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.     

Lactose Composite Carriers for Respiratory Delivery

Purpose  Lactose dry powder inhaler (DPI) carriers, constructed of smaller sub units (composite carriers), were evaluated to assess their potential for minimising drug–carrier adhesion, variability in drug–carrier forces and influence on drug aerosol performance from carrier–drug blends. Methods  Lactose carrier particles were prepared by fusing sub units of lactose (either 2, 6 or 10 μm) in saturated lactose slurry. The resultant composite particles, as well as supplied lactose, were sieve fractioned to obtain a 63–90 μm carriers. The carriers were evaluated in terms of size (laser diffraction) morphology (electron microscopy and atomic force microscopy), crystallinity and drug adhesion (colloid probe microscopy). In addition, blends containing drug and carrier were prepared and evaluated in terms of drug aerosol performance. Results  The surface morphology and physico-chemical properties of the composite carriers were significantly different. Depending on the initial primary lactose size, the composite particles could be prepared with different surface roughness. Variation in composite roughness could be related to the change in drug adhesion (via modification in contact geometry) and thus drug aerosol performance from drug–lactose blends. Conclusion  Composite based carriers are a potential route to control drug–carrier adhesion forces and variability thus allowing more precise control of formulation performance.     

In Vitro Investigation of Drug Particulates Interactions and Aerosol Performance of Pressurised Metered Dose Inhalers

Purpose To determine a relationship between adhesive and cohesive inter-particulate forces of interactions and in vitro performance in pressurised metered dose inhalers (pMDIs) suspension formulations.Methods Interparticulate forces of salbutamol sulphate (SS), budesonide (BUD) and formoterol fumarate dihydrate (FFD) were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H, 3H perfluoropentane (HPFP). Experimental data were analysed using the recently developed cohesive/adhesive analysis method (CAB) and compared with in vitro deposition performances in pMDIs systems using Andersen cascade impactor (ACI).Results The in vitro investigation suggested that the micronised drug materials had significantly different aerosolisation profiles when manufactured as single or combination formulations. In general, the greatest significant differences were observed between SS single drug and SS-BUD and SS-FFD combinations. Analysis of the in vitro performance for the SS only formulation suggested that the cohesive nature of SS (as predicted by the CAB and observed with AFM) led to tightly bound flocs that did not fully deaggregate upon aerosolisation.Conclusions It is suggested that the relationship between interparticulate interactions and in vitro performance of pMDIs suspension systems, when compared to direct measurement of the adhesion/cohesion forces, indicated good correlation. This approach may be useful in expediting the development of pMDI formulation and predicting performance.     

Predicting the behavior of novel sugar carriers for dry powder inhaler formulations via the use of a cohesive-adhesive force balance approach

The aim of this work was to utilize the recently developed cohesive-adhesive balance (CAB) technique for analyzing quantitative AFM measurements to compare the relative forces of interaction of micronized salbutamol sulfate particles and a selection of specifically grown sugar substrates (beta cyclodextrin, lactose, raffinose, trehalose and xylitol). The interfacial behavior was subsequently related to the in-vitro delivery performance of these sugars as carrier particles in dry powder inhalation (DPI) formulations. The CAB analysis indicated that the rank order of adhesion between salbutamol sulfate and the sugars was beta cyclodextrin < lactose < trehalose < raffinose < xylitol. The beta cyclodextrin was the only substrate with which salbutamol sulfate demonstrated a greater cohesive behavior. All other sugars exhibited an adhesive dominance. In-vitro deposition performance of the salbutamol sulfate based carrier DPI formulations showed that the rank order of the fine particle fraction (FPF) was beta cyclodextrin > lactose > raffinose > trehalose > xylitol. A linear correlation (R(2) = 0.9572) was observed between the FPF and cohesive-adhesive ratios of the AFM force measurements. The observed link between CAB analysis of the interactive forces and in-vitro performance of carrier based formulations suggested a fundamental understanding of the relative balance of the various forces of interaction within a dry powder formulation may provide a critical insight into the behavior of these formulations.     

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.     

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.     

Back to basics: the development of a simple, homogenous, two-component dry-powder inhaler formulation for the delivery of budesonide using miscible vinyl polymers

It was hypothesised that formulating a dry-powder inhaler (DPI) using a refined, smooth grade of lactose, without fines and a polymer coated drug microparticle should produce an homogeneous formulation in which aerosolization behaviour could be modified. Hence, the aim of this study was to develop a simple two component polymer coated-budesonide/lactose blend in which the drug microparticle adhesive forces could be optimised by modifying the drug coating in order to improve aerosolization from a DPI. Budesonide microparticles (1.83 +/- 0.03 microm) were coated with the vinyl polymers by adsorption and then spray-dried. The drug was blended with three different types of lactose, checked for uniformity of mixing and loaded into Pulvinal devices. The median volume particle size of all but one of the polymer coated microparticles remained below 4 microm after spray-drying and the content uniformity for all the blends >96%. Coating the budesonide with 0.01% poly(vinyl alcohol) increased the fine particle fraction (FPF) in the next generation impactor (NGI) from 29.1 +/- 0.7% to 52.8 +/- 1.0% and reduced the force of adhesion from 410 +/- 182 to 241 +/- 82 nN with smooth lactose. This illustrates that vinyl polymers could effectively modify adhesive interactions without the need for ternary components such as fines.     

Influence of Humidity on the Electrostatic Charge and Aerosol Performance of Dry Powder Inhaler Carrier based Systems

Abstract To investigate the influence of storage relative humidity (RH) on the aerosolisation efficiency and tribo-electrification of carrier based dry powder inhaler (DPI) formulations using the next generation impactor (NGI) in vitro methodology and the electrostatic low pressure impactor (ELPI). Micronised salbutamol (d _0.5 1.48 ± 0.03 μm) was blended with 63–90 μm sieve fractioned α-lactose monohydrate carrier and stored at a range of humidities (0–84% RH). The aerosolisation efficiency after storage for 24 h periods was investigated using the NGI. The same experiment was conducted using the ELPI, with corona charger switched off, to measure the net charge vs. mass deposition profile. Significant variations in the aerosolisation efficiency of the formulation were observed with respect to storage RH. In general, the fine particle fraction aerosol performance measured by NGI and ELPI (fraction with mass median aerodynamic diameter <4.46 and 4.04 μm, respectively) followed a positive parabola with aerosol performance increasing over the range 0–60% RH before decreasing >60% RH. Analysis of the ELPI charge data suggested that the micronised salbutamol sulphate had an electronegative charge when aerosolised from lactose based carriers, which was most electronegative at low RH. Increased storage RH resulted in a reduction in net charge to mass ratio with the greatest reduction at RH >60%. The aerosol performance of this binary system is dependent on both electrostatic and capillary forces. The use of the ELPI allows a degree of insight into how these forces affect formulation performances after storage at different RH.     

Investigation of Electrostatic Behavior of Dry Powder-Inhaled Model Formulations

The accumulation of electrostatic charge on drug particles and excipient powders arising from interparticulate collisions or contacts with other surfaces can lead to agglomeration and adhesion problems during the manufacturing process, filling, and delivery of dry powder inhaler (DPI) formulations. The objective of the study was to investigate the role of triboelectrification to better understand the influence of electrostatic charge on the performance of DPIs with 2 capsule-based dimensionally similar devices constructed with different materials. In addition, strategies to reduce electrostatic charge build up during the manufacturing process, and the processes involved in this phenomenon were investigated. Electrostatic charge measurements showed that there was a significant difference in electrostatic charge generated between tested formulations and devices. This affects particle detachment from carrier and thus significantly impacts aerosol performance. Conditioning fluticasone DPI capsules at defined temperature and humidity conditions reduced electrostatic charges acquired during manufacturing. Conditioning salmeterol DPI capsules at same conditions seemed disadvantageous for their aerosol performance because of increasing capillary forces and solid bridge formation caused by water absorption. Knowledge and understanding of the role of electrostatic forces in influencing DPI formulation performance was increased by these studies.     

Effect of Dosing Cup Size on the Aerosol Performance of High-Dose Carrier-Based Formulations in a Novel Dry Powder Inhaler

This study investigated how varying the dosing cup size of a novel reservoir dry powder inhaler (DPI) affects the detachment of a micronized active pharmaceutical ingredient from larger carrier particles, and the aerosol performance of a DPI carrier formulation. Three different-sized dosing cups were designed: 3D printed with cup volumes of 16.26 mm³, 55.99 mm³, and 133.04 mm³, and tested with five different carrier type formulations with beclomethasone dipropionate (BDP) concentrations between 1% and 30% (w/w). The morphology of the BDP attached to the carrier was investigated using scanning electron microscopy and the aerosol performance using the Next Generation Impactor. Increasing the volume of the dosing cup led to a reduction of BDP deposition in the Next Generation Impactor preseparator, and an increase in BDP detachment from the carrier was observed, leading to increased aerosol performance. The decreased amount of BDP attached to carrier after aerosolization was attributed to the increased dosing cup void volume. This may enable greater particle-particle and particle-wall collisions, with greater BDP detachment from the carrier and deagglomeration of smaller agglomerates. The dosing cup volume was observed to have significant influence on particle dispersion and the overall aerosol performance of a DPI.     

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.     

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 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 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.     

Investigations on the Mechanism of Magnesium Stearate to Modify Aerosol Performance in Dry Powder Inhaled Formulations

The potential of the force control agent magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient-blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry and single particle aerosol mass spectrometry (SPAMS), and particle size, morphology, and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0% to 10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model active pharmaceutical ingredients were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor and also with SPAMS using a Breezhaler^® inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared with blends without force control agent, low-shear blending of MgSt increases the FPF of the model drug SX, whereas high-shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt, and additional information in terms of dispersibility of fine particles could be generated.     

Effect of Device Design and Formulation on the In Vitro Comparability for Multi-Unit Dose Dry Powder Inhalers

The focus of this investigation was to understand the design space to achieve comparable in vitro performance of two multi-unit dose dry powder inhalers (DPIs)—Flixotide® Accuhaler® (reference product) and MultiHaler® (test product). Flow field, pressure drop and particle trajectories within the test and reference DPI devices were modelled via computational fluid dynamics (CFD). Micronized fluticasone propionate (FP) was characterized to determine particle size distribution (PSD), specific surface area (SSA) and surface interfacial properties using cohesive-adhesive balance (CAB). CFD simulations suggested that the pressure drop and airflow velocity in the MultiHaler® were greater than Accuhaler®. Two modified test devices (MOD MH 1 and MOD MH 2) were manufactured with the introduction of by-pass channels in the airflow path, which achieved comparable specific resistance and airflow path between the test and reference devices. Assessment of reference product formulation in modified test devices suggested that MOD MH 2 achieved comparable in vitro performance to the reference product. CAB analysis suggested that adhesion of all FP batches to lactose was different, with batch D showing greatest and batch A least adhesion to lactose. Test DPI formulations were manufactured using four different batches of FP with milled or sieved lactose, and showed that batch A FP formulated with sieved lactose in MOD MH 2 device demonstrated the highest degree of similarity to the Accuhaler® in vitro deposition. Application of CFD modelling and material characterization of formulation raw materials enabled the modification of device and formulation critical material attributes to create an in vitro comparable device/formulation system to the reference product.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9775-z) contains supplementary material, which is available to authorized users.Key words: aerosolization, computational fluid dynamics, device design, dry powder inhaler, in vitro comparability, in vitro performance     

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).     

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.     

Drug-lactose binding aspects in adhesive mixtures: controlling performance in dry powder inhaler formulations by altering lactose carrier surfaces

For dry powder inhaler formulations, micronized drug powders are commonly mixed with coarse lactose carriers to facilitate powder handling during the manufacturing and powder aerosol delivery during patient use. The performance of such dry powder inhaler formulations strongly depends on the balance of cohesive and adhesive forces experienced by the drug particles under stresses induced in the flow environment during aerosolization. Surface modification with appropriate additives has been proposed as a practical and efficient way to alter the inter-particulate forces, thus potentially controlling the formulation performance, and this strategy has been employed in a number of different ways with varying degrees of success. This paper reviews the main strategies and methodologies published on surface coating of lactose carriers, and considers their effectiveness and impact on the performance of dry powder inhaler formulations.     

Modeling dispersion of dry powders for inhalation. The concepts of total fines, cohesive energy and interaction parameters

A range of carrier based dry powder formulations consisting of micronized drug, carrier lactose and, in some formulations, lactose fines were produced and tested for dispersibility, i.e. fine particle fraction (FPF). Two different drugs were used, budesonide (BUD) and beclomethasone dipropionate (BDP). A model based on the total amount of fines (TF) and the cohesive energy (CE) of the formulation is proposed, where TF is the sum of added drug, lactose fines and the fines inherent to the carrier. The expression for CE is derived from regular solutions theory and allows calculation of interparticle interaction parameters. The model was able to describe experimental data well, such as the decrease in FPF when the proportion of drug is increased at a constant TF level and the non-linear effects seen when a cohesive drug is added to carrier. BDP and BUD were found to be 5.3 times and 1.8 times more cohesive than lactose fines respectively. The model hence provides a link between the macroscopic behavior of a dry powder formulation and the interaction between the different species at the particulate level.