Capsule manufacturers consider many factors when designing and producing hard capsules. Consumer trends are often key considerations, and the industry seeks to accommodate niche demands and cater to small market populations. Although gelatin-based hard capsules continue to dominate the hard-capsule market, use of plant-based hard capsules is growing quickly due to the demands of vegans and vegetarians.
Marketing campaigns often lead consumers to believe that plant-based capsules are inherently better. For vegan or vegetarian consumers—who in principle and practice don’t consume animal-based products—plant-based capsules are a suitable alternative to gelatin-based ones. Some consumers, however, actively seek plant-based capsules based on a misconception that they offer better quality, contribute to better health, or use raw materials that are more sustainable. A closer look at the details reveals that, for many products, gelatin capsules are likely a better choice.
Sustainability
Consumers with environmental concerns may believe plant-based capsules are more environmentally sustainable, but plant-based capsules don’t necessarily support sustainable production. The most commonly used, plant-derived alternative to gelatin for capsule manufacture is hydroxypropyl methylcellulose (HPMC). To process HPMC, the cellulose—generally derived from shredded trees—undergoes a rigorous manufacturing process that involves chemical and synthetic, rather than natural, alteration. Capsule suppliers use volatile liquid propylene oxide, considered to be a carcinogen, and chloromethane gas to process HPMC and must ultimately remove and dispose of these highly reactive substances after production.
While the resulting HPMC hard capsules are currently designated as vegan, plant-based, or vegetarian, a global debate is occurring about the naturalness of HPMC because it is a synthetic, chemically modified product. HPMC is also considered to be a food additive, designated as E464 in the Codex Alimentarius.
Gelatin, on the other hand, is a nonallergenic food, not a food additive. It is derived from the connective tissues of animals, namely cattle and hogs, a widely available byproduct of the global meat industry. Capsule suppliers produce gelatin using an entirely natural and gentle method of hot water extraction, and its use in foods and capsules is essentially unrestricted because it has enjoyed FDA generally recognized as safe (GRAS) status for decades.
Ease of manufacturing
Manufacturing HPMC-based capsules requires some modification to molding machines or to the formulation of the shell’s materials. For instance, you must use heated pins and accurate temperature control in the whole production line. HPMC also requires the capsule manufacturer to use a higher temperature (70°C) for the polymer solution, compared to gelatin (which normally works in a temperature range of 45° to 50°C) and to carefully maintain the temperature of the capsule-forming pins after the dipping process to facilitate gelation until the film dries out1.
While the higher thermostability of HPMC capsules can lead to advantages during filling processes and storing of the capsules, HPMC capsule shell walls are weaker than those of gelatin-made capsules, and removing the formed capsules from the pins, as well as subsequent handling and filling, is more difficult2.
Cost
HPMC capsules are four to five times more costly to make than gelatin capsules due to a lower production yield and conversion ratio compared to the relatively simple and efficient gelatin capsule manufacturing process. Also, HPMC capsule production takes more time and more extensive technology3, and improving the performance of HPMC capsules on a high-speed filling machine often requires treating the capsules’ external surface with a gliding agent4. Oxygen permeability
Gelatin hard capsules have demonstrated excellent protection against oxygen permeability, which is important for formulations that are sensitive to oxidation5. The transmission of oxygen through an HPMC capsule shell is much higher than through a gelatin-based capsule shell. As a result, drug product manufacturers using HPMC capsules must include an antioxidant in the formulation or must package the capsules in a blister package with aluminum foil to protect against oxidation of sensitive active ingredients or excipients6. For both gelatin and HPMC hard capsules, the gap between the capsule body and cap requires additional sealing to avoid oxygen seeping into the capsules.
Performance characteristics
Table 1 compares the performance characteristics of gelatin-based and HPMC-based capsules. Capsule suppliers use gelatin for hard capsules because of its setting properties, gliding characteristics, machinability, dissolution properties, and ability to protect the formulation inside the capsule. For some formulations—those that don’t require a strong barrier to oxygen or fills with very hygroscopic behavior or a high risk of crosslinking— HPMC capsule shells might be the best choice, but for the majority of formulations, the difficulties of producing HPMC capsules often makes gelatin a better choice.
References
1. US Patent 5698155.
2. Malla Vasavi Chandrika, et al., “Alternatives for gelatin in the preparation of capsules,” Advanced Journal of Pharmacie and Life Science Research, 2016, Vol. 4, No. 2, pages 33-42. 3. Shallini Gupta, et al., “Evaluation of capsule labeling for its wall contents as gelatin or non-gelatin,” International Journal of Basic & Clinical Pharmacology, July 2018, Vol. 7, No. 7, pages 1,387-1,390.
4. Sutapa Majee, et al., “HPMC as capsule shell material: Physicochemical, pharmaceutical and biopharmaceutical properties,” International Journal of Pharmacy and Pharmaceutical Sciences, August 2017, Vol. 9, No. 10, pages 1-6. 5. Matt Richardson, “Impact of capsule selection on formulation stability in dry powder inhalers (DPIs),” Inhalation, April 2011, Vol. 2, No. 2.
6. Fridrun Podczeck and Brian E. Jones, Pharmaceutical Capsules, 2nd ed., Pharmaceutical Press, London, 2004, pages 96-98. 7. Ewart T. Cole, et al., “In vitro and in vivo pharmacoscintigraphic evaluation of ibuprofen hypromellose and gelatin capsules,” Pharmaceutical Research, 2004, Vol. 21, No. 5, pages 793-798.
Martin Junginger is chemical engineer, global product management, pharma gelatin, and business development, gelatin, at Gelita, a global supplier of collagen proteins (www.gelita.com).