Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PREPARING LACTULOSE FROM LACTOSE, TN THE FORM OF A
SYRUP OR A CRYSTALLINE PRODUCT
This invention relates to a new process for preparing lactulose
from lactose, in the form of a syrup or a pure crystalline product.
Lactulose or 4-0-~-D-galactopyranosyl-D-fructose is known to be a
synthetic disaccharide which is currently used in the form of
syrup in the treatment of intestinal affections, or in the form
of a crystalline product as a sweeter replacing succors.
Many processes are also known for preparing iactulose by the
epimerisation of lookout which is a widely available natural
disaccharide of formula 4-0-~-D-galactopyranosyl-D-glucose.
lo
Some of these processes are based essentially on the epimerisation
of lactose by strong alkalis such as Kiwi, Noah, OH and strong
organic bases.
These processes have the drawback of leading to the formation of
large percentages of by-products which are difficult to separate
and are colored, and which not only strongly decrease the lactulose
yield but also make it difficult both to use the lactulose syrup
as such, and to prepare it as a crystalline product. - -
A further group of processes uses sodium tetraborate or sodium
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acuminate as the epimerising agent.
Although these processes lead to a higher lactulose yield and a
more pure product, they are industrially unsatisfactory both
because of the difficulty of filtering off the aluninium hydrate
and because of the difficulty of quantitatively removing the boric
acid.
Finally, processes which use strongly alkaline ion exchange resins
for the epimerisation are too costly, and do not allow lactulose
to be produced at market prices.
A lactulose production process has also been proposed in which
lactulose is treated with a basic My derivative in an inert gaseous
15 atmosphere (Spanish patent 397,810).
This process bus never been used in practice because it utilizes
initial lactose solutions which are relatively dilute and is
extremely slow, requiring between 10 and 20 hours for the completion
of epimerisation. Both these factors make the process insignificant
from an industrial viewpoint.
ye have now discovered the subject matter of the present invention,
namely that it is possible to obtain lactulose on an industrial
scale with high yields and high purity by epimerising lactose with
a mixture of equal parts of a basic magnesium salt and sodium
hydrosulphite at a temperature of 90 -100 C.
The basic My salt can be the oxide, hydroxide or carbonate, and
preferably My
The reaction is conducted in the homogeneous phase using an aqueous
lactose solution at a concentration of between 60 and I and
` adding to the solution sodium hydrosulphite and magnesium oxide to
35 the extent of between 0.05 and 0.2% by weight for each of said
.
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~2235~0
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components with respect to the lactose,
The solution obtained is heated to 100 C and then cooled. The
reaction is generally complete in ten minutes
The lactose which separates out on cooling the aqueous solution is
separated by filtration, and the solution is then passed through
a column of strong cat ionic resin and a column of weak anionic
resin in order to remove the My and No ions and the relative anions.
The purified solution is concentrated under vacuum at 60 C until
a density of 1~4 at the concentration temperature is obtained,
Further lactose crystallizes on cooling the aqueous concentrate,
and is separated by filtration or centrifuging.
The syrup composition at this stage is on average the following:
lactulose 5~/0 by weight
galactose 4-5%
lactose 4-5% "
other sugars Lowe I
The yield at this stage is 35-4~/. of lactulose with respect to
the initial lactose,
The syrup is absolutely free from coloration and can be used as such
for all normal pharmaceutical uses,
If lactulose is required in the crystalline state, the syrup can
be further processed as follows.
The syrup is further concentrated to obtain a spongy mass with
owe of residual moisture, after which ethanol is added in the
proportion of about 1:15 with respect to the solid residue, and the
mixture heated under reflex until the mass has dissolved. The
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ethanol used must not contain more than 5% of H20.
On cooling to a temperature of around 15-20 C7 the syrup stratifies
into a solid mass which decants and into an overlying alcoholic
solution
The solid mass, which contains essentially all the lactose and the
other sugars together with part of the lactulose, is separated and
recycled.
on concentrating the clear solution at ordinary pressure, possibly
after seeding, crystalline lactulose is separated with the following
average composition:
lactulose 98-99%
other sugars Lowe/,
Crystalline lactulose at such a high purity has not been obtained
with any of the industrial processes carried out up to the present
time.
The crystalline lactulose yield is 35-40~/~ with respect to that
contained in the starting syrup, which had approximately I of
lactulose.
Thus on an overall basis, taking account of the recycled quantities,
the effective loss of lactulose does not exceed 3-5~.
The ethanol is also recovered by distillation, with a loss not
exceeding Lowe. It is recycled after making-up the missing
quantity,
A practical example is described hereinafter in order to clarify
the operational details of the process according to the present
invention, but it must in no way be considered as limitative of
35 the inventive concept of the present invention.
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The scope of the invention covers all those embodiments and equivalent
means which are apparent to an expert of the art.
EXAMPLE
0.750 kg of lactose, 0.750 g of sodium hydrosulphite and 0.400 kg
of deionized water are fed into a two lithe flask fitted with an
agitator. The lactose is dissolved by heating to 95 C, and 0.750 g
of magnesium oxide are added.
The reaction mixture is heated to 100C and kept at this temperature
for 10 minutes.
It is cooled, and the unrequited lactose is filtered off and reused
for a second preparation.
15
The clear solution is passed firstly through a column of strong
cat ionic resin and then through a column of weak anionic resin.
The solution is concentrated under vacuum to a density of about
1.4 at okay, is cooled firstly with running utter and then with
brine to 5 C, and the additional lactose which precipitates is lit-
toned off.
In this manner 0.530 kg of a clear solution of pi between 4 and 6
is obtained, having the following weight composition:
Lactulose 5070
Galactose 4.3%
Lactose 4.5
Other sugars 2
Yield approximately 35% with respect to the initial lactose.
.
This syrup can be used as such,
The solution was analyzed by HPLC under the following experimental
conditions:
351~
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Column: p mm. 1 = 250 mm
Filling: Lichrosorb NH2 (10 microns)
Column temperature: 40 0.5 C
detector: W spectrophotometer - reading at 192 no
Mobile phase: owe aqueous solution of 0.01 M monobasic
potassium phosphate and owe of acetonitrile
Flow: 2.5 ml/minute
Quantity injected: 20 ye of a solution having an approximate
concentration of owe total sugars
I
0.5 kg of I lactulose syrup obtained in the previous stage is
fed into a 5 lithe flask, and dried under a vacuum of 1-5 Torn
until a white spongy mass is obtained with a residual moisture
content of less than 77v.
I liters of 9~/c ethanol are added, and the mixture heated under
reflex until a clear solution is obtained.
It is cooled to 15-20C until a viscous mass forms and deposits on
20 the container base, after which the overlying alcoholic solution
is decanted and the clear solution concentrated at ordinary pressure
after adding lactulose seed crystals.
When 2.5 liters of alcohol have distilled off, heating is stopped
and agitation is continued, allowing the temperature to fall to
40 45C
The crystallized lactulose is filtered off, washed with ethanol and
dried under vacuum at okay.
Yield 0.100 kg ox crystalline product of the following composition:
lactulose 98.5%
other sugars owe
Yield approximately 40~/. with respect to the lactulose contained in
the syrup.
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.
This crystalline lactulose can be used as a sweetener.
Both the residue from the first alcohol extraction and the sugars
contained in the etbanolic mother liquor from the final lactulose
crystallization were taken up in water and reused for further
processing.
The total lactulose loss was about 3%.
The ethyl alcohol was also recovered both during the solution
concentration and during the drying of the lactulose crystals.
The alcohol loss was 7%, and was made-up by adding alcohol.
