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 capsule 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 properties 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 characteristics 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 importance 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 [1,2,3,4]. The impact of devices on the efficacy of cDPIs is also reported in several scientific articles [5,6,7,8]. 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 conditions, 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 distribution (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) significantly 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 retention 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 container 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 aerodynamic performance of a model carrier-based DPI formulation used with a well-established inhalation device. A complete capsule portfolio was evaluated in parallel using complementary 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 acetonitrile 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).

Download the research paper as PDF: Hydroxypropyl Methylcellulose Capsules Enhance Aerodynamic Performance of Carrier-Based Dry Powder Inhaler Formulations

or continue reading on Hydroxypropyl Methylcellulose Capsules Enhance Aerodynamic Performance of Carrier-Based Dry Powder Inhaler Formulations

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