122
the structure of cyclodextrins was stabilized by the formation of hydrogen bond
between C-2 and C-3 hydroxyl groups of adjacent glucose units. This phenomenon
widely affected, in addition to molecular dimensions, the water solubility of cyclodextrins. The formation of a complete ring of intramolecular hydrogen bonds in
β-cyclodextrin counteracted its hydration and reduced its solubility as compared to
other native cyclodextrins (Szejtli 1978, 1982a, 1995).
2.4.3 Types, Formation, and Structures
of Inclusion Complexes
Development of the optimal technology of producing crystalline cyclodextrin inclusion complexes required a knowledge of the crystallization process. However, the
literature contained little information concerning crystallization temperatures and
other parameters such as pH, concentration, and cooling rate (Saenger 1984;
Connors 1997).
In 1977, Professor Szejtli studied the influence of the conditions of crystallization in such a way that the guest molecule was added to a cyclodextrin solution
warmed to 60 °C (Szejtli and Budai 1977). Under vigorous stirring the solution was
then gradually cooled at a rate of 0.3–0.4 °C/min, and the turbidity was recorded as
a function of temperature. His results clearly showed that both cyclodextrin and the
guest molecule produced well-defined individual turbidity curves from which it was
possible to determine the temperature at which the crystallization started. If the
crystallization temperature of the mixture differed from that characteristics of pure
β-cyclodextrin under the given circumstances, the formation of an inclusion complex was probable.
The same year, Professor Szejtli studied the interaction of hydrochloric acid with
β-cyclodextrin. This work was the first to report adequate kinetic data and activation
parameters (Szejtli 1977b). The results showed that the first-order rate constant for
the hydrochloric acid-catalyzed degradation of β-cyclodextrin increased during the
reaction because the α-1,4-bonds present in the macrocycle and in linear dextrins,
i.e., formed by opening of the macrocycles, were split at different rates. The activation energy for hydrolysis of the glycosidic bond of maltose was 30.5 kcal/mole,
while the opening of the cyclodextrin ring was characterized with a value of
34.2 kcal/mol. At lower temperatures and higher hydrochloric acid concentrations,
a rather stable crystalline acid-cyclodextrin complex was formed with excellent
yield (Fig. 2.16). This complex contained 1.8 molecules of hydrochloric acid per
cyclodextrin unit. After storage at room temperature for 1 year, it still retained 1
mole of hydrochloric acid, and storing the product in sealed vials for 1 year led to
no change in the composition. The complex was adequate for preparing tablets for
supply of gastric acid (Szejtli and Budai 1976, 1977, 1979; Szejtli 1977b). Professor
Szejtli also proposed new analytical methods such as thin-layer chromatography in
chemistry of cyclodextrins (Szejtli 1978).
G. Crini et al.
the structure of cyclodextrins was stabilized by the formation of hydrogen bond
between C-2 and C-3 hydroxyl groups of adjacent glucose units. This phenomenon
widely affected, in addition to molecular dimensions, the water solubility of cyclodextrins. The formation of a complete ring of intramolecular hydrogen bonds in
β-cyclodextrin counteracted its hydration and reduced its solubility as compared to
other native cyclodextrins (Szejtli 1978, 1982a, 1995).
2.4.3 Types, Formation, and Structures
of Inclusion Complexes
Development of the optimal technology of producing crystalline cyclodextrin inclusion complexes required a knowledge of the crystallization process. However, the
literature contained little information concerning crystallization temperatures and
other parameters such as pH, concentration, and cooling rate (Saenger 1984;
Connors 1997).
In 1977, Professor Szejtli studied the influence of the conditions of crystallization in such a way that the guest molecule was added to a cyclodextrin solution
warmed to 60 °C (Szejtli and Budai 1977). Under vigorous stirring the solution was
then gradually cooled at a rate of 0.3–0.4 °C/min, and the turbidity was recorded as
a function of temperature. His results clearly showed that both cyclodextrin and the
guest molecule produced well-defined individual turbidity curves from which it was
possible to determine the temperature at which the crystallization started. If the
crystallization temperature of the mixture differed from that characteristics of pure
β-cyclodextrin under the given circumstances, the formation of an inclusion complex was probable.
The same year, Professor Szejtli studied the interaction of hydrochloric acid with
β-cyclodextrin. This work was the first to report adequate kinetic data and activation
parameters (Szejtli 1977b). The results showed that the first-order rate constant for
the hydrochloric acid-catalyzed degradation of β-cyclodextrin increased during the
reaction because the α-1,4-bonds present in the macrocycle and in linear dextrins,
i.e., formed by opening of the macrocycles, were split at different rates. The activation energy for hydrolysis of the glycosidic bond of maltose was 30.5 kcal/mole,
while the opening of the cyclodextrin ring was characterized with a value of
34.2 kcal/mol. At lower temperatures and higher hydrochloric acid concentrations,
a rather stable crystalline acid-cyclodextrin complex was formed with excellent
yield (Fig. 2.16). This complex contained 1.8 molecules of hydrochloric acid per
cyclodextrin unit. After storage at room temperature for 1 year, it still retained 1
mole of hydrochloric acid, and storing the product in sealed vials for 1 year led to
no change in the composition. The complex was adequate for preparing tablets for
supply of gastric acid (Szejtli and Budai 1976, 1977, 1979; Szejtli 1977b). Professor
Szejtli also proposed new analytical methods such as thin-layer chromatography in
chemistry of cyclodextrins (Szejtli 1978).
G. Crini et al.