Vegetarian Substitutes for Gelatin Soft Capsules

As appeared in January 2020 Tablets & Capsules Copyright CSC Publishing www.tabletscapsules.com capsules

Vegetarian substitutes for gelatin soft Claudia Silva capsules Procaps Kirti Vatsa Beroe

This article provides an overview of the current state of materi- oft capsules, also called softgels, are one of the most als and technology used to produce vegetarian soft capsules widely used solid oral dosage forms, particularly in the and discusses applications, processing, and suitable products nutraceutical market. Traditional softgels are made from Sgelatin, but interest in vegetarian alternatives to gelatin for these alternatives to soft gelatin capsules. 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 Copyright CSC Publishing and suspensions for dietary and cosmetic products [1]. derived from animals, is prone to price fluctuations, and The capsules were made from carrageenan-modified has a relatively large carbon footprint. starch (C-MS), and the encapsulation equipment sub- VSCs have faced some concerns from consumers jected the capsules to a curing step, in which the capsules interested in “clean label” products—defined as products passed through a band of hot air. Later machines included containing only unprocessed or unmodified ingredi- die rolls designed to increase the thickness of the seal and ents—since starches are chemically modified materials. prevent the capsule contents from leaking. Also, carrageenan suffered from a The industry has made continuous long period of concerns that it was car- improvements to the materials, equip- Vegetarian soft cinogenic, causing many food produc- ment, and processes involved in their ers, especially in the US, to stop using manufacture. As a result, vegetarian soft capsules can now be it in their products. However, the FDA capsules can now be produced using considers carrageenan a generally recog- the same type of mixing and encapsula- produced using the nized as safe (GRAS) material. tion equipment used for GSCs at similar encapsulation speeds. same type of mixing VSC materials The most common gelatin substitutes VSC market and encapsulation used to make VSCs are carrageenan, VSC products are currently avail- modified starch, and alginate. Table 1 able in the nutraceutical and cosmetics equipment used for summarizes the market and sourcing markets as well as a few products in the challenges for each. pharmaceutical market. VSCs currently gelatin soft capsules Carrageenan. The global market for constitute approximately 10 to 15 per- carrageenan is approximately 60 to 70 cent of the nutraceutical soft capsule at similar kilotonnes per year, with an expected market in terms of revenue, and their use compound annual growth rate (CAGR) is expected to continue to grow due to encapsulation speeds. of 4 to 5 percent [2]. Seventy to 80 per- increasingly competitive material prices cent of the carrageenan produced is used and optimized processing technology as in the food industry for its gelling, thick- well as expansion into the pharmaceutical market. ening, and stabilizing properties, while less than 10 per- The primary market for VSCs includes consumers cent is used by the pharmaceutical industry. Pharma- who demand vegetarian capsules for cultural, religious, ceutical applications, particularly soft capsules, are still or dietary reasons. VSCs can also be beneficial in appli- considered a niche segment. cations where gelatin is not a suitable capsule polymer, As previously mentioned, the first VSCs consisted of such as high-temperature encapsulation or products with a blend of carrageenan and modified starch (hydroxy- high-pH fill content. Manufacturers are also looking to propyl starch), and most nutraceutical VSCs currently VSC polymers as alternatives to gelatin because gelatin is on the market still use carrageenan-based formulations.

Table 1 Market and supply for gelatin substitutes in soft capsules Material Global market Pharma Major pharma Average Raw material Sourcing challenges in 2018 usage suppliers* price (kilotonnes) ($/kg) Carrageenan 60-70 7% ~10-12 11-12 Red seaweeds Limited supply base and concerns VSC: 500 with feedstock availability may tonnes occur due to climate change. Currently, no supply issue with feedstock in major producing regions. Alginates 40 8-10% ~2-4 12-14 Brown seaweed Highly consolidated supply base and GSC: high entry cost for new suppliers. unknown

Modified 9,000-10,000 10-15% ~5 4-5 Many, Important to track price movement. starch (as an including: excipient) potato, corn, cassava, etc. Source: Beroe analysis * Indicates the number of suppliers who cater to pharmaceutical applications but not necessarily soft capsule shells. Copyright CSC Publishing Manufacturers offering carrageenan-based soft capsules starch, which is derived from the cassava root [9]. Some include Procaps, Ayanda, Captek, Catalent, and Euro- other modified starches such as corn or pea are used in caps, among others. combination with carrageenan for softgel applications. Carrageenan is produced by two species of cultured Alginate. Europe and North America combined red seaweeds, kappaphycus alvarezii and eucheuma spp. account for more than 50 percent of the global algi- Production of these seaweeds was estimated at 8.3 mil- nate market, which is growing at a CAGR of 1 to 3 per- lion tonnes in 2012 [3]. Indonesia and the Philippines are cent. Growth in the Asia-Pacific market is higher due to the two major producers of this raw material, which sells increased demand from the processed food and pharma- for approximately $1,800 per tonne [4, 5]. ceutical industries. The pharmaceutical market for alginate Climate change has the potential to affect the red is consolidated, with two major suppliers that account for seaweed supply, but suppliers are taking actions to avoid more than 90 percent of global market share [10]. shortages. For example, the carrageenan manufacturer Currently, the pharmaceutical alginate supply is suf- Cargill has committed to sourcing 60 percent of its red ficient to meet demand, and if demand should increase seaweed sustainably by 2025 [6]. suddenly, suppliers focused on food-grade alginate could The number of suppliers manufacturing pharmaceu- switch production to pharmaceutical applications, since tical-grade carrageenan suitable for soft capsule pro- all regulatory approvals are in place. duction is limited, but it is expected that suppliers will The sole raw material for commercial-scale alginate expand and improve their product portfolios due to production is brown seaweed, which is time consuming increased demand from end-user industries. and labor intensive to cultivate. Currently, the brown Modified starch. Global production of modified starch seaweed supply is sufficient to meet the needs of the was between 9 and 10 million tonnes in 2017 [7], and the alginate market, and there are no issues with feedstock import price in the European Union was $922 per tonne, capacity. However, because there is a limited number of which represented a 3.9 percent increase over the previ- qualified suppliers and a high entry cost for new suppli- ous year [8]. Starch has good film-forming properties and ers, alginate buyers do not have much negotiating power good raw material availability, which, along with its price with suppliers. 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

Table 2 Comparison of processing steps for GSCs versus VSCs

Gelatin Modified starch Carrageenan-modified starch

Film casting Fast, easy Slow, difficult, sensitive to RH Slow, easy (equipment adaptations)

Polymer mass preparation No No Yes specific mixing system High temperature heated- No Yes Yes (extrusion systems can be required) transfer system

Conventional die rolls Yes No No

Encapsulation Yes spreader boxes design No No (some cases)

Required curing step No No Yes

Tray-drying (days) + ++ + (oil-based capsules)

Batch-to-batch variability No Yes No

Process cost $ $$ $$$

Source: Procaps Copyright CSC Publishing VSC manufacturing Table 2 shows a summary of the technical require- As previously mentioned, the properties of the mate- ments for VSC production and compares the pros and rials used to make VSCs differ from gelatin. Raw mate- cons of VSCs and GSCs. Items in red show processing rial and equipment suppliers have had to learn how to differences compared to GSCs due to new equipment, work with these new materials to overcome challenges adaptations to existing equipment, or additional process- related to the resulting capsules’ physical, chemical, and ing steps, such as heated transfer and curing. functional properties, such as soft- In recent years, modified starch ness, leaking, poor dissolution, and suppliers have offered materials with increased dissolution times at stability Raw material and viscosities of about 40,000 to 50,000 conditions. Also, VSC polymers have centipoise that can be handled in higher viscosities and require higher equipment suppliers GSC equipment. In contrast, C-MS processing temperatures than gelatin, formulations can have viscosities as which makes mixing, deaeration, and have had to learn how high as 90,000 centipoise. As the transfer processes challenging. table shows, such polymer masses With gelatin, film formation is due to work with these new require mixing, heating, transfer, to the tertiary structure of the gelatin and spreading systems designed to induced below the gelation tempera- materials to overcome handle high-viscosity materials. In ture (30° to 40°C). With starch formu- general, starch formulations require lations, film formation proceeds mainly challenges related to the moisture control, because the film is by the swelling and gelatinization of sensitive to RH values higher than 20 the starch (at 90° to 95°C). Gelatiniza- resulting capsules’ to 30 percent. tion refers to irreversible gel formation physical, chemical, and For GSCs, the sealing process due to the release of amylose in the occurs by sol-gel transition (also starch granules when they are heated functional properties. called gelation), but for VSCs, sealing and cooled. occurs through gelatinization of the Gelatin films cast easily and starches. The sealing quality is deter- quickly, are highly elastic and resistant to strain, and dry mined by the film quality, the design quickly. Carrageenan-starch films cast slowly under con- of the die roll, the pressure force, and in some cases by trolled conditions, are elastic and resistant to strain, and processing steps after encapsulation. During encapsula- dry slowly. Starch films cast slowly, are highly suscep- tion, heating the wedge is not required since sealing is tible to relative humidity (RH), have low elasticity and not dependent on temperature. resistance to strain, and dry slowly.

Figure 1 Characterization of VSCs at accelerated stability conditions (40°C, 75% RH)

307.7 100 300.0 288.8 87% 90 79% 83% 248.7 241.6 80 250.0 231.4 231.3 227.8 207.5 210.5 71% 234.8 203.2 70 65% 71% 200.0 60% 60% 57% 58% 60 54% 53% 153.5 50% 53% 52% 49% 50 150.0 45% 134.2 115.8 40 107.6 Seal thickness (%) 100.0 86.4 30 71.8 20 50.0

Hardness/Mechanical resistance (newtons) 10 6.8 5.1 3.7 4.7 3.0 2.0 2.1 2.5 3.4 2.02.8 5.6 5.1 5.2 2.1 2.5 2.7 0.0 0 S1 S2 S4 S5 S6 S7 Products

Hardness Mechanical resistance Seal thickness M0 M1 M2 M0 M1 M2 M0 M1 M2 Copyright CSC Publishing The moisture content in fresh capsule shells may be VSC outlook about 20 percent, depending on the formulation, and While the supply of gelatin-free soft capsules is still drying time is comparable to GSCs. The filling volume in its nascent stage, demand for vegetarian capsule shells, should determine the proper die roll size, since overfill- whether plant derived or synthetic, is growing. VSCs ing affects the seal strength and the shells may contract have the potential to reach a considerable market share in during drying. the future using the gelatin substitutes discussed in this Despite some particular processing requirements, for- article. Decreasing material costs and increasingly opti- mulations containing carrageenan are straightforward mized processes also provide opportunity for growth in to encapsulate compared to modified starch because the number of VSC products on the market. of their consistency batch to batch, Existing products have demon- robust film formation, elasticity, seal strated the feasibility and consistency strength, and stability at varying While the supply of of VSC materials and manufacturing moisture and temperature conditions. processes. While there are some chal- In-process controls include tem- gelatin-free soft capsules lenges associated with VSC manu- peratures at different points in the facturing, the products demonstrated encapsulation machine, film thick- is still in its nascent physical stability at accelerated con- ness, and weight variation. Physical ditions. However, disintegration times testing of the capsules includes hard- stage, demand for were longer for VSCs at stability con- ness, burst test, film and seal thick- ditions compared to GSCs, which ness, and shell moisture content. vegetarian capsule shells, should be evaluated, as disintegration time is a critical quality attribute. T&C Stability of VSC products whether plant derived or Figure 1 shows the results of a References study comparing the hardness, burst synthetic, is growing. 1. Bjorn Vergauwen, “Creat- test, seal percentage, shell moisture ing the perfect capsule,” Pharma content, and disintegration time for Focus Asia, Available at: www.pharmafocusasia.com/ several marketed VSC products at stability conditions. research-development/creating-perfect-capsule. The study compared the properties of two Procaps VSC 2. FAO report. products (S1 and S2) and four commercial VSC products 3. Beroe analysis. made from C-MS at 40°C, 75 percent RH at initial time 4. IMR International, Hydrocolloid Information Cen- (M0), 1 month (M1) and 3 months (M3). ter, “Food Hydrocolloid Extracts 5, 10, or 15 Years,” Avail- In general, VSC hardness has been reported to be as able at: www.hydrocolloid.com/summary_extracts.php. low as 2.0 newtons and not comparable to GSCs. Most 5. Beroe interaction with supplier. VSCs are nutritional products containing either single 6. Katy Askew, “On the frontline of climate change: oils or oily suspensions using only glycerol as a plasti- Cargill building ‘resilience’ into its red seaweed supply cizer. Hardness can be a reference for the final drying chain,” Available at: www.foodnavigator.com/Article/ time, and low hardness values could compromise the 2019/03/14/On-the-frontline-of-climate-change-Cargill- products during bulk storage and transport. Burst test building-resilience-into-its-red-seaweed-supply-chain. and percentage of the trailing seal are a measure of the 7. Beroe analysis based in secondary research. seal quality, ranging roughly from 100 to 300 newtons 8. MarketWatch, “EU Modified Starch Market: Ingre- and 50 to 87 percent, respectively, at the initial time, as dion Inc., Cargill Inc., Bunge Ltd.,” Available at: www. shown in the figure. marketwatch.com/press-release/eu-modified-starch-market- Percent seal values in VSCs can be as high as 80 ingredion-inc-cargill-inc-bunge-ltd-2019-07-01. percent depending on the die roll design. Disintegra- 9. Available at: www.optinutra.com/quality/. tion times were determined under USP conditions for 10. Beroe analysis. rupture time of soft capsules (USP apparatus 2), con- sidering the total disintegration of the shell as final point for visual detection. At stability conditions, phys- Claudia Silva, PhD, is director of new pharmaceutical technol- ical properties tended to decrease but not to an unac- ogies at Procaps (575 371 9000, www.softigel.com). Kirti Vatsa ceptable level, with the exception of the disintegration is principal analyst at Beroe (919 747 4818, www.beroeinc.com). times, which in some cases, were observed to be longer than 30 minutes. While VSCs show a lag time in disso- lution 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 condi- tions is unclear.