Claude Capdepon EMEA & South East Asia application laboratory manager at Rousselot explains how to avoid crosslinking in soft gel formulations.
PItfalls
The popularity of soft gel capsules continues to rise, with the latest market reports predicting a CAGR of 5.46% and a global market value of $3,276 million by 2023. Typically used to carry semi-solids, liquids, gels or paste-like fills, soft gels offer a versatile solution to active pharmaceutical (API) ingredient delivery.
Soft gel capsule design
When designing a soft gel formulation, shelf-life stability, shell dissolution, and formulation versatility must all be carefully considered. Consumer experience is also key – from taste and odour masking, to swallowability. As such, gelatin is the preferred excipient for soft gel applications, due to its robust functional properties, full digestibility, and compliance with stringent regulatory requirements. Plus, as the only clean label excipient, it provides added appeal for an increasing number of consumers.
However, not all gelatin excipients are made equal − manufacturing gelatin-based soft gels requires technical knowledge and specialised gelatins to ensure optimum product stability and avoid common manufacturing pitfalls such as crosslinking.
Avoiding crosslinking
The formation of strong chemical linkages between gelatin chains, crosslinking can cause soft gel shells to become rubbery and insoluble, ultimately affecting the capsule ability to dissolve fully and timely. A purified, soluble protein, gelatin is a polydisperse polymer composed of three alpha chains that cross together to form a triple helix. Along with its specific amino acid composition, this predisposes gelatin, which accounts for 40 to 47% of the total gel mass composition, to crosslinking.
By understanding gelatin’s behaviour under specific circumstances, it has been possible to predict its resistance to crosslinking, and therefore develop specialised solutions to counter it. The reactions involved in crosslinking are often enhanced by the characteristics of the gelatin: viscosity in relation to molecular weight distribution and pH for example can play a key role in making a capsule become unstable and brittle. Rousselot’s research shows that crosslinking occurs as a result of inappropriate storage conditions – namely high temperatures (>30°C) and humidity (>60%), complex fills or APIs containing aldehydes.
Understanding the crosslinking process and reactions led to the development of our StabiCaps solution. Using gelatin from bovine origin, the range of specialised soft gels are designed to reach specific low viscosity profiles and low pH range in a clean label formulation, to ultimately reduce crosslinking. Moreover, additional salts have been added to StabiCaps Plus with the aim of fixing any crosslinking residue and avoid the release of amino acid groups.
A stable future
With outstanding functional properties and clean labelling, gelatin is set to remain the preferred excipient for soft gels. However, ensuring product stability for increasingly complex fills and new API technologies is a key challenge for manufacturers. Specialised gelatin soft gel enable superior performance to be maintained via increased product stability, while also opening up further API formulations options for pharmaceutical soft gel products.