(T1530-07-44) Highlighting the Critical Role of Capsule Selection in Capsule Dry Powder Inhalation Aerosol Performances

Purpose: Ease of use, portability and accuracy make capsule-based dry powder inhalers (cDPIs) an appealing technology to address the growing demand for effective inhalation therapies. While the roles of both formulation and device in influencing cDPI performance have been widely studied, the specific impact of capsule type remains underexplored. To bridge this gap, this study aims to evaluate the impact of different capsule types—including hard gelatin capsules (HGC), PEG-modified gelatin capsules (HGC+PEG), and various hydroxypropyl methylcellulose (HPMC)-based capsules—on the delivery performance to the lungs of a model ternary blend formulation

Methods: Phenytoin was selected as model API. It was micronized using MC50 spiral jet mill (Dv50 =1.8 µm, Dv90=3.3 µm) and further blended, 5.5% w/w, with 15% fine lactose (Lactohale^® L230) and 79.5% coarse lactose (Respitose^® SV003) in a low shear mixer. Five capsule types were selected among Capsugel^® Zephyr^® Inhalation Capsules Portfolio: HGC, PEG-HGC, Vcaps^® (containing a gelling agent), Vcaps^® Plus 1 and Vcaps^® Plus 2 (both obtained by a thermogellation process). Capsules were equilibrated at 45%RH before being filled with 25 mg of phenytoin ternary blend (1.38 mg phenytoin). Performances of the cDPI were tested in vitro with an RS01 DPI device (Berry) using a Next Generation Impactor (NGI), operated at 60 L/min. Phenytoin quantification in each section of the NGI was performed by HPLC-UV and used to determine the following key metrics: mass median aerodynamic diameter (MMAD), emitted fraction, capsule retention, fine particle dose (FPD; < 5 µm), and very fine particle dose (vFPD; < 2 µm). Each test was performed in triplicate. Statistical comparisons were done by ANOVA with appropriate post-hoc tests. To visualize powder retention after emptying, Scanning Electron Microscopy (SEM) images were taken on capsules shells of both empty capsules and capsules filled and emptied in the same conditions as the NGI evaluation (equilibration at 45% RH, filling with 25 mg formulation and emptied at 60L/min with RS01 device).

Results: The MMAD values calculated for all tests were ranging from 3.28 ± 0.07 µm (Vcaps^®) to 3.48 ± 0.13 µm (HGC) with no statistical differences between the capsules types, indicating that the aerodynamic properties of the formulation remained stable throughout the study. SEM images of capsules emptied from the phenytoin formulation show differences in powder retention with higher retention observed in gelatin-based capsules compared to HPMC-based capsules, Figure 1. This could be induced by the differences in shell roughness as important surface variations can be observed on the empty capsules. Quantification of Phenytoin confirmed that capsule type significantly influenced capsule retention with the lowest phenytoin retention measured in Vcaps® while the highest values were observed for both gelatin-based capsules, Figure 2 A. Consequently, the highest Emitted fraction, defined as the fraction of the nominal dose released from both capsule and device, was obtained with Vcaps®, Figure 2 B. HPMC-based capsules showed significantly higher FPF and vFPF compared to HGC and HGC+PEG, Figure 3. The highest values were obtained with Vcaps® Plus 2. The differences in the behavior of the different capsules can be driven by different parameters such as shell roughness, brittleness upon capsule puncturing or electrostatic charges[1–5], which are currently under evaluation.

Conclusion: This study highlights the critical role of capsule in determining the aerosol performances of cDPI products. In the particular case of the tested model phenytoin formulation with RS01 device, HPMC-based capsules, especially Vcaps^® Plus 2, outperformed gelatin-based alternatives. Early-stage evaluation of capsule types can support development of high-performance inhalation therapies.

References: [1] J.T. Pinto, T. Wutscher, M. Stankovic-Brandl, S. Zellnitz, S. Biserni, A. Mercandelli, M. Kobler, F. Buttini, L. Andrade, V. Daza, S. Ecenarro, L. Canalejas, A. Paudel, Evaluation of the Physico-mechanical Properties and Electrostatic Charging Behavior of Different Capsule Types for Inhalation Under Distinct Environmental Conditions, AAPS PharmSciTech 21 (2020) 128. https://doi.org/10.1208/s12249-020-01676-2.
[2] L. Ding, A.D. Brunaugh, R. Thakkar, C. Lee, Q.J. Zhao, J. Kalafat, M. Maniruzzaman, H.D.C. Smyth, Comparison of HPMC Inhalation-Grade Capsules and Their Effect on Aerosol Performance Using Budesonide and Rifampicin DPI Formulations, AAPS PharmSciTech 23 (2022) 52. https://doi.org/10.1208/s12249-021-02175-8.
[3] N. Wauthoz, I. Hennia, S. Ecenarro, K. Amighi, Impact of capsule type on aerodynamic performance of inhalation products: A case study using a formoterol-lactose binary or ternary blend, International Journal of Pharmaceutics 553 (2018) 47–56. https://doi.org/10.1016/j.ijpharm.2018.10.034.
[4] L. Ding, A.D. Brunaugh, S. Stegemann, S.V. Jermain, M.J. Herpin, J. Kalafat, H.D.C. Smyth, A Quality by Design Framework for Capsule-Based Dry Powder Inhalers, Pharmaceutics 13 (2021) 1213. https://doi.org/10.3390/pharmaceutics13081213.
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Acknowledgements: Some data presented in this abstract were published in Respiratory Drug Delivery 2025: Selection of the Best Capsule Type to Maximize the Performance of a Model Carrier-Based Dry Powder Inhalation Formulation. Dumont C et al., in Respiratory Drug Delivery 2025, Editors: Dalby RN, Peart J, Traini D, Young PM and Suman JD. ISBN: 978-1-7396821-4-9


SEM images of the different empty Zephyr® capsules tested (top line) and same capsule type emptied from Phenytoin formulation (middle and bottom lines)


(A) Phenytoin capsule retention after NGI testing with the tested capsules: HGC (orange), HGC+PEG (blue), Vcaps® (green), Vcaps® Plus 1 (grey) and Vcaps® Plus 2 (yellow) and (B) Emitted fraction of phenytoin from both device and capsules, no statistical differences were observed between groups designed by the same letter (p < 0.05)


(A) FPF and (B) vFPF of Phenytoin from model formulations tested with RS01 device and various