Haggis Harris

The Role of Fines in the Modification of the Fluidization and Dispersion Mechanism Within Dry Powder Inhaler Formulations

PurposeTo investigate the role of in situ generated fine excipient particles on the fluidization and aerosolization properties of dry powder inhaler (DPI) formulations.Materials and MethodsCarrier 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.ResultsHigh 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.ConclusionsThe 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.

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.

The Influence of Crystal Habit on the Prediction of Dry Powder Inhalation Formulation Performance Using the Cohesive-Adhesive Force Balance Approach

The aim of this investigation was to study the influence of crystalline habit of active pharmaceutical ingredients on the cohesive–adhesive force balance within model dry powder inhaler (DPI) formulations and the corresponding affect on DPI formulation performance. The cohesive–adhesive balance (CAB) approach to colloid probe atomic force microscopy (AFM) was employed to determine the cohesive and adhesive interactions of micronized budesonide particles against the {102} and {002} faces of budesonide single crystals and crystalline substrates of different sugars (cyclodextrin, lactose, trehalose, raffinose, and xylitol), respectively. These data were used to measure the relative level of cohesion and adhesion via CAB and the possible influence on in vitro performance of a carrier-based DPI formulation. Varying the crystal habit of the drug had a significant effect on the cohesive measurement of micronized budesonide probes, with the cohesive values on the {102} faces being approximately twice that on the {002} crystal faces. However, although different CAB values were measured with the sugars with respect to the crystal faces chosen for the cohesive-based measurement, the overall influence on the rank order of the CAB values was not directly influenced. For these data sets, the CAB gradient indicated that a decrease in the dominance of the adhesive forces led to a concomitant increase in fine particle delivery, reaching a plateau as the cohesive forces became dominant. The study suggested that crystal habit of the primary drug crystals influences the cohesive interactions and the resulting force balance measurements of colloid probe CAB analysis.