Vegetarian substitutes for gelatin soft capsules

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January 02, 2020

Vegetarian substitutes for gelatin soft capsules

 

Claudia Silva, Procaps 
Kirti Vatsa, Beroe


Soft capsules, also called softgels, are one of the most widely used solid oral dosage forms, particularly in the nutraceutical market. Traditional softgels are made from gelatin, but interest in vegetarian alternatives to gelatin soft capsules (GSCs) is growing. 

The materials used to make vegetarian soft capsules (VSCs) have very different properties than gelatin. The first commercially viable VSCs appeared on the market around 2001 and were developed for encapsulating oils and suspensions for dietary and cosmetic products1. The capsules were made from carrageenan-modified starch (CMS), and the encapsulation equipment subjected the capsules to a curing step, in which the capsules passed through a band of hot air. Later machines included die rolls designed to increase the thickness of the seal and prevent the capsule contents from leaking. 

The industry has made continuous improvements to the materials, equip- ment, and processes involved in their manufacture. As a result, vegetarian soft capsules can now be produced using the same type of mixing and encapsulation equipment used for GSCs at similar encapsulation speeds. 

VSC market 

VSC products are currently available in the nutraceutical and cosmetics markets as well as a few products in the pharmaceutical market. VSCs currently constitute approximately 10 to 15 percent of the nutraceutical soft capsule market in terms of revenue, and their use is expected to continue to grow due to increasingly competitive material prices and optimized processing technology as well as expansion into the pharmaceutical market. 

The primary market for VSCs includes consumers who demand vegetarian capsules for cultural, religious, or dietary reasons. VSCs can also be beneficial in applications where gelatin is not a suitable capsule polymer, such as high-temperature encapsulation or products with high-pH fill content. Manufacturers are also looking to VSC polymers as alternatives to gelatin because gelatin is derived from animals, is prone to price fluctuations, and has a relatively large carbon footprint. 

VSCs have faced some concerns from consumers interested in “clean label” products—defined as products containing only unprocessed or unmodified ingredients—since starches are chemically modified materials. 

Also, carrageenan suffered from a long period of concerns that it was carcinogenic, causing many food producers, especially in the US, to stop using it in their products. However, the FDA considers carrageenan a generally recognized as safe (GRAS) material. 

VSC materials 

The most common gelatin substitutes used to make VSCs are carrageenan, modified starch, and alginate. Table 1 summarizes the market and sourcing challenges for each. 

Table 1: Market and supply for gelatin substitutes in soft capsules
Carrageenan

The global market for carrageenan is approximately 60 to 70 kilotonnes per year, with an expected compound annual growth rate (CAGR) of 4 to 5 percent2. Seventy to 80 percent of the carrageenan produced is used in the food industry for its gelling, thickening, and stabilizing properties, while less than 10 percent is used by the pharmaceutical industry. Pharmaceutical applications, particularly soft capsules, are still considered a niche segment.

As previously mentioned, the first VSCs consisted of a blend of carrageenan and modified starch (hydroxy-propyl starch), and most nutraceutical VSCs currently on the market still use carrageenan-based formulations.

Table 2: Comparison of processing steps for GSCs versus VSCs

Manufacturers offering carrageenan-based soft capsules include Procaps, Ayanda, Captek, Catalent, and Eurocaps, among others. 

Carrageenan is produced by two species of cultured red seaweeds, kappaphycus alvarezii and eucheuma spp. Production of these seaweeds was estimated at 8.3 million tonnes in 20123. Indonesia and the Philippines are the two major producers of this raw material, which sells for approximately $1,800 per tonne4, 5. 

Climate change has the potential to affect the red seaweed supply, but suppliers are taking actions to avoid shortages. For example, the carrageenan manufacturer Cargill has committed to sourcing 60 percent of its red seaweed sustainably by 20256. 

The number of suppliers manufacturing pharmaceutical-grade carrageenan suitable for soft capsule production is limited, but it is expected that suppliers will expand and improve their product portfolios due to increased demand from end-user industries. 

Modified starch

Global production of modified starch was between 9 and 10 million tonnes in 20177, and the import price in the European Union was $922 per tonne, which represented a 3.9 percent increase over the previous year8. Starch has good film-forming properties and good raw material availability, which, along with its price advantage, makes starch-based soft capsules a good low-price alternative to GSCs or other vegetarian capsules. 

The world’s first carrageenan-free vegan softgel, Plantgels, replaces carrageenan with modified tapioca starch, which is derived from the cassava root9. Some other modified starches such as corn or pea are used in combination with carrageenan for softgel applications. 

Alginate

Europe and North America combined account for more than 50 percent of the global alginate market, which is growing at a CAGR of 1 to 3 percent. Growth in the Asia-Pacific market is higher due to increased demand from the processed food and pharmaceutical industries. The pharmaceutical market for alginate is consolidated, with two major suppliers that account for more than 90 percent of global market share10.

Currently, the pharmaceutical alginate supply is sufficient to meet demand, and if demand should increase suddenly, suppliers focused on food-grade alginate could switch production to pharmaceutical applications, since all regulatory approvals are in place. 

The sole raw material for commercial-scale alginate production is brown seaweed, which is time consuming and labor intensive to cultivate. Currently, the brown seaweed supply is sufficient to meet the needs of the alginate market, and there are no issues with feedstock capacity. However, because there is a limited number of qualified suppliers and a high entry cost for new suppli- ers, alginate buyers do not have much negotiating power with suppliers.

Figure 1: Characterization of VSCs at accelerated stability conditions (40°C, 75% RH)
The moisture content in fresh capsule shells may be about 20 percent, depending on the formulation, and drying time is comparable to GSCs. The filling volume should determine the proper die roll size, since overfilling affects the seal strength and the shells may contract during drying. 

Despite some particular processing requirements, formulations containing carrageenan are straightforward to encapsulate compared to modified starch because of their consistency batch to batch, robust film formation, elasticity, seal strength, and stability at varying moisture and temperature conditions. 

In-process controls include temperatures at different points in the encapsulation machine, film thickness, and weight variation. Physical testing of the capsules includes hardness, burst test, film and seal thickness, and shell moisture content. 

Stability of VSC products

Figure 1 shows the results of a study comparing the hardness, burst test, seal percentage, shell moisture content, and disintegration time for several marketed VSC products at stability conditions. The study compared the properties of two Procaps VSC products (S1 and S2) and four commercial VSC products made from CMS at 40°C, 75 percent RH at initial time (M0), 1 month (M1) and 3 months (M3). 

In general, VSC hardness has been reported to be as low as 2.0 newtons and not comparable to GSCs. Most VSCs are nutritional products containing either single oils or oily suspensions using only glycerol as a plasticizer. Hardness can be a reference for the final drying time, and low hardness values could compromise the products during bulk storage and transport. Burst test and percentage of the trailing seal are a measure of the seal quality, ranging roughly from 100 to 300 newtons and 50 to 87 percent, respectively, at the initial time, as shown in the figure.

Percent seal values in VSCs can be as high as 80 percent depending on the die roll design. Disintegration times were determined under USP conditions for rupture time of soft capsules (USP apparatus 2), considering the total disintegration of the shell as final point for visual detection. At stability conditions, physical properties tended to decrease but not to an unacceptable level, with the exception of the disintegration times, which in some cases, were observed to be longer than 30 minutes. While VSCs show a lag time in dissolution due to the slow hydration of the shells, they are not prone to crosslinking, as gelatin is, so the cause of the increased disintegration times at stability conditions is unclear.

VSC outlook 

While the supply of gelatin-free soft capsules is still in its nascent stage, demand for vegetarian capsule shells, whether plant derived or synthetic, is growing. VSCs have the potential to reach a considerable market share in the future using the gelatin substitutes discussed in this article. Decreasing material costs and increasingly optimized processes also provide opportunity for growth in the number of VSC products on the market. 

Existing products have demonstrated the feasibility and consistency of VSC materials and manufacturing processes. While there are some challenges associated with VSC manufacturing, the products demonstrated physical stability at accelerated conditions. However, disintegration times were longer for VSCs at stability conditions compared to GSCs, which should be evaluated, as disintegration time is a critical quality attribute. 


References 

1. Bjorn Vergauwen, “Creat- ing the perfect capsule,” Pharma Focus Asia, Available at: www.pharmafocusasia.com/ research-development/creating-perfect-capsule. 

2. FAO report. 

3. Beroe analysis. 

4. IMR International, Hydrocolloid Information Cen- ter, “Food Hydrocolloid Extracts 5, 10, or 15 Years,” Avail- able at: www.hydrocolloid.com/summary_extracts.php. 

5. Beroe interaction with supplier. 

6. Katy Askew, “On the frontline of climate change: Cargill building ‘resilience’ into its red seaweed supply chain,” Available at: www.foodnavigator.com/Article/ 2019/03/14/On-the-frontline-of-climate-change-Cargill- building-resilience-into-its-red-seaweed-supply-chain. 

7. Beroe analysis based in secondary research. 

8. MarketWatch, “EU Modified Starch Market: Ingre- dion Inc., Cargill Inc., Bunge Ltd.,” Available at: www. marketwatch.com/press-release/eu-modified-starch-market- ingredion-inc-cargill-inc-bunge-ltd-2019-07-01. 

9. Available at: www.optinutra.com/quality/. 

10. Beroe analysis. Claudia Silva, PhD, is director of new pharmaceutical technol- ogies at Procaps (575 371 9000, www.softigel.com). 


Kirti Vatsa is principal analyst at Beroe (919 747 4818, www.beroeinc.com).


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