An Investigation into the Dispersion Mechanisms of Ternary Dry Powder Inhaler Formulations by the Quantification of Interparticulate Forces
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To investigate the dispersion mechanism(s) of ternary dry powder inhaler (DPI) formulations by comparison of the interparticulate adhesions and in vitro performance of a number of carrier–drug–fines combinations.
Materials and Methods
The relative levels of adhesion and cohesion between a lactose carrier and a number of drugs and fine excipients were quantified using the cohesion–adhesion balance (CAB) approach to atomic force microscopy. The in vitro performance of formulations produced using these materials was quantified and the particle size distribution of the aerosol clouds produced from these formulations determined by laser diffraction.
Comparison between CAB ratios and formulation performance suggested that the improvement in performance brought about by the addition of fines to which the drug was more adhesive than cohesive might have been due to the formation of agglomerates of drug and fines particles. This was supported by aerosol cloud particle size data. The mechanism(s) underlying the improved performance of ternary formulations where the drug was more cohesive than adhesive to the fines was unclear.
The performance of ternary DPI formulations might be increased by the preferential formation of drug–fines agglomerates, which might be subject to greater deagglomeration forces during aerosolisation than smaller agglomerates, thus producing better formulation performance.
Key wordsadhesion agglomeration atomic force microscope fines ternary interactive mixture
Atomic force microscopy
Coefficient of variation
Dry powder inhaler
Formoterol fumarate dihydrate
Fine particle dose
Fine particle fraction
Geometric standard deviation
High performance liquid chromatography
Mass median aerodynamic diameter
Next Generation Impactor
Root mean square roughness
Scanning electron microscope
The authors gratefully acknowledge the Engineering and Physical Sciences Research Council and GlaxoSmithKline for their generous funding of this work. The authors gratefully acknowledge the assistance of Andy Smith (Sympatec Ltd.) in obtaining the aerosol cloud particle size distribution data.
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