46
development of cyclodextrins, Szejtli played a fundamental role as eminent scientist, visionary, and entrepreneur, creating, in 1989, a private company, CycloLab
Ltd., totally devoted to cyclodextrins. Without Szejtli, the feasible production of
cyclodextrins on an industrial scale probably would not be as advanced as it is today.
In the mid-1980s, advancements in biotechnology led to drastic improvements in
the production and purification of cyclodextrins. Cyclodextrins were then produced
in large quantities with high purity and marketed at a reasonable price, and as a
result, more industrial applications have become possible. In addition, this period
from 1970 to 1980 was also marked by another important event: the first toxicological studies had established that β-cyclodextrin administrated orally was a harmless
substance. Pharmaceutical, food, chromatographic, and cosmetic applications
started to appear and rapidly gained ground. Since then, an increasing interest in
cyclodextrins as raw materials and their possible applications has existed (Szejtli
1982a, 1988; Duchêne 1987, 1991).
1.4.2 Mechanism of Inclusion Complexes
In the mid-1970s, several researchers such as Saenger, a pupil of Cramer, Bender,
and Szejtli pursued and reformulated the interpretations made by Cramer on the
mechanisms of formation of inclusion complexes.
On the basis of the mechanism proposed in 1967 by Cramer, Saenger gave in
1976 three important explanations for the formation of an inclusion complex with
α-cyclodextrin in aqueous solution (Saenger et al. 1976): (1) the guest molecule
directly replaces the water molecules in the cavity; (2) the cyclodextrin molecules
absorb the energy of the water molecules retained in the cavity and take on a relaxed
conformation; in this state, the water molecules can be easily substituted by another
guest; and (3) the guest becomes associated with the outer surface of the cyclodextrin and only enters the cavity once it has absorbed the activation energy, i.e., transfer of the conformation from a state of high energy of the cyclodextrin-water
complex to a state of lower energy of the cyclodextrin-guest molecule complex.
Saenger introduced the notion of the release of the tension energy within the
α-cyclodextrin molecule upon formation of the complex. This relief of strain in the
cyclodextrin ring contributed to the enthalpy of association and to the stabilization
of the inclusion complex. In water, the α-cyclodextrin was in a strained, high-energy
conformation, and that, when another guest molecules displaced the water, thus
forming an inclusion complex, a conformational change of the cyclodextrin molecule occurred, transforming the α-cyclodextrin structures into an unstrained, relaxed
state. This was demonstrated using detailed X-ray diffraction studies. A scheme of
inclusion-complex formation involving relief of strain energy and release of highenergy water is proposed (Fig. 1.22). This scheme shows the possible pathways of
α-cyclodextrin inclusion complex formation in aqueous solution. Owing to the
inclusion of water, the ring of cyclodextrin is distorted, only four of the six possible
hydrogen bonds are formed, and introducing a suitable guest molecule, the ring is
N. Morin-Crini et al.
development of cyclodextrins, Szejtli played a fundamental role as eminent scientist, visionary, and entrepreneur, creating, in 1989, a private company, CycloLab
Ltd., totally devoted to cyclodextrins. Without Szejtli, the feasible production of
cyclodextrins on an industrial scale probably would not be as advanced as it is today.
In the mid-1980s, advancements in biotechnology led to drastic improvements in
the production and purification of cyclodextrins. Cyclodextrins were then produced
in large quantities with high purity and marketed at a reasonable price, and as a
result, more industrial applications have become possible. In addition, this period
from 1970 to 1980 was also marked by another important event: the first toxicological studies had established that β-cyclodextrin administrated orally was a harmless
substance. Pharmaceutical, food, chromatographic, and cosmetic applications
started to appear and rapidly gained ground. Since then, an increasing interest in
cyclodextrins as raw materials and their possible applications has existed (Szejtli
1982a, 1988; Duchêne 1987, 1991).
1.4.2 Mechanism of Inclusion Complexes
In the mid-1970s, several researchers such as Saenger, a pupil of Cramer, Bender,
and Szejtli pursued and reformulated the interpretations made by Cramer on the
mechanisms of formation of inclusion complexes.
On the basis of the mechanism proposed in 1967 by Cramer, Saenger gave in
1976 three important explanations for the formation of an inclusion complex with
α-cyclodextrin in aqueous solution (Saenger et al. 1976): (1) the guest molecule
directly replaces the water molecules in the cavity; (2) the cyclodextrin molecules
absorb the energy of the water molecules retained in the cavity and take on a relaxed
conformation; in this state, the water molecules can be easily substituted by another
guest; and (3) the guest becomes associated with the outer surface of the cyclodextrin and only enters the cavity once it has absorbed the activation energy, i.e., transfer of the conformation from a state of high energy of the cyclodextrin-water
complex to a state of lower energy of the cyclodextrin-guest molecule complex.
Saenger introduced the notion of the release of the tension energy within the
α-cyclodextrin molecule upon formation of the complex. This relief of strain in the
cyclodextrin ring contributed to the enthalpy of association and to the stabilization
of the inclusion complex. In water, the α-cyclodextrin was in a strained, high-energy
conformation, and that, when another guest molecules displaced the water, thus
forming an inclusion complex, a conformational change of the cyclodextrin molecule occurred, transforming the α-cyclodextrin structures into an unstrained, relaxed
state. This was demonstrated using detailed X-ray diffraction studies. A scheme of
inclusion-complex formation involving relief of strain energy and release of highenergy water is proposed (Fig. 1.22). This scheme shows the possible pathways of
α-cyclodextrin inclusion complex formation in aqueous solution. Owing to the
inclusion of water, the ring of cyclodextrin is distorted, only four of the six possible
hydrogen bonds are formed, and introducing a suitable guest molecule, the ring is
N. Morin-Crini et al.