Less known facts about: Pullulan

This article is part of the “Less Known Facts About Excipients” series by Philippe Tschopp.

Pullulan Excipient: Fermentation Origin, Structure, and Standards

Pullulan is a linear glucan produced by fermentation rather than extracted from a plant or animal, unusual among pharmaceutical excipients. Its maltotriose structure gives films that form without plasticizers and carry a strong oxygen barrier, and it is used mainly in capsule shells and coatings [1,7].

Where pullulan comes from

Pullulan is one of the few pharmaceutical excipients that is not extracted from plants or animals. Instead it is produced by fermentation, making it one of the earliest examples of a naturally derived biopolymer manufactured through biotechnology [7]. It is a natural polysaccharide produced by the fungus Aureobasidium pullulans during aerobic fermentation. During its growth, the microorganism secretes pullulan into the fermentation broth, from which it is subsequently recovered and purified [7]. Today it is widely used in pharmaceutical and nutraceutical applications, particularly in capsule shells and film coatings, where its film-forming properties and oxygen barrier performance offer advantages [7].

In its 2025 re-evaluation, the EFSA Panel on Food Additives and Flavourings records that the additive is produced by a non-genetically modified strain of Aureobasidium pullulans deposited at the NITE Biological Resource Center in Japan [1].

How pharmaceutical pullulan is produced

The production process consists of several controlled manufacturing steps [7]:

• Aureobasidium pullulans is cultivated under controlled conditions using carbohydrate sources such as glucose or starch hydrolysates, producing pullulan extracellularly.
• The microbial cells are removed from the fermentation broth by filtration or centrifugation.
• Pullulan is precipitated, washed, and further purified to remove proteins, pigments, and residual fermentation components.
• Drying and milling. The purified polymer is dried and milled into a free-flowing powder meeting pharmaceutical quality specifications.

EFSA describes the same sequence in more operational terms: fermentation of food-grade hydrolyzed starch, removal of the fungal cells by microfiltration, heat sterilization, removal of pigments and impurities by adsorption and chromatography, then concentration, drying, and pulverization [1]. Feedstock alternatives include pullulan production from lignocellulosic biomass and starch-containing coproduct hydrolysates.

The specification is numerical. EFSA reports an assay of not less than 90% glucan on the dried basis, not more than 10% mono- and oligosaccharides expressed as glucose, lead at not more than 1 mg/kg, and molecular weights of 310 to 420 kDa in the commercial samples examined [1]. The microbiological criteria are yeasts and molds at not more than 100 CFU/g, with Salmonella and coliforms absent in 25 g [1].

What makes pullulan structurally unusual

Pullulan is a linear polysaccharide composed of maltotriose units connected by alpha-(1->6) glycosidic linkages. This molecular architecture results in a polymer that combines flexibility with film-forming properties [7]. The regulatory definition matches: under Commission Regulation (EU) No 231/2012, pullulan is a “Linear, neutral glucan consisting mainly of maltotriose units connected by α-1,6 glycosidic bonds” [1].

Both descriptions omit a second linkage type. Within each maltotriose unit, the three glucopyranose rings are themselves joined by alpha-(1->4) linkages, so the chain alternates two alpha-(1->4) bonds with one alpha-(1->6) bond, and the literature credits the presence of both linkage types for pullulan’s distinctive behavior [2]. Each maltotriose unit carries nine hydroxyl groups, making the backbone amenable to site-specific chemical modification [2].

Its most remarkable characteristics include excellent film formation without plasticizers, outstanding oxygen barrier properties, high transparency, low taste and odor, good solubility in water, and broad compatibility with pharmaceutical ingredients [7]. Unlike many natural polysaccharides, pullulan forms smooth, flexible, and mechanically strong films, making it particularly attractive for oral dosage forms [7].

Where it is used in formulation

Pharmaceutical-grade pullulan is used in hard capsule shells, oral films, tablet film coatings, edible films, moisture-sensitive formulations, and nutraceutical dosage forms [7]. Its primary functions include film former, capsule shell material, binder, stabilizer, and oxygen barrier polymer [7]. Related work spans next-generation capsule fabrication, orally disintegrating pullulan and HPMC films, and pullulan as a sustained-release carrier for ocular delivery.

On the food and supplement side the authorization is narrow. Pullulan is listed as E 1204, currently permitted at quantum satis in only two categories: breath-freshening microsweets in film form, and food supplements in capsule or tablet form [1]. The 2025 re-evaluation assessed a request to extend that to 26 further food categories plus liquid food supplements [1]. In the United States, FDA raised no questions about the GRAS notification for pullulan in 2002 under GRN 000099 [3].

Considerations for formulators

As a fermentation-derived polymer, pullulan offers excellent batch-to-batch consistency compared with many plant-derived materials. It is also suitable for vegetarian and vegan formulations, which has contributed to its increasing use as an alternative to gelatin capsules [7]. However, pullulan is generally more expensive than traditional capsule materials, and its moisture management during processing requires careful optimization depending on the formulation and storage conditions [7].

A study of moisture sorption and desorption in gelatin, HPMC, and pullulan hard capsules found pullulan capsules took up less moisture than gelatin capsules [4].

EFSA concluded that “there is no need for a numerical ADI for pullulan (E 1204) and there is no safety concern for the currently reported uses and use levels”, while noting that individuals with high exposure, principally from food supplements, may experience mild gastrointestinal symptoms [1]. Human volunteer studies reported abdominal fullness, flatulence, bloating, and cramping at doses of 10 g per day and above [1]. In vitro, pullulan is broken down by salivary and pancreatic amylase and by intestinal iso-amylase, and is then fermented to short-chain fatty acids in the colon [1].

Although pullulan is produced by a fungus, the final purified polymer contains no viable microorganisms and is highly purified before pharmaceutical use [7]. Its oxygen barrier performance has also carried it into food preservation and edible packaging, showing how a single excipient can serve industries far beyond pharmaceuticals [7].

This article is for informational purposes for pharmaceutical industry professionals and does not constitute regulatory advice. Always refer to the current pharmacopoeial monograph, the supplier’s current technical data sheet, and applicable regulatory guidance for your dosage form, route of administration, and market. Pharma Excipients International AG is not a manufacturer of the excipients discussed.

Sources

1. EFSA Panel on Food Additives and Flavourings (FAF). Re-evaluation of pullulan (E 1204) as a food additive and new application for its extension of use. EFSA Journal, 2025;23(3):e9267. https://doi.org/10.2903/j.efsa.2025.9267
2. Singh RS, Kaur N, Kennedy JF. Pullulan: Microbial sources, production, properties and applications. Carbohydrate Polymers. https://pubmed.ncbi.nlm.nih.gov/28578944/
3. US Food and Drug Administration. GRAS Notice Inventory, GRN 000099: Pullulan, agency response 2002. https://www.hfpappexternal.fda.gov/scripts/fdcc/index.cfm?set=grasnotices&id=99
4. Moisture sorption and desorption properties of gelatin, HPMC and pullulan hard capsules. International Journal of Biological Macromolecules. https://www.sciencedirect.com/science/article/abs/pii/S0141813020332621
5. Leathers TD. Biotechnological production and applications of pullulan. Applied Microbiology and Biotechnology.
6. Rowe RC, Sheskey PJ, Quinn ME (Eds.). Handbook of Pharmaceutical Excipients. Pharmaceutical Press / American Pharmacists Association.
7. Source newsletter: Philippe Tschopp, “Less Known Facts About Excipients #3: Pullulan,” LinkedIn newsletter, 2026. https://www.linkedin.com/pulse/less-known-facts-excipients-3-pullulan-philippe-tschopp-jagde/

Disclaimer

This article is based on publicly available information and industry sources at the time of writing and supported by AI. While every effort has been made to ensure accuracy, completeness, and fair representation, the author does not guarantee that all information is current, error-free, or reflective of the latest developments.

The content is provided for informational and educational purposes only and does not constitute technical, regulatory, or commercial advice. No liability is accepted for decisions made based on this material. Readers are encouraged to consult the original manufacturers and official sources to verify details before making professional or business decisions.

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