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Inhalation JUNE 2016 19 Theoretically, guest particles should be smaller than those of the host so the guest material (i.e., colloidal silica) can form a layer of fine particles. Alternatively, the guest mate- rial is soft and lamellar (i.e., magnesium stearate) so it can be laminated and smeared onto the surface of host parti- cles. Both glidants and lubricants are popular coating materials for oral solid dosage forms. For inhalation pur- poses, the use of colloidal silica may raise concerns about pulmonary cytotoxicity while magnesium stearate has been accepted as safe for use in inhalation and been approved in several inhalation products (i.e., Pulmicort® CFC-free metered dose inhaler (previously marketed by AstraZeneca) and Foradil® Certihaler® (Novartis)). 19 Several patent applications describe the problem solving and applied nature of intensive dry coating techniques for inhalable powder formulations. 20-22 Related preliminary work was conducted at Bath University, showing the potential for improving aerosol performance of carrier- based DPI formulations using mechanofusion-based pro- cessing. 23, 24 A Japanese group also investigated the feasibil- ity of coating a coarse carrier via such a dry coating approach. 25, 26 However, a true fundamental understand- ing of the process and effect of dry coating on aerosoliza- tion of coated powder had not been elucidated. Many critical questions remained, notably: What occurs at the particle surface during the coating process? What are the key characteristics of the coating quality and the relation- ship to bulk behavior? Studies of dry coating To address the later question, systematic and mechanis- tic investigations in the pharmaceutical application of dry coating have been conducted at Monash University, Australia since 2007. In the first series of studies by the Monash University team, milled lactose monohydrate powders with a size range of 5-100 µm were coated with magnesium stearate. Substantially improved flowability and fluidiza- tion were reported for these cohesive powders (from very poor flow to free flow), as measured by both traditional characterization tools of Carr Index and angle of repose, and modern techniques of FT4 powder rheometry. 16, 27 The optimized coating parameters were identified for various milled lactose powders; for example with a D 50 of 20 µm: 0.5-1% w/w magnesium stearate as a coating material; rotation speed of 3,000 rpm; coating time of 5- 10 minutes. 28 It was found the coating efficiency depends on the host particle size, with the most dramatic improvement in flowability observed in the median particle size range of approximately 7-20 µm for milled lactose powders. 28 Larger lactose particles typically bigger than 40 µm flowed well without coating and ultra-fine lactose parti- cles (i.e., approximately 5 µm and below) were not free- flowing even after coating. Optimized coating parame- ters are likely dependent on the properties of both host and guest materials. In subsequent studies, micronized drug particles were coated with magnesium stearate, aiming to engineer DPI powders with improved aerosolization and superior stability. Coating lactose monohydrate particles (D 50 of 4 µm) with 5% w/w magnesium stearate demonstrates substantial improvement in fluidization and disper- sion. 27 Additional model inhalation drugs were also tested, including triamcinolone acetonide, salmeterol xinafoate and salbutamol sulfate. 29 Interestingly, all of the coated drug powders had significantly higher aerosol efficiency but the extent of improvement varied and dif- ferences were attributed to the effect of particulate prop- erties (i.e., particle size, shape, surface chemistry, etc.) on coating efficiency. 29 In a subsequent study, an optimal magnesium stearate concentration was found to be 2% w/w for coating a micronized salbutamol sulfate powder (with a D 50 of 3 µm). 19 Coating quality measured by x-ray photoelectron spectroscopy (XPS) was shown to have a strong impact on aerosolization. 19 A recent patent application has disclosed the usefulness of dry coating to improve the aerosol per- formance of high-dose antibiotics. 30 After dry coating of 1% w/w magnesium stearate for 10 minutes, the emitted dose and FPF of a micronized tobramycin powder improved from 71% to 82% (emitted dose) and 33% to 66% (FPF). This opens a new window for design of high dose DPI products with aerosol performance superior to that of traditional jet-milled formulations. Surface energy of coated powders The improvements in flowability and dispersibility are attributable to the reduced cohesive forces, as the out- come of decreased free surface energy. Surprisingly, an early study reported that the surface dispersive energy was increased for lactose particles coated with magne- sium stearate, as measured by the infinite dilution method of inverse gas chromatography (IGC). 25 These data appeared contradictory to the observed improve- ments in flowability and dispersibility of coated lactose particles. It was believed that such a contradiction could be due to the limitation of the infinite dilution method of IGC in that it only measures the highest surface energy. 31 To resolve this, a finite dilution method of IGC was employed to measure the distribution and hetero- Table 2 Mechanofusion system Cohesion (kPa) Flow Function Nobilta-AMS Mini (lab scale) 0.36 11.7 Nobilta-130 (pilot scale) 0.47 10.7 Table 2. Shear cell data for coated lactose powders with 1% w/w magnesium stearate using pilot and lab-scale mechanofu- sion systems. Data are adopted from references 16 and 17.