Mixing Time Effects on the Dispersion Performance of Adhesive Mixtures for Inhalation

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.

New Mechanisms to Explain the Effects of Added Lactose Fines on the Dispersion Performance of Adhesive Mixtures for Inhalation

“…For example, the use of a finer carrier likely reduces the relevance of the press-on hypothesis and may also greatly affect the potential for agglomeration of the fine components on the carrier surface [19]. Furthermore, the test inhaler used in this study relies predominantly on inertial (collisional, vibrational and rotational) forces for the separation of drug particles from the carrier surface.…”

On the effects of blending, physicochemical properties, and their interactions on the performance of carrier-based dry powders for inhalation — A review

“…The authors explained this as blending induces disorder in the powder bed, which reaches a maximum level after a certain point of time. In another study, Grasmeijer et al [36] showed that the prolonged blending in the Turbula™ mixer (operated at 90 rpm) caused a decrease in drug detachment from carrier particles, with the strongest decline taking place in the first 120 min of blending. This can be explained as increasing the blending time will increase the time during which the press-on forces are enabled, thus small drug particulates become more tightly attached to carrier surface or swept into carrier surface crevices, resulting in an increase in the adhesive tendency of the formulations [31,76,86,87].…”

“…For example, the type of drug was shown to affect the cohesive-adhesive balance (CAB) of drugcarrier adhesive mixtures. Thus it may change the balance of the different principal processes during blending [35] and therefore interact with the effect of blending conditions on drug aerosolisation performance [36] (Fig. 1).…”

“…Surprisingly, the literature reports only a handful number of studies on the effects of blending time on drug-carrier interactions in adhesive mixtures for inhalation [21,36,[74][75][76][77]. Blending time could promote significant changes in the agglomeration state and deposition profiles of drugs aerosolised from DPIs [78].…”

“…Blending, particularly high shear blending, can lead to the formation of fine particulates due to the attrition of the carrier material, i.e., fracturing of cleavage planes found in particles [36,87]. For example, Shur et al [156] showed that, in contrast to low-moderate shear blending (Trubula™ or Whirlmixer™), high shear blending generated intrinsic in situ lactose fines.…”