David A.V. Morton

The cohesive-adhesive balances in dry powder inhaler formulations I: direct quantification by atomic force microscopy

AbstractPurpose. To obtain a quantitative assessment of the cohesive and adhesive force balance within dry powder inhaler formulations. Methods. The atomic force microscope (AFM) colloid probe technique was used to measure the adhesive and cohesive force characteristics of dry powder systems containing an active component (budesonide, salbutamol sulphate) and α-lactose monohydrate. To minimize the variations in contact area between colloid probe and substrates, nanometer smooth crystal surfaces of the drugs and the excipient were prepared. Results. The uniformity in contact area allowed accurate and reproducible force measurements. Cohesive-adhesive balance (CAB) graphs were developed to allow direct comparison of the interaction forces occurring in model carrier-based formulations. A salbutamol sulphate-lactose system revealed a significant tendency for the two materials to adhere, suggesting a propensity for the powder to form a homogenous blend. In contrast, the budesonide-lactose system exhibited strong cohesive properties suggesting that the formulation may exhibit poor blend homogeneity and potential for segregation upon processing and handling. Conclusions. The novel approach provides a fundamental insight into the cohesive-adhesive balances in dry powder formulations and further understanding of powder behavior.

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

AbstractPurpose. 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.

Improving aerosolization of drug powders by reducing powder intrinsic cohesion via a mechanical dry coating approach

The aim of this study was to investigate the effect of coating on the aerosolization of three model micronized powders. Three model powder materials (salbutamol sulphate, salmeterol xinafoate, triamcinolone acetonide) were chosen not only for their different chemical properties but also for their different physical properties such as shape and size distribution. Each powder was coated with 5% (w/w) magnesium stearate using two different dry mechanofusion approaches. After mechanofusion, both poured and tapped densities for all three model drug powders significantly increased. There were significant improvements in aerosolization behavior from an inhaler device for all model powders after mechanofusion. Such improvements in aerosolization were attributed to the reduction in agglomerate strength caused by decreasing powder intrinsic cohesion via surface modification. The work also indicated that the effect of the coating was dependant on the initial particle properties.

New developments in dry powder pulmonary vaccine delivery

Pulmonary immunization has gained increased recognition as a means of triggering both a mucosal and systemic immune response without the use of needles. The appropriate formulation of antigens in a dry, solid state can result in improved stability, thereby removing cold-chain storage complications associated with conventional liquid-based vaccines. The particulate nature of dry powder vaccines could also induce a better immune response. This review describes our current understanding of pulmonary immunization, including possible barriers facing the development of pulmonary vaccines, and discusses recent advances in spray-drying technologies applicable to the production of dry powder formulations for pulmonary vaccine delivery.

Understanding the influence of powder flowability, fluidization and de-agglomeration characteristics on the aerosolization of pharmaceutical model powders

The aim of this study was to investigate the influence of the intrinsic inter-particulate cohesion of model pharmaceutical powders on their aerosolization from a dry powder inhaler. Two cohesive poly-disperse lactose powders with median particle sizes of around 4 and 20 microm were examined. The results showed that after dry coating with magnesium stearate, their flowability, fluidization and de-agglomeration behaviours could be substantially improved, as indicated by powder rheometry, shear testing and laser diffraction aerosol testing. This was achieved by reducing their cohesiveness via surface modification. In contrast to some previous reports, this study demonstrated how powder aerosolization may be improved more significantly and consistently (for widely varying air flow rates) by substantially reducing their inter-particulate cohesive forces. This study contributes to the understanding of the relationship between intrinsic cohesive nature and bulk properties such as flowability, fluidization and de-agglomeration and its impact on their aerosolization, which is fundamental and critical in the optimal design of dry powder inhaler formulations. The intensive mechanical dry coating technique also demonstrated a promising potential to improve aerosolization efficiency of fine cohesive model powders.

The effect of amino acid excipients on morphology and solid-state properties of multi-component spray-dried formulations for pulmonary delivery of biomacromolecules

For a dry powder carrier platform to be suitable for pulmonary delivery of potent biomacromolecules, it has to be aerosolisable and capable of stabilising the biomacromolecules. In the present study, strategies aiming to produce a multi-component spray-dried powder formulation with a stable amorphous glassy matrix containing mannitol, trehalose, glycine and alanine, while using leucine as a particle formation and aerosolisation enhancing agent were investigated. The results from in vitro aerosolisation studies demonstrated high fine particle fractions (FPFs) from several formulations. Scanning electronic micrographs (SEMs) revealed distinct morphological features of these formulations in response to increasing leucine concentration: from the apparent insufficiency for discrete particle formation, to reduced particle agglomeration, to increased surface corrugation. X-ray powder diffraction (XRPD) results indicated that partially ordered leucine resulting from self-assembly on the particle surface is important for the amino acid to function effectively as an encapsulating agent. This may also play a role in inhibiting crystallisation of other components within the formulation. In conclusion, the results suggest that with suitable particle size, good dispersibility and solid-state properties, selected trehalose/leucine combinations appear to have good potential for development into a universal carrier platform for pulmonary delivery of potent biomacromolecules and the work highlights areas deserving further investigation.

Characterization of the surface properties of a model pharmaceutical fine powder modified with a pharmaceutical lubricant to improve flow via a mechanical dry coating approach

The aim of this study is to investigate the changes in physical and chemical surface properties of a fine lactose powder, which has been processed by a mechanical dry coating approach. A commercially available milled lactose monohydrate powder (median diameter around 20 μm) was dry coated with a pharmaceutical lubricant, magnesium stearate (MgSt). Substantial changes in bulk behavior have been shown previously and the purpose of the current work was to understand the relationship between these bulk changes and physico-chemical changes in the surface. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry results demonstrated both qualitatively and quantitatively how the chemical properties of the lactose particle surfaces had been altered. The characterization results indicated that a high-level coverage of a thin coating layer of MgSt has been created through the coating. Inverse gas chromatography was used to probe the surface energetic changes, and at conditions of finite dilution, provided a new insight into surface energy changes. This work demonstrated that the modifications of the surface physical and chemical properties correlated with the reduction in powder cohesion and improvement in powder flow.

Improving Powder Flow Properties of a Cohesive Lactose Monohydrate Powder by Intensive Mechanical Dry Coating

The objective of this study was to improve the cohesive lactose powder flowability. A cohesive lactose monohydrate powder was processed in either a tumbling blender or an intensive mechanical processor with either magnesium stearate or fumed silica. No substantial changes in particle size were detected by laser diffraction following either treatment. The untreated lactose sample exhibited very poor powder flow. Only limited improvements in powder flowability were indicated after the tumbling blending, intensive mechanical processing with the fumed silica or without additives. However, the intensive mechanical processing of the lactose sample with magnesium stearate demonstrated exceptionally large increases in both poured and tapped density as well as notable improvements in all powder flowability indicators examined. Our findings support the use of intensive mechanical processing technique as an effective method to coat cohesive pharmaceutical powders with selected additives, modify the surface nature of the particles, reduce the interparticle cohesive forces and hence improve powder flowability. The subtle differences in powder flow behaviour of lactose samples between the untreated and tumbling blended powders with magnesium stearate were only detected by the powder rheometer using its dynamic mode, indicating its potential advantages over traditional powder flow characterisation approaches.

Determination of the Polar and Total Surface Energy Distributions of Particulates by Inverse Gas Chromatography

This Letter reports a technique of measuring polar surface energy distributions of lactose using inverse gas chromatography (IGC). The significance of this study is that the total surface energy distributions can now be characterized by combining the already known dispersive surface energy distribution with polar surface energy distribution determined in this study. The polar surface energy was calculated from the specific free energies for surface interactions with a monopolar basic probe, ethyl acetate, and a monopolar acidic probe, dichloromethane.

Investigation of the extent of surface coating via mechanofusion with varying additive levels and the influences on bulk powder flow properties.

The objective of this study was to investigate if the coating extent created by a mechanofusion process corresponded with observed changes in bulk powder properties. A fine lactose powder (approximate median diameter 20 μm) was dry coated with magnesium stearate using from 0.1 to 5% (w/w) content. An ultra-thin coating layer of magnesium stearate was anticipated, but previous attempts to determine such thin layers on these fine particles have had limited success, with poor resolution. In this study, the surface coating was examined using the state-of-the-art XPS and ToF-SIMS systems. The powder flow was characterized by Carr index and shear cell testing. XPS was successfully applied to demonstrate variations in surface coverage, as a function of additive levels, and indicated near complete coating coverage at additive levels of 1% (w/w) and above. ToF-SIMS results supported such coating coverage assessment, and indicated coating uniformly across the fine particle surfaces. The flow metrics employed could then be related to the coating coverage metrics. The mechanofusion process also modified the apparent surface roughness observed by SEM and BET. It was suggested that the changes in the surface chemical composition exerted a more evident and direct impact on the powder cohesion and flow characteristics than the changes in the surface morphological properties after the mechanofusion in this study.