A Distribution-Based Metric for Quantifying Dispersibility in Dry Powder Inhalers

Abstract

Background/Objectives: Reproducible evaluation of aerosol dispersibility remains a key challenge in the development of dry powder inhalers (DPIs), where small variations in particle cohesion, morphology, or device resistance can lead to large differences in aerodynamic performance. In passive DPIs, the forces required for powder fluidization and aerosolization arise from the interaction of patient inspiratory airflow with device geometry and must overcome strong interparticle cohesive forces to enable effective lung delivery. Cascade impaction is the gold standard for determining aerodynamic particle size distribution (APSD), but its low throughput and experimental burden limit its utility for systematic formulation and device screening. Prior studies have explored laser diffraction-based particle sizing under varying dispersion energies as indirect metrics of powder dispersibility. Here, we extend this approach by introducing a mathematically rigorous, distribution-based framework that applies the first-order Wasserstein distance (Earth Mover’s Distance) to quantify relative dispersibility with respect to a material-specific maximally dispersed reference state.

Methods: Mannitol, trehalose, and inulin were spray-dried under matched conditions to generate model dry powders. Particle size distributions were measured by laser diffraction (Sympatec HELOS/R) using both a RODOS dry dispersion module to define a maximally dispersed reference state and an INHALER module to generate aerosols under clinically relevant dispersion conditions spanning multiple device resistances and pressure drops. For each condition, the Wasserstein-1 distance (W₁) was computed between cumulative volume-based size distributions obtained under reference and inhaler-based dispersion. Cascade impaction was used as an orthogonal method to characterize aerodynamic performance under a representative dispersion condition.

Results: W₁ captured formulation-, device-, and flow-dependent differences in dispersibility that were not readily separable by visual inspection of particle size distributions alone. Crystalline mannitol exhibited the largest and most flow-rate-dependent W₁ values, whereas amorphous trehalose and polymeric inulin showed smaller W₁ values with distinct, non-monotonic pressure responses that depended on device resistance. W₁ qualitatively aligned with cascade impaction metrics, exhibiting a positive association with mass median aerodynamic diameter and an inverse association with fine particle fraction, while also demonstrating that efficient dose emission can occur despite incomplete deagglomeration.

Conclusions: This study establishes the Wasserstein distance as a physically interpretable, formulation-agnostic metric for quantifying aerosol dispersibility relative to a material-specific reference state. This framework enables systematic comparison of dispersion efficiency across devices and operating conditions using standard laser diffraction data and provides a reproducible basis for mechanistic optimization of DPI formulations and inhaler designs.

Introduction

Dry powder inhalers (DPIs) are widely used for delivering therapies to the respiratory tract, with applications spanning bronchodilators, corticosteroids, antibiotics, and emerging classes such as inhaled biologics and nucleic acid therapeutics. Their appeal lies in device simplicity, portability, chemical stability of solid-state formulations, and the ability to target high local drug concentrations directly to the airways [1,2]. In many cases, active pharmaceutical ingredients (APIs) for delivery via DPI are manufactured as micron-scale particles to reduce the probability of filtration via inertial impaction and enhance deposition in the small airways [3]. However, at this size scale, cohesive and adhesive surface forces dominate over gravitational forces, which promotes particle agglomeration [4,5]. Even when primary particles are initially manufactured within an optimal aerodynamic size range, the extent of fluidization of the powder bed and separation of adhered particles during the inspiratory maneuver ultimately dictates the aerodynamic size distribution governing lung deposition. In passive DPI-based delivery, the shear and flow-induced stresses that promote entrainment and particle interactions arise from the coupling of patient-generated inspiratory flow with inhaler device geometry [6].

Regulatory guidance for orally inhaled drug products reflects this dual nature of dry powder inhaler performance by recommending both geometric particle size characterization of the formulation (e.g., volume-based sizing by laser diffraction) and aerosol performance testing of the delivered dose using cascade impaction under specified flow or pressure drop conditions. These measurements are intended to provide complementary information about the powder as manufactured and the aerosol generated by the device–formulation system, respectively [7]. However, while the guidance recognizes the importance of testing across relevant flow conditions, it does not provide a framework for directly relating a powder’s intrinsic dispersion potential to the extent of dispersion achieved during inhalation. As a result, differences in aerosol performance observed across devices, flow rates, or formulations cannot be readily interpreted in terms of how closely a given inhaler approaches the powder’s dispersion limit, limiting mechanistic insight into deagglomeration efficiency.

Together, these considerations highlight a missing link in current DPI characterization: a quantitative measure of how effectively an inhaler disperses a powder relative to its intrinsic dispersion potential. By comparing inhaler-generated aerosols with those obtained under high-energy, device-independent dispersion conditions that reliably expose the fully dispersed state of the formulation [8], dispersibility can be defined relative to a material-specific reference state rather than inferred solely from aerodynamic outcomes. Distribution-level comparison metrics, such as the Wasserstein (Earth Mover’s) distance, provide a principled and physically interpretable means of quantifying differences between entire particle size distributions [9,10]. Because the Wasserstein distance captures global redistribution across the size spectrum rather than isolated percentiles, it is well suited for problems in which distributional shape carries mechanistic significance [11,12].

Accordingly, the aim of this study is to introduce and experimentally validate a reference-based, distribution-level metric for assessing dry powder dispersibility using the Wasserstein distance. By comparing inhaler-generated particle size distributions with those obtained under high-energy dispersion conditions, this approach quantifies how closely a given inhaler approaches a powder’s intrinsic dispersion limit. We demonstrate that this framework reveals mechanistic differences in deagglomeration across devices and operating conditions, and provides a scalable basis for evaluating DPI powders.

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Materials

Trehalose dihydrate (Fisher Scientific, Waltham, MA, USA), mannitol (Thermo Scientific, Waltham, MA, USA), and inulin (TCI Chemicals, Portland, OR, USA) were selected as model excipients to generate dry powder formulations with distinct physicochemical properties. Sulforhodamine B sodium salt (Fisher Scientific, Waltham, MA, USA) was used as a fluorescent tracer to enable quantification of deposited mass during aerodynamic characterization. Distilled and deionized water (MilliQ; MilliporeSigma, Burlington, MA, USA) was used for preparation of all aqueous solutions.

Capsule-based dry powder inhaler devices from the RS01 platform (Amcor, formerly Berry Global, Osango, IT) were used as the model DPI system. Devices with low, medium, and high intrinsic airflow resistances (RS01 Mod 7 variants for size 3 capsules) were employed to evaluate the influence of device resistance on powder dispersion.

Xia, G.; Dechayont, B.; Che, L.; Comfort, I.; Brunaugh, A.D. A Distribution-Based Metric for Quantifying Dispersibility in Dry Powder Inhalers. Pharmaceutics 2026, 18, 283. https://doi.org/10.3390/pharmaceutics18030283

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