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Breakthrough in safe iodine delivery: Cyclodextrin-based iodophors

  • Iodine has long been used as an antiseptic, but it has many limitations, including poor water solubility.
  • Iodophors are complexes that incorporate iodine in solutions; however, many have adverse effects.
  • Is there an alternative complex that can safely deliver iodine?
  • Dr Danilo Aleo and coworkers at Medivis in Italy synthesised stable cyclodextrin-based complexes that can successfully be used not only in pharmaceuticals but also in fields such as agriculture and materials science.

Iodine has been used as an antiseptic for decades. It can still be found in our local drugstores, sold as a disinfectant for skin cuts and wounds. Unfortunately, developing water-based formulations containing iodine is not a trivial process: iodine has a low solubility in water, making the preparation of aqueous iodine solutions rather difficult.

Several methods have been examined so far, focusing on the incorporation of iodine in various complexes. One example is iodine-containing polymers called iodophors; however, many adverse effects have been reported, such as allergic dermatitis correlated with the polymer nature. It’s clear that there is an urgent need for a new approach to safely deliver iodine.

Dr Danilo Aleo and coworkers at the pharmaceutical company Medivis in Italy discovered a novel way to create iodophors using cyclodextrin. Cyclodextrins consist of sugar molecules linked together in a way that forms a circular or ring-like structure. In practice, cyclodextrins are used by trapping iodine molecules within their ring-shaped structure. The group managed to successfully synthesise cyclodextrin-iodine complexes, yielding stable and safe compounds ready for use.

The tricky iodine

Iodine is an effective disinfectant because of its unique ability to enter the cells of bacteria, protozoa, fungi, or viruses. Once inside the cells, iodine can stop their growth in several ways: by altering important cellular functions such as electron transport, inhibiting cellular respiration and protein synthesis, and destabilising their cell membranes.

Additionally, the use of iodophors with cyclodextrin doesn’t encourage antibiotic resistance – in other words, it’s not easy for the germs to adapt and become immune to the disinfectant power of iodine. Unfortunately, iodine comes with a few limitations, including skin irritation, skin sensitivity, staining, low water solubility, and high vapour pressure, meaning it evaporates at room temperature. Iodine vapour smells bad and can be harmful if inhaled in excessive amounts.

To solve this issue, iodophors – iodine complexes with polymers – were introduced in the early 1950s and marked a significant development in the field. The main idea is the creation of soluble organic compounds which contain iodine in their core. This paved the road for the creation of several iodophors with various applications, such as ointments, foaming creams, film, and other pharmaceutical products.

Aleo’s goal was to establish a universally applicable approach for generating cyclodextrin-iodine complexes that could be used in a wide range of applications.

Polyvinylpyrrolidone iodine (PVP-I), the combination of a synthetic polymer and iodine, is the most used iodophor. Although promising, PVP-I poses some serious concerns in the medical community as it has been found to result in serious adverse effects like anaphylactic shock (a life-threatening allergic reaction) and is also unsuitable for deep wounds. The adverse effects are solely attributed to the polymer nature of the compound, making it necessary to create new iodophors that are polymer-free. Furthermore, iodine delivery using PVP-I as a polymer is limited due to its high molecular weight.

In search for new iodophors

The focus of Aleo’s group is the creation of complexes combining iodine and cyclodextrins (CDs). CDs are synthesised from natural sources, which are formed by glucose units and include α-CD, β-CD, and γ-CD, containing six, seven and eight glucose units, respectively. These molecules have a toroid (donut-like) shape, with a hydrophilic (water-loving) outer surface and a lipophilic (lipid-loving) central cavity able to capture a variety of molecules. Hence, they can be used in fields such as drug delivery, cancer therapy, gene delivery, and biosensing.

Schematic representation of the investigated cyclodextrin/iodine complexes. Photo credit: Dattilo et al, 2023,

It has been known for decades that iodine could be incorporated in CDs in aqueous solutions. However, the isolation and creation of a solid iodophor involving cyclodextrin and iodine were restricted to precipitation techniques (methods to make substances go from a liquid solution to a solid form), primarily feasible for poorly soluble native CDs like native α- and β-cyclodextrins. Aleo’s goal was to establish a universally applicable approach for generating cyclodextrin-iodine complexes that could be employed with all types of CDs and could later be used in a wide range of applications.

Cyclodextrin-iodine preparation methods

Aleo’s group combined cyclodextrin and iodine in minimal solvent or solvent-free conditions. Gentle mechanical action incorporated iodine into cyclodextrin, resulting in a stable and easily manageable iodophor.

Cyclodextrins include α-CD, β-CD, and γ-CD. Photo credit: Dattilo et al, 2023,

The group also compared different methods for preparing iodine complexes with 2-hydroxypropyl cyclodextrins of varying cavity sizes – influencing the amount of iodine that CD could ultimately deliver (see the above figure). In a modified version, hydroxypropyl groups are attached to the glucose units, enhancing its solubility and other properties.

The researchers examined three environmentally friendly solid-state techniques: liquid-assisted grinding (the compound and a minimal amount of water are placed in the mortar, and the pestle is used to crush and grind it into a fine powder), co-evaporation (CD and iodine are co-evaporated from a solvent mixture), and sealed heating (CD and iodine are placed in a sealed container or vessel, which is then heated).

The incorporation of iodine within CDs introduces innovative possibilities, not only in pharmaceuticals but also in fields such as agriculture, food, electrochemistry, and materials science.

The findings showed that the sealed heating method was initially efficient but lacked long-term stability. On the other hand, the co-evaporation and liquid-assisted grinding methods produced more stable complexes. 2-hydroxypropyl-alpha-cyclodextrin was the most stable, maintaining iodine content over time and showing promise as an alternative to povidone-iodine – known by its brand name Betadine, a chemical complex of polyvinylpyrrolidone and elemental iodine – without affecting the antibacterial activity.

Diverse applications

Through this pioneering study, Aleo and his group provided the foundation for creating safer and more natural starting materials in the production of various pharmaceutical formulations. In fact, they are particularly valuable in situations where immediate cyclodextrin-iodine complex formation is impractical, such as in semi-solid pharmaceutical preparations or dry powder inhalers for pulmonary applications.

With enhanced solubility and controlled release of iodine, pharmaceutical products can potentially become more effective in combating infections while minimising adverse effects in patients. The incorporation of iodine within CDs introduces innovative possibilities, not only in pharmaceuticals but also in fields such as agriculture, food, electrochemistry, and materials science, paving the way for new applications beyond imagination.

What inspired you to conduct this research?

I was inspired by Sebastiano Mangiafico, a chemist like me, who founded Medivis. His vision, which he also passed on to me, was to develop eye drops containing low concentrations of iodine. This is where our journey started.

Medivis has always been involved in the innovative delivery of iodine in aqueous media to take full advantage of its antiseptic power. The desire to stabilise and make iodine less volatile in aqueous pharmaceutical formulations led us to study iodine-cyclodextrin complexes, but we soon realised that it would be hard to set up large-scale production with these complexes due to the volatility of iodine and the long formation times of the iodine-cyclodextrin complex; all these limitations were not manageable for large production runs. What had been possible to achieve with PVP-I in previous years seemed to be unfeasible with the iodine-cyclodextrin complex. Fortunately, our studies proved otherwise, so today we have new iodophors that can be used not only in new pharmaceutical formulations but also in a wide range of other applications.

How could CD-iodine complexes be used in agriculture?

Iodine has strong fungicidal, bactericidal and virucidal activity, and there are examples of treating phytopathogenic fungi that infect ornamental plants with diluted Betadine solutions (PVP-I). On the other hand, there are no examples in the literature of PVP-I use in food crops, probably because the massive use of PVP-I might be a cause for concern. Instead, natural cyclodextrins are approved for food use, so CD-iodine would be a safer and more efficient antifungal compound for extensive use in crops, with the advantage that iodine can also be absorbed by plants, promoting their biofortification and growth (see Medrano-Maciàs et al, 2016 and Kiferle et al, 2021). Another possible use could be in aquaculture, where the efficacy of iodine transport by CD could help us to avoid high iodine concentration and help maintain fish microbiota (see Zhang et al, 2023).

Could the CD-iodine complexes be integrated in ointments, foams and creams as well?

Yes, CD-iodine could be integrated in ointments, foams and creams; as a cream, it could be used not only for treating common skin infections but also to prevent infection in burns, lacerations, cuts and abrasions. In addition, formulated as an ointment CD-iodine could be employed for infection control during insertion and care of urinary catheters or suture removal and in general for all procedures where degerming is needed. Similar uses could also be hypothesised for foams.

How could these complexes be used in materials science?

CD-iodine could be employable as an iodine-cathode in high-performance lithium–iodine (Li–I2) batteries, which have increasingly gained attention because of their high energy density, high power density, and low cost. However, in practical applications, they encounter poor cycle performance due to the low thermostability of iodine and easy dissolution of iodine species in electrolytes. Inclusion complexation of iodine with β-cyclodextrin (Cai et al, 2018) and methyl-β-cyclodextrin (Zhang et al, 2020) enhance the electrochemical performance of lithium-iodine. The method preparation that Medivis developed can help to fabricate these promising materials on industrial-scale, high-performance iodine cathodes.

Another use of CD-iodine could be their incorporation as nano-fillers into polymeric matrices (either hydrogel or thermoplastic matrix) to obtain antimicrobial materials with disinfectant function (Palza, 2015). This could be used in various fields, including healthcare and the food and personal care industry, to improve safety and hygiene.

What would you like to investigate in the future?

We are currently developing an eye drop for the treatment of bacterial, fungal, and viral infections of the cornea and a gel for the treatment of deep wounds. In the near future, we are going to prototype applications in all mentioned technological areas and explore further uses of CD-iodine.

Related posts.

Further reading

Dattilo, S, et al, (2023) Solid-state preparation and characterization of 2-hydroxypropylcyclodextrins-iodine complexes as stable iodophors, Biomolecules, 13(3), 474.

Zhang, R, et al, (2023) Povidone iodine exposure alters the immune response and microbiota of the gill and skin in koi carp, Cyprinus carpio, Aquaculture, 563(1).

Kiferle, C, et al, (2021) Evidences for a nutritional role of iodine in plants, Front Plant Sci, Sec Plant Nutrition, 12.

Zhang, Q, et al, (2020) Inclusion complexation enhanced cycling performance of iodine/carbon composites for lithium–iodine battery, Journal of Power Sources, 463, 228212.

Cai, F-S, et al, (2018) Iodine/β-cyclodextrin composite cathode for rechargeable lithium iodine batteries, Journal of Materials Science: Materials in Electronics, 29, 11540–11545.

Medrano-Maciàs, J, et al, (2016) Use of iodine to biofortify and promote growth and stress tolerance in crops, Front Plant Sci, Sec Plant Nutrition, 7.

Palza, H, (2015) Antimicrobial polymers with metal nanoparticles, Int J Mol Sci, 16(1), 2099–2116.

Dr Danilo Aleo

Dr Danilo Aleo is a formulation scientist with a strong background in chemistry, specialising in ocular drug delivery. Aleo has five years of research experience in academia, focusing on solid-phase organic synthesis of oligonucleotides, prostaglandin synthesis, and enzymatic catalysis. Additionally, he accumulated twenty-five years of experience as the Head of Laboratory Drug Development at Medivis.

Contact Details

t: +39 320 249 7625


  • Medivis


  • Sandro Dattilo
  • Fabiola Spitaleri
  • Maria Grazia Saita
  • Angela Patti
  • Barbara Melilli
  • Melina Cro
  • Sebastiano Mangiafico

Competing interest statement

To ensure transparency, Dr Aleo would like to note that this work has, in some aspects, led to the creation of a patent owned by Medivis.

Cite this Article

Aleo, D, (2023) Breakthrough in safe iodine delivery: Cyclodextrin-based iodophors. Research Features, 150.

Creative Commons Licence

(CC BY-NC-ND 4.0) This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Creative Commons License

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