Abstract
The aim of the study was to investigate the specific influence of force control agents (FCAs) (leucine, lecithin and magnesium stearate) on the interfacial properties of a salbutamol sulphate-lactose dry powder inhaler formulation. The influence of FCAs on the cohesive and adhesive force balance was directly assessed via an atomic force microscopy (AFM) colloid probe technique, with a recently developed cohesive-adhesive balance (CAB) graphical analysis procedure. Co-processing of constituent particles was conducted by a novel dry mechanical fusion method (Mechanofusion). The in vitro deposition profile of the model salbutamol sulphate formulations was investigated using a Monohaler® DPI device with a next generation impactor (NGI) apparatus. The CAB-graph analysis of a salbutamol sulphate-lactose binary system suggested a predisposition for an interactive mixture. However, the reduced intermixing coefficient (Fdrug-lactose/Fdrug-drug) suggested that a significant amount of energy would be required to overcome the strong adhesive interaction for efficient dispersion of the drug from a lactose surface. The processing of lactose with leucine, lecithin or magnesium stearate, prior to formulating with the drug, significantly reduced the adhesive interactions of the salbutamol with modified lactose samples. The CAB analyses indicated that the reduced intermixing coefficients shifted to such an extent that cohesive drug interactions dominated. These dramatic shifts in the balance of forces were shown to lead to poor blend homogeneity and potential for significant segregation between drug and carrier particles. Conversely, the conditioning of salbutamol sulphate with leucine, lecithin and magnesium stearate, which modified both the adhesive and cohesive interactions, formed homogenous interactive blends with advantageously weaker drug-lactose interactions. Formulations with pre-conditioned drug, in contrast to conditioned lactose, offered the best drug delivery performances. The use of the colloid AFM technique in combination with the cohesive-adhesive balance (CAB) approach provided a very accurate means of predicting dry powder formulation behaviour and the specific influence of particulate interactions on aerosol performance.
