Softgel capsule or liquid-filled hard capsule: Which one should you choose?
Choosing the right dosage form is a critical decision in pharmaceutical development. For liquid single-unit preparations, selecting between softgel and liquid-filled hard capsules requires careful evaluation. Both options present distinct manufacturing challenges, cost implications, and performance characteristics.
This article explores the key differences between these technologies to help development teams make an informed decision based on formulation needs, manufacturing capabilities, and commercial strategy. We also provide a decision framework below to guide your selection process, considering factors such as development timeline, batch size requirements, fill properties, and manufacturing capabilities.
The Manufacturing Process: Complexity vs. Flexibility
Softgel capsule manufacturing utilizes the rotary-die technology, where the shell formation and filling occur simultaneously. This integrated process requires specialized equipment and expertise but offers high production efficiency for large batches. The shell material, typically gelatin, is processed as a molten mass, which allows for uniform thickness and robust sealing. A drying process is required to remove the excess water and achieve physical stability of the capsules.
In contrast, liquid-filled hard capsules use pre-produced, ready-to-use shells. The capsule fill has to be prepared and filled into the dry capsules, which are then sealed/banded. No drying is required as opposed to the soft gel manufacturing process.his approach, can offer greater flexibility in production, as less equipment and fewer manufacturing steps are required than in the rotary-die process.
Formulation Considerations
One important difference between hard and soft capsules is that the capsule shell of the soft capsules contains a plasticizer and is significantly thicker than the plasticizer-free hard capsules. This plays a crucial role for the compatibility with the fill. While lipophilic fills such as purely lipid solutions, e.g. fish oil or solutions of lipophilic vitamins, have limited interaction with the hydrophilic shell and can be encapsulated into both capsule types, hydrophilic formulations may lead to loss of water and plasticizer in the shell. This effectively makes the capsule shell brittle, unless it is plasticized sufficiently. Such formulations are generally not suitable for encapsulation into hard capsules.
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Another consideration, albeit rarely the limiting one, is the viscosity of the fill formulation at ambient conditions. The temperature of the fill during encapsulation into soft gelatin capsules is limited by the properties of gelatin; this limitation can be overcome by the use of e.g. HPMC hard capsules, or alternative shell materials for softgels.
Timeline and Scope of Development
From a timeline perspective, early development often favors liquid-filled hard capsules. As during early stages of development typically a very low amount of drug substance is available, the possibility to fill even single capsules manually is often an advantage for early entry into the clinical phase.
However, at the same time, there are similar approaches to softgels too, allowing the manual filling and production of a few capsules only to meet first clinical needs.
In contrast to hard capsules, development activities are required for the capsule shell in softgels. However, this is also a great advantage—the shell can be developed to match the characteristics of the fill. For example, with the choice of plasticizer the shell elasticity can be optimized and the oxygen permeability can be modified. This is especially important for drug substances and excipients which are prone to oxidation. A very important aspect is the improvement of the dissolution characteristics by selection an appropriate gelatin type. This flexibility allows formulators to fine-tune the capsule properties to match specific drug release requirements while maintaining excellent protection against environmental factors.
Cost Considerations Across Development Phases
From a cost perspective, both technologies are typically in the hands of Contract Manufacturing Organizations (CMOs). The key difference lies in expertise requirements rather than batch sizes. Liquid-filled hard capsules generally require less specialized know-how and lower capital investment, which can be advantageous for companies with limited experience in liquid oral dosage forms.
However, as production scales increase, softgels offer significant advantages. Their main benefit is versatility across the fill formulation range and easier scale-up due to the continuous manufacturing process. This continuous nature of softgel production allows for efficient scaling from small clinical batches to commercial volumes without major process modifications.
Performance Characteristics: Making the Right Choice
Shell properties play a crucial role in technology selection. Softgel capsules provide superior protection against oxygen and moisture due to their hermetically tight, air-free sealing, as well as the possibility to decrease the oxygen permeability of the shell. Their main advantage lies in versatility regarding formulation aspects - they can accommodate a wide range of fill compositions from simple solutions to complex self-emulsifying systems. In terms of mechanical stability during storage, softgel capsules typically show better performance due to their more elastic shell.
The performance advantages of softgel capsules are particularly evident in their dissolution profile consistency. The shell structure ensures uniform drug release patterns, which can be crucial for compounds with narrow therapeutic windows. While modified release applications were historically a strength of hard capsules, similar systems are now available for softgels as well.
Hard capsules' primary advantage is the lower investment required for simple products and less specialized know-how needed to operate the technology if you're the owner of the manufacturing equipment. The two-piece shell design still offers certain flexibility advantages, particularly for companies with existing hard capsule manufacturing capabilities.
Fill formulation capabilities also differ between the technologies. While both handle liquid fills effectively, softgel capsules generally accommodate a wider range of fill volumes, varying from 0.05 ml to more than 2 ml. Both technologies can incorporate thixotropic systems, though their processing requirements differ significantly.
Decision Framework for Development Teams
Here’s a helpful decision framework for teams looking for the right dosage form.
Making Your Final Decision Between Softgel Capsules and Liquid-Filled Hard Capsules
The choice between softgel capsules and liquid-filled hard capsules should align with your product strategy, technical requirements, and commercial objectives. While softgel technology offers advantages in most scenarios, certain specific situations may warrant consideration of liquid-filled hard capsules.
When softgel capsules excel (recommended for most applications):
Commercial manufacturing at any scale
Moisture-sensitive or oxygen-sensitive formulations
Products requiring robust hermetic sealing
Higher fill volumes (especially exceeding 500mg)
Products where formulation versatility is critical
Applications requiring consistent dissolution profiles
Long-term stability considerations
Situations where liquid-filled hard capsules might be considered:
Organizations with existing hard capsule manufacturing capabilities seeking to minimize new technology investment
Very small batch production needs
Specific modified release applications where shell modifications are advantageous
Products with unique two-phase fill requirements
Development scenarios where specialized softgel expertise is unavailable
For most pharmaceutical and nutraceutical applications, softgel technology offers superior performance characteristics and manufacturing efficiency. The initial investment in specialized technology and expertise typically yields long-term benefits in product quality, stability, and production efficiency.
Selecting the right technology at the outset of development can help streamline formulation, reduce costs, and ensure a smoother path to commercialization. The success of your drug delivery system ultimately depends on matching your specific formulation requirements, production scale, and stability needs to the technology's inherent strengths.
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