Multifunctional molecular encapsulating agents – Cyclodextrins: Physicochemical properties, safety, solubility, bioavailability and applications in pharmaceuticals and foods

Abstract

Cyclodextrins (CDs) are cyclic oligosaccharides made up of α-(1 → 4)-linked d-glucopyranose units and are generally obtained by enzymatic conversion of starch. The purpose of this review is to give a comprehensive overview about the cyclodextrins and their physicochemical properties, safety & toxicological aspects, enhancement of aqueous solubility, stability and bioavailability and applications in pharmaceutical and food system.

The published scientific literature was reviewed as a narrative review to investigate structure, physicochemical properties, safety profile, functional mechanisms, and applications of cyclodextrins. Evidence describing their effects on solubility, dissolution, stability, bioavailability, protection of sensitive ingredients, masking of undesirable tastes and odours, and controlled delivery of bioactive compounds was critically evaluated. The evidence reviewed suggests that cyclodextrins can form a stable inclusion complex with appropriate hydrophobic and/or amphiphilic molecules, which can alter the physicochemical and functional properties of the modified molecule. As a result, cyclodextrins have been studied as excipients for oral, ocular, dermal, nasal and rectal drug-delivery systems. Cyclodextrins have been shown to be useful in food systems for the protection of sensitive flavors and aromas, vitamins, lipids and other bioactive ingredients from environmental degradation.

Their relative ease of safety, especially for suitably chosen and controlled cyclodextrins, also contributes to their technological usefulness. Cyclodextrins are versatile multifunctional excipients and encapsulation materials, which play significant roles in pharmaceutical and food technology. They can form inclusion complexes with great efficacy for enhancing the solubility, stability, dissolution, and bio-accessibility as well as sensory acceptability of a variety of compounds. Native and modified cyclodextrins thus hold a great potential for the formulation of new drug delivery systems, functional foods, nutraceutics and biotechnology products. Future studies are needed to optimize the cyclodextrin–guest interactions, enhance the formulation efficiency, assess the safety of the long-term use, and develop commercially viable and regulatory-approved products based on laboratory research.

Introduction

Macrocyclic cyclodextrins were first discovered in 1891 as a result of the catalytic conversion of starch and subsequently studied in the mid-1930s. Their industrial interest has been evident since the 1970s and thousands of tons of their three forms (α, β, and γ), as well as their chemical analogs and inclusion complexes, are synthesized on a large scale [1]. Cyclodextrins (CDs) are considered useful materials and can be applied in various fields such as food, pharmaceutical and other industries [2], [3]. Antoine Villiers started the discovery of CDs in the late 1800s by studying the enzymatic action of the Bacillus amylobacter (Clostridium butyricum) on potato starch, in which the butyric fermentation is carried out. Villiers was not able to predict the many applications that would flow from his discovery during the next hundred years [4]. Cyclodextrins are 4-linked, α-1 cyclic oligosaccharides that are produced from starch that has been broken down by glucosyl transferase [5].

In naturally occurring CD variants, at least six glucose units are present, but the most common CDs are the ones with six (α-CD), seven (β-CD) and eight (γ-CD) units [6]. According to the literature [7], [8] Food and Drug Administration (FDA, USA) has classified these chemicals (cyclodextrins: α, β and γ CDs) as “Generally Recognized as Safe” (GRAS) (often written as “Generally Regarded as Safe”). Cyclodextrins have a three-dimensional structure of a hollow torus as seen in Fig. 1 and have a polarity both on the outside as well as on the inside [9]. The hydroxyl group of the narrowest rim is the primary hydroxyl group and the hydroxyl group of the widest rim is the secondary hydroxyl group. As noted in [10] the secondary hydroxyls provide strong hydrogen bonds, and contribute to the stiffness of cyclodextrin, whereas primary hydroxyls are able to rotate and may help to reduce cyclodextrin diameter. The structure is unique in that it can hold guest molecules in the CD, creating inclusion complexes. The inclusion complexation of hydrophobic compounds has been said to be mainly due to the hydrophobic interactions between the guest molecules and the cavity walls of the cyclodextrins. Interactions other than guest binding, such as van der Waals or dipole-dipole interactions, may also be associated with guest binding [11].

Rezanka, M. According to (2019) [12] there are numerous cyclodextrin derivatives. There are around 11,000 α-, β-, and γ-CD derivatives, according to the authors’ search. Presently, CDs can be modified to achieve better properties such as use of sulfobutylether-, hydroxypropyl-, or carboxymethyl-type β-CDs for better stability, solubility and physical properties of CD-guest complexes [13], [14]. In addition, as reported by [15] nano-cyclodextrins can be incorporated into different nanosystems to improve several properties, such as stability and solubility [16].

Cyclodextrins (CDs) are cyclic oligosaccharides that contain six or more D-(+)-glucopyranose units linked by α-1,4-glycosidic bonds [17]. The CD is formed by a natural enzyme reaction of starch through cyclodextrin glucanotransferases, CDs are therefore natural [18]. These are shaped like a truncated cone and have an internal hydrophobic chamber and an external hydrophilic surface [19]. Moreover, the solubility of a drug in water is associated with its bioavailability. One of the methods to enhance the low water solubility of a compound is the use of cyclodextrins as excipients. The impact of cyclodextrins on the chemical and physical characteristics of active substances is discussed in this research. Over 40 pharmaceutical medicines are available worldwide containing cyclodextrin as an excipient. In addition, they are also found in food, toiletry and cosmetic products [20], [21].

The purpose of this review is to provide a comprehensive overview of cyclodextrins, detailing their physicochemical characteristics, safety & toxicological considerations, ability to improve aqueous solubility, stability, and bioavailability, as well as their potential to improve pharmaceutical and food systems.

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Subhash Chandra, Shreya Kotnala, Archana Dhyani, Carolina Bandeira Domiciano, Micheline de Azevedo Lima, Henrique Douglas Melo Coutinho, Multifunctional molecular encapsulating agents – Cyclodextrins: Physicochemical properties, safety, solubility, bioavailability and applications in pharmaceuticals and foods,
Biomaterials Advances, Volume 190, 2027, 215177, ISSN 2772-9508, https://doi.org/10.1016/j.bioadv.2026.215177.

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