Capsule Aperture Geometry Modulates the Aerodynamic Performance of Dry Powders for Inhalation

Abstract

Capsule aperture geometry is a tunable design parameter that can markedly influence powder emission and aerosol dispersion in capsule-based dry powder inhalers (cDPIs). This study evaluated how capsule aperture radius (r) and aperture area (πr², expressed as r² in this article for scaling purposes) affect powder aerosolization from the high-resistance RS01 (Plastiape®) inhaler using thin-film freeze-dried (TFFD), jet-milled (JM), and spray-dried (SD) inhalation powders. Aperture radii of 0.1–0.6 mm (diameters 0.2–1.2 mm) were tested using a 4×2 aperture configuration (four holes at each capsule end), and effects of aperture number were further examined for TFFD powder by comparing 4×2 and 1×2 aperture configurations. Statistical analyses indicate that aperture radius predominantly governs fine particle generation and aerodynamic size via increased aperture edge shear as r decreases. While particle emission changes were driven primarily by r, with a secondary contribution from opening area that was evident for SD-VCZ/LEU and TFFD-VCZ/MAN/LEU powders. Sensitivity of aerodynamic performance to aperture geometry was formulation-dependent, with TFFD showing the strongest response due to its brittle matrix morphology. Response-surface modeling and desirability analysis identified the 4×2 configuration with r = 0.1 mm as the most balanced condition between emission and shear-enhanced fine-particle production.

Introduction

Capsule-based dry powder inhalers (cDPIs) are passive devices that rely on the patient’s inspiratory effort for aerosolization. Efficient pulmonary drug delivery requires sufficient airflow and pressure drop to generate turbulence, de-agglomerate dry powders, and entrain particles into the inhaled airstream. An effective DPI should provide efficient and reproducible powder emission while generating an aerosol with an appropriate respirable aerodynamic particle size distribution for deposition in the intended region of the respiratory tract. Because particles with different aerodynamic diameters preferentially deposit in different regions of the respiratory tract, controlling the emitted aerodynamic particle size distribution is critical for achieving the desired pulmonary delivery profile.1, 2 Accordingly, DPI performance is commonly evaluated using complementary metrics, including emitted dose (ED), fine particle dose (FPD), fine particle fraction (FPF), mass median aerodynamic diameter (MMAD), and capsule or device retention. Among these metrics, FPD directly represents the mass of drug within the respirable aerodynamic size range, whereas FPF describes the corresponding proportion of drug normalized to a defined denominator. In this study, FPF was expressed as fine particle fraction of the recovered dose (FPFrec) and fine particle fraction of the emitted dose (FPFed). FPFrec reflects the respirable fraction relative to the total recovered drug and can approximate the respirable fraction of the loaded dose when the recovered dose closely matches the loaded dose. In contrast, FPFed reflects the respirable fraction of the powder emitted from the device and should be interpreted together with ED, because a high FPFed may not necessarily correspond to a high respirable dose if powder emission is limited.

However, many patient populations, such as children, the elderly, and individuals with chronic obstructive pulmonary disease (COPD), are unable to generate the inspiratory flow rates needed for efficient powder dispersion, thereby limiting DPI performance. Consequently, substantial research efforts have focused on optimizing excipients, particle engineering, and powder manufacturing approaches to enhance aerosolization efficiency. Nevertheless, the aerodynamic performance does not only depend on formulation properties but also on the capsule and inhaler device attributes.

Hard gelatin and hypromellose capsules are widely used in cDPIs. Differences in capsule material result in distinct physicochemical and mechanical properties, including moisture content, capsule rigidity, aperture geometry, and flap formation following piercing, all of which can influence the aerosolization and aerodynamic performance of dry powder formulations.3, 4, 5

The design of the inhaler device is also a critical determinant of pulmonary drug delivery efficiency. The structural features of different dry powder inhaler designs have been comprehensively described and illustrated in several well-established publications.4, 6, 7, 8, 9, 10 cDPIs typically consist of five principal components: the mouthpiece, grid, capsule chamber, air inlet, and capsule-opening mechanism. The design and configuration of these components play a critical role in governing airflow patterns, pressure drop, powder dispersion, and ultimately the aerodynamic performance of the inhaled formulation.11, 12, 13, 14, 15, 16

The capsule chamber or holder is designed to securely hold or align capsules with the piercing mechanisms and houses capsules during inspiration. Variation of the capsule chamber geometry affects the emission and dispersion of powders.12, 17, 18, 19 During inspiration, capsules vibrate and collide with the side wall of the chamber and the grid.18, 20 This collision of capsules reduces the adhesion between particle and capsule inner wall, thereby improving powder discharge and reducing powder retention in the capsules.18, 21 The chamber that aligns the long axis of capsules in a direction perpendicular to the incoming airflow has been shown to increase vibration frequency and wall impaction of capsules,17 leading to an increase in deagglomeration. Piercing the outlet aperture closer to the head of the capsule reduced capsule retention but increased powder deposition in the capsule chamber.12 Benque and Khinast demonstrated the dependence of powder discharge on capsule angle with the air inlets. When the capsule apertures face the air inlet, the powder discharge from the Aerolizer® inhaler is reduced.19 These findings suggest that the geometry of capsule chambers not only accommodates the capsules but also controls their impaction behavior against device walls and alignment with the inhaler’s air inlets and outlets, thereby regulating airflow through the capsule and ultimately affecting aerodynamic performance.

A grid is commonly positioned at the junction between the capsule chamber and the mouthpiece to retain the capsule and to promote powder deagglomeration.13, 22 For example, Coates et al. demonstrated that fine grids with low voidage (i.e., the fraction of empty space in the grid) enhance particle impaction and deagglomeration, leading to greater deposition in downstream stages.13 In contrast, grids with larger voidage reduce the impaction on the grid, resulting in diminished deagglomeration and increased particle deposition in the mouthpiece as the particle impaction with the mouthpiece increases due to swirling airflow.13

The mouthpiece geometry also significantly influences powder dispersion and particle deposition.13, 15, 23, 24, 25 Cylindrical mouthpieces have been shown to produce higher throat deposition than circular-conical or oval-conical designs,15 while shorter mouthpieces reduce powder retention within the device.13 The computational fluid dynamics (CFD) study by Lee et al. demonstrated that the spiral mouthpiece enhances swirl and radial velocity of the airflow relative to a non-spiral designed mouthpiece, resulting in higher FPF but lower ED.24 Park et al. reported that the Diskus™ without a mouthpiece generated a narrow, high-axial velocity plume with clustered powder emission, while a helical mouthpiece split the flow into two lower-velocity streams at a wide angle, increasing particle–wall impaction.23 Zhu et al. further showed that, at a 60 L/min flow rate, the Turbuhaler® spiral mouthpiece yields higher FPF than a cylindrical mouthpiece, consistent with greater flow resistance and enhanced dispersion.25 Collectively, these results suggest that helical/spiral-shaped mouthpieces can promote deagglomeration via swirl- and impaction-driven mechanisms.

Coates et al. demonstrated that capsules pierced with different aperture configurations;26 four 0.6 mm apertures (total area 0.36π mm2), a single 1.0 mm aperture (0.25π mm2), and a single 1.5 mm aperture (0.56π mm2); produced markedly different FPFs of spray dried mannitol and concluded that this observation was not directly related to total aperture area, with the 0.25π mm2 configuration yielding the highest FPF, followed by 0.36π and 0.56π mm2.26 However, this interpretation was confounded because aperture size and number were varied simultaneously. In contrast, Behara et al. demonstrated that, when aperture number was held constant, reducing aperture size improved aerosol performance of spray dried powder, with capsules containing two 0.5 mm apertures yielding the highest FPF and smallest MMAD, followed by 0.8 mm and 1.5 mm apertures.17

Prior to actuation, dry powder particles may exist as agglomerates due to interparticle cohesive interactions, including van der Waals forces, hydrogen bonding, electrostatic interactions, capillary liquid bridges resulting from moisture adsorption, solid-bridging mechanisms, and mechanical interlocking.27, 28, 29 During DPI actuation, patient-generated airflow fluidizes the powder bed and exerts aerodynamic forces on the particles, including drag, shear, and turbulence-induced stresses, while also induces collisions of particle-particle, particle-inhaler wall, and capsule-inhaler well.9, 16, 27, 29 These aerodynamic and mechanical stresses promote powder deagglomeration by overcoming interparticle cohesive forces and breaking agglomerates into smaller particles or fragments.30, 31, 32 The deagglomerated particles are then dispersed and entrained into the airflow, forming an aerosol that travels through and deposits within the respiratory tract. The extent of deagglomeration and dispersion directly influences the aerodynamic particle size distribution of the emitted aerosol.33, 34 Insufficient deagglomeration may produce larger agglomerates with higher aerodynamic diameters, increasing mouth, throat, and upper airway deposition.1, 2, 32 In contrast, effective deagglomeration reduces MMAD, increases the respirable fraction, and promotes particle deposition in the lower respiratory tract, particularly for particles in the approximately 1–5 μm aerodynamic size range.2, 35, 36 Therefore, the efficiency of deagglomeration and dispersion is governed by multiple factors, including airflow properties, particle properties, device geometry, and the duration of particle exposure to airflow-induced stresses.

Dry powder manufacturing technologies impart distinct physical characteristics that strongly influence the aerosolization behavior of the powders. Thin-film freeze-dried (TFFD) powders are produced by rapid freezing of solution droplets followed by lyophilization, resulting in a highly porous, low-density, and brittle matrix that readily fragments under low applied stress.37, 38, 39 Jet milling (JM) reduces particle size through high-velocity particle–particle and particle–wall collisions, yielding cohesive agglomerates composed of irregular, angular, sharp-edged crystals.40, 41 Spray drying (SD) relies on solvent evaporation from atomized droplets of a drug solution or suspension, producing a wide range of particle morphologies depending on formulation (e.g., initial solute concentration, solute solubility) and processing parameters (e.g., drying rate).42 SD powders may exhibit corrugated, hollow, or irregular structures under rapid drying conditions, or smooth, dense particles when dried more slowly.42, 43 These physical and morphological property differences can result in distinct dispersion energy thresholds and divergent particle responses under varying inhaler device conditions.44, 45, 46

Because powder deagglomeration is a key determinant of pulmonary drug delivery efficiency, understanding how powder physical properties interact with capsule aperture attributes, specifically size and number, is essential for rational formulation and device optimization for maximizing inhaled therapeutic delivery. Studies examining the combined effects of powder physical properties (e.g., particle size, surface area, and morphology) and capsule aperture attributes (i.e., size and number) on the aerodynamic performance of dry powder inhalers remain limited. We hypothesize that (i) reducing capsule aperture size and/or number can promote powder deagglomeration and/or fragmentation, thereby increasing fine particle fraction and reducing the mass median aerodynamic diameter; and (ii) brittle-matrix powders, such as TFFD powder, are more sensitive to aperture geometry changes than denser powders, such as JM and SD powders. In this study, we systematically investigated the effects of aperture size on the aerodynamic performance of inhalable dry powders produced using different manufacturing technologies, TFFD, JM, and SD, to provide powders with distinct physical characteristics. The influence of aperture number was further examined using TFFD powders.

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Materials

The materials utilized in this study were purchased: voriconazole (Aurobindo Pharma Ltd., Hyderabad, India), mannitol (Pearlitol® PF, Roquette America Inc., IL, USA), L-leucine (Spectrum® Chemical MFG Corp., NJ, USA), acetonitrile (HiSolv, HPLC grade, VWR® Chemicals, PA, USA), anhydrous ethanol (Greenfield Global USA Inc., KY, USA), polysorbate 80 (Fisher Scientific, NJ, USA), methanol (HPLC grade) and trifluoroacetic acid (TFA) (Fisher Scientific, PA, USA). Deionized water was generated by a water deionizer (Evoqua, PA, USA). Qualicaps®-V (HPMC) size #2 capsules were kindly provided by Qualicaps® Inc. (Madrid, Spain). The size #2 capsules were selected for this study instead of the more commonly used size 3 capsules3, 4 as the larger capsule size facilitated manual capsule piercing. Needles with different outer diameters for aperture puncture: 1.2 mm (18G; BD PrecisionGlide™, Becton, Dickinson & Co, NJ, USA), 0.8 mm (21G; Air-Tite Products Co., Inc., VA, USA), 0.6 mm (23G; BD Integra™ retracting needle, Becton, Dickinson & Company, NJ, USA), 0.5 mm (25G; Becton Dickinson & Co, NJ, USA), 0.4 mm (27G; ManorBOX), 0.3 mm (30G; ManorBOX), and 0.2 mm (33G pull-top lancet; Carelife USA, GA, USA). A high-resistance RS01® inhaler designed for size #2 capsules was obtained from Plastiape S.p.A. (Osnago, Italy).

Sorawee Yanwinitchai, Chaeho Moon, Beatriz Behrend-Keim, Donald E. Owens, John J. Koleng, Robert O. Williams, Capsule Aperture Geometry Modulates the Aerodynamic Performance of Dry Powders for Inhalation, Journal of Drug Delivery Science and Technology, 2026, 108712, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108712.

Read also our introduction article on Capsules here: