**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

#### **Figure 6.** *Increasing number of publications on the CDs from the year 1955 to 2020.*

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].
