The Crossover: The Technicalities of Softgel Production and How They Impact Patients

Pierre-Albert Thomas - Global Director, Functional Ingredients, Rousselot.

Gel mass viscosity, crosslinking, shell integrity, ribbon formation, encapsulation, dissolution performance, and capsule stability – do these words mean anything to patients? While each is a vital consideration for manufacturers of softgel capsules, none of them tell us much about why this form of medication has become so popular over the last decade. With the global softgels market projected to post a CAGR of 4.3% from 2023 to 2033,¹ drug producers must be doing something right in attracting patients to capsules. But what do these numbers tell us about the patient experience? Manufacturers are acutely aware of the importance of catering to the needs of their end-users. Indeed, patient compliance is one of the biggest and most pressing trends dominating the industry today, second only perhaps to the need for constant scientific innovation. With this in mind, could it be time to make this combination of ‘head’ and ‘heart’ clearer to patients by injecting the humanity of trend conversations into more technical discussions around optimizing softgel manufacturing?

In this article, we’ll do just that – examining the trends shaping demand for softgel capsules, then diving deep into the capsule manufacturing process to demonstrate the very real value to be gleaned by always centering the patient perspective.

Trend Focus: Why Softgels and Why Gelatin?

Before digging into their production, let’s examine why gelatin-based softgels are such a favorite among today’s manufacturers and patients. Because softgels are, undoubtedly, growing in popularity. Over the last decade, the global softgel capsule market has posted a CAGR of 3.9% to reach a value of over 1.1 billion USD by 2022.² As with any trend, there is a range of explanations behind softgels’ rise to prominence, but perhaps the most important of these factors is the need to encourage patients to take their prescribed medications and self-administered supplements. With instances of chronic disease increasing worldwide, and the proportion of the global population over 60 set to double by 2050, the demand for effective drugs and supplements has never been more pressing.^3,4 And yet, according to some metrics, almost half of long-term medication users do not take treatments as prescribed, an alarming statistic usually attributed to pill fatigue.⁵ This feeling of being overwhelmed by multiple medications can affect anyone but is especially damaging to older patients or those required to take multiple daily doses to manage chronic conditions. With their smooth, rounded exterior and neutral sensory profile, softgel capsules are more convenient and easier to swallow, making them an indispensable tool in the fight against medication non-compliance. What’s more, by encapsulating active ingredients within a stable, yet easily dissolvable gelatin shell, these capsules allow for the efficient delivery of poorly soluble, potent, or unpleasant-tasting active ingredients without leaving a bad taste in users’ mouths.

Many of the prized properties behind softgels’ success stem from one of their most famous ingredients, gelatin. Though by no means are all softgels gelatin-based, this natural, safe, and instantly recognizable polymer has been a staple excipient for the category since its inception. Today it holds an especially rarified position thanks to its dual reputation for safety and versatility, facilitating the development of innovative dosage forms that better serve the needs of a widening patient base. Even better, gelatin is also seen as a ‘zero-loss’ ingredient that promotes a more sustainable approach to drug manufacturing.

Taking all this into account, it’s clear why gelatin-based softgels hold so much sway in the current pharma and nutraceutical markets. In theory, they neatly address some of the thorniest issues impacting patient experience, but even the best ideas rely on good execution to come to fruition. Let’s look at the practicalities of softgel manufacturing and examine the vital role each piece plays in creating a whole that truly delivers for patients.

Magic Materials

First, the building blocks. We know gelatin makes the ideal base for softgels, but within the overall category of gelatin solutions, there are a myriad of options available to pharma/nutraceutical manufacturers – not all of which are created equal. To ensure the success of the final drug and meet end-user preferences, producers often need a specially developed gelatin excipient, built with the right functional properties to optimize production efficiency and mitigate common production challenges.

Gelatin’s unique film-forming functionalities allow it to set quickly and form reproducible films of defined thickness known as ribbons. The film-forming and viscosity properties of the specific gelatin chosen are crucial to the success of the ribbon-forming stage since viscosity (linked to the molecular weight) influences the formation of the gelatin network. Selecting a gelatin with the right visco-elastic behavior is therefore essential to creating the perfect ribbon that ensures perfect production efficiency.

Excipient selection also has implications further down the production line. Once formed, the gelatin ribbon is passed through a wedge which flattens and cuts it into individual shapes ready for filling. In tests on lecithin softgel formulations conducted by Rousselot, it was observed that some types of high-viscosity gelatin with a greater molecular weight were more susceptible to misshaping and shell leakage, requiring a higher wedge temperature during manufacture to encourage proper shell sealing.⁶ It was also observed that softgel capsules manufactured through an alkaline or mixed-method process showed a lower rate of leakage than those made using gelatin produced through an acid process. Factoring in these results, researchers at Rousselot were able to optimize both the type of gelatin and encapsulation wedge used during soft gel manufacture to decrease the rate of leakage from two percent to almost zero – truly demonstrating the power of choosing the right materials.

Strong and Stable Wins the Race

We have our capsules, now it’s time for the active ingredients. One of the principal advantages of the softgel format is its capacity to deliver actives with a low solubility profile– particularly Biopharmaceutics Classification System (BCS) Class II or IV active pharmaceutical ingredients (APIs).⁷ Insoluble compounds like these are among the most challenging to administer effectively since they are so difficult for the body to absorb, and as such are considered poorly bioavailable.⁸ The genius of softgels here is that because they suspend the API within a more readily bioavailable solution, they help even the most challenging compounds reach their intended site of action more effectively than other solid oral dosage forms.⁹ The task for drug manufacturers, therefore, becomes one of producing stable, robust, and high-quality softgels, capable of keeping delicate APIs safe and bioavailable until they reach their final target.

The dynamism of a softgel system is one of the major hurdles facing producers in achieving this all-important API stability. Physical migration of components or chemical reactions between the shell and fill, as well as external stresses, can all cause instability, brittleness, and shell softness, affecting the protection of the API against oxidation and causing possible recrystallization. In PEG-based softgels for instance, the capsule shell often exhibits a vastly different moisture profile from the extremely hydrophilic PEG fill. This causes the migration of water following encapsulation, leading to instability and a less effective capsule. If, however, as discussed above, a manufacturer has chosen the right form of high-quality gelatin excipient, these challenges can be overcome through a robust drying process.

Drying is a crucial step in any gelatin-based production process. We can see the effect final moisture levels can have on the success of softgel capsules in a study conducted by Rousselot on a generic fish oil formulation. Researchers found that a moisture level of more than 11% during the production phase significantly increased the risk of stickiness in the final product.¹⁰ It was determined that parameters such as drying conditions and gelatin kinetics are key to achieving an optimal moisture level and that softgels prepared with plasticizers like PEG require a different drying regime than those featuring glycerol or sorbitol.¹¹ Although a drying temperature of 25°C at 25% relative humidity permitted more water evaporation over the first two days of drying, the study found that 15°C at 15% relative humidity was more effective in lowering overall moisture content, helping prevent stickiness and assure the stability of capsules across the entirety of their shelf life.¹²

The Final Hurdle: Crosslinking

Finally, we turn to the bane of any manufacturers working with gelatin softgels, cross-linking. The term describes a phenomenon in which two or more molecules are joined by a covalent bond, causing a concomitant increase in molecular weight. The crosslinked polymer subsequently becomes less soluble, impacting both bioavailability and capsule opening time. Extensive crosslinking means tough, rubbery, ineffective capsules unlikely to deliver their full payload of active ingredients – in short, a big problem.

Research by Rousselot has revealed that some parameters, including molecular weight distribution, poor storage conditions, and susceptibility to aldehyde contamination, may have an impact on a gelatin ingredient’s propensity for crosslinking and subsequent instability.¹³ Armed with this insight, the company set about developing a gelatin technology specifically designed to minimize crosslinking reactions.

Enter Rousselot’s StabiCaps™ solution, a gelatin ingredient that exhibits higher resistance to chemical stresses and capsule hardening due to aldehyde contamination, resulting in more secure capsule shells with an optimal dissolution and API release profile. These properties drastically reduce the risk of crosslinking, allowing for the production of higher quality capsules with fewer defects, capable of reliably delivering the medications patients need to stay well. So unique and effective is StabiCaps™ in this respect, that the technology was recently granted a patent by the U.S. Patent and Trademark Office (USPTO) (Patent No. US11795489B2), to join its existing recognition by the European Patent Office (EPO) and lend further credence to its revolutionary potential to super-charge softgel production.

The Softer Side of Softgels

 Surveying the points made above, a new perspective on capsule manufacturing comes into focus, one where technical factors are not divorced from the ‘human’, trend-centric business of drug manufacturing. Though experiments like this article aside, it is not always possible or practical to consider the patient's perspective on every individual processing step. But what should be apparent is the immense value such a consideration can bring to pharma brands and their customers. By never forgetting the person at the end of the supply chain and their experience, manufacturers can make a real impact; on the success of their products, patient acceptance, and healthcare outcomes. That is, after all, the goal at the center of every softgel.

References

1. Persistence Market Research - https://www. persistencemarketresearch.com/market-research/softgels-capsules-market.asp
2. FMI, Softgel Capsules Market Snapshot (2022 to 2032), https:// www.futuremarketinsights.com/reports/softgel-capsules-market
3. World Health Organization, Ageing and health, 4 October 2021, https://www.who.int/news-room/fact-sheets/detail/ageing-and-health
4. PWC, Chronic diseases and conditions are on the rise, https:// www.pwc.com/gx/en/industries/healthcare/emerging-trends-pwc-healthcare/chronic-diseases.html
5. Elephant in the Room, US Pharm. 2018;43(1)30-34, https://www. uspharmacist.com/article/medication-adherence-the-elephant-in-the-room
6. Internal Rousselot study, Wenzhou Application Lab, April 2016.
7. Damian F, Harati M, Schwartzenhauer J, Van Cauwenberghe O, Wettig SD. Challenges of Dissolution Methods Development for Soft Gelatin Capsules. Pharmaceutics. 2021 Feb 4;13(2):214. doi: 10.3390/pharmaceutics13020214. PMID: 33557167; PMCID: PMC7913951.
8. Ibid
9. Ibid
10. Liquid-filled Gelatin Capsules. Pharmacopeial Forum 2009 Vol. 35(4)
11. Ibid
12. Ibid
13. Internal Rousselot study, Ghent Application lab, Oct. 2016

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