Quantification and control of cohesive and adhesive forces in dry powder inhaler formulations

Dry powder inhaler (DPI) formulations are commonly based on a mixture of coarse carrier, typically lactose, and micronised drug. The de-aggregation and dispersion properties of respirable particles, as well as the stability of the formulation, are associated with a delicate balance of the cohesive and adhesive interaction forces within the powder blend. This study describes the development of a novel atomic force microscopy (AFM) based technique to assess the dominant particulate interactions governing behaviour of such systems, and the optimisation and control of these interaction forces by the selective introduction of force control agents (FCAs) together with a mixing procedure capable of producing effective nano-layer coating within DPI formulations. 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 the alphalactose monohydrate excipient. To minimise variations in contact area between colloid probes and substrates, nanometre smooth crystal surfaces of the drugs and the excipient were prepared. A cohesive-adhesive balance (CAB) graphs was developed to allow direct comparison of the interaction forces occurring in model carrier-based formulations. Aerodynamic particle analyses together with in vitro characterisation of model DPI formulations revealed a paradoxical relationship between particle cohesive strength and de-agglomeration efficiencies of drug only formulations, where an increase in cohesive strength led to a higher fine particle fraction. A possible explanation for the variation in the fluidisation and aerosolisation properties between low and high cohesive particles was modelled on the relationship between cohesion, metastable agglomerate size and the resulting aerodynamic drag force acting on the fluidised 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. In order to improve dry powder formulation delivery characteristics, the influence of force control agents (FCAs) on the properties and performances of model DPI formulations was investigated. Three FCAs were chosen for their low surface energetic properties: leucine, lecithin and magnesium stearate. The cohesive and adhesive dependencies were controlled by conditioning either the drug or the carrier with an FCA before mixing in order to create selective modifications of the inter-particulate interactions within the dry powder formulation. This was achieved by first using a high energetic process (mechanofusion) following a low energetic process (Turbula). Radical modifications in the behaviour of the formulation performances, anticipated by CAB-graph analyses, were subsequently observed. This work emphasised that the CAB analysis method can be utilised for pre­ formulation studies in the design of new formulation systems for dry powder inhalers. The work also confirmed the potential value of the use of force control agents together with the Mechanofusion process in the preparation of DPI formulations.