Abstract
Capsule-based drug delivery has undergone significant advancements, offering enhanced protection for active pharmaceutical ingredients (APIs) and enabling precise, site-specific release in the gastrointestinal (GI) tract. Recent innovations such as enteric coatings, dual-layer encapsulation (double-dipping), and advanced polymer formulations have expanded the functional capabilities of capsules, offering opportunities to enhance bioavailability and stability of sensitive molecules like peptides, proteins, and RNA-based therapies. Additionally, cutting-edge manufacturing techniques—including injection molding and 3D printing—are facilitating the production of customized capsules with controlled release profiles, thereby minimizing systemic side effects and enhancing patient adherence.
This review examines the technological advancements from single-layer to double-layer capsules, a crucial development to achieve enteric properties and enhance drug protection against degradation in gastric fluids. We explore key capsule manufacturing technologies, including double-dipping, enteric coating, and emerging approaches such as 3D printing and injection molding, which offer new possibilities for precise drug delivery and formulation flexibility. By integrating these advancements, capsule technology continues to evolve as a promising platform for personalized and targeted oral drug delivery. Future research will focus on overcoming production constraints and further refining capsule design to optimize therapeutic efficacy across a broader range of gastrointestinal and systemic diseases.
Introduction
Oral solid dosage forms remain the cornerstone of modern therapeutics, with tablets historically the most common format due to their cost-effectiveness and robust manufacturing processes (Stegemann, 2002). However, capsules have progressively gained attention as a versatile oral dosage form, offering distinct advantages such as the ability to encapsulate powders, semi-solids, liquids, as well as devices (Cole et al., 2002; Hoffmann et al., 2024). Capsules also provide opportunities for rapid product development and flexible dosing, making them especially valuable in both clinical trials and personalized therapies. In addition to their role as inert containers, capsule shell material can actively modify drug release properties depending on the material used for formation (A.M. Dos Santos et al., 2021).
Capsule fabrication technologies have advanced steadily over recent decades. While gelatin-based capsules have a long-established history of use, the dominance of gelatin as the shell forming material of choice has been increasingly challenged by alternative polymers such as hydroxypropyl methylcellulose (HPMC), pullulan, and alginate. These materials offer enhanced functionalities that go beyond structural support, addressing patient-specific needs, and facilitating the development of next-generation drug delivery systems (Sonia and Sharma, 2014; Awad et al., 2022). This technological evolution has enabled innovative approaches to site-specific drug delivery, particularly in the areas of enteric protection and targeted release within the gastrointestinal tract (Grimm et al., 2024).
In parallel, progress in closure mechanisms and manufacturing processes has improved the safety, stability, and reproducibility of capsule-based products. More recently, enabling technologies such as advanced coating methods, double-dipping processes, and even 3D printing have expanded the functional landscape of capsules, transforming them from passive carriers into active components of sophisticated drug delivery strategies (J. Dos Santos et al., 2021; Grimm et al., 2024).
This review provides an integrated perspective on capsule technologies, tracing their historical development through to current innovations. By examining conventional processes, material transitions, functional polymers, and emerging technologies, we highlight the growing role of capsules as a next-generation platform for oral targeted drug delivery, capable of meeting increasingly complex therapeutic demands.
2. Current state of the art in capsule technology
2.1. Historical evolution of capsules
The term “capsule” is derived from the Latin capsula, meaning “small box.” Capsules are classified into two primary types: hard capsules and soft capsules. Hard capsules comprise two distinct, semi-closed cylindrical components namely, the cap and the body while soft capsules are single-unit structures that can adopt various shapes. Hard capsules are predominantly utilized for the encapsulation of powders and granules, whereas soft capsules are more suitable for liquid or semi-solid formulations.
Capsules have been used as an oral dosage form the early 1830s, when gelatin capsules were first developed, primarily for liquid formulations (Podczeck and Jones 2004). In the 1940s, technological advancements led to the encapsulation of powders, significantly expanding their use. At that time, capsule production was entirely manual. Manufacturers used silver-coated metal pins, which were dipped into a gelatin solution and then dried to form the capsules. It wasn’t until 1931 that Arthur Colton industrialized the process. Modern capsule manufacturing still relies on the same fundamental dipping mechanism, though it has been highly automated—particularly in the dipping station and the transfer process from dipping to drying (Stegemann, 2002).
Capsule usage varies across regions, with different sizes and volumes available, typically ranging from size 000 (largest) to size 5 (smallest) (Table 1). Size 0 capsules are predominantly used for oral administration, while size 3 is preferred for respiratory applications.
Table 1. Capsule size with their main characteristics (Lonza 2023).
2.2. Process description of hard capsule shell fabrication
Capsule fabrication is an established process known as dip-molding or dipping. The process generally consists of four main steps: (1) polymer solution or dispersion preparation, (2) dipping, (3) drying, and (4) assembly and joining of the capsule body and cap (Begum et al. 2018). This method requires precise control over multiple parameters to ensure capsules are defect-free and possess the desired mechanical and dimensional properties.
2.2.1. Polymer solution or dispersion for shell preparation
The selection of polymer represents the first critical step in capsule development, with gelatin remaining the most widely used material. Gelatin is derived from the hydrolytic extraction of collagen from animal tissues or bones. In recent years, however, plant-based alternatives such as hydroxypropyl methylcellulose (HPMC) have gained increasing importance, driven by ethical considerations and changing consumer preferences.
Other polymers, including pullulan, blends of HPMC derivatives, and combinations of HPMC with gellan or carrageenan, are also employed at an industrial scale (Bandi et al., 2025). These polymers are particularly suitable for capsule fabrication, as the structural layer must provide sufficient mechanical strength, especially tensile resistance. In addition, the selected polymer must exhibit an appropriate gelation point to support the dip-molding process (Lafargue, 2020).
Beyond these established materials, the growing demand for advanced drug delivery systems has stimulated the exploration of alternative polysaccharides at the laboratory scale. For instance, chitosan and dextran have been investigated for the development of capsules designed for colon-specific drug delivery (Tozaki et al., 2002; Brøndsted et al., 1998).
The capsule shell solution/dispersion preparation is a critical step that requires precise control of formulation parameters to ensure optimal thickness, mechanical properties, and defect-free production. While some polymers readily dissolve at room temperature and can be processed without heating, others exhibit limited solubility under ambient conditions and require elevated temperatures for complete dissolution. For these materials, a hot formulation process is essential to ensure proper solubilization. Alternatively some polymers not soluble in water can be used as dispersion (Lafargue 2020). Maintaining precise temperature control is vital for ensuring stable viscosity and preventing gelation within the tank. For example, in the case of gelatin, the solution is typically maintained at around 55–60 °C in temperature-regulated tanks, then additional components such as colorants, preservatives, and surfactants can be introduced (Jones, Podczeck, and Lukas 2017).
2.2.2. Capsule shell formation
Once prepared, the polymer solution/dispersion is maintained in an overflow dish at a controlled temperature and viscosity, with water regulation to prevent evaporation-induced viscosity changes. Continuous homogenization is needed to maintain a constant bath height and ensure solution uniformity (Lafargue 2020).
The dipping process is essential in capsule fabrication, where temperature-controlled molding pins interact with the polymer solution to initiate gelation and form a uniform film (Fig. 1). The temperature difference between the pins and the solution is key to this process, where cooled pins are employed for heated polymer solution/dispersion whereas heated pins are applied when working with cold polymer solutions. This temperature difference between the pins and the polymer triggers gelation upon contact, forming a uniform film around the pins that will, after drying, created the capsule shell. The viscosity of the solution directly influences the amount of material deposited, thereby determining the final capsule thickness and weight (Jones, Podczeck, and Lukas 2017; Villiers 2004).
2.2.3. Drying of the capsule shell
The drying phase is a critical step in capsule shell fabrication, designed to remove excess water while maintaining the mechanical integrity and flexibility of the capsule shell. This drying process takes place in controlled drying tunnels, where temperature, relative humidity (RH) and air flow are precisely regulated to prevent defects such as cracking and wrinkling (Lafargue 2020).
The drying temperature is adjusted according to the properties of the capsule material. For capsules formed from a solution, the drying temperature should be sufficient to solidify the polymer and remove water, allowing the formation of a continuous and stable film. In the case of capsules made from a dispersion, the temperature must exceed the Minimum Film-Forming Temperature (MFFT) to facilitate uniform drying and maintain structural integrity (Steward, Hearn, and Wilkinson 2000). As illustrated in Fig. 2 drying begins with solvent evaporation, which concentrates the polymer particles on the surface. If the temperature is below the MFFT, particles retain their spherical shape, preventing film formation. In contrast, temperatures above the MFFT cause particle deformation into dodecahedral structures, resulting in a dry, transparent, and handleable film. The final stage involves particle interdiffusion and coalescence, forming a homogeneous film—this step depends on both temperature and particle structure (Keddie and Routh 2010).
Humidity control is equally critical, particularly for hydrophilic polymers where loss of flexibility can occur when moisture levels drop below critical levels. Excessively dry conditions can lead to structural defects, including cracks, wrinkles, or surface irregularities. A controlled process of gradual moisture reduction combined with regulated temperature increases ensures that the capsules achieve optimal mechanical properties while avoiding deformation or brittleness (Jones, Podczeck, and Lukas 2017).
2.2.4. Stripping and cutting
Once dried, the capsules undergo further processing, including stripping, trimming, joining, and final quality checks. During the stripping phase, metal jaws gently remove the capsule parts from the molding pins. To facilitate smooth removal and prevent contamination, the molding pins are lubricated and cleaned after each cycle, ensuring no material residues affect subsequent production batches (Jones, Podczeck, and Lukas 2017).
Capsules are initially formed longer than their final dimension to compensate for potential thickness variations at the base of the cap and body. A trimming (deburring) step eliminates these irregularities, ensuring uniform and precise capsule length. This is a critical step before assembly, where the capsule body is inserted in the cap in pre-lock position (Lafargue 2020).
2.2.5. Joining
The cap and body of a capsule are joined in pre-lock position using different methods depending on the capsule’s design. The simplest approach relies on the natural fit between the cap and body, often supported by pre-formed locking rings that provide basic closure (as Coni-Snap in Fig. 3).
Post filling, additional sealing techniques can be applied to enhance integrity of the final dosage form. One widely used method is banding, in which a thin layer of polymer solution is applied around the junction of the cap and body to ensure tamper evidence and improved protection against leakage. Another approach is fusion sealing, where localized heat or solvents are used to weld the two parts together, resulting in a stronger and more durable joint. More recently, specialized closure systems have been developed that integrate advanced design features directly into the capsule geometry to facilitate sealing (as Licaps in Fig. 3).
Download the full article as PDF here: Next generation capsules
or read more here
Capsules mentioned in the study: Capsugel® Enprotect®
Elisa Millet, Joseph P O’Shea, Brendan T Griffin, Camille Dumont, Vincent Jannin, Next generation capsules: emerging technologies in capsule fabrication and targeted oral drug delivery, European Journal of Pharmaceutical Sciences, Volume 214, 2025, 107277, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107277.
Read also our introduction article on Capsules here:
