Hydroxypropyl Methylcellulose Capsules Enhance Aerodynamic Performance of Carrier-Based Dry Powder Inhaler Formulations: A Comprehensive Evaluation of Capsule Material Effects

Abstract

Background/Objectives: This study aims to investigate the underexplored impact of cap-
sule type on the performances of capsule-based dry powder inhalers (cDPIs). It compares
specific properties of hard gelatin-based capsules (Hard Gelatin Capsules (HGC), HGC
including polyethylene glycol (HGC + PEG)) and hypromellose-based capsules, (Zephyr®
Vcaps® (VC), Zephyr® Vcaps® Plus (VCP) and Vcaps® Plus Zephyr Inhance™ (VCP-I))
with aerosolization performances of model carrier-based formulation, providing insights
into their impact on pulmonary drug delivery efficacy. Methods: Aerosolization proper-
ties of a model phenytoin/lactose blend formulation filled in the different capsules was
evaluated using a Next Generation Impactor (NGI) with RS01 device. Capsule shell charac-
teristics were evaluated in terms of water activity, static charges, and inner surface aspect
and roughness. Results: Hypromellose-based capsules, especially VC and VCP-I , exhibited
significantly higher drug delivery performances compared to gelatin-based capsules. In
particular, VCP-I demonstrated good results with excellent batch-to-batch reproducibility
and 51% of the nominal dose available for lung absorption. Although capsule inner surface
showed clear differences between both polymer families, no clear correlation could be found
between cDPI performances and capsule roughness and density of charge. All capsules
presented good mechanical properties in the conditions of the tests. Conclusions: Capsule
type exerts a significant impact on cDPI performances. These findings highlight the impor-
tance of capsule selection as a critical material attribute in the design and optimization of
inhalation products.

Introduction

Inhalation products are widely used to treat and prevent lung infections such as
asthma and chronic obstructive pulmonary disease. Among the different types of existing
delivery systems for pulmonary administration, dry powder inhalers (DPIs) are extensively
used owing to their accuracy, stability, and facility of use. In particular, capsule-based DPIs (cDPIs) present the advantage of dose flexibility and low development manufacturing costs
with a wide offer of off-the-shelf devices.
The performance of cDPIs is influenced by many factors. Among these, the importance
of formulation is well documented, with numerous studies addressing the impact of
the type of formulation (carrier-based or carrier-free formulation) excipient selection or
importance of API micronization [1– 4]. The impact of devices on the efficacy of cDPIs is also
reported in several scientific articles [ 5– 8]. However, although the interdependence between
formulation, device, and capsule on pulmonary drug delivery is often mentioned, the
impact of the capsule itself is relatively under-investigated. Yet formulators can choose from
a variety of capsule types, and this choice can substantially influence cPDI performance.
Hard gelatin capsules (HGCs), traditionally produced by dipping cold metal pins
into hot gelatin solutions, remain widely used in cDPIs. However, their relatively high
water content (13–16%) makes them prone to brittleness and cracking under the low
relative humidity conditions typical of DPI environments. To overcome this potential
limitation, plasticizers such as polyethylene glycol (PEG) have been added to gelatin to
improve mechanical flexibility of the capsules. Later, hypromellose (HPMC) capsules,
containing reduced water content (3–9%) have emerged as promising alternatives. These
HPMC capsules can be manufactured by the traditional cold-gelation method, including
a gelling agent in the polymer formulation preparation, as for Zephyr® Vcaps® capsule
(VC) and Quali-V® I, or fabricated using a thermo-gelation process without gelling agent.
This method consists in dipping hot metal pins in a cold HPMC solution and is used to
manufacture Zephyr® Vcaps® Plus (VCP) and Vcaps® Plus Zephyr Inhance™ capsule
(VCP-I). The latter capsule is obtained with an improved manufacturing process enabling
reduced capsule variability.
Low water content is particularly advantageous for DPIs because it helps preserve
formulation stability and ensures consistent powder release [ 9 ]. Environmental condi-
tions, particularly temperature and relative humidity (RH), significantly influence the
moisture content and mechanical behavior of capsule polymers, which in turn affects
their physicochemical properties and critical aerosol performance metrics. The polymer
chemistry and water sorption characteristics of HPMC and gelatin capsules create distinct
responses to environmental stress, with implications for aerodynamic particle size distri-
bution (APSD), fine particle fraction (FPF), and emitted dose consistency [ 10 ]. While the
different HPMC capsule variants are recognized for their beneficial characteristics in terms
of low water content and improved control over capsule mechanical properties (avoiding
brittleness) [11 ], their impact on DPI aerosolization performance and drug lung delivery
remains insufficiently understood.
Recent investigations highlight that capsule material (e.g., gelatin versus HPMC) sig-
nificantly influences key performance attributes: for instance, HPMC capsules typically
exhibit lower moisture content and greater mechanical robustness under low-humidity
conditions, translating into improved capsule puncture behavior, reduced powder reten-
tion and enhanced fine-particle dose when compared to gelatin shells [ 12 ]. Moreover,
capsule tribo-electrification behavior, aperture geometry (size, number, orientation of
puncture pins), and capsule-chamber motion dynamics have been shown to interplay
with powder properties and device flow regimes—leading to differences in aerosolization
efficiency and dose reproducibility [13 ]. Hence, the capsule is not merely a passive con-
tainer but a critical component influencing metering, release, dispersion, and ultimately
lung deposition—a fact that warrants systematically including capsule properties in the
quality-by-design framework of cDPI development [6].
This study investigates the underexplored influence of capsule type on the aerody-
namic performance of a model carrier-based DPI formulation used with a well-established inhalation device. A complete capsule portfolio was evaluated in parallel using comple-
mentary techniques to assess both performance and mechanical properties and to correlate
capsule-specific characteristics with drug delivery behavior. The novelty of this work lies in
the first systematic evaluation of the newly developed VCP-I capsule, manufactured using
an improved thermo-gelation process, and in assessing its performance relative to VCP and
cold-gelled capsules. This integrated approach provides new insight into the critical role of
capsules in DPI performance.

Materials

Phenytoin was purchased from Spectrum Chemical Mfg. Corp. (New Brunswick, NJ,
USA). Respitose® SV003 (coarse lactose) and Lactohale®L230 (fine lactose) were obtained
from DFE Pharma (Goch, Germany). Size 3 DPI grade Capsugel® Zephyr® capsules, Hard
Gelatin Capsules (HGC), Hard Gelatin Capsules with 5% PEG (HGC + PEG), Vcaps®
capsules, Vcaps® Plus capsules, and 3 batches of Vcaps® Plus Inhance™ capsules were
used, and their characteristics are listed in Table 1. RS01 high-resistance devices were
kindly provided by Plastiape (Osnago, Italy).

Ultra purified water was produced on-site by milliQ-systems. Methanol and ace-
tonitrile were acquired by Biosolve (Dieuze, France). Isopropanol, ammonium phosphate
dibasic, phosphoric acid 85%, ammonium hydroxide, and hexane were purchased from
Merck (Darmstadt, Germany). Silicone oil was provided by Dow (Midland, MI, USA).

Dumont, C.; Picco, S.; Noriega-Fernandes, B.; Verlhac, P.; Elena Cortez, A.; Boulet, C.; Gallagher, M.; Bock, C.; Jannin, V. Hydroxypropyl Methylcellulose Capsules Enhance Aerodynamic Performance of Carrier-Based Dry Powder Inhaler Formulations: A Comprehensive Evaluation of Capsule Material Effects. Pharmaceutics 2025, 17, 1621. https://doi.org/10.3390/pharmaceutics17121621

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The findings of this study showed that Capsugel® Vcaps® Plus Zephyr Inhance showed 47% higher lung available dose vs. gelatin and 27% vs. prior-gen HPMC capsules.

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