Issue link: https://www.e-digitaleditions.com/i/1469783
28 JUNE 2022 Inhalation mulations. ese mixers act through a combination of high shear and forces applied directly to the (con- ned) particles, in what is sometimes referred to as a "mechanofusion" process [26, 28]. When used for coating of lactose carriers, obtaining a powder with exceptionally good ow properties has been reported [28, 29]. It can be questioned, however, whether such high-energetic, expensive processes are needed for preparation of adhesive mixtures for inhalation. Advances have been made in understanding the forces exerted among particles during high shear mix- ing and how these a ect formulation performance in terms of FPF [19]. e key concept here is the applied mixing energy (ME), which is de ned by: ME=m carrier * v 3 t/r Equation 1. where m carrier is the mass of the carrier particle, v is the peripheral speed, r is the radius of the mixing bowl and t is the mixing time. With revolutions per minute (rpm) instead of peripheral speed, the equa- tion reads: ME=8π 3 m carrier * rpm 3 r 2 t 60 Equation 2. Analogously, the applied mixing force (MF) can be de ned by: MF= m carrier * v 2 r Equation 3. lactose nes are given in Figure 5 and compared to the e ect of an increase in drug load. In both cases, there is an almost linear increase in the FPF within the investigated interval. However, at even higher concentration, the FPF starts to fade [11]. As for the addition of MgSt or other coating agents, small amounts are normally su cient and the typical range used is from 0.1% to 1.0%. [2, 3]. It should be noted, however, that complete coverage of the carrier particles with a coherent layer of coating agent can- not be expected when the coating agent is applied in a dry coating process. is is illustrated in Figure 4, where small areas of uncoated lactose (green) appear, regardless of the mixing time. Processing e two main routes for mixing are low shear mix- ing and high shear mixing [25]. Low shear mixing is carried out in tumbling mixers, such as the Turbula ® (Willy A. Bachofen, Basel, Switzerland) or Bohle (LB Bohle, Ennigerloh, Germany) mixers, with speeds from tens of revolutions per minute (rpm) (or even lower at production scale) to one hundred rpm and mixing times typically ranging from 15 minutes to 1 hour. Tumbling mixers are usually gentle and can operate without causing substantial damage to crys- talline materials. Low shear mixing is appropriate for binary API/carrier blends and for ternary blends that include lactose nes. Attention should be paid to mixing of highly cohesive APIs, as the applied forces may not be su cient to break up API agglomerates. High shear mixers are more e cient than low shear mixers and a few minutes of mixing is nor- mally su cient to achieve good homogeneity. High shear mixing is also recommended for compositions with coating agents, as these agents are more easily smeared with high shear mixing [26]. Still, coating may occur in a tumbling mixer [27]. A comparison of three di erent coating agents revealed that MgSt coated a lactose carrier more rapidly than did sodium stearyl fumarate and L-leucine using a Diosna high shear mixer (Diosna Dierks & Sohne, Osnabrück, Germany) [20]. A main drawback of high shear mixing is that it may lead to generation of amorphous content during pro- cessing which, in turn, could induce stability issues. e e ect is expected to be more pronounced for larger carriers and at higher speeds. Addition of a coating agent may reduce such e ects, as the surfaces become coated as well as lubricated, which protects the underlying lactose crystal lattice. Losses of drug and powder will likely also be larger in high shear mixers than in low shear mixers. Mixers that are even more intense, such as the Cyclo- mix (Hosokawa Micron, Runcorn, UK) and the Nobilta™ (Hosokawa Micron, Runcorn, UK), have also been investigated for preparation of inhaled for- Figure 5 Fine particle fraction plotted as a function of the total content of API plus lactose nes. Circles refer to budesonide and carrier A, triangles to budesonide and carrier B, and X's to 2% budesonide and carrier A, with increasing amounts of lactose nes. Adapted from reference 11. 0 2 4 6 8 10 12 Total of API and lactose nes [% w/w] Fine particle fraction [%] 40 35 30 25 20 15 10 5 0