drug–drug physical contact points and increase the ability of the drug particles to travel into the lower airways. Additionally, a lower drug–carrier contact area, lower drug–carrier press-on forces and easier drug–carrier detachment are suggested in the case of formulations containing more elongated fine mannitol particles. Ternary ‘drug-coarse carrier-elongated fine ternary component’ DPI formulations were more favourable than both ‘drug-coarse carrier’ and ‘drug-elongated coarse carrier’ binary formulations. This study provides a comprehensive approach for formulators to overcome the undesirable properties of dry powder inhalers, as both improved aerosolisation performance and reasonable flow characteristics were obtained using only a small amount of elongated engineered fine mannitol particles.     

Influence of the lactose grade within dry powder formulations of fluticasone propionate and terbutaline sulphate

Dry powder formulations are often composed of fine drug particles and coarser carrier particles, typically alpha-lactose monohydrate. However, the performance of a powder formulation may be highly dependent on the lactose quality and source. This study investigated the characteristics of lactose that influence the drug-to-carrier interaction and the performance of lactose-based dry powder inhaler formulations. The selected lactoses differed in the preparation processes and the content of fine lactose particles. Efficiency testing was done using fluticasone propionate and terbutaline sulphate as model drugs. Inverse gas chromatography was used to determine the surface heterogeneity distribution of different energy sites of the lactose and to understand the mechanism by which the fine carrier particles can improve the performance of dry powder inhalers. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. When the percentage of fine lactose is high, a lower quantity of drug adheres to the lactose and/or the adhesion force is also lower. This was confirmed by the aerosolization assays done in the TSI (twin stage impinger). A correlation was observed between adhesion characteristics and inertial impaction. For both drugs, the fine particle fractions were highest in blends that present a greater proportion of lactose fine particles. A fairly good correlation between the fine particle fractions of both drugs and the peak max value and the AUC (area under curve) were found by inverse gas chromatography. With higher fine particle fraction values, which correspond to higher content of fines, the peak maxima determined by inverse gas chromatography were shifted to higher adsorption potentials, which supports the agglomeration hypothesis.     

Adhesion forces in interactive mixtures for dry powder inhalers--evaluation of a new measuring method.

Dry powder inhalers mostly contain carrier based formulations where micronized drug particles are adhered to coarse carrier particles. The performance of the dry powder inhaler depends on the inhaler device, the inhalation manoeuvre and the formulation. The most important factor influencing the behaviour of the formulation is the adhesion force acting between the active ingredient and the carrier particles, which can be measured using different methods, for example the centrifuge technique or atomic force microscopy. In this study the tensile strength method, usually applied to determine cohesion forces between powder particles of one material, is optimized for adhesion force measurements between powder particles of unlike materials. Adhesion force measurements between the carrier materials lactose or mannitol and the drug substance salbutamol sulphate using the tensile strength method and the atomic force microscopy show higher values with increasing relative humidity. Consequently, the fine particle fraction determined using the Next Generation Impactor decreases with increasing relative humidity as a result of the enhanced interparticle interactions.     

Determination of interparticulate forces in ordered powder mixes

The theory of interparticle bond formation is considered with particular reference to ordered powder mixing. A technique is described for measuring the interparticle adhesion forces between drug and excipient particles bound in ordered units. The method uses a specially constructed ultracentrifuge rotor tube insert such that fine adherent particles can be separated from coarser carrier particles in ordered mixes. The ordered units are held behind a screen in the rotor tube insert and when the forces generated by ultracentrifugation become greater than the interparticle adhesion forces the ordered units break down into their component particles. Adhesion profiles were obtained for four different ordered mixes containing drug and excipient powders by plotting force of adhesion against the cumulative percentage of fine drug particles adhering to the carrier particle surface. The adhesion profile is influenced by the quantity of drug powder adhering to the excipient carrier particle surface. Above a critical drug content, each ordered mix shows a ‘composite' adhesion profile consisting of two distinct curves linked by a lag period. The initial curve, preceding the lag period, appears to correspond to loss of large amounts of weakly bound drug particles; after the lag period only relatively strongly adhered particles are removed and this phase occurs more gradually. The critical drug concentration is related to the surface properties of the excipient and drug particles which determine the strength of adhesion forces within an ordered unit.     

A critical evaluation of the relevant parameters for drug redispersion from adhesive mixtures during inhalation

In this paper, the parameters that are relevant to the drug redispersion from adhesive mixtures during inhalation are discussed and evaluated. The results obtained with air classifier technology give strong evidence for a dominating influence of carrier surface properties on the fraction of drug detached during inhalation at a low carrier payload (< or =1%, w/w), versus a dominating effect of carrier bulk properties at higher payloads. Furthermore, the results indicate that there is a fundamental difference between so-called active carrier sites and large surface discontinuities. The difference refers to the saturation concentrations, the rates of saturation and their effects on drug detachment during inhalation. The degree of saturation of the active sites appears to be proportional with the square root of the carrier surface payload (after 10 min mixing time in a Turbula mixer at 90 rpm). The storage volume of the discontinuities seems largely independent of the carrier diameter for particles derived from the same batch of crystalline lactose. Saturation of these discontinuities is completed at a much lower carrier surface payload than saturation of the active sites. Relatively large discontinuities are beneficial to de-agglomeration principles that make use of inertial separation forces during inhalation, as they provide shelter from inertial and frictional press-on forces during mixing which increase the strength of the interparticulate bonds in the powder mixture. For de-agglomeration principles generating frictional, drag or lift forces, carrier surface depressions and projections are disadvantageous however, as they also provide shelter from these removal forces.     

Agglomerate behaviour of fluticasone propionate within dry powder inhaler formulations

Due to their small size, the respirable drug particles tend to form agglomerates which prevent flowing and aerosolisation. A carrier is used to be mixed with drug in one hand to facilitate the powder flow during manufacturing, in other hand to help the fluidisation upon patient inhalation. Depending on drug concentration, drug agglomerates can be formed in the mixture. The aim of this work was to study the agglomeration behaviour of fluticasone propionate (FP) within interactive mixtures for inhalation. The agglomerate phenomenon of fluticasone propionate after mixing with different fractions of lactose without fine particles of lactose (smaller than 32 μm) was demonstrated by the optical microscopy observation. A technique measuring the FP size in the mixture was developed, based on laser diffraction method. The FP agglomerate sizes were found to be in a linear correlation with the pore size of the carrier powder bed (R(2)=0.9382). The latter depends on the particle size distribution of carrier. This founding can explain the role of carrier size in de-agglomeration of drug particles in the mixture. Furthermore, it gives more structural information of interactive mixture for inhalation that can be used in the investigation of aerosolisation mechanism of powder. According to the manufacturing history, different batches of FP show different agglomeration intensities which can be detected by Spraytec, a new laser diffraction method for measuring aerodynamic size. After mixing with a carrier, Lactohale LH200, the most cohesive batch of FP, generates a lower fine particle fraction. It can be explained by the fact that agglomerates of fluticasone propionate with very large size was detected in the mixtures. By using silica-gel beads as ball-milling agent during the mixing process, the FP agglomerate size decreases accordingly to the quantity of mixing aid. The homogeneity and the aerodynamic performance of the mixtures are improved. The mixing aid based on ball-milling effect could be used to ameliorate the quality of inhalation mixture of cohesive drug, such as fluticasone propionate. However, there is a threshold where an optimal amount of mixing aids should be used. Not only the drug des-aggregation reaches its peak but the increase in drug-carrier adhesion due to high energy input should balance the de-agglomeration capacity of mixing process. This approach provides a potential alternative in DPI formulation processing.     

The Rate of Drug Particle Detachment from Carrier Crystals in an Air Classifier-Based Inhaler

No HeadingPurpose. To investigate the rate with which drug particles are detached from carrier particles in adhesive mixtures when the action of the separation forces during inhalation is sustained by circulation of the powder dose in an air classifier.Methods. Residual drug on retained carrier particles from different adhesive mixture compositions has been analyzed after different circulation times in the classifier (0.5 to 6 s). For calculation of the detachment rate within the first 0.5 s of inhalation, the optical concentration of the aerosol from the classifier has been measured with laser diffraction technique.Results. Drug detachment from carrier crystals during inhalation increases not only with the flow rate but also with the time during which the action of the separation forces (at a constant flow rate) is sustained. The detachment rate at the same flow rate varies with the carrier size fraction and carrier payload and is clearly highest within the first 0.5 s of inhalation.Conclusions. Drug detachment from carrier approaches first-order reaction within the first half-second of inhalation. But at longer circulation times in the classifier, the ratio of removal to adhesive forces decreases dramatically. To increase the detached fraction of drug during inhalation at a constant flow rate, a short residence time for the powder in the de-agglomerator between 0.5 and 2 s is desired.     

Particle interactions involved in aerosol dispersion of ternary interactive mixtures

Purpose. To investigate the mechanism of action of ternary components within dry powder aerosols. Methods. Ternary interactive mixtures were prepared containing salbutamol sulphate (SS), coarse lactose carriers and either micronized lactose (ML) or micronized glucose (MG). In vitro drug and excipient aerosol deposition was performed using a twin-stage impinger (TSI) at 60 L/min with a Rotahaler device. Adhesional properties of the lactose carrier were examined using an atomic force microscope (AFM) colloidal probe technique. Result. The fine particle fraction (FPF) from ternary mixtures were dependent upon carrier type (p < 0.001), ternary concentration (p < 0.001) and ternary component type (p < 0.05). Ternary mixtures produced higher FPF than binary mixtures, except those containing Superfine (SF), which was attributed to the high proportion of intrinsic fine carrier particles. The higher FPF obtained from ternary mixtures was independent of the mixing order (p = 0.08). Increased adhesion force was observed on the carrier surface following the addition of ternary components (p < 0.001). Conclusion. The results confirm that ternary components increase aerosol deposition of powder mixtures. Some results were not entirely consistent with the saturation of active site theory and a hypothesis involving competitive and multilayer adhesion was proposed and requires further testing.