The Great Gelatin Debate
Why we shouldn’t forget gelatin’s longstanding reputation as a reliable and trusted excipient.
Bjorn Vergauwen |
Gelatin has been used for decades on a large scale across many industry sectors. Owing its popularity to its multiple functionalities and nutritional profile, it has huge application potential in the manufacture of various food, nutraceutical and pharmaceutical products. However, similarly to other ingredients of animal origin, gelatin has attracted the attention of vegetarian and vegan consumers, who are increasingly demanding animal-free substitutes. As far as capsules are concerned, for example, a number of plant-based excipients are becoming available on the market for the formulation of vegan shells. Despite the initial appeal of these vegan substitutes, manufacturers argue that gelatin remains the safest, and most convenient functional ingredient with a decade long background of research and application history that no other non-animal protein can offer. Moreover, none of the vegan-friendly excipients can offer a clean label status, which represents a real challenge when it comes to meeting other consumer trends. In light of recent developments, gelatin still represents the most viable choice for capsule formulation. Allow me to explain my view.
Film and gel forming excipients are crucial in the manufacture of high quality hard and soft capsules. By “high quality,” I mean the combination of optimal handling in filling machines, adequate shelf life stability and, of course, optimal in vivo performance. When it comes to excipients, the pharma industry is spoilt for choice. There’s the industry standard – gelatin, which has been used for manufacturing hard and soft capsules for nearly a century. Gelatin is derived from animal sources and has distinct clear label properties. There’s also hydroxypropyl methylcellulose (HPMC), which works well for formulating vegan hard capsules, but isn’t digestible by the body and sometimes requires a gelator (such as kappa-carrageenan or gellan) for adaptation to production process. Another hard capsule shell excipient alternative is pullulan, which is derived from fermented fungus. Like the first-generation HPMC capsules, pullulan shells also require a gelator and need a plasticizer or dissolution enhancer (such as polydextrose, mannitol or sorbitol) to avoid capsule brittleness and improve in-line capsule handling. In the face of increasing industry demands, such as rising costs and sophisticated fill formulations, I believe that gelatin is the reliable and well-established choice.
To really understand the benefits of gelatin, the challenges of capsule formulation must first be discussed. Consumers can be fickle, and they are increasingly demanding more from their capsules. For example, the trend for “all-natural” nutraceuticals is showing no signs of abating. As consumers become less interested in more “processed” products, clean label is an increasingly desirable attribute – a key driver for gelatin remaining a popular excipient choice. Gelatin is the only excipient of those mentioned above that has no e-number, and is therefore not classed as an additive, making it ideal for clean label capsules. A clean label has less effect when it comes to prescription pharmaceuticals, but consumers and patients tend to favor claims such as “free-from additives” and “natural origin.”
More important than labeling is excellent technical performance. Manufacturers favor optimized bioavailability, reduced crosslinking and low oxygen permeability. Compared with other alternatives, gelatin displays outstanding immediate release dosing (1) – an important parameter for capsule-dosed medicine formulation. For alternative excipients, it is more difficult to guarantee equally fast opening times. First generation HPMC, for example, is more unpredictable in releasing APIs (2), which makes it less reliable in the formulation of prescription medicines.
With any excipient, crosslinking is always an important consideration. An excipient’s crosslinking ability can negatively impact soft capsule opening time, therefore affecting bioavailability. Because of its natural amino acid composition, gelatin, in general, is more susceptible to crosslinking in the presence of complex fills, for example, but specific gelatins with reduced crosslinking ability exist. For APIs with complex stability profiles, low oxygen permeability is another important factor that must be considered when formulating capsules with the greatest performance. When the four main excipients are compared, gelatin and pullulan offer superior oxygen barriers, making them the safest choices for capsules (3).
The final challenge for capsule formulation is operational effectiveness. Machinability, cost-efficiency and weight variations are key indicators in determining the right excipient in this area. Gelatin’s thermoreversible property allows a high level of machinability – meaning it can withstand an encapsulation machine and melt at body temperature without affecting its properties or functionality. For manufacturers wanting to reduce expenditure, gelatin-based capsule production outperforms alternatives in terms of cost efficiency. For instance, raw materials for HPMC capsules are priced approximately four times more than gelatin (4).
The four main excipients – gelatin, HPMC, pullulan and modified starch all have GRAS status in pharmaceutical and food applications by bodies such as the World Health Organization – and all offer unique advantages depending on your application. Some in the industry prefer plant-based excipients and are, therefore, turning away from gelatin, but gelatin really does have a longstanding heritage as a trusted, reliable and natural excipient with high effectiveness. Gelatin alternatives, on the other hand, are still in their infancy, and there currently isn’t a plant-based excipient on the market which is completely natural, as cellulosics and starches need to be chemically modified to be used as capsule shell excipient.
- MM Al-Tabakha et al., “Influence of capsule shell composition on the performance indicators of hypromellose capsule in comparison to hard gelatin capsules,” Drug development and industrial pharmacy, 41, 1726-1737 (2015). PMID: 25586554
- N Glube et al., “Capsule shell material impacts the in vitro disintegration and dissolution behaviour of a green tea extract,” Results Pharma. Sc., 13,1-6 (2013). PMID: 25755998
- R Gullapalli and C Mazzitelli, “Gelatin and non-gelatin capsule dosage forms,” J. Pharm. Sci., 106, 1453-1465 (2017). PMID: 28209365
- Business Standard, “Gelatin capsules have technical advantages over HPMC capsules: PHD Chamber to DCGI” (2013). Available at bit.ly/2M5Y1XW. Last accessed August 1, 2018.