Use of Solid Corrugated Particles to Enhance Powder Aerosol Performance Nora Y. K. Chew 1 and Hak-Kim Chan 1,2 Received April 26, 2001; August 3, 2001 Purpose. To study the dispersion performance of non-porous corru- gated particles, with a focus on the effect of particle surface morphol- ogy on aerosolization of bovine serum albumin (BSA) powders. Methods. The solid-state characteristics of the spray-dried BSA pow- ders, one consisting of smooth spherical particles and another corru- gated particles, were characterized by laser diffraction, X-ray powder diffraction, scanning electron microscopy, confocal microscopy, ther- mogravimetric analysis, surface area analyzer, and buoyancy method. The powders were dispersed using the Rotahaler and the Dinki- haler coupled to a four-stage liquid impinger operating at 30 to 120 L/min. Fine particle fraction (FPF) was expressed as the wt. % of BSA particles of size 5 m collected from the liquid impinger. Results. Apart from the morphology and morphology-related prop- erties (specific surface area, envelope density), the corrugated par- ticles and spherical particles of BSA had very similar solid-state char- acteristics (particle size distribution, water content, true density, amorphous nature). Using the Dinkihaler, the FPFs of the corru- gated particles were 10–20 wt. % higher than those of the smooth particles. Similar FPF differences were found for the powders dis- persed by the Rotahaler, but the relative changes were larger. In addition, the differences were inversely proportional to the air flows (17.3% at 30 L/min, 25.2% at 60 L/min, 13.8% at 90, 8.5% at 120 L/min). Depending on the inhaler, capsule and device retention and impaction loss at the impinger throat were lower for the corrugated particles. Conclusions. Enhanced aerosol performance of powders can be ob- tained by surface modification of the particles. The surface asperities of the corrugated particles could lower the true area of contact be- tween the particles, and thus reduce the powder cohesiveness. A distinct advantage of using corrugated particles is that the inhaler choice and air flow become less critical for these particles. KEY WORDS: protein; dry powder aerosol; spherical; corrugated; spray drying. INTRODUCTION Dry powders are increasingly used for the aerosol deliv- ery of small molecule drugs and therapeutic proteins to the lung (1–17). The generation of dry powder aerosols is influ- enced by many factors, including both the inhaler device and the particle characteristics (1). It has been demonstrated that particle morphology could be manipulated by the formulation and the method of preparation (2–5). Spray drying of com- pounds of different compositions (3,5–7) resulted in a change of particle morphology, which is potentially of importance in the development of therapeutic powder aerosol formulations. To date, investigators have observed that large porous particles (∼10–20 m, specific surface area ∼50–100 m 2 /g) im- proved the amount of respirable particles both in vitro (5,6,8) and in vivo (9,10,18). Despite the large physical size, these porous particles showed excellent aerosol performance. This has been attributed to the low particle density (i.e., high po- rosity or voids), which gives rise to small aerodynamic size. On the other hand, French and co-workers found that the inclusion of protein rhG-CSF with mannitol resulted in a less dense powder with surface indentations leading to an increase in the surface area of the powder. The performance of the highly indented mannitol-rhG-CSF particles was better than the mannitol particles alone (19). The improvement was at- tributed to smaller interparticulate cohesive forces resulting from the surface indentation and reduced bulk density. How- ever, the presence of protein in the mannitol particles may also attribute to the weaker cohesion through reducing the Hamaker constant (hence reduced van der Waals force). In contrast to those porous particles, solid, non-porous corrugated particles containing no additives were obtained in the present study. Our aim was to compare the dispersion behavior of the corrugated particles with smooth, spherical particles of similar physical properties. The focus was on the effect of surface morphology on the dispersion of dry powders as aerosols, using bovine serum albumin (BSA) as a model compound. Studies were conducted at various air flows using two inhalers of different dispersion efficiencies. MATERIALS AND METHODS Powder Preparation The powders were obtained by spray drying using a Bu- chi 191 spray dryer (Flawil, Switzerland). The feed solution containing BSA (Fraction V, minimum 98%, lot 97HO984, Sigma Chemical Co., St. Louis, MO) dissolved in deionized water was sprayed at following conditions: aspiration rate 57.6 m 3 /h, feed rate 1.4 mL/min, inlet and outlet air temperatures 45 and 36°C, respectively, and atomizing air pressure 400 and 600 kPa for the corrugated and smooth spherical particles, respectively. Solid-State Characterization Particle Morphology Powder samples were mounted onto metal sample plates and coated with platinum (∼3 nm thick). The samples were then examined under a Jeol JSM 6000F scanning electron microscope (Tokyo, Japan), operating at 2–3 kV. Particle Interior Structure Powder (approximately 1–2 mg) was fixed on a glass slide using glutaraldehyde (0.1 v/v%, Sigma Chemical Co., St. Louis, Missouri), dried overnight, and viewed under a confo- cal microscope (Bio-Rad Radiance Plus scanning system, Hertfordshire, UK). Continuous sectioning along the z-axis of the specimen via the confocal microscope allowed the detec- tion of void(s) in the particle (20). 1 Faculty of Pharmacy, A15, University of Sydney, NSW 2006 Aus- tralia. 2 To whom correspondence should be addressed. (e-mail: kimc@ pharm.usyd.edu.au) Pharmaceutical Research, Vol. 18, No. 11, November 2001 (© 2001) Research Paper 1570 0724-8741/01/1100-1570$19.50/0 © 2001 Plenum Publishing Corporation