Introductory Chapter: Historical Background – Fundamental Structural and Physiochemical Properties of Cyclodextrins (CDs)

1. Introduction

The discovery, by Antoine Villiers, of the biosynthetic cyclic oligosaccharides-based seminatural products consisting of 6, 7, and 8 chiral glucose units, arranged in a donut shape and connected via α-1,4-gycosidic bonds, is generally symbolized as α-, β-, and γ-cyclodextrins (or ACDs, BCDs, and GCDs), respectively. They seem to be the most investigated macrocyclic host molecules in the realm of supramolecular chemistry—a study of the noncovalent interactions. Naturally, they are being obtained from the enzymatic degradation of one of the most indispensable polysaccharides, that is, potato starch in the bacteria (Figure 1) [1]. Sometimes, they also dubbed as the enzyme-modified starch derivatives. These macrocyclic systems comprise the lipophilic inner cavities as well as hydrophilic outer surfaces of the particular interest. Interestingly, the cyclodextrins (CDs) are produced “hundreds-of-thousands” of tons every year by means of environmentally friendlier, simple yet effective techniques and methods. The CDs belong to a family of “cage molecules” in which the core of their structures is unruffled of a very stable hydrophobic cavity, having the distinctive property of encapsulating the hydrophobic entities by virtue of the invaluable host-guest supramolecular interactions. The driving strengths that operate in the inclusion complex formation are van der Waals and electrostatic interactions besides the hydrogen bonding forces. Generally, the complex formation by the CDs depends on the shape and size of the cavities of CDs, chemical nature of the guests, expulsion of the high-energy H₂O molecules, and CD-CD aggregation. More importantly, their vibrant properties can easily be altered significantly through their ability of forming the inclusion complexes and also by means of their apposite functionalizations, as they contain a groups of primary as well as secondary hydroxyl functionalities at the two rims (Figure 2) [2]. The chemical structures of the most popular cyclodextrins, i.e. α-, β-, and γ-CDs, are depicted in Figure 3. As shown in Figure 3, the CDs have “truncated cone shape” rather than the perfect cylindrical structures because of the chair conformations of the glucopyranose units present in these types of cyclic systems. The toroidal structure of the CDs contains a panel of secondary hydroxyl groups on the wider rim, whereas the primary hydroxyl groups are present at the narrower rim side. The hydrophobic cavity is clearly displayed with an arrow inside the truncated cone as displayed in Figure 3. On the other hand, different structural and physiochemical properties of the cyclodextrins are tabulated in Table 1—just to provide a quick glance to the readers so as to compare and have adequate knowledge of about these versatile parameters.

Figure 1.

Parent as well as the modified CDs of the pharmaceutical importance: [RAMEB: randomly methylated β-CD; HP-β-CD: hydroxy propyl β-CD; HE-β-CD: hydroxy ethyl β-CD; DIME-β-CD: heptakis-2,6-dimethyl-β-CD; TRIME-β-CD: heptakis-2,3,6-trimethyl)-β-CD].

Figure 2.

Various possible functionalization sites to generate a variety of modified CDs.

Figure 3.

Structures of α/β/γ-CDs (top), and wrong and correct pictures of CDs (bottom).

S. no.	Characteristics and properties	α-CD	β-CD	γ-CD
1	Number of glucopyranose units	6	7	8
2	Molecular weight (g/mol)	972	1135	1297
3	Internal diameter (Å)	4.7–52	6.0–6.4	7.5–8.3
4	External diameter (Å)	14.6	15.4	17.5
5	Height of torus (Å)	7.8	7.8	7.8
6	Volume of the cavity (Å^3)	174	262	427
7	Solubility in water at 25°C (%, w/w)	145	18.5	233
8	Partial molar volumes in solution (mL mol^−1)	611	703.8	801.2
9	Crystal form (from water)	Hexagonal plates	Monoclinic parallelograms	Quadratic prisms
10	Diffusion constant at 40°C	3.443	3.224	3.000
11	pK (by potentiometry) at 25°C	12,332	12,202	12,081
12	Surface tension (mN/m)	—	71	71
13	50% hemolysis (mM)	—	5.3	8.5
14	Hydrolysis by A. oryzae α-amylase	Negligible	Slow	Fast
15	Melting temperature limits (°C)	255–265	255–260	240–245
16	Water content of the crystal (wt. %)	13.5–14.5	10.2	8.13-17.7
17	Cavity diameter inner (nm)	0.47–0.53	0.60–0.65	0.75–0.83
18	Cavity diameter outer (nm)	1.46	1.54	1.75

Table 1.

Different structural as well as physiochemical properties of the cyclodextrins.

Remarkably, their unique “molecular encapsulation” signatures had already been immensely exploited in a myriad of industrial products, technologies, and analytical services as well. The fascination toward the researchers and industrialists worldwide could be inspected from their diverse potential applications in pharmacy, dyeing, food, medicine, biology, biomedicine, biotechnology, beverage industry, organic solar cells (OSCs), nanotechnology, environmental protection, wastewater treatment, conducting polymeric materials, semiconductors, supercapacitors, agrochemistry, remediation, “cosmetology and hygiene,” catalysis, drug carriers, and ligands engineering, besides their usage in the chiral chromatographic separations (Figure 4) [3]. Moreover, the CDs had also been used as the crucial “bricks” in assembling the vital supramolecular architectures of the meticulous importance, such as catenanes, rotaxanes, polyrotaxanes, supramolecular polymeric assemblies, and so forth [4]. Commercial products entailing the CDs, used in our daily lives, are displayed in Figure 5 [5]. In this particular book based on the CDs, we intended to showcase the new frontiers in this emerging arena with an intention to aware the readers where this wonderful field presently stands, and where it might go in years to come, though fully matured. We anticipated that this new package in the form of book based on the CDs chemistry would be much informative to the researchers working in both academia and industry. Surely, it will also be very helpful to the undergraduate and postgraduate students in addition to the young minds planning to enter into the ever-booming area of research.

Figure 4.

Pictorial representation of diverse potential applications of the CDs.

Figure 5.

Different commercial products consisting of the CDs in our daily-based lives.

2. Historical backgrounds of CDs

Noticeably, until mid-1970s, α-, β-, and γ-CDs were accessible only in small amounts, and they were contemplated as only the “laboratory curiosities.” Because of their presumed toxicity and their high prices in addition to the unavailability of adequate knowledge, their industrial potentials were totally masked at that time. Although CDs have been well known for more than 130 years, they only truly “took off” in 1980s when for the first time “applications of the CDs” in pharmaceutical and food industries were successfully revealed. This progress was made by the production of the α-, β-, and γ-CDs on an industrial scale, and these systems were fruitfully achieved in extremely pure form in 1984. Freudenberg’s research team in 1936 proposed the cyclic structures for both α- and β-dextrins, and in 1953, his group had published the first ever patent in this field related to the pharmaceutical formulations [6]. Remarkably, the low cost of these cyclic polysaccharides vastly impacted their long range developments, particularly that of the β-CD.

Nomenclature: During the groundbreaking discovery of the CDs in 1891 by A. Villiers (1854–1932), a France chemist and pharmacist, the CDs were dubbed as “cellulosine” because of their similar properties (i.e. nonreducing, crystalline, resistant to the acid hydrolysis, and water-soluble) as cellulose. Soon after these findings, F. Schardinger, the so-called “Founding Father of the CDs,” identified the naturally occurring α- and β-CDs, and at that time denoted them as ‘Schardinger sugars’ but later on famed as cyclodextrins. Whereas, French in 1942 recommended Schardinger’s dextrins as the cycloamyloses. On the other hand, the γ-CD was discovered by the research team of Schardinger in the year 1948. Moreover, Cramer in 1956 introduced and described the notion for inclusion complexes. The metal complexes involving CDs were achieved by means of the monotosylation approach in 1990s [7].

Timeline history: Noticeably, in a beautiful review published by G. Crini [1], history of the CDs was divided into five vital periods: (1) discovery by Villiers and the characterization chemistry by Schardinger in the period of 1891–1911; (2) the 25 years period (1911–1935) of doubt and disagreements (between Pringsheim and Karrer), but at that time Pringsheim from Germany was the leading researcher in this particular arena and demonstrated that CDs formed stable aq. complexes with numerous substances of particular interest; (3) research explorations in the time period of 1935–1950; (4) the important period of maturation, i.e. 1950–1970, when notions become fully fledged, and in this period of time, the CDs had been structurally as well as chemically characterized, besides many more novel complexes were effectively studied; (5) historical landmarks—a period of diverse potential applications of CDs (i.e. since 1970s to the till date) in which the massive work has successfully been accomplished by a plethora of research groups globally. Importantly, at present, innumerable patents and research articles and books had already been published, and a lavish scientific literature has already been built up, accounting the wonderful chemistry of these beautifully simple yet much effectual supramolecular architectures. The research publications appeared in the scientific literature, in a time period of 1955–2020, are diagrammatically displaced in Figure 6 [8].

Figure 6.

Increasing number of publications on the CDs from the year 1955 to 2020.

3. Applications of CDs in drug delivery

Interestingly, cyclodextrins which are undoubtedly very effective complexing agents, and denoted with the different synonyms like cyclic oligosaccharides, cycloamyloses, cavitron, cycloglucan, cellulosine, and Schardinger sugars, are also invaluable from the drug delivery perspectives. These multipurpose CDs have also successfully found applications as drug delivery systems in nanoparticles, microcapsules, liposomes, oral drug delivery, nasal drug delivery, parenteral drug delivery, rectal drug delivery, peptide and protein delivery, dermal/transdermal delivery, and controlled drug delivery. Herewith, as can be inspected from Table 2, various approved and marketed drugs available in different countries worldwide are tabulated [9].

Name of drugs	Administration route	Trade name	Marketed in
α-Cyclodextrin
Alprostadil (PGE1)	Intravenous	Prostavastin, Caverject, Edex	Europe, Japan, United States
Cefotiam hexetil HCl	Oral	Pansporin T	Japan
Limaprost	Oral	Opalmon, Prorenal	Japan
β-Cyclodextrin
Benexate	Oral	Ulgut, Lonmiel	Japan
Dexamethasone	Derma	Glymesason	Japan
Iodine	Topical	Mena-Gargle	Japan
Nicotine	Sublingual	Nicorette	Europe
Nimesulide	Oral	Nimedex, Mesulid	Europe
Nitroglycerin	Sublingual	Nitropen	Japan
Omeprazole	Oral	Omebeta	Europe
Dinoprostone (PGE2)	Sublingual	Prostarmon E	Japan
Piroxicam	Oral	Brexin	Europe
2-Hydroxypropyl-β-cyclodextrin
Cisapride	Rectal	Propulsid	Europe
Hydrocortisone	Buccal	Dexocort	Europe
Indomethacin	Eye drops	Indocid	Europe
Itraconazole	Oral, intravenous	Sporanox	Europe, United States
Mitomycin	Intravenous	Mitozytrex	United States
Randomly methylated β-cyclodextrin
17β-Oestradiol	Nasal spray	Aerodiol	Europe
Chloramphenicol	Eye drops	Clorocil	Europe
Sulphobutylether β-cyclodextrin
Voriconazole	Intravenous	Vfend	Europe, United States
Ziprasidone maleate	Intramuscular	Geodon, Zeldox	Europe, United States
2-Hydroxypropyl-γ-cyclodextrin
Diclofenac sodium	Eye drops	Voltaren	Europe

Table 2.

Approved and marketed drug-CD complexes in different markets worldwide.

4. Concluding remarks with future perspective

In this way, the chemistry of CDs is fully ripped, but there are always rooms to be occupied for newer advancements. I personally believe that the CDs will continue to garner the deepest interest from the scientific community across the world for several years in future, and that the newer potential applications of the CDs have yet to be exposed.

Remarkably, in the past few decades, the CDs have been catapulted into the distinction due to their enzyme mimic, catalysis, drug encapsulation, complexation, and molecular recognition behavior, etc. Moreover, they have also been attractively involved in the purification, polymerization, stabilization of the products, chemical treatment, food preservation, and other industrial processes. Finally, because of their chiral nature, selective modifications in their structures might further exploit their potential uses in modern asymmetric synthesis, molecular switches, molecular recognition, chiral separations, etc. Last but not least, because of their nontoxic character in addition to having the capabilities of complex formation with a varied vitamins, flavors, essential oils, perfumes, etc., they definitely have a gifted future in health-related products as well as biodegradable materials.