Issue link: http://www.e-digitaleditions.com/i/686898
Wet coating of particles One such option is to coat milled particles with a thin (even down to nano-scale) layer of an additive or "force control agent," notably a pharmaceutical lubricant such as magnesium stearate. The aim is to address the stability and low-efficiency issues with one step. The concept is simple: put a ubiquitous, ultra-thin coating onto the cohesive milled particles to make them not only achieve much improved flowability and dispersibility than the uncoated milled particles, but also perform more consis- tently over the time of storage. Traditionally, pharma- ceutical coating has been dominated by wet coating approaches (e.g., using a fluid bed) which have been used extensively to coat much larger particles or pellets. For example, Chan, et al. coated coarse lactose carriers (64 µm) with micronized lactose fine particles (4 µm). 9 However, it is extremely challenging to wet-coat fine inhalable particles with aerodynamic diameters < 5 µm in a relatively scalable and cost effective process. 10 For example, as the consequence of liquid bridging, either the aggregates (rather than the individual particles) are coated or granules are formed. Even at the laboratory scale, success in coating ultra-fine particles is rare and can be associated with inability to scale up. Dry coating In contrast, dry coating has proven to be a relatively sim- ple and easy-to-control process, with proven scale-up feasibility in the manufacture of toners and cosmetics and in the powder metallurgy industries. As a single step process, without solvents to handle and remove, dry coating is quicker, safer, lower cost and more environ- mentally friendly, compared to the solvent-based coat- ing approaches. 11 After approximately 40 years of development of mechan- ical dry coating technology, there are several systems avail- able including the Hybridizer (Nara), Magnetically Assisted Impaction Coater (MAIC, New Jersey Institute of Technology), Mechanofusion (Hosokawa Micron) and Theta-Composer (Tokuju). 12 Other equipment such as the high shear mixer Cyclomix® (Hosokawa Micron) 13 and the Quadro® Comil ® 14 for co-milling have also been employed to coat cohesive powders. The configurations of various dry coating equipment vary, but the general principles are the same: high-shear and high-energy inter- actions between particle/particle or particle/device are used to coat the surface of host particles with guest mater- ial. For example, the Nanocular mechanofusion system (Hosakawa Micron) comprises a solid circular blade with two semi-circular press heads that compress powders against the internal vessel wall (Figure 1C). Literally, the dry coater is a highly energetic variant of a high-shear mixer, employing maximum surface interactions and minimum milling effects. The operation of these dry coating systems is relatively simple, involving loading the powder, processing for a set time (often around 5-15 minutes) then unloading the powder. Each process is optimized and validated. Contin- uous manufacturing is also feasible for some dry coating devices. Studies have shown that batch variation is low (Table 1) 15 and scaled-up bulk properties are comparable between, for example, milled lactose powders coated with a lab-scale mechanofusion system (Nobilta-AMS Mini, powder load up to 0.1 L) and a pilot-scale system (Nobilta-130, powder load up to 0.5 L) (Hosokawa Micron) (Table 2). By comparison, a commercially avail- able mechanofusion system may have a processing capac- ity of 1,000 L. Mechanofusion has been the most extensively examined process for inhalation formulations, likely due to its high efficiency and ease of use. Other techniques have also been attempted. For example, co-jet-milling of micronized salbutamol sulfate with magnesium stearate has shown a reduced dispersive surface energy and more homogenous energy distribution. 18 18 JUNE 2016 Inhalation Figure 1 Figure 1. (A) Diagram of dry coating process; (B) Image of mechanofusion AMS-Mini system with a Nobilta processor; (C) Image of mechanofusion AMS-Mini system with a Nanocu- lar processor. Figures B and C are reprinted from reference 29 with permission from Elsevier. Table 1. Powder properties of mechanofused salbutamol sul- fate from three different batches have shown process repro- ducibility in fine particle fraction (FPF) and emitted dose (ED). Mean ± SD, n = 4. Data are adopted from reference 15. Table 1 Press head Powder Chamber Batch 1 Batch 2 Batch 3 FPF (%) 68.6 ± 1.6 66.4 ± 2.7 67.5 ± 2.1 ED (%) 68.0 ± 1.2 69.2 ± 1.0 67.4 ± 0.7