Dry Powder Inhalers: Study of the Parameters Influencing Adhesion and Dispersion of Fluticasone Propionate

Abstract

Abstract. Interactions between particles are dependent on the physicochemical characteristics of the interacting particles but it is also important to consider the manufacturing process. Blending active pharmaceutical ingredient (API) with carrier is a critical stage that determines the blend homogeneity and is the first step towards obtaining the final quality of the powder blend. The aim of this work was to study parameters that influence the interactions between API and carrier in adhesive mixtures used in DPI and their effect on API dispersion. The study was done with fluticasone propionate blended with lactose 'Lactohale 200'. The study was based on the influence of the operating conditions (speed, mixing time, resting steps during mixing), the size of the carrier and the storage conditions on the blend properties and on the API dispersion. The quality of the blends was examined by analysing the API content uniformity. Adhesion characteristics were evaluated by submitting mixtures to a sieving action by air depression with the Alpine air-jet sieve. Aerodynamic evaluation of fine particle fraction (FPF) was obtained using a Twin Stage Impinger; the FPF being defined as the mass percentage of API below 6.4 μm. For good dispersion and therefore good homogeneity of the API in the carrier particles, speed and powder blending time have to be sufficient, but not too long to prevent the appearance of static electricity, which is not favourable to homogeneity and stability. The FPF increases with the decrease in the carrier size. The storage conditions have also to be taken into consideration. Higher humidity favours the adhesion of API on the carrier and decreases the FPF.

DEM analysis of particle adhesion during powder mixing for dry powder inhaler formulation development

“…The particle-particle interaction forces have to be sufficiently strong that fine API particles can adhere with the carriers or form large agglomerates to be transported, but weak enough that they can be detached or dispersed by a deagglomeration process and thus allow the delivery of the API particles into the respiratory tracts and lungs. Therefore, particle-particle interactions play a significant role in controlling the performance of DPIs and hence many studies have been performed to explore the dependency of these interactions on particle size [7,8], material properties [9,10], particle concentration [11,12], particle morphology [13,14], particle surface roughness [15,16], storage conditions [17,18], surface area [19], density and porosity [20], and crystal form [21]. For example, Kaialy et al [7] experimentally examined the influence of the particle size of lactose carrier on the DPI performance and demonstrated that the DPI performance improved with decreasing carrier particle size.…”

“…Le et al [17] employed a twin stage impinger to evaluate the dispersion performance at various humidity conditions and found that the FPF decreased as the relative humidity is increased. Cline and Dalby [19] found that the FPF increased with the increased surface area.…”

“…This is generally realised through mixing APIs with carriers in a blender, which determines the formulation quality and efficiency [17,[22][23][24]. Both mixing conditions (e.g.…”

“…They argued that this was due to the formation of drug-drug aggregates on the surface of the carrier particles as more drug particles were adhered over time. However, Le et al [17] investigated the influence of mixing conditions on the API content and demonstrated that the mean values of the blends were poorly correlated with the mixing time.…”

“…1-30 min by Selvam et al [22] and 60-180 min by Le et al [17]) and different materials investigated (i.e. Selvam et al [22] used budesonide drug and polyolefin medical packaging films, while Le et al [17] considered lactose carrier and Fluticasone Propionate drug).…”