207
hydrogen bond system between secondary O-2 and O-3 hydroxyls of the adjacent
glucopyranose units.
Among the early derivatives, methylated cyclodextrins were considered as promising candidates. Szejtli’s team in Hungary was studying the properties of methylated beta-cyclodextrins aiming to find a pharmaceutical solubilizer complexing
agent. Among methylated cyclodextrins, they found heptakis(2,6-di-O-methyl)beta- cyclodextrin a particularly promising compound (Szejtli et al. 1980b; Szejtli
1983). They also filed a number of patents disclosing the synthesis and use of
cyclodextrin- methyl-ethers, e.g., methylation (Szejtli et al. 1988a), complexes of
dibenzopyran derivatives (Nógrádi et al. 1985), bile substitute (Szejtli et al. 1988b),
and methyl carboxyacyl-cyclodextrins (Szabó et al. 1989). However, it was found
that these beta-cyclodextrin-methyl ethers exhibited high cell membrane activity.
This affinity to membrane lipids such as cholesterol resulted in cytotoxicity which
prevented their utility as solubilizers in parenteral/liquid formulations.
Finally, the optimum cyclodextrin derivative was found in the early 1980s. This
compound was a cyclodextrin-ether derivative, 2-hydroxypropyl-beta-cyclodextrin.
In 1981, Josef Pitha, head of Macromolecular Chemistry Section at National
Institute of Health Gerontology Research Center in Baltimore, prepared and studied
a novel derivative with optimal properties: solubilizing power for lipophile, noncrystalline, non-crystalizing composite mixture, low parenteral toxicity, and slight
membrane activity. The first synthetic route that Pitha applied to obtain this compound was a two-step method: (1) allylation of parent beta-cyclodextrin and (2)
oxymercuration/demercuration of allyl beta-cyclodextrin resulting in 2- hydroxypro
pyl- beta-cyclodextrin (Pitha et al. 1986).
As this synthetic method was not easy to scale up, neither was it economic, Pitha
decided to move forward with the well-known propylene oxide condensation reaction. This hydroxyalkylation method was used first by industrial starch companies
similarly to hydroxypropylation of starch, dextrins, and cellulose to improve their
aqueous solubility. The propylene oxide condensation reaction was well applicable
for cyclodextrin derivatization, too (Gramera and Caimi 1969; Parmenter et al.
1969). Pitha’s team soon optimized the hydroxypropylation reaction to obtain
hydroxypropyl-beta-cyclodextrin with a relatively narrow and symmetrical distribution of the degree of substitution (Pitha 1988). Besides this reaction, they developed
methods for purification of hydroxypropyl-beta-cyclodextrins from the contaminating oligopropylene glycols and for reduction of propylene glycol to an acceptable
level. It was also reported that these hydroxypropyl-beta-cyclodextrin preparations
with lower degree of substitution than 8 could be transformed into non-hygroscopic
amorphous powders. The derivatives with a degree of substitution higher than 12–14
were all semi-solids or glassy syrups of lower solubilization power (Pitha et al. 1986).
Soon after the seminal works by Pitha, Szejtli’s group in Chinoin developed and
optimized an upscalable industrial synthesis process for hydroxypropyl cyclodextrins. This method applied unique amounts of alkali during hydroxyalkylation step
and so resulted in products where the distribution patterns of hydroxypropyl groups
along the cyclodextrin ring were different from those obtained by Pitha’s method
(Szabó et al. 1991). The hydroxyalkylation was performed between 0 and 35 °C
4 History of Cyclodextrin Production in Hungary
hydrogen bond system between secondary O-2 and O-3 hydroxyls of the adjacent
glucopyranose units.
Among the early derivatives, methylated cyclodextrins were considered as promising candidates. Szejtli’s team in Hungary was studying the properties of methylated beta-cyclodextrins aiming to find a pharmaceutical solubilizer complexing
agent. Among methylated cyclodextrins, they found heptakis(2,6-di-O-methyl)beta- cyclodextrin a particularly promising compound (Szejtli et al. 1980b; Szejtli
1983). They also filed a number of patents disclosing the synthesis and use of
cyclodextrin- methyl-ethers, e.g., methylation (Szejtli et al. 1988a), complexes of
dibenzopyran derivatives (Nógrádi et al. 1985), bile substitute (Szejtli et al. 1988b),
and methyl carboxyacyl-cyclodextrins (Szabó et al. 1989). However, it was found
that these beta-cyclodextrin-methyl ethers exhibited high cell membrane activity.
This affinity to membrane lipids such as cholesterol resulted in cytotoxicity which
prevented their utility as solubilizers in parenteral/liquid formulations.
Finally, the optimum cyclodextrin derivative was found in the early 1980s. This
compound was a cyclodextrin-ether derivative, 2-hydroxypropyl-beta-cyclodextrin.
In 1981, Josef Pitha, head of Macromolecular Chemistry Section at National
Institute of Health Gerontology Research Center in Baltimore, prepared and studied
a novel derivative with optimal properties: solubilizing power for lipophile, noncrystalline, non-crystalizing composite mixture, low parenteral toxicity, and slight
membrane activity. The first synthetic route that Pitha applied to obtain this compound was a two-step method: (1) allylation of parent beta-cyclodextrin and (2)
oxymercuration/demercuration of allyl beta-cyclodextrin resulting in 2- hydroxypro
pyl- beta-cyclodextrin (Pitha et al. 1986).
As this synthetic method was not easy to scale up, neither was it economic, Pitha
decided to move forward with the well-known propylene oxide condensation reaction. This hydroxyalkylation method was used first by industrial starch companies
similarly to hydroxypropylation of starch, dextrins, and cellulose to improve their
aqueous solubility. The propylene oxide condensation reaction was well applicable
for cyclodextrin derivatization, too (Gramera and Caimi 1969; Parmenter et al.
1969). Pitha’s team soon optimized the hydroxypropylation reaction to obtain
hydroxypropyl-beta-cyclodextrin with a relatively narrow and symmetrical distribution of the degree of substitution (Pitha 1988). Besides this reaction, they developed
methods for purification of hydroxypropyl-beta-cyclodextrins from the contaminating oligopropylene glycols and for reduction of propylene glycol to an acceptable
level. It was also reported that these hydroxypropyl-beta-cyclodextrin preparations
with lower degree of substitution than 8 could be transformed into non-hygroscopic
amorphous powders. The derivatives with a degree of substitution higher than 12–14
were all semi-solids or glassy syrups of lower solubilization power (Pitha et al. 1986).
Soon after the seminal works by Pitha, Szejtli’s group in Chinoin developed and
optimized an upscalable industrial synthesis process for hydroxypropyl cyclodextrins. This method applied unique amounts of alkali during hydroxyalkylation step
and so resulted in products where the distribution patterns of hydroxypropyl groups
along the cyclodextrin ring were different from those obtained by Pitha’s method
(Szabó et al. 1991). The hydroxyalkylation was performed between 0 and 35 °C
4 History of Cyclodextrin Production in Hungary