The effect of mixing time on drug agglomeration and detachment for adhesive mixtures containing fine lactose carriers

Background: In a previous study it was hypothesised that the effect of mixing time on drug agglomeration and detachment for a coarse lactose carrier is dependent on the presence of large carrier surface discontinuities. To test this hypothesis, experiments were repeated with a fine lactose carrier that contains smaller surface discontinuities. Methods: Mixtures of lactose (63-90 μm) and salmeterol xinafoate or fluticasone propionate were prepared using a Turbula mixer at 90 rpm for 0.5 to 780 minutes. Laser diffraction analysis of undissolved drug clusters in an aqueous suspension after dissolution of the carrier was performed to follow drug agglomeration behaviour in the blends. A classifier based test inhaler was used to determine drug detachment at 20 and 60 L/min. Mixtures were imaged by SEM. Results: Decreasing drug detachment was observed for both drugs at both flow rates with increased mixing time. Until 60-120 minutes of mixing this was accompanied by a decrease in agglomerate size, whereas with prolonged mixing increased dissolution of salmeterol and a gradual film formation by submicron fluticasone particles on the carrier surface were observed. Conclusions: Mechanical forces have a more pronounced negative effect on drug detachment with increased mixing time for a fine lactose carrier of 63-90 μm than for a coarse carrier of 250-315 μm. In addition to drug deagglomeration, continued low shear blending can cause enhanced solubility of salmeterol and film formation by fluticasone. These findings stress the importance of reducing mechanical stress on drug particles during the mixing process, for example, by using carriers with increased macro surface roughness.