201
to 50% and crystallized, resulting in gamma-cyclodextrin with 40% yield, calculated on the basis of total cyclodextrin content of the initial mother liquor (Seres
1980b). After satisfying an initial, approximately 10 kg beta-cyclodextrin demand
of Chinoin research, a concentrated attention was focused on targeted manufacturing of other cyclodextrins.
To retrieve a remaining considerable amount of gamma-cyclodextrin from xylene
complex, the filtered cake was re-suspended in water, and the xylene was eliminated
from the destroyed complex by steam distillation. The yield for gamma- cyclodextrin
was 2.5%, expressed on initial corn starch base. Based on 1977–1979 experiments,
laboratory documentation was issued in 1980, from Chinoin Biotechnology
Department (Seres 1980b).
Because of continuous development of the beta-cyclodextrin processing technology, mother liquor reprocessing turned into uneconomically slow. The average
yields both for alpha-cyclodextrin and gamma-cyclodextrin reduced below 1%. The
faster the demand raised from world market for cyclodextrins, the greater effort was
focused on developing special manufacturing technologies for target conversion, for
not only beta-cyclodextrin but alpha-cyclodextrin and gamma-cyclodextrin, too.
Laboratory conversion experiments were initiated in the late 1970s to get alphacyclodextrin and gamma-cyclodextrin in intentional and selective conversion models. This work started with substantial screening experiments to find a specific
cyclodextrin precipitant to achieve high alpha-cyclodextrin or gamma-cyclodextrin
conversion rates (Seres 1980a, b). Moreover, researchers of Chinoin Biotechnology
Department screened various starch substrates, too. Laboratory-scale microconversions were carried out in a thermostatted block reactor, equipped with 3 mL
wells. The resulting conversion mixtures were concentrated by evaporation.
Residual organic precipitant content was removed by combination of chromatography and activated carbon thereafter.
Micro-reaction mixtures were analyzed either by thin layer chromatography or
overpressured layer chromatography. The latter method was a revolutionary new
Hungarian investment that time (Tyihák et al. 1985). By means of this equipment,
hundreds of chemicals were screened as potentially selective alpha-cyclodextrin or
gamma-cyclodextrin complexants.
The pilot plant production of gamma-cyclodextrin was realized in Chinoin plant
CH-VIII (Seres 1980c, 1985). A 70 kg quantity of corn starch was prehydrolized
with B. subtilis alpha amylase. This partially degraded starch was converted to a
mostly gamma-cyclodextrin-containing conversion mixture using Chinoinmanufactured B. macerans cyclodextrin glucosyltransferase, at 40 °C, and neutral
pH, in presence of 1-naphtol and methyl ethyl ketone precipitants. After filtration of
the conversion mixture, the cyclodextrin-enriched filter cake was suspended in
methanol, refluxed, and separated. After centrifugation the resulting naftolcontaining raffinate was removed, and the residue re-suspended in methanol-water
mixture and refluxed again in presence of active carbon. After centrifugation the
supernatant was passed through Varion KS and Varion AD ion-exchange columns.
The column effluent was concentrated by evaporation, and the product crystallized
from water. Processing of raw gamma-cyclodextrin, based on ternary complexation
4 History of Cyclodextrin Production in Hungary
to 50% and crystallized, resulting in gamma-cyclodextrin with 40% yield, calculated on the basis of total cyclodextrin content of the initial mother liquor (Seres
1980b). After satisfying an initial, approximately 10 kg beta-cyclodextrin demand
of Chinoin research, a concentrated attention was focused on targeted manufacturing of other cyclodextrins.
To retrieve a remaining considerable amount of gamma-cyclodextrin from xylene
complex, the filtered cake was re-suspended in water, and the xylene was eliminated
from the destroyed complex by steam distillation. The yield for gamma- cyclodextrin
was 2.5%, expressed on initial corn starch base. Based on 1977–1979 experiments,
laboratory documentation was issued in 1980, from Chinoin Biotechnology
Department (Seres 1980b).
Because of continuous development of the beta-cyclodextrin processing technology, mother liquor reprocessing turned into uneconomically slow. The average
yields both for alpha-cyclodextrin and gamma-cyclodextrin reduced below 1%. The
faster the demand raised from world market for cyclodextrins, the greater effort was
focused on developing special manufacturing technologies for target conversion, for
not only beta-cyclodextrin but alpha-cyclodextrin and gamma-cyclodextrin, too.
Laboratory conversion experiments were initiated in the late 1970s to get alphacyclodextrin and gamma-cyclodextrin in intentional and selective conversion models. This work started with substantial screening experiments to find a specific
cyclodextrin precipitant to achieve high alpha-cyclodextrin or gamma-cyclodextrin
conversion rates (Seres 1980a, b). Moreover, researchers of Chinoin Biotechnology
Department screened various starch substrates, too. Laboratory-scale microconversions were carried out in a thermostatted block reactor, equipped with 3 mL
wells. The resulting conversion mixtures were concentrated by evaporation.
Residual organic precipitant content was removed by combination of chromatography and activated carbon thereafter.
Micro-reaction mixtures were analyzed either by thin layer chromatography or
overpressured layer chromatography. The latter method was a revolutionary new
Hungarian investment that time (Tyihák et al. 1985). By means of this equipment,
hundreds of chemicals were screened as potentially selective alpha-cyclodextrin or
gamma-cyclodextrin complexants.
The pilot plant production of gamma-cyclodextrin was realized in Chinoin plant
CH-VIII (Seres 1980c, 1985). A 70 kg quantity of corn starch was prehydrolized
with B. subtilis alpha amylase. This partially degraded starch was converted to a
mostly gamma-cyclodextrin-containing conversion mixture using Chinoinmanufactured B. macerans cyclodextrin glucosyltransferase, at 40 °C, and neutral
pH, in presence of 1-naphtol and methyl ethyl ketone precipitants. After filtration of
the conversion mixture, the cyclodextrin-enriched filter cake was suspended in
methanol, refluxed, and separated. After centrifugation the resulting naftolcontaining raffinate was removed, and the residue re-suspended in methanol-water
mixture and refluxed again in presence of active carbon. After centrifugation the
supernatant was passed through Varion KS and Varion AD ion-exchange columns.
The column effluent was concentrated by evaporation, and the product crystallized
from water. Processing of raw gamma-cyclodextrin, based on ternary complexation
4 History of Cyclodextrin Production in Hungary