Abstract
This paper deals with the effects of mixing time on the homogeneity and dispersion performance of adhesive mixtures for inhalation. Interactions between these effects and the carrier size fraction, the type of drug and the inhalation flow rate were studied. Furthermore, it was examined whether or not changes in the dispersion performance as a result of prolonged mixing can be explained with a balance of three processes that occur during mixing, knowing drug redistribution over the lactose carrier; (de-) agglomeration of the drug (and fine lactose) particles; and compression of the drug particles onto the carrier surface. For this purpose, mixtures containing salmeterol xinafoate or fluticasone propionate were mixed for different periods of time with a fine or coarse crystalline lactose carrier in a Turbula mixer. Drug detachment experiments were performed using a classifier based inhaler at different flow rates. Scanning electron microscopy and laser diffraction techniques were used to measure drug distribution and agglomeration, whereas changes in the apparent solubility were measured as a means to monitor the degree of mechanical stress imparted on the drug particles. No clear trend between mixing time and content uniformity was observed. Quantitative and qualitative interactions between the effect of mixing time on drug detachment and the type of drug, the carrier size fraction and the flow rate were measured, which could be explained with the three processes mentioned. Generally, prolonged mixing caused drug detachment to decrease, with the strongest decline occurring in the first 120 minutes of mixing. For the most cohesive drug (salmeterol) and the coarse carrier, agglomerate formation seemed to dominate the overall effect of mixing time at a low inhalation flow rate, causing drug detachment to increase with prolonged mixing. The optimal mixing time will thus depend on the formulation purpose and the choice for other, interacting variables.
Highlights
Lacey was one of the first to describe the mixing process as the creation of disorder by allowing chance to determine the positions of the particles
The theoretical ‘random’ mixing process addressed by Lacey excludes particle interaction phenomena and is fundamentally different from the ‘ordered’, or rather, ‘total’ mixing process that best describes the formation of adhesive mixtures for inhalation [2,3,4]
The inhomogeneous nature of lactose carrier surfaces allows for redistribution of drug particles to occur between surface sites with a different binding activity or sites with a different capacity to offer sheltering to drug particles from the redistribution forces during further mixing [2,4,8,9]
Summary
Lacey was one of the first to describe the mixing process as the creation of disorder by allowing chance to determine the positions of the particles. The theoretical ‘random’ mixing process addressed by Lacey excludes particle interaction phenomena and is fundamentally different from the ‘ordered’, or rather, ‘total’ mixing process that best describes the formation of adhesive mixtures for inhalation [2,3,4]. In both instances the role of mixing time is essentially the same, in that it allows chance effects to accumulate and determines the extent to which certain processes within the mixture take place. Lactose fines might be generated by attrition of the carrier, but this process seems to be restricted to high shear blending operations [13,14]
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