Comparative Evaluation of Gelatin and HPMC Inhalation Capsule Shells Exposed to Simulated Humidity Conditions

Abstract

Background/Objectives: This study investigates the impact of high humidity (25 °C, 75% relative humidity) on gelatin and hydroxypropyl methylcellulose (HPMC) capsules used in dry powder inhalers (DPIs), focusing on moisture dynamics, structural responses, and mechanical performance, with an emphasis on understanding how different capsule types respond to prolonged exposure to humid conditions.

Methods: Capsules were exposed to controlled humidity conditions, and moisture uptake was measured via thermal analysis. Visual observations of silica bead color changes were performed to assess moisture absorption, while surface wettability was measured using the sessile drop method. Hardness testing, mechanical deformation, and puncture tests were performed to evaluate structural and mechanical changes. Positron annihilation lifetime spectroscopy (PALS) was used to analyze free volume expansion.

Results: HPMC capsules exhibited rapid moisture uptake, attributed to their lower equilibrium moisture content and ability to rearrange dynamically, preventing brittleness. In contrast, gelatin capsules showed slower moisture absorption but reached higher equilibrium levels, resulting in plasticization and softening. Mechanical testing showed that HPMC capsules retained structural integrity with minimal deformation, while gelatin capsules became softer and exhibited reduced puncture resistance. Structural analysis revealed greater free volume expansion in HPMC capsules, consistent with their amorphous nature, compared with gelatin’s semi-crystalline matrix.

Conclusions: HPMC capsules demonstrated superior humidity resilience, making them more suitable for protecting moisture-sensitive active pharmaceutical ingredients (APIs) in DPI formulations. These findings underline the importance of appropriate storage conditions, as outlined in the Summary of Product Characteristics, to ensure optimal capsule performance throughout patient use.

Introduction

Inhalation therapy has a rich historical background, having been used for centuries as a means of delivering medicinal substances to alleviate respiratory ailments. While early methods involved inhaling various medicinal vapors and fumes, significant advancements in inhalation devices have been made over the last few decades [1,2,3]. Among these innovations, dry powder inhalers (DPIs) have emerged as a leading option to manage respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) due to their unique advantages and effective drug delivery systems [4,5,6]. Recent advances in microparticle formulations and inhaler technologies further highlight the evolving field of pulmonary drug delivery [7]. DPIs facilitate direct medication delivery to the lungs, enabling rapid absorption and minimizing systemic exposure, which ultimately enhances therapeutic outcomes, patient adherence, and overall quality of life [2,8].

The growing preference for DPIs stems from their propellant-free formulations, which not only address environmental concerns associated with traditional inhalers but also provide greater chemical stability compared with liquid alternatives [5,9,10,11]. Moreover, DPIs are user-friendly, requiring minimal coordination during use, making them suitable for a broad demographic, including children and elderly patients. Their breath-actuated design enhances their usability and effectiveness, as they eliminate the need for additional devices such as spacers [10,12].

Despite these advantages, DPI performance is influenced by various factors, including the physicochemical characteristics of the drug formulations (such as moisture sensitivity), the inhaler design, and the patient’s inhalation technique [12,13]. Furthermore, patient behavior can significantly impact DPI effectiveness. For instance, a study of 738 patients conducted in 2016 found that two-thirds rarely checked inhaler expiry dates, often used them after expiry, and had not received proper storage guidance (from doctors, nurses, or pharmacists) [14]. In particular, improper storage (such as removing capsules from their original packaging) can compromise their integrity and reduce therapeutic efficacy. Exposure of capsules to ambient air outside their blister pack (e.g., in pill boxes) has been shown to reduce the fine particle dose (FPD) by approximately 18% within 24 h [15]. Moreover, storing capsules under accelerated humid conditions (40 °C, 75% RH) resulted in a ~50% reduction in FPD for certain DPIs [16,17]. These findings highlight the critical role of capsule packaging and proper patient handling in maintaining DPI performance, particularly in humid environments. Consistent drug delivery remains a challenge, prompting innovations in device and formulation design.

The effectiveness and reliability of DPIs are closely tied to the properties of their capsule shells, which protect and deliver the powdered medication [18]. Ding et al. found that the capsule type significantly affects the performance in carrier-free formulations, with minor variability observed in the carrier-based ones [19]. The study also highlighted how capsule hardness influences flap detachment during piercing, impacting aerosol performance. These findings emphasize the need for careful capsule selection to optimize inhaled formulation performance.

Buttini et al. also highlighted the importance of capsules in inhalation therapies, describing key criteria for ideal inhalation capsules [10]. These include easy puncturing without excessive shell shedding, attached and open flaps that facilitate powder discharge, and minimal retention of powders. Capsule performance is influenced by factors such as material, moisture content, and lubrication. While hard gelatin capsules have been used for over 30 years, humidity-related instability is one of the primary challenges associated with them, often compromising shell strength and limiting suitable fill materials. This has led to growing interest in alternative capsule materials [20]. Gelatin capsules, in particular, can become brittle with low moisture, posing inhalation risks. Modified capsules with plasticizers and hydroxypropyl methylcellulose (HPMC) capsules have been introduced to enhance stability and aerosolization. HPMC capsules, with lower moisture content (4.5–6.5%) compared with gelatin (13–16%), do not become brittle and are of plant origin. They show superior stability, perform better in puncturing tests, and are less prone to moisture-related issues. Ultimately, the choice between gelatin and HPMC capsules depends on their interaction with specific formulations.

This study investigates the behavior of these two types of DPI capsules—gelatin and HPMC—under prolonged exposure to elevated humidity and controlled temperature. By examining empty shells without any active ingredients, this research aims to assess the impact of moisture on the physical and chemical characteristics of the capsule materials. The specific condition was selected based on real-life observations as well as regulatory precedents and relevance to DPI performance under moisture stress. According to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), long-term stability studies are typically conducted at 25 °C ± 2 °C/60% RH ± 5% or 30 °C ± 2 °C/65% RH ± 5% for 12 months, with accelerated conditions set at 40 °C ± 2 °C/75% RH ± 5% for 6 months [21]. However, these protocols are intended for general pharmaceutical products and do not account for short-term, device-specific humidity exposures. The FDA’s draft guidance for MDIs and DPIs recommends “in-use” stability testing of opened inhalers at around 30 °C/65% RH to reflect patient use and storage conditions [22]. Because no universal standard exists for DPI moisture stress testing, we selected a 24 h exposure at 25 °C/75% RH to simulate a realistic yet challenging humidity scenario to assess capsule integrity and aerosol performance.

To assess moisture uptake and its effect, several measurements were conducted. These included mass measurements to track moisture absorption over time and visual tracking using humidity-indicating silica beads. Changes in mechanical strength were evaluated through hardness testing, while moisture content was quantified directly through thermal analysis. Surface wettability was measured using the sessile drop method to detect changes in hydrophilicity. Mechanical performance was further examined through horizontal and vertical deformation tests, along with puncture testing, which is critical for evaluating the capsules’ suitability for DPI applications. Additionally, positron annihilation lifetime spectroscopy (PALS) was used, as it is widely recognized as one of the primary methods for assessing the size and distribution of free volumes. It provided insights into the free volume and microstructural changes within the polymer matrices of the capsules, which are not detectable by conventional structural testing methods [23,24].

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Materials

Size 0 empty hard gelatin and HPMC capsules were used in this study. The hard gelatin capsules (Capsugel® Coni-Snap®) and HPMC capsules (Capsugel® Vcaps® Plus) were both obtained from Lonza (Basel, Switzerland). To evaluate the effects of moisture exposure, the capsules were stored in a climate chamber (Memmert Constant climate chamber HPP110ECO, Büchenbach, Germany) at 25 °C and 75% relative humidity (RH) for predefined durations: 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h. For each capsule type (gelatin and HPMC), dry capsules (0 h) were included in the experiments as a reference for comparison.

Magramane, S.; Kállai-Szabó, N.; Farkas, D.; Süvegh, K.; Zelkó, R.; Antal, I. Comparative Evaluation of Gelatin and HPMC Inhalation Capsule Shells Exposed to Simulated Humidity Conditions. Pharmaceutics 2025, 17, 877. https://doi.org/10.3390/pharmaceutics17070877