Soft capsules have been a staple of medical life for almost two centuries. They were invented back in the 1830s, by a pair of French pharmacists called Dublanc and Mothes, who hoped their new gelatine capsules would literally be easier to swallow for patients facing long medicinal courses. Not, of course, that this first foray into soft pills would be wholly successful. To soften their mixture, after all, the Parisian pioneers would first dip their gelatine into a leather pouch holding mercury, hardly ideal for already-sick punters.
Yet from these uncertain beginnings, soft capsules would endure, prodded along by the invention of the softgel capsule machine in the early 1930s. These days, soft capsules are a thoroughgoing staple of chemists everywhere, representing an industry worth nearly $5bn globally. Nor is this enthusiasm tough to understand. Quite apart from their palatability – particularly compared to their hardshelled cousins – they’re also ideally suited for liquid or semi-solid fillings. That’s true both in the straight pharma or wider ingredients spaces.
The way these capsules actually look is surely helpful too, their translucent colour allowing consumers to see the medicine inside. Yet as Dublanc and Mothes discovered back in the 1830s, actually creating marketable capsules is easier said than done. From soft shell formulation to manufacturing and storage, there are a range of factors to consider here. That’s even as this most august of sectors is moving in interesting new directions too, with consumers increasingly demanding animal-free alternatives to the old gelatine staples. Combine that with a rising push towards recycling and sustainability, and soft capsules have never been so exciting – with important consequences for consumers and pharma giants alike.
Going soft
Despite their small size, soft capsules are remarkably versatile products. Available in a range of colours, sizes and shapes, oral products can boast liquid or semi-solid fillings. That variety continues elsewhere too, with manufacturers often equipping their drugs with delayed or controlled release systems depending on the pharmaceutical at hand. Soft capsules can also differ in administration format. Though swallowable pills are prominent here, the skin or eyes can be occasional delivery methods too, as can suppositories.
$4.8 billion
The size of the global softgel capsule market in 2021, with the sector expected to enjoy CAGR of over 9% through 2030.
Polaris Market Research
Yet whatever their bewildering spread, soft capsules of all stripes arguably share more similarities than differences. That’s undoubtedly clear in terms of their manifold advantages, whether their ability to deliver low drug doses or else their usefulness at masking unpleasant odours. For Dr Shawn Wettig, softgels are more palatable in other ways too. “As you take a soft gelatine capsule,” explains the biophysical chemistry professor at the University of Waterloo in Canada, “it will surround itself with a layer of moisture from the saliva – and that makes it much easier to swallow than a traditional hard pill.”
As Wettig hints, meanwhile, crucial here are the gelatine shells that surround the active ingredients of soft capsule medications. Because they rapidly dissolve when swallowed, they’re ideal for getting fast-acting drugs into the body. At the same time, the fact that shells are hermetically sealed ensures the ingredients inside don’t oxidise. Yet despite these strengths, soft capsule design comes with a range of challenges. That’s arguably clearest when around what Wettig calls “managing the potential interactions” between a capsule’s shell and its filling. Especially when combined with higher temperatures or humidity, or else when a shell’s colouring agents react with the liquid inside, the product’s stability can decline. That, in turn, often leads to leakage – hardly ideal from an aesthetic or commercial perspective, let alone a regulatory one.
A related difficulty involves securing the right gelatine for the capsule at hand. Bovine and porcine varieties differ in thickness and strength, while an animal’s age, breed and sex can also make the resulting gelatine hard to manipulate. Extraction methods are also important to reflect on, especially when some result in gelatine with stronger smells. Nor are manufacturing techniques only relevant from a chemical perspective. On the contrary, softgel capsules require sophisticated machinery to produce, with some encapsulation devices going for many thousands of dollars.
Breaking down
Given these assorted challenges, how can soft capsule manufacturers ensure their products work as intended? From a scientific perspective, the answer can plausibly be answered in a single word: plasticisers. Often made from glycerin, Wettig says they add “flexibility” to the gelatine, adding softness, decreasing viscosity and generally making the material easier to handle. The amount of plasticiser needed for a particular soft capsule depends on several factors, including the gelatine used and filling type. But given they affect everything from elasticity to rigidity, it’s surely surprising that the global plasticisers market was currently worth $16.9bn in 2023, a figure that could rise to nearly $30bn by 2034. That’s especially true when you add materials like sorbitol into the mix, which don’t interact with gelatine directly, but rather help keep it moist.
After perfecting their gelatine, at any rate, softgel manufacturers must then consider how a medication’s shell intersects with the active ingredient within. Once again, a robust appreciation of the underlying chemistry is crucial here – given, for instance, that oilbased fillings are less likely to interact with the shell than water-based alternatives. Preservatives need to be understood here too, not least when the fragile chemical nature of some soft capsules means they could break down without sorbic acid or potassium sorbate to keep them together.
In practice, pharma firms tend to work through this chemical jamboree using a series of experiments. One of the most popular is the so-called ‘tensile strength’ test, which helps examine the toughness of a capsule’s gelatine shell. Puncture tests can be similarly helpful, as can viscosity and hardness exams. That, of course, still leaves the actual manufacturing process. But here too, the sector has stepped up to the plate. Perhaps the most striking development of recent times here is the high-speed encapsulation machine. Coming in at over $100,000 each, these devices are doubtless expensive – but upfront costs are surely outweighed by their remarkable productivity, with the latest models capable of pumping out 400,000 pills an hour.
Not having a cow
Through a clever combination of intelligent chemistry and new machinery, it’s clear that the soft capsule sector is becoming more efficient all the time. But if titans like Aenova and Capcium now straddle a sector set to enjoy a CAGR of 9.2% through 2030, laboratory tinkering isn’t immune to broader market forces. Veganism, after all, already boasts a food market worth $16bn, even as the meat-free pharma market is increasingly buoyant too. These numbers, it goes without saying, pose serious challenges for soft capsules – a sector long predicated on animal gelatine. No wonder Wettig says that manufacturers are pressing ahead with alternatives, including synthetic polymers and plant-derived hydrocolloids.
That’s echoed by advances elsewhere too. In France, to give one example, Roquette recently announced a new vegan softgel formula. But what really stands out here isn’t so much the pea-starch alternative to bovine gelatine – but rather the fact the Roquette product is made plasticiser-free, allowing end users to tweak the final product to fit the active ingredient. Nor are these forays into gelatine-free capsules merely allowing consumers to avoid meat. On the contrary, products like Vegicaps (from Catalent) and VegaGels (from Aenova) are furnished with omega-3 made from algae, ensuring customers are confident that both the shell and the filling of their capsules aren’t tainted by meat.
As so often in the vegan space, moreover, specific questions around ingredients intersect with broader sustainability concerns. Certainly, there’s plenty of scope for change here. “When you’ve got the encapsulation process,” Wettig explains, “you’ll have left over gelatine after you’ve punched out the capsule.” A fair point: though gelatine films are generally biodegradable, wastage during the manufacturing process can reach 50%. With this in mind, it makes sense that companies should be looking to sharpen their production processes, with one Chinese firm using new mould designs to cut gelatine waste by 5–10%. In a similar vein, reusing leftovers is rising in popularity too, especially when gelatine scraps can contaminate wastewater treatment plants further down the supply chain.
5–10%
The percentage a new Chinese-built mould machine may be able to cut gelatine wastage in soft capsule manufacturing.
Wiley Online Library
And if there are still some issues for the sector to sort out here – in practice, left over gelatine needs to be purified before it can be repurposed – the sector is equally rushing ahead with fully-fledged recycling schemes. Once again, purification is crucial here, with companies obliged to first purge gelatine of lubricating oils and additives. All the same, there are signs that scientists are making progress here too, with new patents hinting that raw gelatine might soon be redeployed for future softgel production. Given its versatility, moreover, it’s unsurprising that gelatine is equally being recycled for uses outside the medical space. As a paper in the Journal of Applied Polymer Science explains, one potential use case is to mix gelatine waste with sawdust and sugar cane to make a herbicide. Another, reports a North Carolina company, is converting it to glue. If only Dublanc and Mothes could come back and see that.
